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Bogomolova AP, Katrukha IA. Troponins and Skeletal Muscle Pathologies. BIOCHEMISTRY. BIOKHIMIIA 2024; 89:2083-2106. [PMID: 39865025 DOI: 10.1134/s0006297924120010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Academic Contribution Register] [Received: 05/02/2024] [Revised: 11/19/2024] [Accepted: 12/01/2024] [Indexed: 01/28/2025]
Abstract
Skeletal muscles account for ~30-40% of the total weight of human body and are responsible for its most important functions, including movement, respiration, thermogenesis, and glucose and protein metabolism. Skeletal muscle damage negatively impacts the whole-body functioning, leading to deterioration of the quality of life and, in severe cases, death. Therefore, timely diagnosis and therapy for skeletal muscle dysfunction are important goals of modern medicine. In this review, we focused on the skeletal troponins that are proteins in the thin filaments of muscle fibers. Skeletal troponins play a key role in regulation of muscle contraction. Biochemical properties of these proteins and their use as biomarkers of skeletal muscle damage are described in this review. One of the most convenient and sensitive methods of protein biomarker measurement in biological liquids is immunochemical analysis; hence, we examined the factors that influence immunochemical detection of skeletal troponins and should be taken into account when developing diagnostic test systems. Also, we reviewed the available data on the skeletal troponin mutations that are considered to be associated with pathologies leading to the development of diseases and discussed utilization of troponins as drug targets for treatment of the skeletal muscle disorders.
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Affiliation(s)
- Agnessa P Bogomolova
- Faculty of Biology, Lomonosov Moscow State University, Moscow, 119234, Russia.
- Hytest Ltd., Turku, Finland
| | - Ivan A Katrukha
- Faculty of Biology, Lomonosov Moscow State University, Moscow, 119234, Russia
- Hytest Ltd., Turku, Finland
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2
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Kaneguchi A, Sakitani N, Umehara T. Histological changes in skeletal muscle induced by heart failure in human patients and animal models: A scoping review. Acta Histochem 2024; 126:152210. [PMID: 39442432 DOI: 10.1016/j.acthis.2024.152210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/27/2024] [Revised: 10/15/2024] [Accepted: 10/15/2024] [Indexed: 10/25/2024]
Abstract
OBJECTIVE This scoping review aimed to characterize the histological changes in skeletal muscle after heart failure (HF) and to identify gaps in knowledge. METHODS On April 03, 2024, systematic searches were performed for papers in which histological analyses were conducted on skeletal muscle sampled from patients with HF or animal models of HF. Screening and data extraction were conducted by two independent authors. RESULTS AND CONCLUSION A total of 118 papers were selected, including 33 human and 85 animal studies. Despite some disagreements among studies, some trends were observed. These trends included a slow-to-fast transition, a decrease in muscle fiber size, capillary to muscle fiber ratio, and mitochondrial activity and content, and an increase in apoptosis. These changes may contribute to the fatigability and decrease in muscle strength observed after HF. Although there were some disagreements between the results of human and animal studies, the results were generally similar. Animal models of HF will therefore be useful in elucidating the histological changes in skeletal muscle that occur in human patients with HF. Because the muscles subjected to histological analysis were mostly thigh muscles in humans and mostly lower leg muscles in animals, it remains uncertain whether changes similar to those seen in lower limb (hindlimb) muscles after HF also occur in upper limb (forelimb) muscles. The results of this review will consolidate the current knowledge on HF-induced histological changes in skeletal muscle and consequently aid in the rehabilitation of patients with HF and future studies.
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Affiliation(s)
- Akinori Kaneguchi
- Department of Rehabilitation, Faculty of Rehabilitation, Hiroshima International University, Kurose-Gakuendai 555-36, Higashi-Hiroshima, Hiroshima, 739-2695, Japan.
| | - Naoyoshi Sakitani
- Department of Life Science and Biotechnology, National Institute of Advanced Industrial Science and Technology, Hayashi-cho 2217-4, Takamatsu, Kagawa, 761-0395, Japan
| | - Takuya Umehara
- Department of Rehabilitation, Faculty of Rehabilitation, Hiroshima International University, Kurose-Gakuendai 555-36, Higashi-Hiroshima, Hiroshima, 739-2695, Japan
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3
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Euler L, Deinert K, Wagener F, Walpurgis K, Thevis M. Identification of human metabolites of fast skeletal troponin activators Tirasemtiv and Reldesemtiv for doping control purposes. Drug Test Anal 2024. [PMID: 39138120 DOI: 10.1002/dta.3786] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/02/2024] [Revised: 07/17/2024] [Accepted: 07/24/2024] [Indexed: 08/15/2024]
Abstract
The fast skeletal troponin activators (FSTAs) Reldesemtiv and Tirasemtiv were developed for patients suffering from neuro-degenerative diseases of the motor nervous system, e.g. amyotrophic lateral sclerosis (ALS). The drug candidates can increase the sensitivity of troponin C to calcium by selectively activating the troponin complex resulting in increased skeletal muscle contraction. Although the development of the drug candidates is currently discontinued because of missed end points in phase III clinical studies with patients with ALS, phase I clinical trials showed an increase in muscle contraction force in healthy humans. This effect could be abused by athletes to enhance performance in sports. As the substances are listed on the 2024 edition of the World Anti-Doping Agency's Prohibited List, the aim of this study was to identify and characterize metabolites of Reldesemtiv and Tirasemtiv to ensure their reliable identification in doping control analyses. The biotransformation of the drug candidates was studied in vitro using pooled human liver microsomes and 3D cultivated human hepatic cells of the cell line HepaRG, yielding a total of 11 metabolites of Reldesemtiv and eight of Tirasemtiv. In addition, a human elimination study was conducted to investigate the metabolism and elimination profile of Tirasemtiv and Reldesemtiv in vivo, suggesting the N-glucuronide of Tirasemtiv and hydroxylated 3-fluoro-2-(3-fluoro-1-methylcyclobutyl)pyridine as well as its glucuronide as suitable target analytes for routine doping controls. Applying a validating HPLC-MS/MS method, optimized to detect Reldesemtiv and Tirasemtiv in human urine, microdosing (50 μg) of each substance was traceable for 24-72 h.
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Affiliation(s)
- Luisa Euler
- Center for Preventive Doping Research Institute of Biochemistry, German Sport University Cologne, Cologne, Germany
| | - Kim Deinert
- Center for Preventive Doping Research Institute of Biochemistry, German Sport University Cologne, Cologne, Germany
- Technical University of Kaiserslautern, Kaiserslautern, Germany
| | - Felicitas Wagener
- Center for Preventive Doping Research Institute of Biochemistry, German Sport University Cologne, Cologne, Germany
| | - Katja Walpurgis
- Center for Preventive Doping Research Institute of Biochemistry, German Sport University Cologne, Cologne, Germany
| | - Mario Thevis
- Center for Preventive Doping Research Institute of Biochemistry, German Sport University Cologne, Cologne, Germany
- European Monitoring Center for Emerging Doping Agents, Cologne, Germany
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4
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Hartman JJ, Hwee DT, Robert-Paganin J, Chuang C, Chin ER, Edell S, Lee KH, Madhvani R, Paliwal P, Pernier J, Sarkar SS, Schaletzky J, Schauer K, Taheri KD, Wang J, Wehri E, Wu Y, Houdusse A, Morgan BP, Malik FI. Aficamten is a small-molecule cardiac myosin inhibitor designed to treat hypertrophic cardiomyopathy. NATURE CARDIOVASCULAR RESEARCH 2024; 3:1003-1016. [PMID: 39196032 PMCID: PMC11358156 DOI: 10.1038/s44161-024-00505-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Academic Contribution Register] [Received: 09/12/2022] [Accepted: 06/06/2024] [Indexed: 08/29/2024]
Abstract
Hypertrophic cardiomyopathy (HCM) is an inherited disease of the sarcomere resulting in excessive cardiac contractility. The first-in-class cardiac myosin inhibitor, mavacamten, improves symptoms in obstructive HCM. Here we present aficamten, a selective small-molecule inhibitor of cardiac myosin that diminishes ATPase activity by strongly slowing phosphate release, stabilizing a weak actin-binding state. Binding to an allosteric site on the myosin catalytic domain distinct from mavacamten, aficamten prevents the conformational changes necessary to enter the strongly actin-bound force-generating state. In doing so, aficamten reduces the number of functional myosin heads driving sarcomere shortening. The crystal structure of aficamten bound to cardiac myosin in the pre-powerstroke state provides a basis for understanding its selectivity over smooth and fast skeletal muscle. Furthermore, in cardiac myocytes and in mice bearing the hypertrophic R403Q cardiac myosin mutation, aficamten reduces cardiac contractility. Our findings suggest aficamten holds promise as a therapy for HCM.
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Affiliation(s)
- James J Hartman
- Research and Non-Clinical Development, Cytokinetics, South San Francisco, CA, USA.
| | - Darren T Hwee
- Research and Non-Clinical Development, Cytokinetics, South San Francisco, CA, USA
| | - Julien Robert-Paganin
- Structural Motility, Institut Curie, Université Paris Sciences et Lettres, Sorbonne Université, CNRS UMR144, Paris, France
| | - Chihyuan Chuang
- Research and Non-Clinical Development, Cytokinetics, South San Francisco, CA, USA
| | - Eva R Chin
- Research and Non-Clinical Development, Cytokinetics, South San Francisco, CA, USA
| | - Samantha Edell
- Research and Non-Clinical Development, Cytokinetics, South San Francisco, CA, USA
| | - Ken H Lee
- Research and Non-Clinical Development, Cytokinetics, South San Francisco, CA, USA
| | - Roshni Madhvani
- Research and Non-Clinical Development, Cytokinetics, South San Francisco, CA, USA
| | - Preeti Paliwal
- Research and Non-Clinical Development, Cytokinetics, South San Francisco, CA, USA
| | - Julien Pernier
- Tumor Cell Dynamics Unit, Inserm U1279 Gustave Roussy Institute, Université Paris-Saclay, Villejuif, France
| | | | - Julia Schaletzky
- Research and Non-Clinical Development, Cytokinetics, South San Francisco, CA, USA
| | - Kristine Schauer
- Tumor Cell Dynamics Unit, Inserm U1279 Gustave Roussy Institute, Université Paris-Saclay, Villejuif, France
| | - Khanha D Taheri
- Research and Non-Clinical Development, Cytokinetics, South San Francisco, CA, USA
| | - Jingying Wang
- Research and Non-Clinical Development, Cytokinetics, South San Francisco, CA, USA
| | - Eddie Wehri
- Research and Non-Clinical Development, Cytokinetics, South San Francisco, CA, USA
| | - Yangsong Wu
- Research and Non-Clinical Development, Cytokinetics, South San Francisco, CA, USA
| | - Anne Houdusse
- Structural Motility, Institut Curie, Université Paris Sciences et Lettres, Sorbonne Université, CNRS UMR144, Paris, France
| | - Bradley P Morgan
- Research and Non-Clinical Development, Cytokinetics, South San Francisco, CA, USA
| | - Fady I Malik
- Research and Non-Clinical Development, Cytokinetics, South San Francisco, CA, USA
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5
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van den Berg M, Shi Z, Claassen WJ, Hooijman P, Lewis CTA, Andersen JL, van der Pijl RJ, Bogaards SJP, Conijn S, Peters EL, Begthel LPL, Uijterwijk B, Lindqvist J, Langlais PR, Girbes ARJ, Stapel S, Granzier H, Campbell KS, Ma W, Irving T, Hwee DT, Hartman JJ, Malik FI, Paul M, Beishuizen A, Ochala J, Heunks L, Ottenheijm CAC. Super-relaxed myosins contribute to respiratory muscle hibernation in mechanically ventilated patients. Sci Transl Med 2024; 16:eadg3894. [PMID: 39083588 PMCID: PMC11586073 DOI: 10.1126/scitranslmed.adg3894] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/22/2022] [Revised: 02/12/2024] [Accepted: 07/11/2024] [Indexed: 08/02/2024]
Abstract
Patients receiving mechanical ventilation in the intensive care unit (ICU) frequently develop contractile weakness of the diaphragm. Consequently, they may experience difficulty weaning from mechanical ventilation, which increases mortality and poses a high economic burden. Because of a lack of knowledge regarding the molecular changes in the diaphragm, no treatment is currently available to improve diaphragm contractility. We compared diaphragm biopsies from ventilated ICU patients (N = 54) to those of non-ICU patients undergoing thoracic surgery (N = 27). By integrating data from myofiber force measurements, x-ray diffraction experiments, and biochemical assays with clinical data, we found that in myofibers isolated from the diaphragm of ventilated ICU patients, myosin is trapped in an energy-sparing, super-relaxed state, which impairs the binding of myosin to actin during diaphragm contraction. Studies on quadriceps biopsies of ICU patients and on the diaphragm of previously healthy mechanically ventilated rats suggested that the super-relaxed myosins are specific to the diaphragm and not a result of critical illness. Exposing slow- and fast-twitch myofibers isolated from the diaphragm biopsies to small-molecule compounds activating troponin restored contractile force in vitro. These findings support the continued development of drugs that target sarcomere proteins to increase the calcium sensitivity of myofibers for the treatment of ICU-acquired diaphragm weakness.
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Affiliation(s)
- Marloes van den Berg
- Amsterdam UMC, Location VUmc, Department of Physiology, Amsterdam 1081, HV, Netherlands
- Bispebjerg Hospital, Institute of Sports Medicine, Copenhagen 2400, Denmark
| | - Zhonghua Shi
- Amsterdam UMC, Location VUmc, Department of Physiology, Amsterdam 1081, HV, Netherlands
- Amsterdam UMC, Location VUmc, Department of Intensive Care Medicine, Amsterdam 1081, HV, Netherlands
- Sanbo Brain Hospital, Capital Medical University, Intensive Care Medicine, Beijing 100093, China
| | - Wout J. Claassen
- Amsterdam UMC, Location VUmc, Department of Physiology, Amsterdam 1081, HV, Netherlands
| | - Pleuni Hooijman
- Amsterdam UMC, Location VUmc, Department of Physiology, Amsterdam 1081, HV, Netherlands
| | - Christopher T. A. Lewis
- University of Copenhagen, Department of Biomedical Sciences, Copenhagen 2200, Denmark
- Research and Early Development, Novo Nordisk A/S, Måløv 2760, Denmark
| | - Jesper L. Andersen
- Bispebjerg Hospital, Institute of Sports Medicine, Copenhagen 2400, Denmark
| | | | - Sylvia J. P. Bogaards
- Amsterdam UMC, Location VUmc, Department of Physiology, Amsterdam 1081, HV, Netherlands
| | - Stefan Conijn
- Amsterdam UMC, Location VUmc, Department of Physiology, Amsterdam 1081, HV, Netherlands
| | - Eva L. Peters
- Department of Cellular and Molecular Medicine, University of Arizona, Tucson AZ 85721, USA
| | - Leon P. L. Begthel
- Amsterdam UMC, Location VUmc, Department of Physiology, Amsterdam 1081, HV, Netherlands
- Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK
| | - Bas Uijterwijk
- Amsterdam UMC, Location VUmc, Department of Physiology, Amsterdam 1081, HV, Netherlands
| | - Johan Lindqvist
- Department of Cellular and Molecular Medicine, University of Arizona, Tucson AZ 85721, USA
| | - Paul R. Langlais
- Department of Endocrinology, University of Arizona, Tucson, AZ 85721, USA
| | - Armand R. J. Girbes
- Amsterdam UMC, Location VUmc, Department of Intensive Care Medicine, Amsterdam 1081, HV, Netherlands
| | - Sandra Stapel
- Amsterdam UMC, Location VUmc, Department of Intensive Care Medicine, Amsterdam 1081, HV, Netherlands
| | - Henk Granzier
- Department of Cellular and Molecular Medicine, University of Arizona, Tucson AZ 85721, USA
| | - Kenneth S. Campbell
- Division of Cardiovascular Medicine, University of Kentucky College of Medicine, Lexington, KY 40536, USA
| | - Weikang Ma
- BioCAT, Illinois Institute of Technology, Lemont, IL 60439, USA
| | - Thomas Irving
- BioCAT, Illinois Institute of Technology, Lemont, IL 60439, USA
| | - Darren T. Hwee
- Research and Early Development, Cytokinetics Inc., South San Francisco, CA 94080, USA
| | - James J. Hartman
- Research and Early Development, Cytokinetics Inc., South San Francisco, CA 94080, USA
| | - Fady I. Malik
- Research and Early Development, Cytokinetics Inc., South San Francisco, CA 94080, USA
| | - Marinus Paul
- Amsterdam UMC, Location VUmc, Department of Cardiothoracic Surgery, Amsterdam 1081, HV, Netherlands
| | - Albertus Beishuizen
- Medisch Spectrum Twente, Intensive Care Center, Enschede 7511, HN, Netherlands
| | - Julien Ochala
- University of Copenhagen, Department of Biomedical Sciences, Copenhagen 2200, Denmark
| | - Leo Heunks
- Radboud UMC, Department of Intensive Care, Nijmegen 6525, GA, Netherlands
| | - Coen A. C. Ottenheijm
- Amsterdam UMC, Location VUmc, Department of Physiology, Amsterdam 1081, HV, Netherlands
- Department of Cellular and Molecular Medicine, University of Arizona, Tucson AZ 85721, USA
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6
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Lapp HS, Freigang M, Friese J, Bernsen S, Tüngler V, von der Hagen M, Weydt P, Günther R. Troponin T is elevated in a relevant proportion of patients with 5q-associated spinal muscular atrophy. Sci Rep 2024; 14:6634. [PMID: 38503830 PMCID: PMC10951305 DOI: 10.1038/s41598-024-57185-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/07/2023] [Accepted: 03/14/2024] [Indexed: 03/21/2024] Open
Abstract
Troponin T concentration (TNT) is commonly considered a marker of myocardial damage. However, elevated concentrations have been demonstrated in numerous neuromuscular disorders, pointing to the skeletal muscle as a possible extracardiac origin. The aim of this study was to determine disease-related changes of TNT in 5q-associated spinal muscular atrophy (SMA) and to screen for its biomarker potential in SMA. We therefore included 48 pediatric and 45 adult SMA patients in this retrospective cross-sequential observational study. Fluid muscle integrity and cardiac markers were analyzed in the serum of treatment-naïve patients and subsequently under disease-modifying therapies. We found a TNT elevation in 61% of SMA patients but no elevation of the cardiospecific isoform Troponin I (TNI). TNT elevation was more pronounced in children and particularly infants with aggressive phenotypes. In adults, TNT correlated to muscle destruction and decreased under therapy only in the subgroup with elevated TNT at baseline. In conclusion, TNT was elevated in a relevant proportion of patients with SMA with emphasis in infants and more aggressive phenotypes. Normal TNI levels support a likely extracardiac origin. Although its stand-alone biomarker potential seems to be limited, exploring TNT in SMA underlines the investigation of skeletal muscle integrity markers.
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Affiliation(s)
- Hanna Sophie Lapp
- Department of Neurology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Maren Freigang
- Department of Neurology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Johannes Friese
- Department of Neuropediatrics, University Hospital Bonn, Bonn, Germany
| | - Sarah Bernsen
- Department of Neurodegenerative Diseases, University Hospital Bonn, Bonn, Germany
| | - Victoria Tüngler
- Department of Neuropediatrics, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Maja von der Hagen
- Department of Neuropediatrics, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Patrick Weydt
- Department of Neurodegenerative Diseases, University Hospital Bonn, Bonn, Germany
| | - René Günther
- Department of Neurology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
- German Center for Neurodegenerative Diseases, Dresden, Germany.
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7
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Shefner JM, Jacobsen B, Kupfer S, Malik FI, Meng L, Wei J, Wolff AA, Rudnicki SA. Relationship between quantitative strength and functional outcomes in the phase 2 FORTITUDE-ALS trial. Amyotroph Lateral Scler Frontotemporal Degener 2024; 25:162-169. [PMID: 37641579 DOI: 10.1080/21678421.2023.2252468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/13/2023] [Revised: 08/21/2023] [Accepted: 08/23/2023] [Indexed: 08/31/2023]
Abstract
OBJECTIVE To assess the relationship among measurements of strength, function, and quality of life in an amyotrophic lateral sclerosis (ALS) clinical trial. METHODS In the FORTITUDE-ALS clinical trial (NCT03160898), 456 participants in the full-analysis set were treated with either reldesemtiv or placebo for 12 weeks; this post hoc analysis included all participants regardless of treatment assignments. Assessments included slow vital capacity (SVC), the ALS Functional Rating Scale-Revised (ALSFRS-R), and the 5-item ALS Assessment Questionnaire (ALSAQ-5). Muscle strength was measured quantitatively with hand-held dynamometry, and grip strength with a dedicated dynamometer. The relationship between strength and ALSFRS-R fine and gross motor domain scores, or responses to ALSAQ-5 questions on hand function and walking, was assessed with Spearman's rank correlation. The relationship between mean upper- or lower-extremity muscle strength and specific ALSFRS-R domains was modeled using principal-components analysis. RESULTS Upper-extremity muscle strength and hand grip were highly correlated with ALSFRS-R fine motor scores and the ALSAQ-5 hand function question. Similarly, lower-extremity strength correlated well with ALSFRS-R gross motor domain and the ALSAQ-5 walking question. For SVC, correlation was poor with the ALSFRS-R respiratory domain, but stronger with the total score, potentially reflecting the insensitivity of the respiratory questions in the scale. Upper- and lower-extremity strength were both strong predictors of ALSFRS-R domain scores. CONCLUSIONS In this analysis of data from an ALS clinical trial, muscle strength quantified by dynamometry was strongly correlated with functional capacity. These results suggest that muscle strength directly relates to specific functions of importance to people with ALS.
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Affiliation(s)
- Jeremy M Shefner
- Barrow Neurological Institute, University of Arizona, and Creighton University, Phoenix, AZ, USA and
| | - Bill Jacobsen
- Barrow Neurological Institute, University of Arizona, and Creighton University, Phoenix, AZ, USA and
| | - Stuart Kupfer
- Cytokinetics, Incorporated, South San Francisco, CA, USA
| | - Fady I Malik
- Cytokinetics, Incorporated, South San Francisco, CA, USA
| | - Lisa Meng
- Cytokinetics, Incorporated, South San Francisco, CA, USA
| | - Jenny Wei
- Cytokinetics, Incorporated, South San Francisco, CA, USA
| | - Andrew A Wolff
- Cytokinetics, Incorporated, South San Francisco, CA, USA
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8
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Lapp HS, Freigang M, Hagenacker T, Weiler M, Wurster CD, Günther R. Biomarkers in 5q-associated spinal muscular atrophy-a narrative review. J Neurol 2023; 270:4157-4178. [PMID: 37289324 PMCID: PMC10421827 DOI: 10.1007/s00415-023-11787-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/12/2023] [Revised: 05/15/2023] [Accepted: 05/16/2023] [Indexed: 06/09/2023]
Abstract
5q-associated spinal muscular atrophy (SMA) is a rare genetic disease caused by mutations in the SMN1 gene, resulting in a loss of functional SMN protein and consecutive degeneration of motor neurons in the ventral horn. The disease is clinically characterized by proximal paralysis and secondary skeletal muscle atrophy. New disease-modifying drugs driving SMN gene expression have been developed in the past decade and have revolutionized SMA treatment. The rise of treatment options led to a concomitant need of biomarkers for therapeutic guidance and an improved disease monitoring. Intensive efforts have been undertaken to develop suitable markers, and numerous candidate biomarkers for diagnostic, prognostic, and predictive values have been identified. The most promising markers include appliance-based measures such as electrophysiological and imaging-based indices as well as molecular markers including SMN-related proteins and markers of neurodegeneration and skeletal muscle integrity. However, none of the proposed biomarkers have been validated for the clinical routine yet. In this narrative review, we discuss the most promising candidate biomarkers for SMA and expand the discussion by addressing the largely unfolded potential of muscle integrity markers, especially in the context of upcoming muscle-targeting therapies. While the discussed candidate biomarkers hold potential as either diagnostic (e.g., SMN-related biomarkers), prognostic (e.g., markers of neurodegeneration, imaging-based markers), predictive (e.g., electrophysiological markers) or response markers (e.g., muscle integrity markers), no single measure seems to be suitable to cover all biomarker categories. Hence, a combination of different biomarkers and clinical assessments appears to be the most expedient solution at the time.
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Affiliation(s)
- H S Lapp
- Department of Neurology, University Hospital Carl Gustav Carus at TU Dresden, Fetscherstraße 74, 01307, Dresden, Germany
| | - M Freigang
- Department of Neurology, University Hospital Carl Gustav Carus at TU Dresden, Fetscherstraße 74, 01307, Dresden, Germany
| | - T Hagenacker
- Department of Neurology and Center for Translational Neuro- and Behavioral Science (C-TNBS), University Medicine Essen, Essen, Germany
| | - M Weiler
- Department of Neurology, Heidelberg University Hospital, Heidelberg, Germany
| | - C D Wurster
- Department of Neurology, University Hospital Ulm, Ulm, Germany
- German Center for Neurodegenerative Diseases (DZNE) Ulm, Ulm, Germany
| | - René Günther
- Department of Neurology, University Hospital Carl Gustav Carus at TU Dresden, Fetscherstraße 74, 01307, Dresden, Germany.
- German Center for Neurodegenerative Diseases (DZNE) Dresden, Dresden, Germany.
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9
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Claassen WJ, Baelde RJ, Galli RA, de Winter JM, Ottenheijm CAC. Small molecule drugs to improve sarcomere function in those with acquired and inherited myopathies. Am J Physiol Cell Physiol 2023; 325:C60-C68. [PMID: 37212548 PMCID: PMC10281779 DOI: 10.1152/ajpcell.00047.2023] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/03/2023] [Revised: 05/15/2023] [Accepted: 05/15/2023] [Indexed: 05/23/2023]
Abstract
Muscle weakness is a hallmark of inherited or acquired myopathies. It is a major cause of functional impairment and can advance to life-threatening respiratory insufficiency. During the past decade, several small-molecule drugs that improve the contractility of skeletal muscle fibers have been developed. In this review, we provide an overview of the available literature and the mechanisms of action of small-molecule drugs that modulate the contractility of sarcomeres, the smallest contractile units in striated muscle, by acting on myosin and troponin. We also discuss their use in the treatment of skeletal myopathies. The first of three classes of drugs discussed here increase contractility by decreasing the dissociation rate of calcium from troponin and thereby sensitizing the muscle to calcium. The second two classes of drugs directly act on myosin and stimulate or inhibit the kinetics of myosin-actin interactions, which may be useful in patients with muscle weakness or stiffness.NEW & NOTEWORTHY During the past decade, several small molecule drugs that improve the contractility of skeletal muscle fibers have been developed. In this review, we provide an overview of the available literature and the mechanisms of action of small molecule drugs that modulate the contractility of sarcomeres, the smallest contractile units in striated muscle, by acting on myosin and troponin.
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Affiliation(s)
- Wout J Claassen
- Amsterdam UMC Location Vrije Universiteit Amsterdam, Physiology, De Boelelaan, Amsterdam, Netherlands
| | - Rianne J Baelde
- Amsterdam UMC Location Vrije Universiteit Amsterdam, Physiology, De Boelelaan, Amsterdam, Netherlands
| | - Ricardo A Galli
- Amsterdam UMC Location Vrije Universiteit Amsterdam, Physiology, De Boelelaan, Amsterdam, Netherlands
| | - Josine M de Winter
- Amsterdam UMC Location Vrije Universiteit Amsterdam, Physiology, De Boelelaan, Amsterdam, Netherlands
| | - Coen A C Ottenheijm
- Amsterdam UMC Location Vrije Universiteit Amsterdam, Physiology, De Boelelaan, Amsterdam, Netherlands
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10
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Dysfunctional mitochondria accumulate in a skeletal muscle knockout model of Smn1, the causal gene of spinal muscular atrophy. Cell Death Dis 2023; 14:162. [PMID: 36849544 PMCID: PMC9971247 DOI: 10.1038/s41419-023-05573-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/18/2022] [Revised: 01/07/2023] [Accepted: 01/09/2023] [Indexed: 03/01/2023]
Abstract
The approved gene therapies for spinal muscular atrophy (SMA), caused by loss of survival motor neuron 1 (SMN1), greatly ameliorate SMA natural history but are not curative. These therapies primarily target motor neurons, but SMN1 loss has detrimental effects beyond motor neurons and especially in muscle. Here we show that SMN loss in mouse skeletal muscle leads to accumulation of dysfunctional mitochondria. Expression profiling of single myofibers from a muscle specific Smn1 knockout mouse model revealed down-regulation of mitochondrial and lysosomal genes. Albeit levels of proteins that mark mitochondria for mitophagy were increased, morphologically deranged mitochondria with impaired complex I and IV activity and respiration and that produced excess reactive oxygen species accumulated in Smn1 knockout muscles, because of the lysosomal dysfunction highlighted by the transcriptional profiling. Amniotic fluid stem cells transplantation that corrects the SMN knockout mouse myopathic phenotype restored mitochondrial morphology and expression of mitochondrial genes. Thus, targeting muscle mitochondrial dysfunction in SMA may complement the current gene therapy.
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11
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Ispizua-Rodriguez X, Krishnamurti V, Carpio V, Barrett C, Prakash GKS. Copper-Catalyzed Synthesis of Difluoromethyl Alkynes from Terminal and Silyl Acetylenes. J Org Chem 2023; 88:1194-1199. [PMID: 36622772 DOI: 10.1021/acs.joc.2c02799] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 01/10/2023]
Abstract
An efficient method for the direct C(sp)-H difluoromethylation of terminal alkynes and the desilylation-difluoromethylation of (trimethylsilyl)acetylenes is disclosed. The copper-catalyzed transformation provides access to a wide range of structurally diverse CF2H alkynes in good yields, utilizing a (difluoromethyl)zinc reagent and an organic oxidant. The difluoromethylation of important synthons and API's is showcased. The synthetic utility of these (difluoromethyl)alkynes is demonstrated by selected cycloaddition reactions. Additionally, a slight modification to the reaction conditions allowed the selective preparation of a 2-difluoromethylindole.
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Affiliation(s)
- Xanath Ispizua-Rodriguez
- Loker Hydrocarbon Research Institute and Department of Chemistry, University of Southern California, Los Angeles, California 90089-1661, United States
| | - Vinayak Krishnamurti
- Loker Hydrocarbon Research Institute and Department of Chemistry, University of Southern California, Los Angeles, California 90089-1661, United States
| | - Vanessa Carpio
- Loker Hydrocarbon Research Institute and Department of Chemistry, University of Southern California, Los Angeles, California 90089-1661, United States
| | - Colby Barrett
- Loker Hydrocarbon Research Institute and Department of Chemistry, University of Southern California, Los Angeles, California 90089-1661, United States
| | - G K Surya Prakash
- Loker Hydrocarbon Research Institute and Department of Chemistry, University of Southern California, Los Angeles, California 90089-1661, United States
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12
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Kumar RA, Hahn D, Kelley RC, Muscato DR, Shamoun A, Curbelo-Bermudez N, Butler WG, Yegorova S, Ryan TE, Ferreira LF. Skeletal muscle Nox4 knockout prevents and Nox2 knockout blunts loss of maximal diaphragm force in mice with heart failure with reduced ejection fraction. Free Radic Biol Med 2023; 194:23-32. [PMID: 36436728 PMCID: PMC10191720 DOI: 10.1016/j.freeradbiomed.2022.11.025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 10/18/2022] [Revised: 11/14/2022] [Accepted: 11/14/2022] [Indexed: 11/27/2022]
Abstract
Patients with heart failure with reduced ejection fraction (HFrEF) experience diaphragm weakness that contributes to the primary disease symptoms of fatigue, dyspnea, and exercise intolerance. Weakness in the diaphragm is related to excessive production of reactive oxygen species (ROS), but the exact source of ROS remains unknown. NAD(P)H Oxidases (Nox), particularly the Nox2 and 4 isoforms, are important sources of ROS within skeletal muscle that contribute to optimal cell function. There are reports of increased Nox activity in the diaphragm of patients and animal models of HFrEF, implicating these complexes as possible sources of diaphragm dysfunction in HFrEF. To investigate the role of these proteins on diaphragm weakness in HFrEF, we generated inducible skeletal muscle specific knockouts of Nox2 or Nox4 using the Cre-Lox system and assessed diaphragm function in a mouse model of HFrEF induced by myocardial infarction. Diaphragm maximal specific force measured in vitro was depressed by ∼20% with HFrEF. Skeletal muscle knockout of Nox4 provided full protection against the loss of maximal force (p < 0.01), while the knockout of Nox2 provided partial protection (7% depression, p < 0.01). Knockout of Nox2 from skeletal myofibers improved survival from 50 to 80% following myocardial infarction (p = 0.026). Our findings show an important role for skeletal muscle NAD(P)H Oxidases contributing to loss of diaphragm maximal force in HFrEF, along with systemic pathophysiological responses following myocardial infarction.
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Affiliation(s)
- Ravi A Kumar
- Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL, USA; King's College London British Heart Foundation Centre of Excellence, School of Cardiovascular Medicine & Sciences, London, United Kingdom
| | - Dongwoo Hahn
- Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL, USA; Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN, USA
| | - Rachel C Kelley
- Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL, USA; Endocrine Society, Washington, D.C, USA
| | - Derek R Muscato
- Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL, USA
| | - Alex Shamoun
- Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL, USA
| | - Nuria Curbelo-Bermudez
- Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL, USA
| | - W Greyson Butler
- Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL, USA
| | - Svetlana Yegorova
- Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL, USA
| | - Terence E Ryan
- Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL, USA
| | - Leonardo F Ferreira
- Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL, USA.
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13
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Bofanova NS, Eliseeva AR, Onchina VS. [Modern principles of therapy for patients with spinal muscular atrophy]. Zh Nevrol Psikhiatr Im S S Korsakova 2023; 123:34-40. [PMID: 36946394 DOI: 10.17116/jnevro202312303134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 03/23/2023]
Abstract
Spinal muscular atrophy (SMA) is a common cause of childhood mortality among hereditary diseases of the central nervous system, which are caused by the processes of degeneration and death of motor neurons of the anterior horns of the spinal cord. An urgent issue of modern neurology is pathogenetic therapy for this group of patients, the purpose of which is to increase the level of motoneuron survival protein. We performed a search on current methods of treating SMA in Web of Science, Scopus, PubMed, Embase by the keywords: spinal muscular atrophy, neuromuscular diseases, pathogenetic therapy. Significant progress has been made in the treatment of SMA over the past 7 years. A major advance is the introduction of disease-modifying therapies using SMN2 splicing modulation or gene replacement therapy. At the moment, there are 3 FDA-approved drugs for pathogenetic therapy: Nusinersen, Risdiplam, Zolgensma. The article compares the drugs, evaluates their safety and effectiveness according to the available literature. Modern drugs for the pathogenetic therapy of SMA are highly effective and reduce the mortality rate. The results of clinical trials predict the emergence of new modern drugs. This suggests a favorable prognosis for the treatment of patients with SMA.
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14
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Mahmud Z, Tikunova S, Belevych N, Wagg CS, Zhabyeyev P, Liu PB, Rasicci DV, Yengo CM, Oudit GY, Lopaschuk GD, Reiser PJ, Davis JP, Hwang PM. Small Molecule RPI-194 Stabilizes Activated Troponin to Increase the Calcium Sensitivity of Striated Muscle Contraction. Front Physiol 2022; 13:892979. [PMID: 35755445 PMCID: PMC9213791 DOI: 10.3389/fphys.2022.892979] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/09/2022] [Accepted: 05/10/2022] [Indexed: 11/13/2022] Open
Abstract
Small molecule cardiac troponin activators could potentially enhance cardiac muscle contraction in the treatment of systolic heart failure. We designed a small molecule, RPI-194, to bind cardiac/slow skeletal muscle troponin (Cardiac muscle and slow skeletal muscle share a common isoform of the troponin C subunit.) Using solution NMR and stopped flow fluorescence spectroscopy, we determined that RPI-194 binds to cardiac troponin with a dissociation constant KD of 6-24 μM, stabilizing the activated complex between troponin C and the switch region of troponin I. The interaction between RPI-194 and troponin C is weak (KD 311 μM) in the absence of the switch region. RPI-194 acts as a calcium sensitizer, shifting the pCa50 of isometric contraction from 6.28 to 6.99 in mouse slow skeletal muscle fibers and from 5.68 to 5.96 in skinned cardiac trabeculae at 100 μM concentration. There is also some cross-reactivity with fast skeletal muscle fibers (pCa50 increases from 6.27 to 6.52). In the slack test performed on the same skinned skeletal muscle fibers, RPI-194 slowed the velocity of unloaded shortening at saturating calcium concentrations, suggesting that it slows the rate of actin-myosin cross-bridge cycling under these conditions. However, RPI-194 had no effect on the ATPase activity of purified actin-myosin. In isolated unloaded mouse cardiomyocytes, RPI-194 markedly decreased the velocity and amplitude of contractions. In contrast, cardiac function was preserved in mouse isolated perfused working hearts. In summary, the novel troponin activator RPI-194 acts as a calcium sensitizer in all striated muscle types. Surprisingly, it also slows the velocity of unloaded contraction, but the cause and significance of this is uncertain at this time. RPI-194 represents a new class of non-specific troponin activator that could potentially be used either to enhance cardiac muscle contractility in the setting of systolic heart failure or to enhance skeletal muscle contraction in neuromuscular disorders.
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Affiliation(s)
- Zabed Mahmud
- Department of Biochemistry, University of Alberta, Edmonton, AB, Canada
| | - Svetlana Tikunova
- Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH, United States
| | - Natalya Belevych
- Division of Biosciences, College of Dentistry, The Ohio State University, Columbus, OH, United States
| | - Cory S Wagg
- Department of Pediatrics, University of Alberta, Edmonton, AB, Canada
| | - Pavel Zhabyeyev
- Department of Medicine, University of Alberta, Edmonton, AB, Canada
| | - Philip B Liu
- Department of Medicine, University of Alberta, Edmonton, AB, Canada
| | - David V Rasicci
- Department of Cellular and Molecular Physiology, College of Medicine, Pennsylvania State University, University Park, PA, United States
| | - Christopher M Yengo
- Department of Cellular and Molecular Physiology, College of Medicine, Pennsylvania State University, University Park, PA, United States
| | - Gavin Y Oudit
- Department of Medicine, University of Alberta, Edmonton, AB, Canada
| | - Gary D Lopaschuk
- Department of Pediatrics, University of Alberta, Edmonton, AB, Canada
| | - Peter J Reiser
- Division of Biosciences, College of Dentistry, The Ohio State University, Columbus, OH, United States
| | - Jonathan P Davis
- Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH, United States
| | - Peter M Hwang
- Department of Biochemistry, University of Alberta, Edmonton, AB, Canada.,Department of Medicine, University of Alberta, Edmonton, AB, Canada
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15
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López-Cortés A, Echeverría-Garcés G, Ramos-Medina MJ. Molecular Pathogenesis and New Therapeutic Dimensions for Spinal Muscular Atrophy. BIOLOGY 2022; 11:biology11060894. [PMID: 35741415 PMCID: PMC9219894 DOI: 10.3390/biology11060894] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Academic Contribution Register] [Received: 04/05/2022] [Revised: 05/04/2022] [Accepted: 05/06/2022] [Indexed: 11/16/2022]
Abstract
The condition known as 5q spinal muscular atrophy (SMA) is a devastating autosomal recessive neuromuscular disease caused by a deficiency of the ubiquitous protein survival of motor neuron (SMN), which is encoded by the SMN1 and SMN2 genes. It is one of the most common pediatric recessive genetic diseases, and it represents the most common cause of hereditary infant mortality. After decades of intensive basic and clinical research efforts, and improvements in the standard of care, successful therapeutic milestones have been developed, delaying the progression of 5q SMA and increasing patient survival. At the same time, promising data from early-stage clinical trials have indicated that additional therapeutic options are likely to emerge in the near future. Here, we provide updated information on the molecular underpinnings of SMA; we also provide an overview of the rapidly evolving therapeutic landscape for SMA, including SMN-targeted therapies, SMN-independent therapies, and combinational therapies that are likely to be key for the development of treatments that are effective across a patient’s lifespan.
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Affiliation(s)
- Andrés López-Cortés
- Programa de Investigación en Salud Global, Facultad de Ciencias de la Salud, Universidad Internacional SEK, Quito 170302, Ecuador
- Facultad de Medicina, Universidad de Las Américas, Quito 170124, Ecuador
- Latin American Network for the Implementation and Validation of Clinical Pharmacogenomics Guidelines (RELIVAF-CYTED), 28001 Madrid, Spain; (G.E.-G.); (M.J.R.-M.)
- Correspondence:
| | - Gabriela Echeverría-Garcés
- Latin American Network for the Implementation and Validation of Clinical Pharmacogenomics Guidelines (RELIVAF-CYTED), 28001 Madrid, Spain; (G.E.-G.); (M.J.R.-M.)
| | - María José Ramos-Medina
- Latin American Network for the Implementation and Validation of Clinical Pharmacogenomics Guidelines (RELIVAF-CYTED), 28001 Madrid, Spain; (G.E.-G.); (M.J.R.-M.)
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16
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Dominguez CE, Cunningham D, Venkataramany AS, Chandler DS. Heat increases full-length SMN splicing: promise for splice-augmenting therapies for SMA. Hum Genet 2022; 141:239-256. [PMID: 35088120 DOI: 10.1007/s00439-021-02408-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/27/2021] [Accepted: 11/30/2021] [Indexed: 11/28/2022]
Abstract
Spinal muscular atrophy (SMA) is a debilitating neurodegenerative pediatric disease characterized by low levels of the survival motor protein (SMN). Humans have two SMN genes that produce identical SMN proteins, but they differ at a key nucleotide in exon 7 that induces differential mRNA splicing. SMN1 primarily produces full-length SMN protein, but due to the spliceosome's inability to efficiently recognize exon 7, SMN2 transcripts are often truncated. SMA occurs primarily through mutations or deletions in the SMN1 gene; therefore, current therapies use antisense oligonucleotides (ASOs) to target exon 7 inclusion in SMN2 mRNA and promote full-length SMN protein production. Here, we explore additional methods that can target SMN splicing and therapeutically increase full-length SMN protein. We demonstrate that in vitro heat treatment of cells increases exon 7 inclusion and relative abundance of full-length SMN2 mRNA and protein, a response that is modulated through the upregulation of the positive splicing factor TRA2 beta. We also observe that HSP90, but not HSP40 or HSP70, in the heat shock response is essential for SMN2 exon 7 splicing under hyperthermic conditions. Finally, we show that pulsatile heat treatments for one hour in vitro and in vivo are effective in increasing full-length SMN2 levels. These findings suggest that timed interval treatments could be a therapeutic alternative for SMA patients who do not respond to current ASO-based therapies or require a unique combination regimen.
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Affiliation(s)
- Catherine E Dominguez
- Molecular, Cellular and Developmental Biology Graduate Program and The Center for RNA Biology, The Ohio State University, Columbus, OH, USA.,Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH, 43205, USA
| | - David Cunningham
- Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH, 43205, USA
| | - Akila S Venkataramany
- Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH, 43205, USA.,Biomedical Sciences Graduate Program, The Ohio State University, Columbus, OH, USA.,Medical Scientist Training Program, The Ohio State University, Columbus, OH, USA
| | - Dawn S Chandler
- Molecular, Cellular and Developmental Biology Graduate Program and The Center for RNA Biology, The Ohio State University, Columbus, OH, USA. .,Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH, 43205, USA. .,Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA.
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17
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Jablonka S, Hennlein L, Sendtner M. Therapy development for spinal muscular atrophy: perspectives for muscular dystrophies and neurodegenerative disorders. Neurol Res Pract 2022; 4:2. [PMID: 34983696 PMCID: PMC8725368 DOI: 10.1186/s42466-021-00162-9] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/20/2021] [Accepted: 10/21/2021] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Major efforts have been made in the last decade to develop and improve therapies for proximal spinal muscular atrophy (SMA). The introduction of Nusinersen/Spinraza™ as an antisense oligonucleotide therapy, Onasemnogene abeparvovec/Zolgensma™ as an AAV9-based gene therapy and Risdiplam/Evrysdi™ as a small molecule modifier of pre-mRNA splicing have set new standards for interference with neurodegeneration. MAIN BODY Therapies for SMA are designed to interfere with the cellular basis of the disease by modifying pre-mRNA splicing and enhancing expression of the Survival Motor Neuron (SMN) protein, which is only expressed at low levels in this disorder. The corresponding strategies also can be applied to other disease mechanisms caused by loss of function or toxic gain of function mutations. The development of therapies for SMA was based on the use of cell culture systems and mouse models, as well as innovative clinical trials that included readouts that had originally been introduced and optimized in preclinical studies. This is summarized in the first part of this review. The second part discusses current developments and perspectives for amyotrophic lateral sclerosis, muscular dystrophies, Parkinson's and Alzheimer's disease, as well as the obstacles that need to be overcome to introduce RNA-based therapies and gene therapies for these disorders. CONCLUSION RNA-based therapies offer chances for therapy development of complex neurodegenerative disorders such as amyotrophic lateral sclerosis, muscular dystrophies, Parkinson's and Alzheimer's disease. The experiences made with these new drugs for SMA, and also the experiences in AAV gene therapies could help to broaden the spectrum of current approaches to interfere with pathophysiological mechanisms in neurodegeneration.
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Affiliation(s)
- Sibylle Jablonka
- Institute of Clinical Neurobiology, University Hospital of Wuerzburg, Versbacher Str. 5, 97078, Wuerzburg, Germany.
| | - Luisa Hennlein
- Institute of Clinical Neurobiology, University Hospital of Wuerzburg, Versbacher Str. 5, 97078, Wuerzburg, Germany
| | - Michael Sendtner
- Institute of Clinical Neurobiology, University Hospital of Wuerzburg, Versbacher Str. 5, 97078, Wuerzburg, Germany.
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18
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Collibee SE, Bergnes G, Chuang C, Ashcraft L, Gardina J, Garard M, Jamison CR, Lu K, Lu PP, Muci A, Romero A, Valkevich E, Wang W, Warrington J, Yao B, Durham N, Hartman J, Marquez A, Hinken A, Schaletzky J, Xu D, Hwee DT, Morgans D, Malik FI, Morgan BP. Discovery of Reldesemtiv, a Fast Skeletal Muscle Troponin Activator for the Treatment of Impaired Muscle Function. J Med Chem 2021; 64:14930-14941. [PMID: 34636234 DOI: 10.1021/acs.jmedchem.1c01067] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/29/2022]
Abstract
The discovery of reldesemtiv, a second-generation fast skeletal muscle troponin activator (FSTA) that increases force production at submaximal stimulation frequencies, is reported. Property-based optimization of high throughput screening hit 1 led to compounds with improved free exposure and in vivo muscle activation potency compared to the first-generation FSTA, tirasemtiv. Reldesemtiv demonstrated increased muscle force generation in a phase 1 clinical trial and is currently being evaluated in clinical trials for the treatment of amyotrophic lateral sclerosis.
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Affiliation(s)
- Scott E Collibee
- Cytokinetics, Inc., 280 East Grand Avenue, South San Francisco, California 94080, United States
| | - Gustave Bergnes
- Cytokinetics, Inc., 280 East Grand Avenue, South San Francisco, California 94080, United States
| | - Chihyuan Chuang
- Cytokinetics, Inc., 280 East Grand Avenue, South San Francisco, California 94080, United States
| | - Luke Ashcraft
- Cytokinetics, Inc., 280 East Grand Avenue, South San Francisco, California 94080, United States
| | - Jeffrey Gardina
- Cytokinetics, Inc., 280 East Grand Avenue, South San Francisco, California 94080, United States
| | - Marc Garard
- Cytokinetics, Inc., 280 East Grand Avenue, South San Francisco, California 94080, United States
| | - Chris R Jamison
- Cytokinetics, Inc., 280 East Grand Avenue, South San Francisco, California 94080, United States
| | - Kevin Lu
- Cytokinetics, Inc., 280 East Grand Avenue, South San Francisco, California 94080, United States
| | - Pu-Ping Lu
- Cytokinetics, Inc., 280 East Grand Avenue, South San Francisco, California 94080, United States
| | - Alexander Muci
- Cytokinetics, Inc., 280 East Grand Avenue, South San Francisco, California 94080, United States
| | - Antonio Romero
- Cytokinetics, Inc., 280 East Grand Avenue, South San Francisco, California 94080, United States
| | - Ellen Valkevich
- Cytokinetics, Inc., 280 East Grand Avenue, South San Francisco, California 94080, United States
| | - Wenyue Wang
- Cytokinetics, Inc., 280 East Grand Avenue, South San Francisco, California 94080, United States
| | - Jeffrey Warrington
- Cytokinetics, Inc., 280 East Grand Avenue, South San Francisco, California 94080, United States
| | - Bing Yao
- Cytokinetics, Inc., 280 East Grand Avenue, South San Francisco, California 94080, United States
| | - Nickie Durham
- Cytokinetics, Inc., 280 East Grand Avenue, South San Francisco, California 94080, United States
| | - James Hartman
- Cytokinetics, Inc., 280 East Grand Avenue, South San Francisco, California 94080, United States
| | - Anna Marquez
- Cytokinetics, Inc., 280 East Grand Avenue, South San Francisco, California 94080, United States
| | - Aaron Hinken
- Cytokinetics, Inc., 280 East Grand Avenue, South San Francisco, California 94080, United States
| | - Julia Schaletzky
- Cytokinetics, Inc., 280 East Grand Avenue, South San Francisco, California 94080, United States
| | - Donghong Xu
- Cytokinetics, Inc., 280 East Grand Avenue, South San Francisco, California 94080, United States
| | - Darren T Hwee
- Cytokinetics, Inc., 280 East Grand Avenue, South San Francisco, California 94080, United States
| | - David Morgans
- Cytokinetics, Inc., 280 East Grand Avenue, South San Francisco, California 94080, United States
| | - Fady I Malik
- Cytokinetics, Inc., 280 East Grand Avenue, South San Francisco, California 94080, United States
| | - Bradley P Morgan
- Cytokinetics, Inc., 280 East Grand Avenue, South San Francisco, California 94080, United States
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19
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McCormack NM, Villalón E, Viollet C, Soltis AR, Dalgard CL, Lorson CL, Burnett BG. Survival motor neuron deficiency slows myoblast fusion through reduced myomaker and myomixer expression. J Cachexia Sarcopenia Muscle 2021; 12:1098-1116. [PMID: 34115448 PMCID: PMC8350220 DOI: 10.1002/jcsm.12740] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 06/16/2020] [Revised: 05/05/2021] [Accepted: 05/21/2021] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND Spinal muscular atrophy is an inherited neurodegenerative disease caused by insufficient levels of the survival motor neuron (SMN) protein. Recently approved treatments aimed at increasing SMN protein levels have dramatically improved patient survival and have altered the disease landscape. While restoring SMN levels slows motor neuron loss, many patients continue to have smaller muscles and do not achieve normal motor milestones. While timing of treatment is important, it remains unclear why SMN restoration is insufficient to fully restore muscle size and function. We and others have shown that SMN-deficient muscle precursor cells fail to efficiently fuse into myotubes. However, the role of SMN in myoblast fusion is not known. METHODS In this study, we show that SMN-deficient myoblasts readily fuse with wild-type myoblasts, demonstrating fusion competency. Conditioned media from wild type differentiating myoblasts do not rescue the fusion deficit of SMN-deficient cells, suggesting that compromised fusion may primarily be a result of altered membrane dynamics at the cell surface. Transcriptome profiling of skeletal muscle from SMN-deficient mice revealed altered expression of cell surface fusion molecules. Finally, using cell and mouse models, we investigate if myoblast fusion can be rescued in SMN-deficient myoblast and improve the muscle pathology in SMA mice. RESULTS We found reduced expression of the muscle fusion proteins myomaker (P = 0.0060) and myomixer (P = 0.0051) in the muscle of SMA mice. Suppressing SMN expression in C2C12 myoblast cells reduces expression of myomaker (35% reduction; P < 0.0001) and myomixer, also known as myomerger and minion, (30% reduction; P < 0.0001) and restoring SMN levels only partially restores myomaker and myomixer expression. Ectopic expression of myomixer improves myofibre number (55% increase; P = 0.0006) and motor function (35% decrease in righting time; P = 0.0089) in SMA model mice and enhances motor function (82% decrease in righting time; P < 0.0001) and extends survival (28% increase; P < 0.01) when administered in combination with an antisense oligonucleotide that increases SMN protein levels. CONCLUSIONS Here, we identified reduced expression of muscle fusion proteins as a key factor in the fusion deficits of SMN-deficient myoblasts. This discovery provides a novel target to improve SMA muscle pathology and motor function, which in combination with SMN increasing therapy could enhance clinical outcomes for SMA patients.
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Affiliation(s)
- Nikki M McCormack
- Department of Anatomy, Physiology, and Genetics, Uniformed Services University of the Health Sciences, F. Edward Hébert School of Medicine, Bethesda, MD, USA
| | - Eric Villalón
- Bond Life Sciences Center, University of Missouri, Columbia, MO, USA.,Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO, USA
| | - Coralie Viollet
- Collaborative Health Initiative Research Program, Uniformed Services University of the Heath Sciences, Bethesda, MD, USA
| | - Anthony R Soltis
- Collaborative Health Initiative Research Program, Uniformed Services University of the Heath Sciences, Bethesda, MD, USA.,Henry M. Jackson Foundation, Bethesda, MD, USA
| | - Clifton L Dalgard
- Department of Anatomy, Physiology, and Genetics, Uniformed Services University of the Health Sciences, F. Edward Hébert School of Medicine, Bethesda, MD, USA.,Collaborative Health Initiative Research Program, Uniformed Services University of the Heath Sciences, Bethesda, MD, USA.,The American Genome Center, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
| | - Christian L Lorson
- Bond Life Sciences Center, University of Missouri, Columbia, MO, USA.,Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO, USA
| | - Barrington G Burnett
- Department of Anatomy, Physiology, and Genetics, Uniformed Services University of the Health Sciences, F. Edward Hébert School of Medicine, Bethesda, MD, USA
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20
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Nutritional, Gastrointestinal and Endo-Metabolic Challenges in the Management of Children with Spinal Muscular Atrophy Type 1. Nutrients 2021; 13:nu13072400. [PMID: 34371910 PMCID: PMC8308588 DOI: 10.3390/nu13072400] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/04/2021] [Revised: 07/08/2021] [Accepted: 07/10/2021] [Indexed: 12/18/2022] Open
Abstract
The management of patients with spinal muscular atrophy type 1 (SMA1) is constantly evolving. In just a few decades, the medical approach has switched from an exclusively palliative therapy to a targeted therapy, transforming the natural history of the disease, improving survival time and quality of life and creating new challenges and goals. Many nutritional problems, gastrointestinal disorders and metabolic and endocrine alterations are commonly identified in patients affected by SMA1 during childhood and adolescence. For this reason, a proper pediatric multidisciplinary approach is then required in the clinical care of these patients, with a specific focus on the prevention of most common complications. The purpose of this narrative review is to provide the clinician with a practical and usable tool about SMA1 patients care, through a comprehensive insight into the nutritional, gastroenterological, metabolic and endocrine management of SMA1. Considering the possible horizons opened thanks to new therapeutic frontiers, a nutritional and endo-metabolic surveillance is a crucial element to be considered for a proper clinical care of these patients.
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21
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Behera B. Nusinersen, an exon 7 inclusion drug for spinal muscular atrophy: A minireview. World J Meta-Anal 2021; 9:277-285. [DOI: 10.13105/wjma.v9.i3.277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 12/03/2020] [Revised: 05/20/2021] [Accepted: 06/17/2021] [Indexed: 02/06/2023] Open
Abstract
Spinal muscular atrophy is an autosomal recessive neuromuscular disease with incidence of 1 in 5000 to 10000 live births and is produced by homozygous deletion of exons 7 and 8 in the SMN1 gene. The SMN1 and SMN2 genes encode the survival motor neuron protein, a crucial protein for the preservation of motor neurons. Use of the newer drug, Nusinersen, from early infancy has shown improvement in clinical outcomes of spinal muscular atrophy patients.
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Affiliation(s)
- Bijaylaxmi Behera
- Department of Neonatology, Chaitanya Hospital, Chandigarh 160044, India
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22
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Servais L, Baranello G, Scoto M, Daron A, Oskoui M. Therapeutic interventions for spinal muscular atrophy: preclinical and early clinical development opportunities. Expert Opin Investig Drugs 2021; 30:519-527. [PMID: 33749510 DOI: 10.1080/13543784.2021.1904889] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative neuromuscular disease that presents primarily in children. Abnormalities in the SMN1 gene cause reduced levels of the survival motor neuron (SMN) protein, while a second gene, SMN2, produces low levels of functional SMN protein. Currently available drugs do not cure, so a significant unmet need remains for patients treated after symptom onset. AREAS COVERED Drugs available in the clinic, investigational agents and key questions for researchers are discussed. A pragmatic search of the literature was performed to identify therapies in late stages of preclinical, or in early stages of clinical development. This list was compared to the CureSMA pipeline for completeness. Drugs approved for indications that have potential for impact for SMA were included. These drugs target the primary deficiency in SMN protein or other pathways involved in SMA pathophysiology that are not SMN-protein dependent. EXPERT OPINION Children treated after the onset of symptoms continue to have significant disability. Given the heterogeneity of the population phenotype evidenced by variable response to initial therapy, age at treatment onset and the need to demonstrate added value beyond approved therapeutics, the clinical development of new drugs will be challenging.
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Affiliation(s)
- Laurent Servais
- MDUK Neuromuscular Center, Department of Paediatrics, University of Oxford, Oxford, UK.,Neuromuscular Reference Center Disease, Department of Paediatrics, Liege, Belgium and University of Liege, Liège, Belgium
| | - Giovanni Baranello
- Dubowitz Neuromuscular Centre, NIHR Great Ormond Street Hospital Biomedical Research Centre, Great Ormond Street Institute of Child Health, University College London, London, UK
| | - Mariacristina Scoto
- Dubowitz Neuromuscular Centre, NIHR Great Ormond Street Hospital Biomedical Research Centre, Great Ormond Street Institute of Child Health, University College London, London, UK
| | - Aurore Daron
- Neuromuscular Reference Center Disease, Department of Paediatrics, Liege, Belgium and University of Liege, Liège, Belgium
| | - Maryam Oskoui
- Departments of Pediatrics and Neurology & Neurosurgery, McGill University, Montreal, QC, Canada
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23
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Nicolau S, Waldrop MA, Connolly AM, Mendell JR. Spinal Muscular Atrophy. Semin Pediatr Neurol 2021; 37:100878. [PMID: 33892848 DOI: 10.1016/j.spen.2021.100878] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/07/2020] [Revised: 12/07/2020] [Accepted: 12/07/2020] [Indexed: 02/07/2023]
Abstract
Spinal muscular atrophy is one of the most common neuromuscular disorders of childhood and has high morbidity and mortality. Three different disease-modifying treatments were introduced in the last 4 years: nusinersen, onasemnogene abeparvovec, and risdiplam. These agents have demonstrated safety and efficacy, but their long-term benefits require further study. Newborn screening programs are enabling earlier diagnosis and treatment and better outcomes, but respiratory care and other supportive measures retain a key role in the management of spinal muscular atrophy. Ongoing efforts seek to optimize gene therapy vectors, explore new therapeutic targets beyond motor neurons, and evaluate the role of combination therapy.
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Affiliation(s)
- Stefan Nicolau
- Center for Gene Therapy, The Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH.
| | - Megan A Waldrop
- Center for Gene Therapy, The Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH; Departments of Pediatrics and Neurology, Ohio State University, Columbus, OH
| | - Anne M Connolly
- Center for Gene Therapy, The Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH; Departments of Pediatrics and Neurology, Ohio State University, Columbus, OH
| | - Jerry R Mendell
- Center for Gene Therapy, The Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH; Departments of Pediatrics and Neurology, Ohio State University, Columbus, OH
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24
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Rudnicki SA, Andrews JA, Duong T, Cockroft BM, Malik FI, Meng L, Wei J, Wolff AA, Genge A, Johnson NE, Tesi-Rocha C, Connolly AM, Darras BT, Felice K, Finkel RS, Shieh PB, Mah JK, Statland J, Campbell C, Habib AA, Kuntz NL, Oskoui M, Day JW. Reldesemtiv in Patients with Spinal Muscular Atrophy: a Phase 2 Hypothesis-Generating Study. Neurotherapeutics 2021; 18:1127-1136. [PMID: 33624184 PMCID: PMC8423982 DOI: 10.1007/s13311-020-01004-3] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Accepted: 12/30/2020] [Indexed: 02/07/2023] Open
Abstract
This phase 2, double-blind, placebo-controlled, hypothesis-generating study evaluated the effects of oral reldesemtiv, a fast skeletal muscle troponin activator, in patients with spinal muscular atrophy (SMA). Patients ≥ 12 years of age with type II, III, or IV SMA were randomized into 2 sequential, ascending reldesemtiv dosing cohorts (cohort 1: 150 mg bid or placebo [2:1]; cohort 2: 450 mg bid or placebo [2:1]). The primary objective was to determine potential pharmacodynamic effects of reldesemtiv on 8 outcome measures in SMA, including 6-minute walk distance (6MWD) and maximum expiratory pressure (MEP). Changes from baseline to weeks 4 and 8 were determined. Pharmacokinetics and safety were also evaluated. Patients were randomized to reldesemtiv 150 mg, 450 mg, or placebo (24, 20, and 26, respectively). The change from baseline in 6MWD was greater for reldesemtiv 450 mg than for placebo at weeks 4 and 8 (least squares [LS] mean difference, 35.6 m [p = 0.0037] and 24.9 m [p = 0.058], respectively). Changes from baseline in MEP at week 8 on reldesemtiv 150 and 450 mg were significantly greater than those on placebo (LS mean differences, 11.7 [p = 0.038] and 13.2 cm H2O [p = 0.03], respectively). For 6MWD and MEP, significant changes from placebo were seen in the highest reldesemtiv peak plasma concentration quartile (Cmax > 3.29 μg/mL; LS mean differences, 43.3 m [p = 0.010] and 28.8 cm H2O [p = 0.0002], respectively). Both dose levels of reldesemtiv were well tolerated. Results suggest reldesemtiv may offer clinical benefit and support evaluation in larger SMA patient populations.
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Affiliation(s)
| | - Jinsy A Andrews
- Cytokinetics, Incorporated, South San Francisco, CA, USA
- Columbia University, New York, NY, USA
| | | | - Bettina M Cockroft
- Cytokinetics, Incorporated, South San Francisco, CA, USA
- Sangamo Therapeutics, Brisbane, CA, USA
| | - Fady I Malik
- Cytokinetics, Incorporated, South San Francisco, CA, USA
| | - Lisa Meng
- Cytokinetics, Incorporated, South San Francisco, CA, USA
| | - Jenny Wei
- Cytokinetics, Incorporated, South San Francisco, CA, USA
| | - Andrew A Wolff
- Cytokinetics, Incorporated, South San Francisco, CA, USA
| | - Angela Genge
- Montreal Neurological Institute, Montreal, QC, Canada
| | - Nicholas E Johnson
- Virginia Commonwealth University, Richmond, VA, USA
- University of Utah, Salt Lake City, UT, USA
| | | | - Anne M Connolly
- Nationwide Children's Hospital, Columbus, OH, USA
- Washington University, St Louis, MO, USA
| | - Basil T Darras
- Boston Children's Hospital and Harvard Medical School, Boston, MA, USA
| | | | - Richard S Finkel
- Nemours Children's Hospital, Orlando, FL, USA
- St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Perry B Shieh
- University of California, Los Angeles, Los Angeles, CA, USA
| | - Jean K Mah
- University of Calgary, Alberta Children's Hospital, Calgary, AB, Canada
| | | | - Craig Campbell
- Department of Pediatrics, Epidemiology and Clinical Neurological Sciences, University of Western Ontario, London Health Sciences Centre, London, ON, Canada
| | - Ali A Habib
- University of California, Irvine, Orange, CA, USA
| | - Nancy L Kuntz
- Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA
| | - Maryam Oskoui
- McGill University Health Centre Research Institute, Montreal, QC, Canada
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25
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Mangner N, Garbade J, Heyne E, van den Berg M, Winzer EB, Hommel J, Sandri M, Jozwiak-Nozdrzykowska J, Meyer AL, Lehmann S, Schmitz C, Malfatti E, Schwarzer M, Ottenheijm CAC, Bowen TS, Linke A, Adams V. Molecular Mechanisms of Diaphragm Myopathy in Humans With Severe Heart Failure. Circ Res 2021; 128:706-719. [PMID: 33535772 DOI: 10.1161/circresaha.120.318060] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Indexed: 11/16/2022]
Abstract
[Figure: see text].
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Affiliation(s)
- Norman Mangner
- Department of Internal Medicine and Cardiology (N.M., E.B.W., J.H., C.S., A.L. V.A.), Herzzentrum Dresden, Technische Universität Dresden, Germany
| | - Jens Garbade
- Department of Cardiac Surgery (J.G., S.L.), Heart Center Leipzig - University Hospital, Germany
| | - Estelle Heyne
- Department of Cardiothoracic Surgery, Jena University Hospital - Friedrich Schiller University of Jena, Germany (E.H., M.S.)
| | | | - Ephraim B Winzer
- Department of Internal Medicine and Cardiology (N.M., E.B.W., J.H., C.S., A.L. V.A.), Herzzentrum Dresden, Technische Universität Dresden, Germany
| | - Jennifer Hommel
- Department of Internal Medicine and Cardiology (N.M., E.B.W., J.H., C.S., A.L. V.A.), Herzzentrum Dresden, Technische Universität Dresden, Germany
| | - Marcus Sandri
- Department of Cardiology (M.S., J.J.-N.), Heart Center Leipzig - University Hospital, Germany
- Department of Cardiothoracic Surgery, Jena University Hospital - Friedrich Schiller University of Jena, Germany (E.H., M.S.)
| | | | - Anna L Meyer
- Cardiac Surgery, Heart and Marfan Center, University of Heidelberg, Germany (A.L.M.)
| | - Sven Lehmann
- Department of Cardiac Surgery (J.G., S.L.), Heart Center Leipzig - University Hospital, Germany
| | - Clara Schmitz
- Department of Internal Medicine and Cardiology (N.M., E.B.W., J.H., C.S., A.L. V.A.), Herzzentrum Dresden, Technische Universität Dresden, Germany
| | - Edoardo Malfatti
- Neurology, Centre de Référence Maladies Neuromusculaires Nord-Est-Ile-de-France, CHU Raymond-Poincaré, Garches, France (E.M.). U1179 UVSQ-INSERM, Université Versailles-Saint-Quentin-en-Yvelines, France
| | | | - Coen A C Ottenheijm
- Physiology, Amsterdam UMC (location VUmc), the Netherlands (M.v.d.B., C.A.C.O.)
| | - T Scott Bowen
- School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, United Kingdom (T.S.B.)
| | - Axel Linke
- Department of Internal Medicine and Cardiology (N.M., E.B.W., J.H., C.S., A.L. V.A.), Herzzentrum Dresden, Technische Universität Dresden, Germany
- Dresden Cardiovascular Research Institute and Core Laboratories GmbH, Dresden, Germany (A.L., V.A.)
| | - Volker Adams
- Department of Internal Medicine and Cardiology (N.M., E.B.W., J.H., C.S., A.L. V.A.), Herzzentrum Dresden, Technische Universität Dresden, Germany
- Dresden Cardiovascular Research Institute and Core Laboratories GmbH, Dresden, Germany (A.L., V.A.)
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26
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Li MX, Mercier P, Hartman JJ, Sykes BD. Structural Basis of Tirasemtiv Activation of Fast Skeletal Muscle. J Med Chem 2021; 64:3026-3034. [PMID: 33703886 DOI: 10.1021/acs.jmedchem.0c01412] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 01/04/2023]
Abstract
Troponin regulates the calcium-mediated activation of skeletal muscle. Muscle weakness in diseases such as amyotrophic lateral sclerosis and spinal muscular atrophy occurs from diminished neuromuscular output. The first direct fast skeletal troponin activator, tirasemtiv, amplifies the response of muscle to neuromuscular input. Tirasemtiv binds selectively and strongly to fast skeletal troponin, slowing the rate of calcium release and sensitizing muscle to calcium. We report the solution NMR structure of tirasemtiv bound to a fast skeletal troponin C-troponin I chimera. The structure reveals that tirasemtiv binds in a hydrophobic pocket between the regulatory domain of troponin C and the switch region of troponin I, which overlaps with that of Anapoe in the X-ray structure of skeletal troponin. Multiple interactions stabilize the troponin C-troponin I interface, increase the affinity of troponin C for the switch region of fast skeletal troponin I, and drive the equilibrium toward the active state.
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Affiliation(s)
- Monica X Li
- Department of Biochemistry, University of Alberta, Edmonton, AB T6G 2H7, Canada
| | - Pascal Mercier
- National High Field NMR Centre, University of Alberta, Edmonton, AB T6G 2E1, Canada
| | - James J Hartman
- Cytokinetics, Inc., South San Francisco, California 94080, United States
| | - Brian D Sykes
- Department of Biochemistry, University of Alberta, Edmonton, AB T6G 2H7, Canada
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27
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Yegorova S, Yegorov O, Ferreira LF. RNA-sequencing reveals transcriptional signature of pathological remodeling in the diaphragm of rats after myocardial infarction. Gene 2020; 770:145356. [PMID: 33333219 DOI: 10.1016/j.gene.2020.145356] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/03/2020] [Revised: 11/11/2020] [Accepted: 12/01/2020] [Indexed: 12/21/2022]
Abstract
The diaphragm is the main inspiratory muscle, and the chronic phase post-myocardial infarction (MI) is characterized by diaphragm morphological, contractile, and metabolic abnormalities. However, the mechanisms of diaphragm weakness are not fully understood. In the current study, we aimed to identify the transcriptome changes associated with diaphragm abnormalities in the chronic stage MI. We ligated the left coronary artery to cause MI in rats and performed RNA-sequencing (RNA-Seq) in diaphragm samples 16 weeks post-surgery. The sham group underwent thoracotomy and pericardiotomy but no artery ligation. We identified 112 differentially expressed genes (DEGs) out of a total of 9664 genes. Myocardial infarction upregulated and downregulated 42 and 70 genes, respectively. Analysis of DEGs in the framework of skeletal muscle-specific biological networks suggest remodeling in the neuromuscular junction, extracellular matrix, sarcomere, cytoskeleton, and changes in metabolism and iron homeostasis. Overall, the data are consistent with pathological remodeling of the diaphragm and reveal potential biological targets to prevent diaphragm weakness in the chronic stage MI.
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Affiliation(s)
- Svetlana Yegorova
- Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL 32611, USA.
| | - Oleg Yegorov
- Department of Neurosurgery, University of Florida, Gainesville, FL 32611, USA.
| | - Leonardo F Ferreira
- Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL 32611, USA.
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28
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Vu-Han TL, Weiß C, Pumberger M. Novel therapies for spinal muscular atrophy are likely changing the patient phenotype. Spine J 2020; 20:1893-1898. [PMID: 32858169 DOI: 10.1016/j.spinee.2020.08.013] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 07/24/2020] [Revised: 08/21/2020] [Accepted: 08/23/2020] [Indexed: 02/03/2023]
Affiliation(s)
- Tu-Lan Vu-Han
- Center for Musculoskeletal Surgery Berlin Mitte; Charité University Medicine Berlin, Charitéplatz 1, Berlin 10117, Germany.
| | - Claudia Weiß
- Center for chronically sick children, Department of Neuropediatrics; Charité University, Medicine Berlin, Augustenburger Platz 1, Berlin 13353, Germany
| | - Matthias Pumberger
- Center for Musculoskeletal Surgery Berlin Mitte; Charité University Medicine Berlin, Charitéplatz 1, Berlin 10117, Germany
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29
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Cheng AJ, Ström J, Hwee DT, Malik FI, Westerblad H. Fast skeletal muscle troponin activator CK-2066260 mitigates skeletal muscle weakness independently of the underlying cause. J Cachexia Sarcopenia Muscle 2020; 11:1747-1757. [PMID: 32954682 PMCID: PMC7749611 DOI: 10.1002/jcsm.12624] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 03/07/2020] [Revised: 08/08/2020] [Accepted: 08/23/2020] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Muscle weakness is a common symptom in numerous diseases and a regularly occurring problem associated with ageing. Prolonged low-frequency force depression (PLFFD) is a form of exercise-induced skeletal muscle weakness observed after exercise. Three different intramuscular mechanisms underlying PLFFD have been identified: decreased sarcoplasmic reticulum Ca2+ release, decreased myofibrillar Ca2+ sensitivity, and myofibrillar dysfunction. We here used these three forms of PLFFD as models to study the effectiveness of a fast skeletal muscle troponin activator, CK-2066260, to mitigate muscle weakness. METHODS Experiments were performed on intact single muscle fibres or fibre bundles from mouse flexor digitorum brevis, which were stimulated with electrical current pulses, while force and the free cytosolic [Ca2+ ] ([Ca2+ ]i ) were measured. PLFFD was induced by three different stimulation protocols: (i) repeated isometric contractions at low intensity (350 ms tetani given every 5 s for 100 contractions); (ii) repeated isometric contractions at high intensity (250 ms tetani given every 0.5 s for 300 contractions); and (iii) repeated eccentric contractions (350 ms tetani with 20% length increase given every 20 s for 10 contractions). The extent and cause of PLFFD were assessed by comparing the force-[Ca2+ ]i relationship at low (30 Hz) and high (120 Hz) stimulation frequencies before (control) and 30 min after induction of PLFFD, and after an additional 5 min of rest in the presence of CK-2066260 (10 μM). RESULTS Prolonged low-frequency force depression following low-intensity and high-intensity fatiguing contractions was predominantly due to decreased sarcoplasmic reticulum Ca2+ release and decreased myofibrillar Ca2+ sensitivity, respectively. CK-2066260 exposure resulted in marked increases in 30 Hz force from 52 ± 16% to 151 ± 13% and from 6 ± 4% to 98 ± 40% of controls with low-intensity and high-intensity contractions, respectively. Following repeated eccentric contractions, PLFFD was mainly due to myofibrillar dysfunction, and it was not fully reversed by CK-2066260 with 30 Hz force increasing from 48 ± 8% to 76 ± 6% of the control. CONCLUSIONS The fast skeletal muscle troponin activator CK-2066260 effectively mitigates muscle weakness, especially when it is caused by impaired activation of the myofibrillar contractile machinery due to either decreased sarcoplasmic reticulum Ca2+ release or reduced myofibrillar Ca2+ sensitivity.
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Affiliation(s)
- Arthur J Cheng
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.,School of Kinesiology and Health Science, Faculty of Health, York University, Toronto, Canada
| | - Jennifer Ström
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Darren T Hwee
- Research and Early Development, Cytokinetics, Inc., South San Francisco, CA, USA
| | - Fady I Malik
- Research and Early Development, Cytokinetics, Inc., South San Francisco, CA, USA
| | - Håkan Westerblad
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
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30
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AAV9-DOK7 gene therapy reduces disease severity in Smn 2B/- SMA model mice. Biochem Biophys Res Commun 2020; 530:107-114. [PMID: 32828271 DOI: 10.1016/j.bbrc.2020.07.031] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/25/2020] [Accepted: 07/07/2020] [Indexed: 11/23/2022]
Abstract
Spinal Muscular Atrophy (SMA) is an autosomal recessive neuromuscular disease caused by deletions or mutations in the survival motor neuron (SMN1) gene. An important hallmark of disease progression is the pathology of neuromuscular junctions (NMJs). Affected NMJs in the SMA context exhibit delayed maturation, impaired synaptic transmission, and loss of contact between motor neurons and skeletal muscle. Protection and maintenance of NMJs remains a focal point of therapeutic strategies to treat SMA, and the recent implication of the NMJ-organizer Agrin in SMA pathology suggests additional NMJ organizing molecules may contribute. DOK7 is an NMJ organizer that functions downstream of Agrin. The potential of DOK7 as a putative therapeutic target was demonstrated by adeno-associated virus (AAV)-mediated gene therapy delivery of DOK7 in Amyotrophic Lateral Sclerosis (ALS) and Emery Dreyefuss Muscular Dystrophy (EDMD). To assess the potential of DOK7 as a disease modifier of SMA, we administered AAV-DOK7 to an intermediate mouse model of SMA. AAV9-DOK7 treatment conferred improvements in NMJ architecture and reduced muscle fiber atrophy. Additionally, these improvements resulted in a subtle reduction in phenotypic severity, evidenced by improved grip strength and an extension in survival. These findings reveal DOK7 is a novel modifier of SMA.
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31
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Villalón E, Kline RA, Smith CE, Lorson ZC, Osman EY, O'Day S, Murray LM, Lorson CL. AAV9-Stathmin1 gene delivery improves disease phenotype in an intermediate mouse model of spinal muscular atrophy. Hum Mol Genet 2020; 28:3742-3754. [PMID: 31363739 DOI: 10.1093/hmg/ddz188] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/24/2019] [Revised: 07/12/2019] [Accepted: 07/23/2019] [Indexed: 02/06/2023] Open
Abstract
Spinal muscular atrophy (SMA) is a devastating infantile genetic disorder caused by the loss of survival motor neuron (SMN) protein that leads to premature death due to loss of motor neurons and muscle atrophy. The approval of an antisense oligonucleotide therapy for SMA was an important milestone in SMA research; however, effective next-generation therapeutics will likely require combinatorial SMN-dependent therapeutics and SMN-independent disease modifiers. A recent cross-disease transcriptomic analysis identified Stathmin-1 (STMN1), a tubulin-depolymerizing protein, as a potential disease modifier across different motor neuron diseases, including SMA. Here, we investigated whether viral-based delivery of STMN1 decreased disease severity in a well-characterized SMA mouse model. Intracerebroventricular delivery of scAAV9-STMN1 in SMA mice at P2 significantly increased survival and weight gain compared to untreated SMA mice without elevating Smn levels. scAAV9-STMN1 improved important hallmarks of disease, including motor function, NMJ pathology and motor neuron cell preservation. Furthermore, scAAV9-STMN1 treatment restored microtubule networks and tubulin expression without affecting tubulin stability. Our results show that scAAV9-STMN1 treatment improves SMA pathology possibly by increasing microtubule turnover leading to restored levels of stable microtubules. Overall, these data demonstrate that STMN1 can significantly reduce the SMA phenotype independent of restoring SMN protein and highlight the importance of developing SMN-independent therapeutics for the treatment of SMA.
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Affiliation(s)
- E Villalón
- Bond Life Sciences Center, University of Missouri, Columbia, MO 65211, USA
- Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO 65211, USA
| | - R A Kline
- Bond Life Sciences Center, University of Missouri, Columbia, MO 65211, USA
- Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO 65211, USA
| | - C E Smith
- Bond Life Sciences Center, University of Missouri, Columbia, MO 65211, USA
- Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO 65211, USA
| | - Z C Lorson
- Bond Life Sciences Center, University of Missouri, Columbia, MO 65211, USA
- Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO 65211, USA
| | - E Y Osman
- Bond Life Sciences Center, University of Missouri, Columbia, MO 65211, USA
- Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO 65211, USA
| | - S O'Day
- Bond Life Sciences Center, University of Missouri, Columbia, MO 65211, USA
- Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO 65211, USA
| | - L M Murray
- Centre for Integrative Physiology, University of Edinburgh, Edinburgh, UK
- Euan MacDonald Centre for Motor Neuron Disease Research, University of Edinburgh, Edinburgh, UK
| | - C L Lorson
- Bond Life Sciences Center, University of Missouri, Columbia, MO 65211, USA
- Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO 65211, USA
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32
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New and Developing Therapies in Spinal Muscular Atrophy: From Genotype to Phenotype to Treatment and Where Do We Stand? Int J Mol Sci 2020; 21:ijms21093297. [PMID: 32392694 PMCID: PMC7246502 DOI: 10.3390/ijms21093297] [Citation(s) in RCA: 76] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/12/2020] [Revised: 05/03/2020] [Accepted: 05/04/2020] [Indexed: 02/08/2023] Open
Abstract
Spinal muscular atrophy (SMA) is a congenital neuromuscular disorder characterized by motor neuron loss, resulting in progressive weakness. SMA is notable in the health care community because it accounts for the most common cause of infant death resulting from a genetic defect. SMA is caused by low levels of the survival motor neuron protein (SMN) resulting from SMN1 gene mutations or deletions. However, patients always harbor various copies of SMN2, an almost identical but functionally deficient copy of the gene. A genotype–phenotype correlation suggests that SMN2 is a potent disease modifier for SMA, which also represents the primary target for potential therapies. Increasing comprehension of SMA pathophysiology, including the characterization of SMN1 and SMN2 genes and SMN protein functions, has led to the development of multiple therapeutic approaches. Until the end of 2016, no cure was available for SMA, and management consisted of supportive measures. Two breakthrough SMN-targeted treatments, either using antisense oligonucleotides (ASOs) or virus-mediated gene therapy, have recently been approved. These two novel therapeutics have a common objective: to increase the production of SMN protein in MNs and thereby improve motor function and survival. However, neither therapy currently provides a complete cure. Treating patients with SMA brings new responsibilities and unique dilemmas. As SMA is such a devastating disease, it is reasonable to assume that a unique therapeutic solution may not be sufficient. Current approaches under clinical investigation differ in administration routes, frequency of dosing, intrathecal versus systemic delivery, and mechanisms of action. Besides, emerging clinical trials evaluating the efficacy of either SMN-dependent or SMN-independent approaches are ongoing. This review aims to address the different knowledge gaps between genotype, phenotypes, and potential therapeutics.
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Abstract
Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease caused by deletions or mutations in the survival motor neuron (SMN1) gene. SMA is characterized by loss of lower motor neurons (anterior horn cells) in the spinal cord and brainstem nuclei, leading to progressive symmetrical muscle weakness and atrophy. It affects approximately 1 in 6,000 to 1 in 10,000 individuals and is the most common inherited cause of childhood mortality, but this may soon change given recent developments. In December 2016, nusinersen, an antisense oligonucleotide drug, was approved by the United States Food and Drug Administration for the treatment of SMA, and in July 2018, SMA was added to the recommended uniform screening panel, a list of conditions that all states are encouraged to include in their newborn screening (NBS) panels. In this review, we begin with a brief clinical history of the diagnosis of SMA, discuss the current SMA clinical classification system, describe the current treatment, and discuss evolving treatment guidelines. We then discuss the path to include SMA in NBS programs as well as the controversies it engenders because the variability in age at symptom onset means early identification of asymptomatic patients who will not require therapy for years or decades. We also consider alternate population screening opportunities. Next, we consider experimental treatments. We conclude by supporting NBS for SMA with the caveat that a long-term follow-up registry is ethically essential to ensure that the benefits outweigh the harms for all screened infants, including those with milder and/or later-onset forms of SMA.
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Affiliation(s)
- Lainie Friedman Ross
- Departments of Pediatrics, Medicine, Surgery and the College; MacLean Center for Clinical Medical Ethics, University of Chicago, Chicago, IL
| | - Jennifer M Kwon
- Department of Neurology, University of Wisconsin School of Medicine and Public Health, Madison, WI
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Wirth B, Karakaya M, Kye MJ, Mendoza-Ferreira N. Twenty-Five Years of Spinal Muscular Atrophy Research: From Phenotype to Genotype to Therapy, and What Comes Next. Annu Rev Genomics Hum Genet 2020; 21:231-261. [PMID: 32004094 DOI: 10.1146/annurev-genom-102319-103602] [Citation(s) in RCA: 146] [Impact Index Per Article: 29.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/22/2022]
Abstract
Twenty-five years ago, the underlying genetic cause for one of the most common and devastating inherited diseases in humans, spinal muscular atrophy (SMA), was identified. Homozygous deletions or, rarely, subtle mutations of SMN1 cause SMA, and the copy number of the nearly identical copy gene SMN2 inversely correlates with disease severity. SMA has become a paradigm and a prime example of a monogenic neurological disorder that can be efficiently ameliorated or nearly cured by novel therapeutic strategies, such as antisense oligonucleotide or gene replacement therapy. These therapies enable infants to survive who might otherwise have died before the age of two and allow individuals who have never been able to sit or walk to do both. The major milestones on the road to these therapies were to understand the genetic cause and splice regulation of SMN genes, the disease's phenotype-genotype variability, the function of the protein and the main affected cellular pathways and tissues, the disease's pathophysiology through research on animal models, the windows of opportunity for efficient treatment, and how and when to treat patients most effectively.This review aims to bridge our knowledge from phenotype to genotype to therapy, not only highlighting the significant advances so far but also speculating about the future of SMA screening and treatment.
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Affiliation(s)
- Brunhilde Wirth
- Institute of Human Genetics, Center for Molecular Medicine Cologne and Center for Rare Diseases, University Hospital of Cologne, University of Cologne, 50931 Cologne, Germany;
| | - Mert Karakaya
- Institute of Human Genetics, Center for Molecular Medicine Cologne and Center for Rare Diseases, University Hospital of Cologne, University of Cologne, 50931 Cologne, Germany;
| | - Min Jeong Kye
- Institute of Human Genetics, Center for Molecular Medicine Cologne and Center for Rare Diseases, University Hospital of Cologne, University of Cologne, 50931 Cologne, Germany;
| | - Natalia Mendoza-Ferreira
- Institute of Human Genetics, Center for Molecular Medicine Cologne and Center for Rare Diseases, University Hospital of Cologne, University of Cologne, 50931 Cologne, Germany;
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Wadman RI, van der Pol WL, Bosboom WMJ, Asselman F, van den Berg LH, Iannaccone ST, Vrancken AFJE. Drug treatment for spinal muscular atrophy types II and III. Cochrane Database Syst Rev 2020; 1:CD006282. [PMID: 32006461 PMCID: PMC6995983 DOI: 10.1002/14651858.cd006282.pub5] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND Spinal muscular atrophy (SMA) is caused by a homozygous deletion of the survival motor neuron 1 (SMN1) gene on chromosome 5, or a heterozygous deletion in combination with a (point) mutation in the second SMN1 allele. This results in degeneration of anterior horn cells, which leads to progressive muscle weakness. Children with SMA type II do not develop the ability to walk without support and have a shortened life expectancy, whereas children with SMA type III develop the ability to walk and have a normal life expectancy. This is an update of a review first published in 2009 and previously updated in 2011. OBJECTIVES To evaluate if drug treatment is able to slow or arrest the disease progression of SMA types II and III, and to assess if such therapy can be given safely. SEARCH METHODS We searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, and ISI Web of Science conference proceedings in October 2018. In October 2018, we also searched two trials registries to identify unpublished trials. SELECTION CRITERIA We sought all randomised or quasi-randomised trials that examined the efficacy of drug treatment for SMA types II and III. Participants had to fulfil the clinical criteria and have a homozygous deletion or hemizygous deletion in combination with a point mutation in the second allele of the SMN1 gene (5q11.2-13.2) confirmed by genetic analysis. The primary outcome measure was change in disability score within one year after the onset of treatment. Secondary outcome measures within one year after the onset of treatment were change in muscle strength, ability to stand or walk, change in quality of life, time from the start of treatment until death or full-time ventilation and adverse events attributable to treatment during the trial period. Treatment strategies involving SMN1-replacement with viral vectors are out of the scope of this review, but a summary is given in Appendix 1. Drug treatment for SMA type I is the topic of a separate Cochrane Review. DATA COLLECTION AND ANALYSIS We followed standard Cochrane methodology. MAIN RESULTS The review authors found 10 randomised, placebo-controlled trials of treatments for SMA types II and III for inclusion in this review, with 717 participants. We added four of the trials at this update. The trials investigated creatine (55 participants), gabapentin (84 participants), hydroxyurea (57 participants), nusinersen (126 participants), olesoxime (165 participants), phenylbutyrate (107 participants), somatotropin (20 participants), thyrotropin-releasing hormone (TRH) (nine participants), valproic acid (33 participants), and combination therapy with valproic acid and acetyl-L-carnitine (ALC) (61 participants). Treatment duration was from three to 24 months. None of the studies investigated the same treatment and none was completely free of bias. All studies had adequate blinding, sequence generation and reporting of primary outcomes. Based on moderate-certainty evidence, intrathecal nusinersen improved motor function (disability) in children with SMA type II, with a 3.7-point improvement in the nusinersen group on the Hammersmith Functional Motor Scale Expanded (HFMSE; range of possible scores 0 to 66), compared to a 1.9-point decline on the HFMSE in the sham procedure group (P < 0.01; n = 126). On all motor function scales used, higher scores indicate better function. Based on moderate-certainty evidence from two studies, the following interventions had no clinically important effect on motor function scores in SMA types II or III (or both) in comparison to placebo: creatine (median change 1 higher, 95% confidence interval (CI) -1 to 2; on the Gross Motor Function Measure (GMFM), scale 0 to 264; n = 40); and combination therapy with valproic acid and carnitine (mean difference (MD) 0.64, 95% CI -1.1 to 2.38; on the Modified Hammersmith Functional Motor Scale (MHFMS), scale 0 to 40; n = 61). Based on low-certainty evidence from other single studies, the following interventions had no clinically important effect on motor function scores in SMA types II or III (or both) in comparison to placebo: gabapentin (median change 0 in the gabapentin group and -2 in the placebo group on the SMA Functional Rating Scale (SMAFRS), scale 0 to 50; n = 66); hydroxyurea (MD -1.88, 95% CI -3.89 to 0.13 on the GMFM, scale 0 to 264; n = 57), phenylbutyrate (MD -0.13, 95% CI -0.84 to 0.58 on the Hammersmith Functional Motor Scale (HFMS) scale 0 to 40; n = 90) and monotherapy of valproic acid (MD 0.06, 95% CI -1.32 to 1.44 on SMAFRS, scale 0 to 50; n = 31). Very low-certainty evidence suggested that the following interventions had little or no effect on motor function: olesoxime (MD 2, 95% -0.25 to 4.25 on the Motor Function Measure (MFM) D1 + D2, scale 0 to 75; n = 160) and somatotropin (median change at 3 months 0.25 higher, 95% CI -1 to 2.5 on the HFMSE, scale 0 to 66; n = 19). One small TRH trial did not report effects on motor function and the certainty of evidence for other outcomes from this trial were low or very low. Results of nine completed trials investigating 4-aminopyridine, acetyl-L-carnitine, CK-2127107, hydroxyurea, pyridostigmine, riluzole, RO6885247/RG7800, salbutamol and valproic acid were awaited and not available for analysis at the time of writing. Various trials and studies investigating treatment strategies other than nusinersen (e.g. SMN2-augmentation by small molecules), are currently ongoing. AUTHORS' CONCLUSIONS Nusinersen improves motor function in SMA type II, based on moderate-certainty evidence. Creatine, gabapentin, hydroxyurea, phenylbutyrate, valproic acid and the combination of valproic acid and ALC probably have no clinically important effect on motor function in SMA types II or III (or both) based on low-certainty evidence, and olesoxime and somatropin may also have little to no clinically important effect but evidence was of very low-certainty. One trial of TRH did not measure motor function.
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Affiliation(s)
- Renske I Wadman
- University Medical Center Utrecht, Brain Center Rudolf MagnusDepartment of NeurologyHeidelberglaan 100UtrechtNetherlands3584 CX
| | - W Ludo van der Pol
- University Medical Center Utrecht, Brain Center Rudolf MagnusDepartment of NeurologyHeidelberglaan 100UtrechtNetherlands3584 CX
| | - Wendy MJ Bosboom
- Onze Lieve Vrouwe Gasthuis locatie WestDepartment of NeurologyAmsterdamNetherlands
| | - Fay‐Lynn Asselman
- University Medical Center Utrecht, Brain Center Rudolf MagnusDepartment of NeurologyHeidelberglaan 100UtrechtNetherlands3584 CX
| | - Leonard H van den Berg
- University Medical Center Utrecht, Brain Center Rudolf MagnusDepartment of NeurologyHeidelberglaan 100UtrechtNetherlands3584 CX
| | - Susan T Iannaccone
- University of Texas Southwestern Medical CenterDepartment of Pediatrics5323 Harry Hines BoulevardDallasTexasUSA75390
| | - Alexander FJE Vrancken
- University Medical Center Utrecht, Brain Center Rudolf MagnusDepartment of NeurologyHeidelberglaan 100UtrechtNetherlands3584 CX
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Zeng L, Gu N, Chen J, Jin G, Zheng Y. IRX1 hypermethylation promotes heart failure by inhibiting CXCL14 expression. Cell Cycle 2019; 18:3251-3262. [PMID: 31640472 DOI: 10.1080/15384101.2019.1673099] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/28/2022] Open
Abstract
To identify the mechanism and functions of IRX1 in heart failure (HF) and provide evidence for new therapies. Bioinformatic analysis was performed to select target genes in HF cells compared to normal groups. Experimental rats were treated in a controllable manner to explore how IRX1 methylation accounted for this disease in vivo. Cardiac ultrasonic and morphologic examinations were conducted to test the mouse heart and evaluate the degree of cardiac impairment at in the level of organization. GSEA analysis revealed the relative enrichment of functions. Immunofluorescent assays, western blotting and qRT-PCR were used to determine the DNA methylation and expression levels. IRX1 was hypermethylated in heart failure and identified as a target gene by bioinformatic analysis. Transverse aortic constriction (TAC) induced heart failure in rats, while 5-aza-2'-deoxycytidine (5-Aza) alleviated heart failure in rats according to medical cardiac indexes. Western blotting and qRT-PCR revealed that a conspicuous difference in the expression of IRX1 and CXCL14 between HF and normal cardiac cells. As a result of gene methylation, left ventricular hypertrophy and cardiac fibrosis is usually accompanied by heart failure. Moreover, is the results implied that the demethylation of IRX1 improves heart failure in vivo and in vitro. IRX1 methylation induced damaged cardiac function and even heart failure, which has important implications for HF treatment and diagnosis.
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Affiliation(s)
- Longhuan Zeng
- Department of Intensive Care Unit, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, No. 261 Huansha Road, Hangzhou, 310006, China
| | - Nanyuan Gu
- Department of Intensive Care Unit, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, No. 261 Huansha Road, Hangzhou, 310006, China
| | - Jiayi Chen
- Department of Intensive Care Unit, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, No. 261 Huansha Road, Hangzhou, 310006, China
| | - Guangyong Jin
- Department of Intensive Care Unit, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, No. 261 Huansha Road, Hangzhou, 310006, China
| | - Yongke Zheng
- Department of Intensive Care Unit, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, No. 261 Huansha Road, Hangzhou, 310006, China
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Cheng AJ, Hwee DT, Kim LH, Durham N, Yang HT, Hinken AC, Kennedy AR, Terjung RL, Jasper JR, Malik FI, Westerblad H. Fast skeletal muscle troponin activator CK-2066260 increases fatigue resistance by reducing the energetic cost of muscle contraction. J Physiol 2019; 597:4615-4625. [PMID: 31246276 PMCID: PMC6851859 DOI: 10.1113/jp278235] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/02/2019] [Accepted: 06/26/2019] [Indexed: 01/26/2023] Open
Abstract
Key points
Skeletal muscle fatigue limits performance in various physical activities, with exercise intolerance being a key symptom in a broad spectrum of diseases. We investigated whether a small molecule fast skeletal troponin activator (FSTA), CK‐2066260, can mitigate muscle fatigue by reducing the cytosolic free [Ca2+] required to produce a given submaximal force and hence decreasing the energy requirement. Isolated intact single mouse muscle fibres and rat muscles in‐situ treated with CK‐2066260 showed improved muscle endurance., which was accompanied by decreased ATP demand and reduced glycogen usage. CK‐2066260 treatment improved in‐vivo exercise capacity in healthy rats and in a rat model of peripheral artery insufficiency. In conclusion, we show that the FSTA CK‐2066260 effectively counteracts muscle fatigue in rodent skeletal muscle in vitro, in situ, and in vivo. This may translate to humans and provide a promising pharmacological treatment to patients suffering from severe muscle weakness and exercise intolerance. Abstract Skeletal muscle fatigue limits performance during physical exercise and exacerbated muscle fatigue is a prominent symptom among a broad spectrum of diseases. The present study investigated whether skeletal muscle fatigue is affected by the fast skeletal muscle troponin activator (FSTA) CK‐2066260, which increases myofibrillar Ca2+ sensitivity and amplifies the submaximal force response. Because more force is produced for a given Ca2+, we hypothesized that CK‐2066260 could mitigate muscle fatigue by reducing the energetic cost of muscle activation. Isolated single mouse muscle fibres were fatigued by 100 repeated 350 ms contractions while measuring force and the cytosolic free [Ca2+] or [Mg2+] ([Mg2+]i). When starting fatiguing stimulation at matching forces (i.e. lower stimulation frequency with CK‐2066260): force was decreased by ∼50% with and by ∼75% without CK‐2066260; [Mg2+]i was increased by ∼10% with and ∼32% without CK‐2066260, reflecting a larger decrease in [ATP] in the latter. The glycogen content in in situ stimulated rat muscles fatigued by repeated contractions at matching forces was about two times higher with than without CK‐2066260. Voluntary exercise capacity, assessed by rats performing rotarod exercise and treadmill running, was improved in the presence of CK‐2066260. CK‐2066260 treatment also increased skeletal muscle fatigue resistance and exercise performance in a rat model of peripheral artery insufficiency. In conclusion, we demonstrate that the FSTA CK‐2066260 mitigates skeletal muscle fatigue by reducing the metabolic cost of force generation.
Skeletal muscle fatigue limits performance in various physical activities, with exercise intolerance being a key symptom in a broad spectrum of diseases. We investigated whether a small molecule fast skeletal troponin activator (FSTA), CK‐2066260, can mitigate muscle fatigue by reducing the cytosolic free [Ca2+] required to produce a given submaximal force and hence decreasing the energy requirement. Isolated intact single mouse muscle fibres and rat muscles in‐situ treated with CK‐2066260 showed improved muscle endurance., which was accompanied by decreased ATP demand and reduced glycogen usage. CK‐2066260 treatment improved in‐vivo exercise capacity in healthy rats and in a rat model of peripheral artery insufficiency. In conclusion, we show that the FSTA CK‐2066260 effectively counteracts muscle fatigue in rodent skeletal muscle in vitro, in situ, and in vivo. This may translate to humans and provide a promising pharmacological treatment to patients suffering from severe muscle weakness and exercise intolerance.
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Affiliation(s)
- Arthur J Cheng
- Department of Physiology and Pharmacology, Karolinska Institutet, 171 77, Stockholm, Sweden
| | - Darren T Hwee
- Research and Early Development, Cytokinetics, Inc., South San Francisco, CA, 94080, USA
| | - Leo H Kim
- Research and Early Development, Cytokinetics, Inc., South San Francisco, CA, 94080, USA
| | - Nickie Durham
- Research and Early Development, Cytokinetics, Inc., South San Francisco, CA, 94080, USA
| | - Hsiao T Yang
- Department of Biomedical Sciences, University of Missouri, Columbia, MO, 65211, USA
| | - Aaron C Hinken
- Research and Early Development, Cytokinetics, Inc., South San Francisco, CA, 94080, USA
| | - Adam R Kennedy
- Research and Early Development, Cytokinetics, Inc., South San Francisco, CA, 94080, USA
| | - Ronald L Terjung
- Department of Biomedical Sciences, University of Missouri, Columbia, MO, 65211, USA
| | - Jeffrey R Jasper
- Research and Early Development, Cytokinetics, Inc., South San Francisco, CA, 94080, USA
| | - Fady I Malik
- Research and Early Development, Cytokinetics, Inc., South San Francisco, CA, 94080, USA
| | - Håkan Westerblad
- Department of Physiology and Pharmacology, Karolinska Institutet, 171 77, Stockholm, Sweden
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Abstract
The study of muscle and contractility is an unusual scientific endeavour since it has from the start been focussed on one problem-What makes muscle work?-and yet has needed a vast range of different approaches and techniques to study it. Its uniqueness lies in the fundamental fascination of a large scale molecular machine that converts chemical energy into mechanical energy at ambient temperature and with high efficiency that is also controlled by an exquisitely intricate yet utterly reliable regulatory system and is an essential component of animal life. The investigation of muscle is as innovative as any other field of research. As soon as one approach appears to be played out another comes along. It is instructive to consider this as a series of waves of novel and heightened activity starting in the 1950s. The thesis of this article is that we are approaching the fourth wave with the recent rise of interest in small molecules as research tools and possible therapies for muscle diseases.
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Affiliation(s)
- Steven Marston
- Cardiovascular Division, National Heart and Lung Institute, Imperial Centre for Translational and Experimental Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London, W12 0NN, UK.
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Wang S, Cheng Z, Chen X. Promotion of PTEN on apoptosis through PI3K/Akt signal in vascular smooth muscle cells of mice model of coronary heart disease. J Cell Biochem 2019; 120:14636-14644. [PMID: 31090947 DOI: 10.1002/jcb.28725] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/26/2018] [Revised: 03/05/2019] [Accepted: 03/15/2019] [Indexed: 01/30/2023]
Abstract
Previous studies have shown that phosphatase and tensin homolog (PTEN) are key regulators of the development of many malignant tumors and other diseases. However, its regulatory effect on coronary heart disease (CHD) has rarely been reported. Therefore, the regulatory effect of PTEN on the survival and cell death of vascular smooth muscle cells (VSMCs) in CHD mice was elucidated in this study. It was found that the protein and messenger RNA expressions of PTEN in VSMCs of 10 CHD mice were lower than those of normal mice. Then PTEN was overexpressed in VSMCs. It was suggested that the upregulation of PTEN was not conducive to the proliferation and survival of VSMCs in the 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and colony formation assay. The flow cytometry (Annexin V-Fluorescein isothiocyanate (FITC)/propidium iodide) and the terminal deoxynucleotidyl transferase dUTP nick end labeling assay were used to detect the apoptotic rate of overexpressing PTEN cells. Some data showed that the expression of PTEN could lead to increased apoptotic rate. It was shown that antiapoptotic Bcl-2 levels were decreased, but cleaved caspase-3 and proapoptotic Bax levels were promoted by SIRT6 overexpression in Western blot analysis. Moreover, PI3K/Akt expression and phosphorylation were significantly decreased in cells expressing PTEN. Recovery of PI3K expression inhibited the suppressive influence of PTEN on VSMC survival, as evidenced by the activated PI3K/Akt pathway, increased cell proliferative rate, reduced the apoptotic level, and reversed expression patterns of Bcl-2 and Bax. Therefore, the findings in this study provide a new idea on the occurrence and development mechanism of CHD and may promote the discovery of innovative therapies.
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Affiliation(s)
- Sheng Wang
- Henan Provincial People's Hospital Heart Center, Fuwai Central China Cardiovascular Hospital, Zhengzhou, Henan, China
| | - Zhaoyun Cheng
- Henan Provincial People's Hospital Heart Center, Fuwai Central China Cardiovascular Hospital, Zhengzhou, Henan, China
| | - Xianjie Chen
- Henan Provincial People's Hospital Heart Center, Fuwai Central China Cardiovascular Hospital, Zhengzhou, Henan, China
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Shorrock HK, Gillingwater TH, Groen EJN. Overview of Current Drugs and Molecules in Development for Spinal Muscular Atrophy Therapy. Drugs 2019; 78:293-305. [PMID: 29380287 PMCID: PMC5829132 DOI: 10.1007/s40265-018-0868-8] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 01/09/2023]
Abstract
Spinal muscular atrophy (SMA) is a neurodegenerative disease primarily characterized by a loss of spinal motor neurons, leading to progressive paralysis and premature death in the most severe cases. SMA is caused by homozygous deletion of the survival motor neuron 1 (SMN1) gene, leading to low levels of SMN protein. However, a second SMN gene (SMN2) exists, which can be therapeutically targeted to increase SMN levels. This has recently led to the first disease-modifying therapy for SMA gaining formal approval from the US Food and Drug Administration (FDA) and European Medicines Agency (EMA). Spinraza (nusinersen) is a modified antisense oligonucleotide that targets the splicing of SMN2, leading to increased SMN protein levels, capable of improving clinical phenotypes in many patients. In addition to Spinraza, several other therapeutic approaches are currently in various stages of clinical development. These include SMN-dependent small molecule and gene therapy approaches along with SMN-independent strategies, such as general neuroprotective factors and muscle strength-enhancing compounds. For each therapy, we provide detailed information on clinical trial design and pharmacological/safety data where available. Previous clinical studies are also discussed to provide context on SMA clinical trial development and the insights these provided for the design of current studies.
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Affiliation(s)
- Hannah K Shorrock
- Edinburgh Medical School: Biomedical Sciences, University of Edinburgh, Hugh Robson Building, 15 George Square, Edinburgh, EH8 9XD, UK.,Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Hugh Robson Building, 15 George Square, Edinburgh, EH8 9XD, UK
| | - Thomas H Gillingwater
- Edinburgh Medical School: Biomedical Sciences, University of Edinburgh, Hugh Robson Building, 15 George Square, Edinburgh, EH8 9XD, UK.,Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Hugh Robson Building, 15 George Square, Edinburgh, EH8 9XD, UK
| | - Ewout J N Groen
- Edinburgh Medical School: Biomedical Sciences, University of Edinburgh, Hugh Robson Building, 15 George Square, Edinburgh, EH8 9XD, UK. .,Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Hugh Robson Building, 15 George Square, Edinburgh, EH8 9XD, UK.
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Abstract
Great progress has been made in the clinical translation of several therapeutic strategies for spinal muscular atrophy (SMA), including measures to selectively address Survival Motor Neuron (SMN) protein deficiency with SMN1 gene replacement or modulation of SMN2 encoded protein levels, as well as neuroprotective approaches and supporting muscle strength and function. This review highlights these novel therapies. This is particularly vital with the advent of the first disease modifying therapy, which has brought to the fore an array of questions surrounding who, how and when to treat, and stimulated challenges in resource limited healthcare systems to streamline access for those eligible for drug therapy. The overhaul of the landscape for all those involved in SMA extends to the design of further drug trials and the necessity of multidisciplinary supportive care to potentiate the effects of disease modifying medications. The impact of respiratory complications in SMA is central to management in the current era of emerging novel therapies. These fundamental changes in our knowledge and management approach to those with SMA are explored further in this review.
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Abstract
Spinal muscular atrophy (SMA) is a severe disorder of motor neurons and the most frequent genetic cause of mortality in childhood, due to respiratory complications. The disease occurs due to mutations in the survival motor neuron 1 (SMN1) gene that leads to a reduction in the SMN protein, causing degeneration of lower motor neurons, muscle weakness and atrophy. Recently, the Food and Drug Administration (FDA) and the European Medical Agency (EMA) approved the antisense oligonucleotide nusinersen, the first disease-modifying treatment for SMA. Encouraging results from SMN1 gene therapy studies have raised hope for other therapeutic approaches that might arise in the coming years. However, nusinersen licensing has created ethical, medical, and financial implications that will need to be addressed. In this review, the history and challenges of the new SMA therapeutic strategies are highlighted.
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Affiliation(s)
- Sonia Messina
- Department of Clinical and Experimental Medicine, University of Messina, 98100 Messina, Italy.
- NEuroMuscular Omnicentre (NEMO) Sud Clinical Centre, University Hospital "G. Martino", 98125 Messina, Italy.
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Bowerman M, Becker CG, Yáñez-Muñoz RJ, Ning K, Wood MJA, Gillingwater TH, Talbot K. Therapeutic strategies for spinal muscular atrophy: SMN and beyond. Dis Model Mech 2018; 10:943-954. [PMID: 28768735 PMCID: PMC5560066 DOI: 10.1242/dmm.030148] [Citation(s) in RCA: 67] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/12/2022] Open
Abstract
Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder characterized by loss of motor neurons and muscle atrophy, generally presenting in childhood. SMA is caused by low levels of the survival motor neuron protein (SMN) due to inactivating mutations in the encoding gene SMN1. A second duplicated gene, SMN2, produces very little but sufficient functional protein for survival. Therapeutic strategies to increase SMN are in clinical trials, and the first SMN2-directed antisense oligonucleotide (ASO) therapy has recently been licensed. However, several factors suggest that complementary strategies may be needed for the long-term maintenance of neuromuscular and other functions in SMA patients. Pre-clinical SMA models demonstrate that the requirement for SMN protein is highest when the structural connections of the neuromuscular system are being established, from late fetal life throughout infancy. Augmenting SMN may not address the slow neurodegenerative process underlying progressive functional decline beyond childhood in less severe types of SMA. Furthermore, individuals receiving SMN-based treatments may be vulnerable to delayed symptoms if rescue of the neuromuscular system is incomplete. Finally, a large number of older patients living with SMA do not fulfill the present criteria for inclusion in gene therapy and ASO clinical trials, and may not benefit from SMN-inducing treatments. Therefore, a comprehensive whole-lifespan approach to SMA therapy is required that includes both SMN-dependent and SMN-independent strategies that treat the CNS and periphery. Here, we review the range of non-SMN pathways implicated in SMA pathophysiology and discuss how various model systems can serve as valuable tools for SMA drug discovery. Summary: Translational research for spinal muscular atrophy (SMA) should address the development of non-CNS and survival motor neuron (SMN)-independent therapeutic approaches to complement and enhance the benefits of CNS-directed and SMN-dependent therapies.
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Affiliation(s)
- Melissa Bowerman
- Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK
| | - Catherina G Becker
- Euan MacDonald Centre for Motor Neurone Disease Research and Centre for Neuroregeneration, University of Edinburgh, Edinburgh EH16 4SB, UK
| | - Rafael J Yáñez-Muñoz
- AGCTlab.org, Centre for Biomedical Sciences, School of Biological Sciences, Royal Holloway, University of London, Egham Hill, Egham, Surrey TW20 0EX, UK
| | - Ke Ning
- Department of Neuroscience, Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield S10 2HQ, UK
| | - Matthew J A Wood
- Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK
| | - Thomas H Gillingwater
- Euan MacDonald Centre for Motor Neurone Disease Research and Centre for Integrative Physiology, University of Edinburgh, Edinburgh EH8 9XD, UK
| | - Kevin Talbot
- Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK
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Wood MJA, Talbot K, Bowerman M. Spinal muscular atrophy: antisense oligonucleotide therapy opens the door to an integrated therapeutic landscape. Hum Mol Genet 2018; 26:R151-R159. [PMID: 28977438 DOI: 10.1093/hmg/ddx215] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/31/2017] [Accepted: 06/02/2017] [Indexed: 01/03/2023] Open
Abstract
Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder characterized by loss of spinal cord motor neurons, muscle atrophy and infantile death or severe disability. It is caused by severe reduction of the ubiquitously expressed survival motor neuron (SMN) protein, owing to loss of the SMN1 gene. This would be completely incompatible with survival without the presence of a quasi-identical duplicated gene, SMN2, specific to humans. SMN2 harbours a silent point mutation that favours the production of transcripts lacking exon 7 and a rapidly degraded non-functional SMNΔ7 protein, but from which functional full length SMN protein is produced at very low levels (∼10%). Since the seminal discovery of the SMA-causing gene in 1995, research has focused on the development of various SMN replacement strategies culminating, in December 2016, in the approval of the first precise molecularly targeted therapy for SMA (nusinersen), and a pivotal proof of principle that therapeutic antisense oligonucleotide (ASO) treatment can effectively target the central nervous system (CNS) to treat neurological and neuromuscular disease. Nusinersen is a steric block ASO that binds the SMN2 messenger RNA and promotes exon 7 inclusion and thus increases full length SMN expression. Here, we consider the implications of this therapeutic landmark for SMA therapeutics and discuss how future developments will need to address the challenges of delivering ASO therapies to the CNS, with appropriate efficiency and activity, and how SMN-based therapy should be used in combination with complementary strategies to provide an integrated approach to treat CNS and peripheral pathologies in SMA.
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Affiliation(s)
- Matthew J A Wood
- Department of Physiology, Anatomy and Genetics, University of Oxford OX1 3QX, Oxford, UK
| | - Kevin Talbot
- Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK
| | - Melissa Bowerman
- Department of Physiology, Anatomy and Genetics, University of Oxford OX1 3QX, Oxford, UK
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Diaphragm abnormalities in heart failure and aging: mechanisms and integration of cardiovascular and respiratory pathophysiology. Heart Fail Rev 2018; 22:191-207. [PMID: 27000754 DOI: 10.1007/s10741-016-9549-4] [Citation(s) in RCA: 68] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Indexed: 12/16/2022]
Abstract
Inspiratory function is essential for alveolar ventilation and expulsive behaviors that promote airway clearance (e.g., coughing and sneezing). Current evidence demonstrates that inspiratory dysfunction occurs during healthy aging and is accentuated by chronic heart failure (CHF). This inspiratory dysfunction contributes to key aspects of CHF and aging cardiovascular and pulmonary pathophysiology including: (1) impaired airway clearance and predisposition to pneumonia; (2) inability to sustain ventilation during physical activity; (3) shallow breathing pattern that limits alveolar ventilation and gas exchange; and (4) sympathetic activation that causes cardiac arrhythmias and tissue vasoconstriction. The diaphragm is the primary inspiratory muscle; hence, its neuromuscular integrity is a main determinant of the adequacy of inspiratory function. Mechanistic work within animal and cellular models has revealed specific factors that may be responsible for diaphragm neuromuscular abnormalities in CHF and aging. These include phrenic nerve and neuromuscular junction alterations as well as intrinsic myocyte abnormalities, such as changes in the quantity and quality of contractile proteins, accelerated fiber atrophy, and shifts in fiber type distribution. CHF, aging, or CHF in the presence of aging disturbs the dynamics of circulating factors (e.g., cytokines and angiotensin II) and cell signaling involving sphingolipids, reactive oxygen species, and proteolytic pathways, thus leading to the previously listed abnormalities. Exercise-based rehabilitation combined with pharmacological therapies targeting the pathways reviewed herein hold promise to treat diaphragm abnormalities and inspiratory muscle dysfunction in CHF and aging.
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Groen EJN, Talbot K, Gillingwater TH. Advances in therapy for spinal muscular atrophy: promises and challenges. Nat Rev Neurol 2018; 14:214-224. [PMID: 29422644 DOI: 10.1038/nrneurol.2018.4] [Citation(s) in RCA: 159] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/13/2022]
Abstract
Spinal muscular atrophy (SMA) is a devastating motor neuron disease that predominantly affects children and represents the most common cause of hereditary infant mortality. The condition results from deleterious variants in SMN1, which lead to depletion of the survival motor neuron protein (SMN). Now, 20 years after the discovery of this genetic defect, a major milestone in SMA and motor neuron disease research has been reached with the approval of the first disease-modifying therapy for SMA by US and European authorities - the antisense oligonucleotide nusinersen. At the same time, promising data from early-stage clinical trials of SMN1 gene therapy have indicated that additional therapeutic options are likely to emerge for patients with SMA in the near future. However, the approval of nusinersen has generated a number of immediate and substantial medical, ethical and financial implications that have the potential to resonate beyond the specific treatment of SMA. Here, we provide an overview of the rapidly evolving therapeutic landscape for SMA, highlighting current achievements and future opportunities. We also discuss how these developments are providing important lessons for the emerging second generation of combinatorial ('SMN-plus') therapies that are likely to be required to generate robust treatments that are effective across a patient's lifespan.
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Affiliation(s)
- Ewout J N Groen
- Edinburgh Medical School: Biomedical Sciences, University of Edinburgh, Edinburgh, UK.,Euan MacDonald Centre for Motor Neuron Disease Research, University of Edinburgh, Edinburgh, UK
| | - Kevin Talbot
- Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, Oxford, UK
| | - Thomas H Gillingwater
- Edinburgh Medical School: Biomedical Sciences, University of Edinburgh, Edinburgh, UK.,Euan MacDonald Centre for Motor Neuron Disease Research, University of Edinburgh, Edinburgh, UK
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47
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Wang LH, Weiss MD. A muscle strength enhancer for all seasons? Muscle Nerve 2017; 57:697-698. [PMID: 29266321 DOI: 10.1002/mus.26044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/05/2017] [Revised: 12/11/2017] [Accepted: 12/15/2017] [Indexed: 11/10/2022]
Affiliation(s)
- Leo H Wang
- Division of Neuromuscular Diseases, Department of Neurology, University of Washington, 1959 NE Pacific Street, Campus Box 356115, Seattle, Washington, 98195, USA
| | - Michael D Weiss
- Division of Neuromuscular Diseases, Department of Neurology, University of Washington, 1959 NE Pacific Street, Campus Box 356115, Seattle, Washington, 98195, USA
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Andrews JA, Miller TM, Vijayakumar V, Stoltz R, James JK, Meng L, Wolff AA, Malik FI. CK-2127107 amplifies skeletal muscle response to nerve activation in humans. Muscle Nerve 2017; 57:729-734. [PMID: 29150952 PMCID: PMC6681065 DOI: 10.1002/mus.26017] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/25/2017] [Revised: 11/10/2017] [Accepted: 11/14/2017] [Indexed: 12/12/2022]
Abstract
Introduction Three studies evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of CK‐2127107 (CK‐107), a next‐generation fast skeletal muscle troponin activator (FSTA), in healthy participants. We tested the hypothesis that CK‐107 would amplify the force‐frequency response of muscle in humans. Methods: To assess the force‐frequency response, participants received single doses of CK‐107 and placebo in a randomized, double‐blind, 4‐period, crossover study. The force‐frequency response of foot dorsiflexion following stimulation of the deep fibular nerve to activate the tibialis anterior muscle was assessed. Results: CK‐107 significantly increased tibialis anterior muscle response with increasing dose and plasma concentration in a frequency‐dependent manner; the largest increase in peak force was ∼60% at 10 Hz. Discussion: CK‐107 appears more potent and produced larger increases in force than tirasemtiv—a first‐generation FSTA—in a similar pharmacodynamic study, thereby supporting its development for improvement of muscle function of patients. Muscle Nerve57: 729–734, 2018
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Affiliation(s)
- Jinsy A Andrews
- Cytokinetics, Inc., 280 East Grand Avenue, South San Francisco, California, 94080, USA
| | - Timothy M Miller
- Cytokinetics, Inc., 280 East Grand Avenue, South San Francisco, California, 94080, USA
| | - Vipin Vijayakumar
- Cytokinetics, Inc., 280 East Grand Avenue, South San Francisco, California, 94080, USA
| | | | - Joyce K James
- Cytokinetics, Inc., 280 East Grand Avenue, South San Francisco, California, 94080, USA
| | - Lisa Meng
- Cytokinetics, Inc., 280 East Grand Avenue, South San Francisco, California, 94080, USA
| | - Andrew A Wolff
- Cytokinetics, Inc., 280 East Grand Avenue, South San Francisco, California, 94080, USA
| | - Fady I Malik
- Cytokinetics, Inc., 280 East Grand Avenue, South San Francisco, California, 94080, USA
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Rietz A, Li H, Quist KM, Cherry JJ, Lorson CL, Burnett BG, Kern NL, Calder AN, Fritsche M, Lusic H, Boaler PJ, Choi S, Xing X, Glicksman MA, Cuny GD, Androphy EJ, Hodgetts KJ. Discovery of a Small Molecule Probe That Post-Translationally Stabilizes the Survival Motor Neuron Protein for the Treatment of Spinal Muscular Atrophy. J Med Chem 2017; 60:4594-4610. [PMID: 28481536 DOI: 10.1021/acs.jmedchem.6b01885] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 01/29/2023]
Abstract
Spinal muscular atrophy (SMA) is the leading genetic cause of infant death. We previously developed a high-throughput assay that employs an SMN2-luciferase reporter allowing identification of compounds that act transcriptionally, enhance exon recognition, or stabilize the SMN protein. We describe optimization and characterization of an analog suitable for in vivo testing. Initially, we identified analog 4m that had good in vitro properties but low plasma and brain exposure in a mouse PK experiment due to short plasma stability; this was overcome by reversing the amide bond and changing the heterocycle. Thiazole 27 showed excellent in vitro properties and a promising mouse PK profile, making it suitable for in vivo testing. This series post-translationally stabilizes the SMN protein, unrelated to global proteasome or autophagy inhibition, revealing a novel therapeutic mechanism that should complement other modalities for treatment of SMA.
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Affiliation(s)
- Anne Rietz
- Department of Dermatology, Indiana University School of Medicine , Indianapolis, Indiana 46202, United States
| | - Hongxia Li
- Department of Dermatology, Indiana University School of Medicine , Indianapolis, Indiana 46202, United States
| | - Kevin M Quist
- Department of Dermatology, Indiana University School of Medicine , Indianapolis, Indiana 46202, United States
| | - Jonathan J Cherry
- Department of Dermatology, Indiana University School of Medicine , Indianapolis, Indiana 46202, United States
| | - Christian L Lorson
- Department of Veterinary Pathobiology, Bond Life Sciences Center, University of Missouri , Columbia, Missouri 65201, United States
| | - Barrington G Burnett
- Department of Anatomy, Physiology and Genetics, F. Edward Hebert School of Medicine, Uniformed Services University of the Health Sciences , Bethesda, Maryland 20814, United States
| | - Nicholas L Kern
- Laboratory for Drug Discovery in Neurodegeneration, Brigham & Women's Hospital and Harvard Medical School , 65 Landsdowne Street, Cambridge, Massachusetts 02139, United States
| | - Alyssa N Calder
- Laboratory for Drug Discovery in Neurodegeneration, Brigham & Women's Hospital and Harvard Medical School , 65 Landsdowne Street, Cambridge, Massachusetts 02139, United States
| | - Melanie Fritsche
- Laboratory for Drug Discovery in Neurodegeneration, Brigham & Women's Hospital and Harvard Medical School , 65 Landsdowne Street, Cambridge, Massachusetts 02139, United States
| | - Hrvoje Lusic
- Laboratory for Drug Discovery in Neurodegeneration, Brigham & Women's Hospital and Harvard Medical School , 65 Landsdowne Street, Cambridge, Massachusetts 02139, United States
| | - Patrick J Boaler
- Laboratory for Drug Discovery in Neurodegeneration, Brigham & Women's Hospital and Harvard Medical School , 65 Landsdowne Street, Cambridge, Massachusetts 02139, United States
| | - Sungwoon Choi
- Laboratory for Drug Discovery in Neurodegeneration, Brigham & Women's Hospital and Harvard Medical School , 65 Landsdowne Street, Cambridge, Massachusetts 02139, United States
| | - Xuechao Xing
- Laboratory for Drug Discovery in Neurodegeneration, Brigham & Women's Hospital and Harvard Medical School , 65 Landsdowne Street, Cambridge, Massachusetts 02139, United States
| | - Marcie A Glicksman
- Laboratory for Drug Discovery in Neurodegeneration, Brigham & Women's Hospital and Harvard Medical School , 65 Landsdowne Street, Cambridge, Massachusetts 02139, United States
| | - Gregory D Cuny
- Laboratory for Drug Discovery in Neurodegeneration, Brigham & Women's Hospital and Harvard Medical School , 65 Landsdowne Street, Cambridge, Massachusetts 02139, United States
| | - Elliot J Androphy
- Department of Dermatology, Indiana University School of Medicine , Indianapolis, Indiana 46202, United States
| | - Kevin J Hodgetts
- Laboratory for Drug Discovery in Neurodegeneration, Brigham & Women's Hospital and Harvard Medical School , 65 Landsdowne Street, Cambridge, Massachusetts 02139, United States
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Tizzano EF, Finkel RS. Spinal muscular atrophy: A changing phenotype beyond the clinical trials. Neuromuscul Disord 2017; 27:883-889. [PMID: 28757001 DOI: 10.1016/j.nmd.2017.05.011] [Citation(s) in RCA: 84] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/24/2017] [Revised: 05/03/2017] [Accepted: 05/11/2017] [Indexed: 01/14/2023]
Abstract
Spinal muscular atrophy is a monogenic, progressive motor neuron disorder caused by deletion or mutation in the SMN1 gene. A broad range of phenotypic severity, from very weak infants (Type 1) to ambulant children (type 3), is modified mainly by the number of copies of the "backup" SMN2 gene. Since the discovery of the role of both genes, basic research into the pathobiology of SMA, with in vitro and animal model studies, has identified therapeutic targets. Development of clinical outcome measures, natural history studies and standard of care guidelines have contributed to the development of protocols for therapeutic drugs now under clinical investigation. Following regulatory approval of the first drug treatment for SMA in the US (December, 2016) and marketing authorization in Europe (June, 2017), the prospects for care of these patients have changed. The evolution of the phenotype of SMA now needs to be considered beyond the clinical trials. This perspective review discusses potential new trajectories in the phenotype of SMA and the need for multidisciplinary teams to prepare for this changing landscape.
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Affiliation(s)
- Eduardo F Tizzano
- Department of Clinical and Molecular Genetics and Rare Disease Unit, CIBERER, Hospital Valle Hebron, Barcelona, Spain
| | - Richard S Finkel
- Nemours Children's Hospital, Orlando, FL, USA; University of Central Florida College of Medicine, Orlando, FL, USA.
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