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Shefner JM, Cudkowicz ME, Genge A, Hardiman O, Al-Chalabi A, Andrews JA, Chio A, Corcia P, Couratier P, de Carvalho M, Heiman-Patterson T, Henderson RD, Ingre C, Johnston W, Ludolph A, Maragakis NJ, Miller TM, Mora JS, Petri S, Simmons Z, van den Berg LH, Zinman L, Kupfer S, Malik FI, Meng L, Simkins TJ, Wei J, Wolff AA, Rudnicki SA. Reldesemtiv in Amyotrophic Lateral Sclerosis: Results From the COURAGE-ALS Randomized Clinical Trial. JAMA Neurol 2025; 82:477-485. [PMID: 40126464 PMCID: PMC11933997 DOI: 10.1001/jamaneurol.2025.0241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Collaborators] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Accepted: 11/09/2024] [Indexed: 03/25/2025]
Abstract
Importance Treatment options for amyotrophic lateral sclerosis (ALS) remain suboptimal. Results from a phase 2 study of reldesemtiv in ALS suggested that it may slow disease progression. Objective To assess the effect of reldesemtiv vs placebo on functional outcomes in ALS. Design, Setting, and Participants A Study to Evaluate the Efficacy and Safety of Reldesemtiv in Patients With Amyotrophic Lateral Sclerosis (COURAGE-ALS) was a double-blind, placebo-controlled phase 3 randomized clinical trial conducted at 83 ALS centers in 16 countries from August 2021 to July 2023. The first 24-week period was placebo controlled vs reldesemtiv. All participants received reldesemtiv during the second 24-week period with a 4-week follow-up. Two interim analyses were planned, the first for futility and the second for futility and possible resizing. This was a hybrid decentralized trial with approximately half the trial visits performed remotely and the remaining visits in the clinic. Eligible participants met criteria for definite, probable, or possible ALS with lower motor neuron signs by modified El Escorial Criteria, ALS symptoms for 24 months or less, ALS Functional Rating Scale-Revised (ALSFRS-R) total score of 44 or less, and forced vital capacity of greater than or equal to 65% of predicted. Interventions Oral reldesemtiv, 300 mg, or placebo twice daily. Main Outcomes and Measures The primary end point was change in ALSFRS-R total score from baseline to week 24. Results Of the 696 participants screened, 207 were screen failures. A total of 486 participants (mean [SD] age, 59.4 [10.9] years; 309 male [63.6%]) were randomized to reldesemtiv (n = 325) or placebo (n = 161); 3 randomized patients were not dosed. The second interim analysis at 24 weeks after randomization included 256 participants. The data monitoring committee recommended that the trial should end due to futility, and the sponsor agreed. The mean (SE) group difference in the ALSFRS-R score from baseline to week 24 was -1.1 (0.53; 95% CI, -2.17 to -0.08; P = .04, favoring placebo). Given excess missing data from early termination, the combined assessment assumed greater importance; it, too, failed to show a benefit from treatment with reldesemtiv (win probability was 0.44 for reldesemtiv and 0.49 for placebo, with a win ratio of 0.91; 95% CI of win ratio, 0.77-1.10; P = .11). Conclusions and Relevance This randomized clinical trial failed to demonstrate efficacy for reldesemtiv in slowing functional decline in ALS. Trial Registration ClinicalTrials.gov Identifier: NCT04944784.
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Affiliation(s)
- Jeremy M. Shefner
- Department of Neurology, Barrow Neurological Institute, University of Arizona, Phoenix
- Creighton University, Phoenix, Arizona
| | | | - Angela Genge
- Montreal Neurological Institute, Montréal, Québec, Canada
| | | | | | - Jinsy A. Andrews
- The Neurological Institute of New York, Columbia University Irving Medical Center, New York
| | - Adriano Chio
- Department of Neuroscience, University of Turin, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Turin, Italy
| | | | | | - Mamede de Carvalho
- Faculty of Medicine-University of Lisbon, Hospital de Santa Maria-CHULN, Lisbon, Portugal
| | - Terry Heiman-Patterson
- Neurology Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
| | | | | | | | - Albert Ludolph
- University of, Ulm, Germany
- Deutsches Zentrum für Neurodegenerative Erkrankungen e. V. (DZNE), Ulm, Germany
| | | | | | | | | | - Zachary Simmons
- Penn State Health Milton S. Hershey Medical Center, Hershey, Pennsylvania
| | | | - Lorne Zinman
- ALS/Neuromuscular Clinic, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
| | - Stuart Kupfer
- Cytokinetics Incorporated, South San Francisco, California
| | - Fady I. Malik
- Cytokinetics Incorporated, South San Francisco, California
| | - Lisa Meng
- Cytokinetics Incorporated, South San Francisco, California
| | | | - Jenny Wei
- Cytokinetics Incorporated, South San Francisco, California
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Collaborators
Matthew C Kiernan, David Schultz, Merrilee Needham, Steve Vucic, Genevieve Matte, Colleen M O'Connell, Lawrence Korngut, Annie Dionne, John Turnbull, Kerri Schellenberg, Christen Shoesmith, Jocelyn Zwicker, Lisette Salveson, Emilien Bernard, Froncois Salachas, Veronique Danel, Shahram Attarian, Marie-Helene Soriani, Annekathrin Rodiger, Julian Großkreutz, Patrick Weydt, Thomas Meyer, Vincenzo Silani, Frederica Cerri, Andrea Calvo, Christian Lunetta, Magdelena Kusma-Kozakiewicz, Jaun Francisco Vazquez-Costa, Monica Povedano, Christer Nilsson, Markus Weber, Caroline Young, Deborah Bradshaw, Sabrina Paganoni, Jeffrey Statland, James Grogan, Jeffrey Rothstein, Bjorn Oskarrson, Tuen Vu, Nicholas Olney, Richared Lewis, Jonnathon Katz, Dianna Quan, Leonard H Mccluskey, Namita Goyal, Pantellis Pavlakis, Andrea Swenson, Elham Bayat, Stephen Goutman, Dominic Fee, Peter Creigh, Amanda Peltier, Daragh Heitzman, Gary Patee, Cynthia Bodkin, Margeret Owegi, Ximena Arcilla-London, Nizar Chahin, Shafeeq Ladha, Yuen So, Kourosh Rezania, Rup Tandan, Rebecca Kuenzler, Kelly Gwathmey, Michael Pulley,
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Revi N, Nandeshwar M, Harijan D, Sankaranarayanan SA, Joshi M, Prabusankar G, Rengan AK. Acridine Benzimidazolium Derivatives Induced Protective Microglia Polarization and In Silico TDP-43 Interaction─Potential Implications for Amyotrophic Lateral Sclerosis. ACS Chem Neurosci 2025; 16:1103-1116. [PMID: 40029136 DOI: 10.1021/acschemneuro.4c00791] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/05/2025] Open
Abstract
Abnormal protein aggregation and associated neuronal-glial cell cytotoxicity lead to a plethora of neurodegenerative disorders. Most of the earlier investigations on understanding neurodegenerative disease progression and cure focused on neuronal damage and restoration potential. With increased evidence on the role of glial cells like microglia and astrocytes in mediating these disorders, more studies are dedicated to understanding the role of inflammatory responses mediated by glial cells and how they lead to neuroinflammation. Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disorder caused by TDP-43 aggregation that affects motor neurons. Pro-inflammatory microglia are considered to aggravate the disorder condition. In the current study, a previously reported molecule with TDP-43 inhibition, 3,3'-(acridine-4,5-diylbis(methylene))bis(1-(carboxymethyl)imidazol-3-ium) dibromide salt (AIM4), is analyzed for its microglia polarization properties along with two other derivatives, 3,3'-(acridine-4,5-diylbis(methylene))bis(1-(2-ethoxy-2-oxoethyl)benzimidazol-3-ium) dibromide salt (ABE) and 3,3'-(acridine-4,5-diylbis(methylene))bis(1-(carboxymethyl)benzoimidazol-3-ium) dibromide salt (ABA). The 3,3'-(acridine-4,5-diylbis(methylene))bis(1-(2-ethoxy-2-oxoethyl)benzimidazol-3-ium) dibromide salt (ABE) and 3,3'-(acridine-4,5-diylbis(methylene))bis(1-(carboxymethyl) benzimidazol-3-ium) dibromide salt (ABA) display the increased ability to maintain microglial cells to anti-inflammatory state and TDP-43 binding as compared to 3,3'-(acridine-4,5-diylbis(methylene)) bis(carboxymethyl)imidazolium dibromide salt (AIM4). This was confirmed from total nitrite levels, mitochondria membrane potential analysis, and molecular docking studies. The selected pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) displayed decreased levels, and anti-inflammatory cytokines IL-4 and IL-10 displayed increased levels, however not very significantly, upon treatment with all acridine derivatives. The compounds were investigated on lipopolysaccharides (LPS)-triggered mouse microglial cells and Danio rerio embryos displaying no significant cytotoxicity and physiological changes (cardiac rhythm), respectively. In molecular docking studies, alanine at 315 mutated to glutamate of TDP-43 directly interacts with AIM4. However, π-σ interactions of the aromatic backbone of acridine in ABE and ABA with 313 phenylalanine of TDP-43 along with hydrogen bonds formed between 309, 310 glycine amino acids and imidazolium bromide side chains rendered a stronger binding of these acridine derivatives with the protein potentially inhibiting fibrillation. Conclusion: ABA, ABE, and AIM4 maintain microglia in an anti-inflammatory state. However, more studies are required to understand its interaction with TDP-43 and the mechanism of its anti-inflammatory nature.
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Affiliation(s)
- Neeraja Revi
- Department of Biotechnology, Indian Institute of Technology Hyderabad, Hyderabad, Telangana 502284, India
| | - Muneshwar Nandeshwar
- Department of Chemistry, Indian Institute of Technology Hyderabad, Hyderabad, Telangana 502284, India
| | - Dinesh Harijan
- Department of Chemistry, Indian Institute of Technology Hyderabad, Hyderabad, Telangana 502284, India
| | | | - Meet Joshi
- Department of Biomedical Engineering, Indian Institute of Technology Hyderabad, Hyderabad, Telangana 502284, India
| | - Ganesan Prabusankar
- Department of Chemistry, Indian Institute of Technology Hyderabad, Hyderabad, Telangana 502284, India
| | - Aravind Kumar Rengan
- Department of Biomedical Engineering, Indian Institute of Technology Hyderabad, Hyderabad, Telangana 502284, India
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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] [Scholar 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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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] [Scholar 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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5
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Galli RA, Borsboom TC, Gineste C, Brocca L, Rossi M, Hwee DT, Malik FI, Bottinelli R, Gondin J, Pellegrino MA, de Winter JM, Ottenheijm CA. Tirasemtiv enhances submaximal muscle tension in an Acta1:p.Asp286Gly mouse model of nemaline myopathy. J Gen Physiol 2024; 156:e202313471. [PMID: 38376469 PMCID: PMC10876480 DOI: 10.1085/jgp.202313471] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Revised: 12/01/2023] [Accepted: 01/30/2024] [Indexed: 02/21/2024] Open
Abstract
Nemaline myopathies are the most common form of congenital myopathies. Variants in ACTA1 (NEM3) comprise 15-25% of all nemaline myopathy cases. Patients harboring variants in ACTA1 present with a heterogeneous disease course characterized by stable or progressive muscle weakness and, in severe cases, respiratory failure and death. To date, no specific treatments are available. Since NEM3 is an actin-based thin filament disease, we tested the ability of tirasemtiv, a fast skeletal muscle troponin activator, to improve skeletal muscle function in a mouse model of NEM3, harboring the patient-based p.Asp286Gly variant in Acta1. Acute and long-term tirasemtiv treatment significantly increased muscle contractile capacity at submaximal stimulation frequencies in both fast-twitch extensor digitorum longus and gastrocnemius muscle, and intermediate-twitch diaphragm muscle in vitro and in vivo. Additionally, long-term tirasemtiv treatment in NEM3 mice resulted in a decreased respiratory rate with preserved minute volume, suggesting more efficient respiration. Altogether, our data support the therapeutic potential of fast skeletal muscle troponin activators in alleviating skeletal muscle weakness in a mouse model of NEM3 caused by the Acta1:p.Asp286Gly variant.
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Affiliation(s)
- Ricardo A. Galli
- Amsterdam UMC Location Vrije Universiteit Amsterdam, Physiology, Amsterdam, The Netherlands
- Amsterdam Movement Sciences, Musculoskeletal Health and Tissue Function and Regeneration, Amsterdam, The Netherlands
| | - Tamara C. Borsboom
- Amsterdam UMC Location Vrije Universiteit Amsterdam, Physiology, Amsterdam, The Netherlands
| | | | - Lorenza Brocca
- Department of Molecular Medicine, University of Pavia, Pavia, Italy
| | - Maira Rossi
- Department of Molecular Medicine, University of Pavia, Pavia, Italy
| | - 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
| | - Roberto Bottinelli
- Department of Molecular Medicine, University of Pavia, Pavia, Italy
- IRCCS Mondino Foundation, Pavia, Italy
| | - Julien Gondin
- Aix-Marseille University, CNRS, CRMBM, Marseille, France
- Institut NeuroMyoGène, Unité Physiopathologie et Génétique du Neurone et du Muscle, Université Claude Bernard Lyon 1, CNRS UMR 5261, INSERM U1315, Université Lyon, Lyon, France
| | | | - Josine M. de Winter
- Amsterdam UMC Location Vrije Universiteit Amsterdam, Physiology, Amsterdam, The Netherlands
- Amsterdam Movement Sciences, Musculoskeletal Health and Tissue Function and Regeneration, Amsterdam, The Netherlands
- Amsterdam Cardiovascular Sciences, Heart Failure and Arrhythmias, Amsterdam, The Netherlands
| | - Coen A.C. Ottenheijm
- Amsterdam UMC Location Vrije Universiteit Amsterdam, Physiology, Amsterdam, The Netherlands
- Amsterdam Cardiovascular Sciences, Pulmonary Hypertension and Atherosclerosis, Amsterdam, The Netherlands
- Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ, USA
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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] [Scholar 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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Li Y, Zeng H, Wei Y, Ma X, He Z. An Overview of the Therapeutic Strategies for the Treatment of Spinal Muscular Atrophy. Hum Gene Ther 2023; 34:180-191. [PMID: 36762938 DOI: 10.1089/hum.2022.189] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/11/2023] Open
Abstract
Spinal muscular atrophy (SMA) is a recessive, neurodegenerative disorder. It is one of the most common genetic causes of infant mortality and is characterized by muscle weakness, loss of ambulation, and respiratory failure. SMA is primarily caused by a homozygous deletion or mutation of the survival motor neuron 1 (SMN1) gene. Humans possess a second, nearly identical copy of SMN, known as the SMN2 gene. Although the disease severity correlates inversely with the number of SMN2 copies present, it can never completely compensate for the loss of SMN1 in patients with SMA; SMN2 expresses only a fraction of the functional SMN transcript. The SMN protein is ubiquitous in human cells and plays several roles, ranging from assembling the spliceosome machinery to autophagy, RNA metabolism, signal transduction, cellular homeostasis, DNA repair, and recombination. Although the underlying mechanism remains unclear, anterior horn cells of the spinal cord gray matter are highly vulnerable to decreased SMN protein levels. To harness SMN2's ability to provide SMN function, two treatment strategies have been approved by the Food and Drug Administration (FDA), including an antisense oligonucleotide, nusinersen (Spinraza), and a small molecule, risdiplam (Evrysdi). Onasemnogene abeparvovec (Zolgensma) is an FDA-approved adeno-associated virus 9-mediated gene replacement therapy that creates a copy of the human SMN1 gene. In this review, we summarize the SMA etiology and FDA-approved therapies, and discuss the development of SMA therapeutic strategies and the challenges we faced.
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Affiliation(s)
- Yueyi Li
- Division of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Hongyu Zeng
- Division of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
- West China School of Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Yuhao Wei
- Division of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
- West China School of Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Xuelei Ma
- Division of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Zhiyao He
- Division of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, China
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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] [Scholar 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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Gebrehiwet P, Meng L, Rudnicki SA, Sarocco P, Wei J, Wolff AA, Chiò A, Andrews JA, Genge A, Jackson CE, Lechtzin N, Miller TM, Shefner JM. MiToS and King’s staging as clinical outcome measures in ALS: a retrospective analysis of the FORTITUDE-ALS trial. Amyotroph Lateral Scler Frontotemporal Degener 2022; 24:304-310. [PMID: 36503310 DOI: 10.1080/21678421.2022.2154678] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
OBJECTIVE To evaluate the Milano-Torino staging (MiToS) and King's staging systems as potential outcome measures for clinical trials in amyotrophic lateral sclerosis (ALS) by assessing these outcomes in FORTITUDE-ALS. METHODS This was a post hoc analysis of the phase 2b FORTITUDE-ALS trial (NCT03160898), a double-blind, randomized, dose-ranging, placebo-controlled, parallel-group study of reldesemtiv in patients with ALS. The treatment period was 12 weeks, with a follow-up assessment at week 16. Patients were retrospectively classified into MiToS and King's stages. Outcomes were the mean time maintaining baseline stage and risk of progression from the baseline stage to a later stage. RESULTS The full analysis set consisted of 456 patients randomized 3:1 (reldesemtiv n = 342, placebo n = 114) who received at least one dose of double-blind study drug and had at least one post-baseline assessment. At baseline, MiToS and King's stages were balanced between the reldesemtiv and placebo groups: >99% of patients were in MiToS stage 0 or 1 and King's stage 1, 2 or 3. Time of maintaining the baseline stage was similar in both groups, for each staging system. The two staging systems exhibited considerably disparate results for risk of progression from baseline to a later stage: hazard ratio (HR) = 0.62 (95% confidence interval [CI] 0.38, 0.99) for MiToS and HR = 0.96 (95% CI 0.63, 1.44) for King's. CONCLUSION This exploratory analysis showed the feasibility of MiToS and King's staging as potential outcome measures in ALS. Additional studies of these staging systems are needed to further explore their utility in ALS clinical trials.
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Affiliation(s)
| | - Lisa Meng
- Cytokinetics, Incorporated, South San Francisco, CA, USA
| | | | - Phil Sarocco
- Cytokinetics, Incorporated, South San Francisco, CA, USA
| | - Jenny Wei
- Cytokinetics, Incorporated, South San Francisco, CA, USA
| | | | - Adriano Chiò
- Rita Levi Montalcini Department of Neuroscience, University of Turin, Turin, Italy
| | - Jinsy A. Andrews
- The Neurological Institute, Columbia University, New York, NY, USA
| | - Angela Genge
- Montreal Neurological Institute, Montreal, QC, Canada
| | | | - Noah Lechtzin
- Johns Hopkins School of Medicine, Baltimore, MD, USA
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Fisher G, Mackels L, Markati T, Sarkozy A, Ochala J, Jungbluth H, Ramdas S, Servais L. Early clinical and pre-clinical therapy development in Nemaline myopathy. Expert Opin Ther Targets 2022; 26:853-867. [PMID: 36524401 DOI: 10.1080/14728222.2022.2157258] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
INTRODUCTION Nemaline myopathies (NM) represent a group of clinically and genetically heterogeneous congenital muscle disorders with the common denominator of nemaline rods on muscle biopsy. NEB and ACTA1 are the most common causative genes. Currently, available treatments are supportive. AREAS COVERED We explored experimental treatments for NM, identifying at least eleven mainly pre-clinical approaches utilizing murine and/or human muscle cells. These approaches target either i) the causative gene or associated genes implicated in the same pathway; ii) pathophysiologically relevant biochemical mechanisms such as calcium/myosin regulation of muscle contraction; iii) myogenesis; iv) other therapies that improve or optimize muscle function more generally; v) and/or combinations of the above. The scope and efficiency of these attempts is diverse, ranging from gene-specific effects to those widely applicable to all NM-associated genes. EXPERT OPINION The wide range of experimental therapies currently under consideration for NM is promising. Potential translation into clinical use requires consideration of additional factors such as the potential muscle type specificity as well as the possibility of gene expression remodeling. Challenges in clinical translation include the rarity and heterogeneity of genotypes, phenotypes, and disease trajectories, as well as the lack of longitudinal natural history data and validated outcomes and biomarkers.
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Affiliation(s)
- Gemma Fisher
- MDUK Neuromuscular Centre, Department of Paediatrics, University of Oxford, Oxford, UK
| | - Laurane Mackels
- MDUK Neuromuscular Centre, Department of Paediatrics, University of Oxford, Oxford, UK.,Neuromuscular Reference Center, University and University Hospital of Liège, Liège, Belgium
| | - Theodora Markati
- MDUK Neuromuscular Centre, Department of Paediatrics, University of Oxford, Oxford, UK
| | - Anna Sarkozy
- Dubowitz Neuromuscular Centre, UCL Great Ormond Street Hospital, Institute of Child Health, London, UK
| | - Julien Ochala
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Heinz Jungbluth
- Department of Paediatric Neurology - Neuromuscular Service, Evelina Children's Hospital, Guy's & St Thomas' NHS Foundation Trust, London, UK.,Randall Centre for Cell and Molecular Biophysics, Muscle Signalling Section, Faculty of Life Sciences and Medicine (FoLSM), King's College London, London, UK
| | - Sithara Ramdas
- MDUK Neuromuscular Centre, Department of Paediatrics, University of Oxford, Oxford, UK.,Department of Paediatric Neurology, John Radcliffe Hospital, Oxford, UK
| | - Laurent Servais
- MDUK Neuromuscular Centre, Department of Paediatrics, University of Oxford, Oxford, UK.,Neuromuscular Reference Center, University and University Hospital of Liège, Liège, Belgium
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11
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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: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar 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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12
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Rudnicki SA, Andrews JA, Genge A, Jackson C, Lechtzin N, Miller TM, Cockroft BM, Malik FI, Meng L, Wei J, Wolff AA, Shefner JM. Prescription and acceptance of durable medical equipment in FORTITUDE-ALS, a study of reldesemtiv in ALS: post hoc analyses of a randomized, double-blind, placebo-controlled clinical trial. Amyotroph Lateral Scler Frontotemporal Degener 2022; 23:263-270. [PMID: 34218726 DOI: 10.1080/21678421.2021.1946083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 06/11/2021] [Accepted: 06/14/2021] [Indexed: 10/20/2022]
Abstract
Objective: To evaluate the possible effect of reldesemtiv, a fast skeletal muscle troponin activator, on prescription and acceptance of durable medical equipment (DME) in the FORTITUDE-ALS trial. Methods: Health economic outcome information was collected in FORTITUDE-ALS (NCT03160898); sites recorded if and when DME, specifically manual or power wheelchairs, gastrostomy tubes, noninvasive ventilators, or augmentative language devices, was prescribed by a physician and accepted by the patient (DME-PAP) during the trial. Acceptance was defined as the patient agreeing the item was needed. Cox regression analysis compared time to DME-PAP for each reldesemtiv dose with placebo. Post hoc analyses evaluated all reldesemtiv doses compared with placebo. Results: At least one DME item was prescribed and accepted by 33/114 (28.9%) of placebo patients, 19/112 (17.0%) of patients receiving reldesemtiv 150 mg bid, 24/113 (21.2%) receiving 300 mg bid, and 29/117 (24.8%) receiving 450 mg bid. The proportion of new DME-PAP was significantly lower in patients receiving reldesemtiv 150 mg bid vs placebo (17.0% vs 28.9%, p = 0.032). The hazard ratio versus placebo for accepting at least one DME item for all reldesemtiv doses combined was 0.61 (confidence interval: 0.39, 0.96, p = 0.032). 25% of placebo patients were prescribed and agreed to obtain a DME item by 84 days; this threshold was met for reldesemtiv-treated patients at 120 days. Conclusions: Results suggest ALS patients receiving reldesemtiv may have lower risk of and delayed need for DME related to impaired mobility, breathing, swallowing, or speaking; this delay is consistent with other measures indicating delay in disease progression.
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Affiliation(s)
| | - Jinsy A Andrews
- The Neurological Institute, Columbia University, New York, NY, USA
| | - Angela Genge
- Montreal Neurological Institute, Montreal, QC, Canada
| | - Carlayne Jackson
- Departments of Neurology and Otolaryngology, University of Texas Health Science Center, San Antonio, TX, USA
| | - Noah Lechtzin
- Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Timothy M Miller
- Department of Neurology, Washington University School of Medicine, St. Louis, MO, 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
| | - Jeremy M Shefner
- Department of Neurology, Barrow Neurological Institute, Phoenix, AZ, USA
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13
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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: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar 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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14
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Spinal muscular atrophy: Where are we now? Current challenges and high hopes. POSTEP HIG MED DOSW 2022. [DOI: 10.2478/ahem-2022-0030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Abstract
Spinal muscular atrophy (SMA) is a neuromuscular disorder characterized by muscle weakness. It causes movement issues and severe physical disability. SMA is classified into four types based on the level of function achieved, age of onset, and maximum function achieved. The deletion or point mutation in the Survival of Motor Neuron 1 (SMN1) gene causes SMA. As a result, no full-length protein is produced. A nearly identical paralog, SMN2, provides enough stable protein to prevent death but not enough to compensate for SMN1's loss. The difference between SMN1 and SMN2 is due to different exon 7 alternative splicing patterns. SMA molecular therapies currently focus on restoring functional SMN protein by splicing modification of SMN2 exon 7 or elevated SMN protein levels. Nusinersen, an antisense oligonucleotide targeting the ISS-N1 sequence in SMN2 intron 7, was the first drug approved by the Food and Drug Administration. Risdiplam, a novel therapeutic that acts as an SMN2 exon 7 splicing modifier, was recently approved. All of these drugs result in the inclusion of SMN2 exon 7, and thus the production of functional SMN protein. Onasemnogene abeparvovec is a gene therapy that uses a recombinant adeno-associated virus that encodes the SMN protein. There are also experimental therapies available, such as reldesemtiv and apitegromab (SRK-015), which focus on improving muscle function or increasing muscle tissue growth, respectively. Although approved therapies have been shown to be effective, not all SMA patients can benefit from them due to age or weight, but primarily due to their high cost. This demonstrates the significance of continuous treatment improvement in today's medical challenges.
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15
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Edinoff AN, Nguyen LH, Odisho AS, Maxey BS, Pruitt JW, Girma B, Cornett EM, Kaye AM, Kaye AD. The Antisense Oligonucleotide Nusinersen for Treatment of Spinal Muscular Atrophy. Orthop Rev (Pavia) 2021; 13:24934. [PMID: 34745470 DOI: 10.52965/001c.24934] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Accepted: 06/17/2021] [Indexed: 01/25/2023] Open
Abstract
Spinal muscular atrophy (SMA) is a rare, autosomal recessive neuromuscular degenerative disease characterized by loss of spinal cord motor neurons leading to progressive muscle wasting. The most common pathology results from a homozygous disruption in the survival motor neuron 1 (SMN1) gene on chromosome 5q13 via deletion, conversion, or mutation. SMN2 is a near duplicate of SMN1 that can produce full-length SMN mRNA transcripts, but its overall production capability of these mRNA transcripts is lower than that seen in SMN1. This leads to lower levels of functional SMN protein within motor neurons. The FDA approved nusinersen in December 2016 to treat SMA associated with SMN1 gene mutation. It is administered directly to the central nervous system by intrathecal injection. An antisense oligonucleotide (ASO) drug, nusinersen, provides an upcoming and promising treatment option for SMA and represents a novel pharmacological approach with a mechanism of action relevant for other neurodegenerative disorders. Nusinersen begins with four initial loading doses that are followed by three maintenance doses per year. Three major studies (CHERISH, ENDEAR, and NURTURE) have shown to improve motor function in early and late-onset individuals and reduce the chances of ventilator requirements in pre-symptomatic infants. Studies investigating the timing of drug delivery in mouse models of SMA report the best outcomes when drugs are delivered early before any significant motor function is lost. Nusinersen is a novel therapeutic approach with consistent results in all three studies and is proof of the novel concept for treating SMA and other neurodegenerative disorders in the future.
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Affiliation(s)
| | - Long H Nguyen
- Louisiana State University Health Science Center Shreveport
| | - Amira S Odisho
- Louisiana State University Health Science Center Shreveport
| | | | - John W Pruitt
- Louisiana State University Health Science Center Shreveport
| | - Brook Girma
- Louisiana State University Health Science Center Shreveport
| | | | - Adam M Kaye
- Thomas J. Long School of Pharmacy and Health Sciences, University of the Pacific
| | - Alan D Kaye
- Louisiana State University Health Science Center Shreveport
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16
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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: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar 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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17
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van de Locht M, Borsboom TC, Winter JM, Ottenheijm CAC. Troponin Variants in Congenital Myopathies: How They Affect Skeletal Muscle Mechanics. Int J Mol Sci 2021; 22:ijms22179187. [PMID: 34502093 PMCID: PMC8430961 DOI: 10.3390/ijms22179187] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 08/19/2021] [Accepted: 08/23/2021] [Indexed: 02/05/2023] Open
Abstract
The troponin complex is a key regulator of muscle contraction. Multiple variants in skeletal troponin encoding genes result in congenital myopathies. TNNC2 has been implicated in a novel congenital myopathy, TNNI2 and TNNT3 in distal arthrogryposis (DA), and TNNT1 and TNNT3 in nemaline myopathy (NEM). Variants in skeletal troponin encoding genes compromise sarcomere function, e.g., by altering the Ca2+ sensitivity of force or by inducing atrophy. Several potential therapeutic strategies are available to counter the effects of variants, such as troponin activators, introduction of wild-type protein through AAV gene therapy, and myosin modulation to improve muscle contraction. The mechanisms underlying the pathophysiological effects of the variants in skeletal troponin encoding genes are incompletely understood. Furthermore, limited knowledge is available on the structure of skeletal troponin. This review focusses on the physiology of slow and fast skeletal troponin and the pathophysiology of reported variants in skeletal troponin encoding genes. A better understanding of the pathophysiological effects of these variants, together with enhanced knowledge regarding the structure of slow and fast skeletal troponin, will direct the development of treatment strategies.
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18
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Chong LC, Gandhi G, Lee JM, Yeo WWY, Choi SB. Drug Discovery of Spinal Muscular Atrophy (SMA) from the Computational Perspective: A Comprehensive Review. Int J Mol Sci 2021; 22:8962. [PMID: 34445667 PMCID: PMC8396480 DOI: 10.3390/ijms22168962] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Accepted: 01/27/2021] [Indexed: 01/02/2023] Open
Abstract
Spinal muscular atrophy (SMA), one of the leading inherited causes of child mortality, is a rare neuromuscular disease arising from loss-of-function mutations of the survival motor neuron 1 (SMN1) gene, which encodes the SMN protein. When lacking the SMN protein in neurons, patients suffer from muscle weakness and atrophy, and in the severe cases, respiratory failure and death. Several therapeutic approaches show promise with human testing and three medications have been approved by the U.S. Food and Drug Administration (FDA) to date. Despite the shown promise of these approved therapies, there are some crucial limitations, one of the most important being the cost. The FDA-approved drugs are high-priced and are shortlisted among the most expensive treatments in the world. The price is still far beyond affordable and may serve as a burden for patients. The blooming of the biomedical data and advancement of computational approaches have opened new possibilities for SMA therapeutic development. This article highlights the present status of computationally aided approaches, including in silico drug repurposing, network driven drug discovery as well as artificial intelligence (AI)-assisted drug discovery, and discusses the future prospects.
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Affiliation(s)
- Li Chuin Chong
- Centre for Bioinformatics, School of Data Sciences, Perdana University, Suite 9.2, 9th Floor, Wisma Chase Perdana, Changkat Semantan, Kuala Lumpur 50490, Malaysia; (L.C.C.); (J.M.L.)
| | - Gayatri Gandhi
- Perdana University Graduate School of Medicine, Perdana University, Suite 9.2, 9th Floor, Wisma Chase Perdana, Changkat Semantan, Kuala Lumpur 50490, Malaysia; (G.G.); (W.W.Y.Y.)
| | - Jian Ming Lee
- Centre for Bioinformatics, School of Data Sciences, Perdana University, Suite 9.2, 9th Floor, Wisma Chase Perdana, Changkat Semantan, Kuala Lumpur 50490, Malaysia; (L.C.C.); (J.M.L.)
| | - Wendy Wai Yeng Yeo
- Perdana University Graduate School of Medicine, Perdana University, Suite 9.2, 9th Floor, Wisma Chase Perdana, Changkat Semantan, Kuala Lumpur 50490, Malaysia; (G.G.); (W.W.Y.Y.)
| | - Sy-Bing Choi
- Centre for Bioinformatics, School of Data Sciences, Perdana University, Suite 9.2, 9th Floor, Wisma Chase Perdana, Changkat Semantan, Kuala Lumpur 50490, Malaysia; (L.C.C.); (J.M.L.)
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19
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Abstract
PURPOSE OF REVIEW This article provides an overview of the pathophysiology and clinical presentations of spinal muscular atrophy (SMA) and reviews therapeutic developments, including US Food and Drug Administration (FDA)-approved gene-targeted therapies and mainstays of supportive SMA care. RECENT FINDINGS Over the past decades, an understanding of the role of SMN protein in the development and maintenance of the motor unit and the intricate genetics underlying SMA has led to striking developments in therapeutics with three FDA-approved treatments for SMA, one targeting SMN1 gene replacement (onasemnogene abeparvovec-xioi) and two others enhancing SMN protein production from the SMN2 gene (nusinersen and risdiplam). These therapies are most effective in infants treated at younger ages, and improvement is most striking in babies treated as neonates. Despite improvements in motor function, patients (especially those treated at older ages) continue to experience significant weakness and require continued close monitoring of respiratory and orthopedic symptoms. SUMMARY Striking therapeutic advancements have changed the clinical course of SMA dramatically, although supportive care continues to play an important role in patient care.
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20
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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] [Scholar 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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21
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de Winter JM, Gineste C, Minardi E, Brocca L, Rossi M, Borsboom T, Beggs AH, Bernard M, Bendahan D, Hwee DT, Malik FI, Pellegrino MA, Bottinelli R, Gondin J, Ottenheijm CAC. Acute and chronic tirasemtiv treatment improves in vivo and in vitro muscle performance in actin-based nemaline myopathy mice. Hum Mol Genet 2021; 30:1305-1320. [PMID: 33909041 PMCID: PMC8255131 DOI: 10.1093/hmg/ddab112] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 03/09/2021] [Accepted: 04/07/2021] [Indexed: 12/13/2022] Open
Abstract
Nemaline myopathy, a disease of the actin-based thin filament, is one of the most frequent congenital myopathies. To date, no specific therapy is available to treat muscle weakness in nemaline myopathy. We tested the ability of tirasemtiv, a fast skeletal troponin activator that targets the thin filament, to augment muscle force-both in vivo and in vitro-in a nemaline myopathy mouse model with a mutation (H40Y) in Acta1. In Acta1H40Y mice, treatment with tirasemtiv increased the force response of muscles to submaximal stimulation frequencies. This resulted in a reduced energetic cost of force generation, which increases the force production during a fatigue protocol. The inotropic effects of tirasemtiv were present in locomotor muscles and, albeit to a lesser extent, in respiratory muscles, and they persisted during chronic treatment, an important finding as respiratory failure is the main cause of death in patients with congenital myopathy. Finally, translational studies on permeabilized muscle fibers isolated from a biopsy of a patient with the ACTA1H40Y mutation revealed that at physiological Ca2+ concentrations, tirasemtiv increased force generation to values that were close to those generated in muscle fibers of healthy subjects. These findings indicate the therapeutic potential of fast skeletal muscle troponin activators to improve muscle function in nemaline myopathy due to the ACTA1H40Y mutation, and future studies should assess their merit for other forms of nemaline myopathy and for other congenital myopathies.
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Affiliation(s)
- Josine M de Winter
- Department of Physiology, Amsterdam UMC (location VUmc), Amsterdam 1081 HV, The Netherlands
| | | | - Elisa Minardi
- Department of Molecular Medicine, University of Pavia, Pavia 27100, Italy
| | - Lorenza Brocca
- Department of Molecular Medicine, University of Pavia, Pavia 27100, Italy
| | - Maira Rossi
- Department of Molecular Medicine, University of Pavia, Pavia 27100, Italy
| | - Tamara Borsboom
- Department of Physiology, Amsterdam UMC (location VUmc), Amsterdam 1081 HV, The Netherlands
| | - Alan H Beggs
- Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Monique Bernard
- Aix-Marseille Univ, CNRS, CRMBM, UMR 7339, 13005 Marseille, France
| | - David Bendahan
- Aix-Marseille Univ, CNRS, CRMBM, UMR 7339, 13005 Marseille, France
| | - Darren T Hwee
- 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
| | - Maria Antonietta Pellegrino
- Department of Molecular Medicine, University of Pavia, Pavia 27100, Italy
- Interdipartimental Centre for Biology and Sport Medicine, University of Pavia, Pavia 27100, Italy
| | - Roberto Bottinelli
- Department of Molecular Medicine, University of Pavia, Pavia 27100, Italy
- Istituti Clinici Maugeri (IRCCS), Scientific Institute of Pavia, Pavia 27100, Italy
| | - Julien Gondin
- Aix-Marseille Univ, CNRS, CRMBM, UMR 7339, 13005 Marseille, France
- Institut NeuroMyoGène, Université Claude Bernard Lyon 1, CNRS 5310, INSERM U1217, 69008, Lyon, France
| | - Coen A C Ottenheijm
- Department of Physiology, Amsterdam UMC (location VUmc), Amsterdam 1081 HV, The Netherlands
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22
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van de Locht M, Donkervoort S, de Winter JM, Conijn S, Begthel L, Kusters B, Mohassel P, Hu Y, Medne L, Quinn C, Moore SA, Foley AR, Seo G, Hwee DT, Malik FI, Irving T, Ma W, Granzier HL, Kamsteeg EJ, Immadisetty K, Kekenes-Huskey P, Pinto JR, Voermans N, Bönnemann CG, Ottenheijm CA. Pathogenic variants in TNNC2 cause congenital myopathy due to an impaired force response to calcium. J Clin Invest 2021; 131:145700. [PMID: 33755597 PMCID: PMC8087209 DOI: 10.1172/jci145700] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Accepted: 03/18/2021] [Indexed: 12/11/2022] Open
Abstract
Troponin C (TnC) is a critical regulator of skeletal muscle contraction; it binds Ca2+ to activate muscle contraction. Surprisingly, the gene encoding fast skeletal TnC (TNNC2) has not yet been implicated in muscle disease. Here, we report 2 families with pathogenic variants in TNNC2. Patients present with a distinct, dominantly inherited congenital muscle disease. Molecular dynamics simulations suggested that the pathomechanisms by which the variants cause muscle disease include disruption of the binding sites for Ca2+ and for troponin I. In line with these findings, physiological studies in myofibers isolated from patients' biopsies revealed a markedly reduced force response of the sarcomeres to [Ca2+]. This pathomechanism was further confirmed in experiments in which contractile dysfunction was evoked by replacing TnC in myofibers from healthy control subjects with recombinant, mutant TnC. Conversely, the contractile dysfunction of myofibers from patients was repaired by replacing endogenous, mutant TnC with recombinant, wild-type TnC. Finally, we tested the therapeutic potential of the fast skeletal muscle troponin activator tirasemtiv in patients' myofibers and showed that the contractile dysfunction was repaired. Thus, our data reveal that pathogenic variants in TNNC2 cause congenital muscle disease, and they provide therapeutic angles to repair muscle contractility.
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Affiliation(s)
- Martijn van de Locht
- Deptartment of Physiology, Amsterdam UMC (location VUmc), Amsterdam, Netherlands
| | - Sandra Donkervoort
- Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, Maryland, USA
| | - Josine M. de Winter
- Deptartment of Physiology, Amsterdam UMC (location VUmc), Amsterdam, Netherlands
| | - Stefan Conijn
- Deptartment of Physiology, Amsterdam UMC (location VUmc), Amsterdam, Netherlands
| | - Leon Begthel
- Deptartment of Physiology, Amsterdam UMC (location VUmc), Amsterdam, Netherlands
| | - Benno Kusters
- Department of Neurology and Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands
| | - Payam Mohassel
- Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, Maryland, USA
| | - Ying Hu
- Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, Maryland, USA
| | - Livija Medne
- Division of Human Genetics, Department of Pediatrics, Individualized Medical Genetics Center, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Colin Quinn
- Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Steven A. Moore
- Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA
| | - A. Reghan Foley
- Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, Maryland, USA
| | - Gwimoon Seo
- Protein Expression Facility, Institute of Molecular Biophysics, The Florida State University, Tallahassee, Florida, USA
| | - Darren T. Hwee
- Research and Early Development, Cytokinetics Inc., South San Francisco, California, USA
| | - Fady I. Malik
- Research and Early Development, Cytokinetics Inc., South San Francisco, California, USA
| | - Thomas Irving
- BioCAT, Illinois Institute of Technology, Chicago, Illinois, USA
| | - Weikang Ma
- BioCAT, Illinois Institute of Technology, Chicago, Illinois, USA
| | - Henk L. Granzier
- Department of Cellular and Molecular Medicine, University of Arizona, Tucson, Arizona, USA
| | - Erik-Jan Kamsteeg
- Department of Neurology and Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands
| | - Kalyan Immadisetty
- Department of Cell and Molecular Physiology, Loyola University, Chicago, Illinois, USA
| | - Peter Kekenes-Huskey
- Department of Cell and Molecular Physiology, Loyola University, Chicago, Illinois, USA
| | - José R. Pinto
- Department of Biomedical Sciences, The Florida State University College of Medicine, Tallahassee, Florida, USA
| | - Nicol Voermans
- Department of Neurology and Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands
| | - Carsten G. Bönnemann
- Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, Maryland, USA
| | - Coen A.C. Ottenheijm
- Deptartment of Physiology, Amsterdam UMC (location VUmc), Amsterdam, Netherlands
- Department of Cellular and Molecular Medicine, University of Arizona, Tucson, Arizona, USA
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23
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Karpicheva OE. Hallmark Features of the Tropomyosin
Regulatory Function in Several Variants of Congenital Myopathy. J EVOL BIOCHEM PHYS+ 2021. [DOI: 10.1134/s0022093021030133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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24
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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: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar 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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25
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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] [Scholar 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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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] [Scholar 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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Emerging Medical Treatment for Hypertrophic Cardiomyopathy. J Clin Med 2021; 10:jcm10050951. [PMID: 33804412 PMCID: PMC7957690 DOI: 10.3390/jcm10050951] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 02/18/2021] [Accepted: 02/19/2021] [Indexed: 02/06/2023] Open
Abstract
Hypertrophic cardiomyopathy (HCM) is a common myocardial disease characterized by otherwise unexplained left ventricular hypertrophy. The main cause of disabling symptoms in patients with HCM is left ventricular outflow tract (LVOT) obstruction. This phenomenon is multifactorial, determined both by anatomical and functional abnormalities: myocardial hypercontractility is believed to represent one of its major determinants. The anatomical anomalies are targeted by surgical interventions, whereas attenuating hypercontractility is the objective of old and new drugs including the novel class of allosteric myosin inhibitors. This review summarizes the current treatment modalities and discusses the emerging therapeutical opportunities focusing on the recently developed cardiac myosin ATPase inhibitors Mavacamten and CK-274. Novel surgical and interventional approaches are also discussed.
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28
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In Search of a Cure: The Development of Therapeutics to Alter the Progression of Spinal Muscular Atrophy. Brain Sci 2021; 11:brainsci11020194. [PMID: 33562482 PMCID: PMC7915832 DOI: 10.3390/brainsci11020194] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 01/29/2021] [Accepted: 02/01/2021] [Indexed: 12/19/2022] Open
Abstract
Until the recent development of disease-modifying therapeutics, spinal muscular atrophy (SMA) was considered a devastating neuromuscular disease with a poor prognosis for most affected individuals. Symptoms generally present during early childhood and manifest as muscle weakness and progressive paralysis, severely compromising the affected individual’s quality of life, independence, and lifespan. SMA is most commonly caused by the inheritance of homozygously deleted SMN1 alleles with retention of one or more copies of a paralog gene, SMN2, which inversely correlates with disease severity. The recent advent and use of genetically targeted therapies have transformed SMA into a prototype for monogenic disease treatment in the era of genetic medicine. Many SMA-affected individuals receiving these therapies achieve traditionally unobtainable motor milestones and survival rates as medicines drastically alter the natural progression of this disease. This review discusses historical SMA progression and underlying disease mechanisms, highlights advances made in therapeutic research, clinical trials, and FDA-approved medicines, and discusses possible second-generation and complementary medicines as well as optimal temporal intervention windows in order to optimize motor function and improve quality of life for all SMA-affected individuals.
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29
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Alsulami K, Marston S. Small Molecules acting on Myofilaments as Treatments for Heart and Skeletal Muscle Diseases. Int J Mol Sci 2020; 21:E9599. [PMID: 33339418 PMCID: PMC7767104 DOI: 10.3390/ijms21249599] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 12/11/2020] [Accepted: 12/11/2020] [Indexed: 01/10/2023] Open
Abstract
Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) are the most prevalent forms of the chronic and progressive pathological condition known as cardiomyopathy. These diseases have different aetiologies; however, they share the feature of haemodynamic abnormalities, which is mainly due to dysfunction in the contractile proteins that make up the contractile unit known as the sarcomere. To date, pharmacological treatment options are not disease-specific and rather focus on managing the symptoms, without addressing the disease mechanism. Earliest attempts at improving cardiac contractility by modulating the sarcomere indirectly (inotropes) resulted in unwanted effects. In contrast, targeting the sarcomere directly, aided by high-throughput screening systems, could identify small molecules with a superior therapeutic value in cardiac muscle disorders. Herein, an extensive literature review of 21 small molecules directed to five different targets was conducted. A simple scoring system was created to assess the suitability of small molecules for therapy by evaluating them in eight different criteria. Most of the compounds failed due to lack of target specificity or poor physicochemical properties. Six compounds stood out, showing a potential therapeutic value in HCM, DCM or heart failure (HF). Omecamtiv Mecarbil and Danicamtiv (myosin activators), Mavacamten, CK-274 and MYK-581 (myosin inhibitors) and AMG 594 (Ca2+-sensitiser) are all small molecules that allosterically modulate troponin or myosin. Omecamtiv Mecarbil showed limited efficacy in phase III GALACTIC-HF trial, while, results from phase III EXPLORER-HCM trial were recently published, indicating that Mavacamten reduced left ventricular outflow tract (LVOT) obstruction and diastolic dysfunction and improved the health status of patients with HCM. A novel category of small molecules known as "recouplers" was reported to target a phenomenon termed uncoupling commonly found in familial cardiomyopathies but has not progressed beyond preclinical work. In conclusion, the contractile apparatus is a promising target for new drug development.
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Affiliation(s)
- Khulud Alsulami
- Imperial Centre for Translational and Experimental Medicine, Cardiovascular Division, National Heart and Lung Institute, Imperial College London, London W12 0NN, UK;
- National Centre for Pharmaceutical Technology, King Abdulaziz City for Science and Technology, Riyadh 11461, Saudi Arabia
| | - Steven Marston
- Imperial Centre for Translational and Experimental Medicine, Cardiovascular Division, National Heart and Lung Institute, Imperial College London, London W12 0NN, UK;
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30
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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] [Scholar 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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31
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Singh RN, Ottesen EW, Singh NN. The First Orally Deliverable Small Molecule for the Treatment of Spinal Muscular Atrophy. Neurosci Insights 2020; 15:2633105520973985. [PMID: 33283185 PMCID: PMC7691903 DOI: 10.1177/2633105520973985] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 10/27/2020] [Indexed: 12/12/2022] Open
Abstract
Spinal muscular atrophy (SMA) is 1 of the leading causes of infant mortality. SMA
is mostly caused by low levels of Survival Motor Neuron (SMN) protein due to
deletion of or mutation in the SMN1 gene. Its nearly identical
copy, SMN2, fails to compensate for the loss of
SMN1 due to predominant skipping of exon 7. Correction of
SMN2 exon 7 splicing by an antisense oligonucleotide (ASO),
nusinersen (Spinraza™), that targets the intronic splicing silencer N1 (ISS-N1)
became the first approved therapy for SMA. Restoration of SMN levels using gene
therapy was the next. Very recently, an orally deliverable small molecule,
risdiplam (Evrysdi™), became the third approved therapy for SMA. Here we discuss
how these therapies are positioned to meet the needs of the broad phenotypic
spectrum of SMA patients.
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Affiliation(s)
- Ravindra N Singh
- Department of Biomedical Sciences, Iowa State University, Ames, IA, USA
| | - Eric W Ottesen
- Department of Biomedical Sciences, Iowa State University, Ames, IA, USA
| | - Natalia N Singh
- Department of Biomedical Sciences, Iowa State University, Ames, IA, USA
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32
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Shefner JM, Andrews JA, Genge A, Jackson C, Lechtzin N, Miller TM, Cockroft BM, Meng L, Wei J, Wolff AA, Malik FI, Bodkin C, Brooks BR, Caress J, Dionne A, Fee D, Goutman SA, Goyal NA, Hardiman O, Hayat G, Heiman-Patterson T, Heitzman D, Henderson RD, Johnston W, Karam C, Kiernan MC, Kolb SJ, Korngut L, Ladha S, Matte G, Mora JS, Needham M, Oskarsson B, Pattee GL, Pioro EP, Pulley M, Quan D, Rezania K, Schellenberg KL, Schultz D, Shoesmith C, Simmons Z, Statland J, Sultan S, Swenson A, Berg LHVD, Vu T, Vucic S, Weiss M, Whyte-Rayson A, Wymer J, Zinman L, Rudnicki SA. A Phase 2, Double-Blind, Randomized, Dose-Ranging Trial Of Reldesemtiv In Patients With ALS. Amyotroph Lateral Scler Frontotemporal Degener 2020; 22:287-299. [PMID: 32969758 PMCID: PMC8117790 DOI: 10.1080/21678421.2020.1822410] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Objective: To evaluate safety, dose response, and preliminary efficacy of reldesemtiv over 12 weeks in patients with amyotrophic lateral sclerosis (ALS). Methods: Patients (≤2 years since diagnosis) with slow upright vital capacity (SVC) of ≥60% were randomized 1:1:1:1 to reldesemtiv 150, 300, or 450 mg twice daily (bid) or placebo; active treatment was 12 weeks with 4-week follow-up. Primary endpoint was change in percent predicted SVC at 12 weeks; secondary measures included ALS Functional Rating Scale-Revised (ALSFRS-R) and muscle strength mega-score. Results: Patients (N = 458) were enrolled; 85% completed 12-week treatment. The primary analysis failed to reach statistical significance (p = 0.11); secondary endpoints showed no statistically significant effects (ALSFRS-R, p = 0.09; muscle strength megascore, p = 0.31). Post hoc analyses pooling all active reldesemtiv-treated patients compared against placebo showed trends toward benefit in all endpoints (progression rate for SVC, ALSFRS-R, and muscle strength mega-score (nominal p values of 0.10, 0.01 and 0.20 respectively)). Reldesemtiv was well tolerated, with nausea and fatigue being the most common side effects. A dose-dependent decrease in estimated glomerular filtration rate was noted, and transaminase elevations were seen in approximately 5% of patients. Both hepatic and renal abnormalities trended toward resolution after study drug discontinuation. Conclusions: Although the primary efficacy analysis did not demonstrate statistical significance, there were trends favoring reldesemtiv for all three endpoints, with effect sizes generally regarded as clinically important. Tolerability was good; modest hepatic and renal abnormalities were reversible. The impact of reldesemtiv on patients with ALS should be assessed in a pivotal Phase 3 trial. (ClinicalTrials.gov Identifier: NCT03160898)
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Affiliation(s)
| | - Jinsy A Andrews
- The Eleanor and Lou Gehrig ALS Center, The Neurological Institute, New York, NY, USA
| | - Angela Genge
- Montreal Neurological Institute, Montreal, QC, Canada
| | | | - Noah Lechtzin
- Johns Hopkins School of Medicine, Baltimore, MD, USA
| | | | | | - Lisa Meng
- Cytokinetics, Inc, South San Francisco, CA, USA
| | - Jenny Wei
- Cytokinetics, Inc, South San Francisco, CA, USA
| | | | | | - Cynthia Bodkin
- Indiana University School of Medicine, Indianapolis, IN, USA
| | - Benjamin R Brooks
- Atrium Health Neurosciences Institute-Carolinas Neuromuscular/ALS MDA Care Center, Charlotte, NC, USA
| | - James Caress
- Wake Forest Health Sciences, Winston-Salem, NC, USA
| | | | - Dominic Fee
- Medical College of Wisconsin, Milwaukee, WI, USA
| | | | - Namita A Goyal
- The ALS & Neuromuscular Center, UCI Health, Orange, CA, USA
| | | | | | | | | | | | | | - Chafic Karam
- Oregon Health & Science University, Portland, OR, USA
| | - Matthew C Kiernan
- Royal Prince Alfred Hospital, University of Sydney, Sydney, Australia
| | - Stephen J Kolb
- Wexner Medical Center, Ohio State University, Columbus, OH, USA
| | | | - Shafeeq Ladha
- St. Joseph's Hospital and Medical Center, Neurological Institute, AZ, USA Barrow Phoenix
| | - Genevieve Matte
- Centre Hospitalier de l'Université de Montréal, Montreal, QC, Canada
| | | | - Merrilee Needham
- Perron Institute, Department of Neurology, Fiona Stanley Hospital, The University of Notre Dame Australia, Murdoch University, Perth, Australia
| | | | | | | | | | - Dianna Quan
- University of Colorado Denver, Aurora, CO, USA
| | | | | | | | | | | | | | | | | | - Leonard H Van Den Berg
- Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Tuan Vu
- University of South Florida, Tampa, FL, USA
| | | | | | | | | | - Lorne Zinman
- ALS/Neuromuscular Clinic Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada
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New Treatments in Spinal Muscular Atrophy: Positive Results and New Challenges. J Clin Med 2020; 9:jcm9072222. [PMID: 32668756 PMCID: PMC7408870 DOI: 10.3390/jcm9072222] [Citation(s) in RCA: 90] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 07/01/2020] [Accepted: 07/10/2020] [Indexed: 12/24/2022] Open
Abstract
Spinal muscular atrophy (SMA) is one of the most common autosomal recessive diseases with progressive weakness of skeletal and respiratory muscles, leading to significant disability. The disorder is caused by mutations in the survival motor neuron 1 (SMN1) gene and a consequent decrease in the SMN protein leading to lower motor neuron degeneration. Recently, Food and Drug Administration (FDA) and European Medical Agency (EMA) approved the antisense oligonucleotide nusinersen, the first SMA disease-modifying treatment and gene replacement therapy by onasemnogene abeparvovec. Encouraging results from phase II and III clinical trials have raised hope that other therapeutic options will enter soon in clinical practice. However, the availability of effective approaches has raised up ethical, medical and financial issues that are routinely faced by the SMA community. This review covers the available data and the new challenges of SMA therapeutic strategies.
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Shefner JM, Cudkowicz ME, Hardiman O, Cockcroft BM, Lee JH, Malik FI, Meng L, Rudnicki SA, Wolff AA, Andrews JA. A phase III trial of tirasemtiv as a potential treatment for amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener 2020; 0:1-11. [PMID: 31081694 DOI: 10.1080/21678421.2019.1612922] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Objective To assess the efficacy of tirasemtiv, a fast skeletal muscle troponin activator, vs. placebo in patients with amyotrophic lateral sclerosis. Methods: VITALITY-ALS (NCT02496767) was a multinational, double-blind, randomized, placebo-controlled clinical trial. Participants tolerating 2 weeks of open-label tirasemtiv (125 mg twice daily) were randomized 3:2:2:2 to placebo or one of three target tirasemtiv dose levels, using an escalating dosage protocol lasting 28 days. The primary outcome measure was changed in slow vital capacity (SVC) at 24 weeks. Secondary endpoints included a change in muscle strength and time to respiratory milestones of disease progression. Results Of 744 participants, 565 tolerated open-label tirasemtiv and received randomized treatment. By 24 weeks, 23 (12.2%) placebo-treated participants discontinued study treatment vs. 129 (34.2%) randomized to tirasemtiv. SVC declined by 14.4% (95% CI: −16.8, −11.9) in the placebo group and 13.4% (95% CI: −15.3, −11.6) in the tirasemtiv group (p = 0.56). Secondary endpoints did not show significant differences. However, participants who tolerated tirasemtiv at their randomized dose showed a numeric trend toward a dose-related slowing of decline in SVC (p = 0.11). Dizziness, fatigue, nausea, weight loss, and insomnia occurred more frequently on tirasemtiv. Serious adverse events were similar across groups. Conclusions Tirasemtiv did not alter the decline of SVC or significantly impact secondary outcome measures. Poor tolerability of tirasemtiv may have contributed to this result. However, participants tolerating their intended dose exhibited a trend toward treatment benefit on SVC, suggesting the underlying mechanism of action may still hold promise, as is being tested with a different fast skeletal muscle troponin activator (NCT03160898).
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Affiliation(s)
- Jeremy M Shefner
- Barrow Neurological Institute, Phoenix, Arizona.,Department of Neurology, University of Arizona, Phoenix, AZ, USA
| | - Merit E Cudkowicz
- Department of Neurology, Neurological Clinical Research Institute, Massachusetts General Hospital, Boston, MA, USA
| | - Orla Hardiman
- Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College, Dublin, Ireland
| | | | | | - Fady I Malik
- Cytokinetics, Inc., South San Francisco, California, USA
| | - Lisa Meng
- Cytokinetics, Inc., South San Francisco, California, USA
| | | | - Andrew A Wolff
- Cytokinetics, Inc., South San Francisco, California, USA
| | - Jinsy A Andrews
- The Neurological Institute, Columbia University, New York, NY, USA
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Wobst HJ, Mack KL, Brown DG, Brandon NJ, Shorter J. The clinical trial landscape in amyotrophic lateral sclerosis-Past, present, and future. Med Res Rev 2020; 40:1352-1384. [PMID: 32043626 PMCID: PMC7417284 DOI: 10.1002/med.21661] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Revised: 12/08/2019] [Accepted: 01/27/2020] [Indexed: 12/11/2022]
Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease marked by progressive loss of muscle function. It is the most common adult-onset form of motor neuron disease, affecting about 16 000 people in the United States alone. The average survival is about 3 years. Only two interventional drugs, the antiglutamatergic small-molecule riluzole and the more recent antioxidant edaravone, have been approved for the treatment of ALS to date. Therapeutic strategies under investigation in clinical trials cover a range of different modalities and targets, and more than 70 different drugs have been tested in the clinic to date. Here, we summarize and classify interventional therapeutic strategies based on their molecular targets and phenotypic effects. We also discuss possible reasons for the failure of clinical trials in ALS and highlight emerging preclinical strategies that could provide a breakthrough in the battle against this relentless disease.
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Affiliation(s)
- Heike J Wobst
- Neuroscience, BioPharmaceuticals R&D, AstraZeneca, Boston, Massachusetts
| | - Korrie L Mack
- Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
- Merck & Co, Inc, Kenilworth, New Jersey
| | - Dean G Brown
- Hit Discovery, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Boston, Massachusetts
| | - Nicholas J Brandon
- Neuroscience, BioPharmaceuticals R&D, AstraZeneca, Boston, Massachusetts
| | - James Shorter
- Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
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Liscic RM, Alberici A, Cairns NJ, Romano M, Buratti E. From basic research to the clinic: innovative therapies for ALS and FTD in the pipeline. Mol Neurodegener 2020; 15:31. [PMID: 32487123 PMCID: PMC7268618 DOI: 10.1186/s13024-020-00373-9] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Accepted: 03/27/2020] [Indexed: 12/11/2022] Open
Abstract
Amyotrophic lateral sclerosis (ALS) and Frontotemporal Degeneration (FTD) are neurodegenerative disorders, related by deterioration of motor and cognitive functions and short survival. Aside from cases with an inherited pathogenic mutation, the causes of the disorders are still largely unknown and no effective treatment currently exists. It has been shown that FTD may coexist with ALS and this overlap occurs at clinical, genetic, and molecular levels. In this work, we review the main pathological aspects of these complex diseases and discuss how the integration of the novel pathogenic molecular insights and the analysis of molecular interaction networks among all the genetic players represents a critical step to shed light on discovering novel therapeutic strategies and possibly tailoring personalized medicine approaches to specific ALS and FTD patients.
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Affiliation(s)
- Rajka Maria Liscic
- Department of Neurology, Johannes Kepler University, Linz, Austria
- School of Medicine, University of Osijek, Osijek, Croatia
| | - Antonella Alberici
- Neurology Unit, Department of Neurological Sciences and Vision, ASST-Spedali Civili-University of Brescia, Brescia, Italy
| | - Nigel John Cairns
- College of Medicine and Health and Living Systems Institute, University of Exeter, Exeter, UK
| | - Maurizio Romano
- Department of Life Sciences, Via Valerio 28, University of Trieste, 34127, Trieste, Italy
| | - Emanuele Buratti
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Padriciano 99, 34149, Trieste, Italy.
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Calzetta L, Ritondo BL, Matera MG, Pezzuto G, Cazzola M, Rogliani P. Investigational treatments in phase I and II clinical trials: a systematic review in chronic obstructive pulmonary disease (COPD). Expert Opin Investig Drugs 2020; 29:723-738. [PMID: 32401655 DOI: 10.1080/13543784.2020.1769064] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Introduction. The current pharmacological treatments for the management of stable COPD permit the reduction of symptoms and frequency and severity of exacerbations, and the improvement of exercise tolerance and health status. However, they do not modify the long-term decline in lung function and patient health. Consequently, there is the strong need for 'highly innovative' medications that are focused on new targets and/or mechanisms for the treatment of COPD. Areas covered. This systematic review assesses investigational agents in Phase I and II clinical trials over the last six years. It offers insights on whether drugs and/or formulations in clinical development offer future effective treatments of COPD. Expert opinion. There is no evidence to suggest that current investigational agents can reduce lung function decline and cure COPD. However, looking forward, investigational, innovative treatments in combination with the therapies already recommended by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) may provide future suitable tools to counteract the progression of COPD.
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Affiliation(s)
- Luigino Calzetta
- Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome "Tor Vergata" , Rome, Italy
| | - Beatrice Ludovica Ritondo
- Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome "Tor Vergata" , Rome, Italy
| | - Maria Gabriella Matera
- Unit of Pharmacology, Department of Experimental Medicine, University of Campania Luigi Vanvitelli , Naples, Italy
| | - Gabriella Pezzuto
- Division of Respiratory Medicine, University Hospital "Tor Vergata" , Rome, Italy
| | - Mario Cazzola
- Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome "Tor Vergata" , Rome, Italy
| | - Paola Rogliani
- Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome "Tor Vergata" , Rome, Italy
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Abstract
Objectives: The beneficial effects of many substances have been discovered because of regular dietary consumption. This is also the case with curcumin, whose effects have been known for more than 4,000 years in Eastern countries such as China and India. A curcumin-rich diet has been known to counteract many human diseases, including cancer and diabetes, and has been shown to reduce inflammation. The effect of a curcumin treatment for neurological diseases, such as spinal muscular atrophy; Alzheimer's disease; Parkinson's disease; amyotrophic lateral sclerosis; multiple sclerosis; and others, has only recently been brought to the attention of researchers and the wider population.Methods: In this paper, we summarise the studies on this natural product, from its isolation two centuries ago to its characterisation a century later.Results: We describe its role in the treatment of neurological diseases, including its cellular and common molecular mechanisms, and we report on the clinical trials of curcumin with healthy people and patients.Discussion: Commenting on the different approaches adopted by the efforts made to increase its bioavailability.
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Affiliation(s)
- Raffaella Adami
- Department of Health Sciences, University of Milan, Milan, Italy
| | - Daniele Bottai
- Department of Health Sciences, University of Milan, Milan, Italy
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Chen TH. New and Developing Therapies in Spinal Muscular Atrophy: From Genotype to Phenotype to Treatment and Where Do We Stand? Int J Mol Sci 2020; 21:3297. [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] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar 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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Affiliation(s)
- Tai-Heng Chen
- Section of Neurobiology, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA;
- Division of Pediatric Emergency, Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Ph.D. Program in Translational Medicine, Graduate Institute of Clinical Medicine, Kaohsiung Medical University and Academia Sinica, Taipei 11529, Taiwan
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Disease-modifying therapies in amyotrophic lateral sclerosis. Neuropharmacology 2020; 167:107986. [DOI: 10.1016/j.neuropharm.2020.107986] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Revised: 01/21/2020] [Accepted: 01/31/2020] [Indexed: 02/08/2023]
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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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Abstract
The use of an acetylene (ethynyl) group in medicinal chemistry coincides with the launch of the Journal of Medicinal Chemistry in 1959. Since then, the acetylene group has been broadly exploited in drug discovery and development. As a result, it has become recognized as a privileged structural feature for targeting a wide range of therapeutic target proteins, including MAO, tyrosine kinases, BACE1, steroid receptors, mGlu5 receptors, FFA1/GPR40, and HIV-1 RT. Furthermore, a terminal alkyne functionality is frequently introduced in chemical biology probes as a click handle to identify molecular targets and to assess target engagement. This Perspective is divided into three parts encompassing: (1) the physicochemical properties of the ethynyl group, (2) the advantages and disadvantages of the ethynyl group in medicinal chemistry, and (3) the impact of the ethynyl group on chemical biology approaches.
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Affiliation(s)
- Tanaji T Talele
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, New York 11439, United States
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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: 157] [Impact Index Per Article: 31.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar 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, Cochrane Neuromuscular Group. 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] [Scholar 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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Schorling DC, Pechmann A, Kirschner J. Advances in Treatment of Spinal Muscular Atrophy - New Phenotypes, New Challenges, New Implications for Care. J Neuromuscul Dis 2020; 7:1-13. [PMID: 31707373 PMCID: PMC7029319 DOI: 10.3233/jnd-190424] [Citation(s) in RCA: 140] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Spinal Muscular Atrophy (SMA) is caused by autosomal recessive mutations in SMN1 and results in the loss of motor neurons and progressive muscle weakness. The spectrum of disease severity ranges from early onset with respiratory failure during the first months of life to a mild, adult-onset type with slow rate of progression. Over the past decade, new treatment options such as splicing modulation of SMN2 and SMN1 gene replacement by gene therapy have been developed. First drugs have been approved for treatment of patients with SMA and if initiated early they can significantly modify the natural course of the disease. As a consequence, newborn screening for SMA is explored and implemented in an increasing number of countries. However, available evidence for these new treatments is often limited to a small spectrum of patients concerning age and disease stage. In this review we provide an overview of available and emerging therapies for spinal muscular atrophy and we discuss new phenotypes and associated challenges in clinical care. Collection of real-world data with standardized outcome measures will be essential to improve both the understanding of treatment effects in patients of all SMA subtypes and the basis for clinical decision-making in SMA.
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Affiliation(s)
- David C. Schorling
- Department of Neuropediatrics and Muscle Disorders, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Astrid Pechmann
- Department of Neuropediatrics and Muscle Disorders, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Janbernd Kirschner
- Department of Neuropediatrics and Muscle Disorders, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Department of Neuropediatrics, University Hospital Bonn, Germany
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Allen DG. Calcium sensitivity and muscle disease. J Physiol 2019; 597:4435-4436. [DOI: 10.1113/jp278471] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Affiliation(s)
- David G. Allen
- School of Medical SciencesFaculty of MedicineUniversity of Sydney Australia
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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: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar 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
PURPOSE OF REVIEW In this review, we discuss the clinical and genetic features of 5q spinal muscular atrophy and highlight approved and upcoming therapies. RECENT FINDINGS We emphasize that multidisciplinary care has been a key component of the improved quality and length of life seen in these individuals in the past decade. We discuss the evidence leading to the approval of nusinersen and the evidence leading to the anticipated approval of onasemnogene abeparvovec-xioi. Additional clinical therapies that are on the horizon are discussed and the importance of continued multidisciplinary care even after treatment is emphasized. The pursuit of therapies for spinal muscular atrophy is becoming a success story and continued development of biomarkers will allow for more informed therapeutic decision making and eventual cost-effective utilization of available therapies.
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Affiliation(s)
- Megan A Waldrop
- Center for Gene Therapy, Nationwide Children's Hospital, Columbus, OH, USA.,Department of Pediatrics, The Ohio State University Wexner Medical Center, Columbus, OH, USA.,Department of Neurology, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Stephen J Kolb
- Department of Neurology, The Ohio State University Wexner Medical Center, Columbus, OH, USA. .,Department of Biological Chemistry & Pharmacology, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
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Howell K, Gibbs RM, Rubin LL. Spinal Muscular Atrophy: Huge Steps. CEREBRUM : THE DANA FORUM ON BRAIN SCIENCE 2019; 2019:cer-03-19. [PMID: 32206168 PMCID: PMC7075499] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Spinal muscular atrophy is the number one genetic cause of infant death. Until recently, half the babies born with it would die before their second birthdays, their hearts and lungs becoming too weak to continue. Medical care improved the odds somewhat, but new discoveries and therapeutic developments have improved survival rates significantly-and more good news may be on the horizon.
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Prasad A, Bharathi V, Sivalingam V, Girdhar A, Patel BK. Molecular Mechanisms of TDP-43 Misfolding and Pathology in Amyotrophic Lateral Sclerosis. Front Mol Neurosci 2019; 12:25. [PMID: 30837838 PMCID: PMC6382748 DOI: 10.3389/fnmol.2019.00025] [Citation(s) in RCA: 506] [Impact Index Per Article: 84.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2018] [Accepted: 01/21/2019] [Indexed: 12/11/2022] Open
Abstract
TAR DNA binding protein 43 (TDP-43) is a versatile RNA/DNA binding protein involved in RNA-related metabolism. Hyper-phosphorylated and ubiquitinated TDP-43 deposits act as inclusion bodies in the brain and spinal cord of patients with the motor neuron diseases: amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). While the majority of ALS cases (90-95%) are sporadic (sALS), among familial ALS cases 5-10% involve the inheritance of mutations in the TARDBP gene and the remaining (90-95%) are due to mutations in other genes such as: C9ORF72, SOD1, FUS, and NEK1 etc. Strikingly however, the majority of sporadic ALS patients (up to 97%) also contain the TDP-43 protein deposited in the neuronal inclusions, which suggests of its pivotal role in the ALS pathology. Thus, unraveling the molecular mechanisms of the TDP-43 pathology seems central to the ALS therapeutics, hence, we comprehensively review the current understanding of the TDP-43's pathology in ALS. We discuss the roles of TDP-43's mutations, its cytoplasmic mis-localization and aberrant post-translational modifications in ALS. Also, we evaluate TDP-43's amyloid-like in vitro aggregation, its physiological vs. pathological oligomerization in vivo, liquid-liquid phase separation (LLPS), and potential prion-like propagation propensity of the TDP-43 inclusions. Finally, we describe the various evolving TDP-43-induced toxicity mechanisms, such as the impairment of endocytosis and mitotoxicity etc. and also discuss the emerging strategies toward TDP-43 disaggregation and ALS therapeutics.
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Affiliation(s)
| | | | | | | | - Basant K. Patel
- Department of Biotechnology, Indian Institute of Technology Hyderabad, Sangareddy, India
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