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Basak S, Biswas N, Gill J, Ashili S. Spinal Muscular Atrophy: Current Medications and Re-purposed Drugs. Cell Mol Neurobiol 2024; 44:75. [PMID: 39514016 PMCID: PMC11549153 DOI: 10.1007/s10571-024-01511-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/31/2024] [Accepted: 10/30/2024] [Indexed: 11/16/2024]
Abstract
Spinal muscular atrophy (SMA) is an autosomal recessive genetic neuromuscular disorder that is characterized by gradual muscle weakness and atrophy due to the degeneration of alpha motor neurons that are present on the anterior horn of the spinal cord. Despite the comprehensive investigations conducted by global scientists, effective treatments or interventions remain elusive. The time- and resource-intensive nature of the initial stages of drug research underscores the need for alternate strategies like drug repurposing. This review explores the repurposed drugs that have shown some improvement in treating SMA, including branaplam, riluzole, olesoxime, harmine, and prednisolone. The current strategy for medication repurposing, however, lacks systematicity and frequently depends more on serendipitous discoveries than on organized approaches. To speed up the development of successful therapeutic interventions, it is apparent that a methodical approach targeting the molecular origins of SMA is strictly required.
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Affiliation(s)
| | - Nupur Biswas
- Rhenix Lifesciences, Hyderabad, 500038, Telangana, India.
- CureScience, 5820 Oberlin Dr, Suite 202, San Diego, CA, 92121, USA.
| | - Jaya Gill
- CureScience, 5820 Oberlin Dr, Suite 202, San Diego, CA, 92121, USA
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2
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Haque US, Yokota T. Recent Progress in Gene-Targeting Therapies for Spinal Muscular Atrophy: Promises and Challenges. Genes (Basel) 2024; 15:999. [PMID: 39202360 PMCID: PMC11353366 DOI: 10.3390/genes15080999] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/28/2024] [Revised: 07/20/2024] [Accepted: 07/22/2024] [Indexed: 09/03/2024] Open
Abstract
Spinal muscular atrophy (SMA) is a severe genetic disorder characterized by the loss of motor neurons, leading to progressive muscle weakness, loss of mobility, and respiratory complications. In its most severe forms, SMA can result in death within the first two years of life if untreated. The condition arises from mutations in the SMN1 (survival of motor neuron 1) gene, causing a deficiency in the survival motor neuron (SMN) protein. Humans possess a near-identical gene, SMN2, which modifies disease severity and is a primary target for therapies. Recent therapeutic advancements include antisense oligonucleotides (ASOs), small molecules targeting SMN2, and virus-mediated gene replacement therapy delivering a functional copy of SMN1. Additionally, recognizing SMA's broader phenotype involving multiple organs has led to the development of SMN-independent therapies. Evidence now indicates that SMA affects multiple organ systems, suggesting the need for SMN-independent treatments along with SMN-targeting therapies. No single therapy can cure SMA; thus, combination therapies may be essential for comprehensive treatment. This review addresses the SMA etiology, the role of SMN, and provides an overview of the rapidly evolving therapeutic landscape, highlighting current achievements and future directions.
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Affiliation(s)
- Umme Sabrina Haque
- Department of Neuroscience, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada;
- Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada
| | - Toshifumi Yokota
- Department of Neuroscience, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada;
- Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada
- The Friends of Garrett Cumming Research & Muscular Dystrophy Canada HM Toupin Neurological Science Research, Edmonton, AB T6G 2H7, Canada
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3
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Bagga P, Singh S, Ram G, Kapil S, Singh A. Diving into progress: a review on current therapeutic advancements in spinal muscular atrophy. Front Neurol 2024; 15:1368658. [PMID: 38854961 PMCID: PMC11157111 DOI: 10.3389/fneur.2024.1368658] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/11/2024] [Accepted: 04/29/2024] [Indexed: 06/11/2024] Open
Abstract
Spinal muscular atrophy (SMA) is an uncommon disorder associated with genes characterized by the gradual weakening and deterioration of muscles, often leading to substantial disability and premature mortality. Over the past decade, remarkable strides have been made in the field of SMA therapeutics, revolutionizing the landscape of patient care. One pivotal advancement is the development of gene-targeted therapies, such as nusinersen, onasemnogene abeparvovec and risdiplam which have demonstrated unprecedented efficacy in slowing disease progression. These therapies aim to address the root cause of SMA by targeting the survival motor neuron (SMN) gene, effectively restoring deficient SMN protein levels. The advent of these innovative approaches has transformed the prognosis for many SMA patients, offering a glimmer of hope where there was once limited therapeutic recourse. Furthermore, the emergence of small molecule compounds and RNA-targeting strategies has expanded the therapeutic arsenal against SMA. These novel interventions exhibit diverse mechanisms of action, including SMN protein stabilization and modulation of RNA splicing, showcasing the multifaceted nature of SMA treatment research. Collective efforts of pharmaceutical industries, research centers, and patient advocacy groups have played an important role in expediting the translation of scientific discoveries into visible clinical benefits. This review not only highlights the remarkable progress achieved in SMA therapeutics but also generates the ray of hope for the ongoing efforts required to enhance accessibility, optimize treatment strategies, rehabilitation (care and therapies) and ultimately pave the way for an improved quality of life for individuals affected by SMA.
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Affiliation(s)
- Pankaj Bagga
- School of Bioengineering & Biosciences, Lovely Professional University (LPU), Phagwara, India
| | - Sudhakar Singh
- School of Bioengineering & Biosciences, Lovely Professional University (LPU), Phagwara, India
| | - Gobind Ram
- PG Department of Biotechnology, Layalpur Khalsa College, Jalandhar, India
| | - Subham Kapil
- Department of Zoology, DAV College Jalandhar, Jalandhar, India
| | - Avtar Singh
- School of Electrical Engineering and Computing (SoEEC), Adama Science and Technology University (AS-TU), Adama, Ethiopia
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4
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Kolić D, Šinko G, Jean L, Chioua M, Dias J, Marco-Contelles J, Kovarik Z. Cholesterol Oxime Olesoxime Assessed as a Potential Ligand of Human Cholinesterases. Biomolecules 2024; 14:588. [PMID: 38785995 PMCID: PMC11117805 DOI: 10.3390/biom14050588] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/08/2024] [Revised: 05/10/2024] [Accepted: 05/14/2024] [Indexed: 05/25/2024] Open
Abstract
Olesoxime, a cholesterol derivative with an oxime group, possesses the ability to cross the blood-brain barrier, and has demonstrated excellent safety and tolerability properties in clinical research. These characteristics indicate it may serve as a centrally active ligand of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), whose disruption of activity with organophosphate compounds (OP) leads to uncontrolled excitation and potentially life-threatening symptoms. To evaluate olesoxime as a binding ligand and reactivator of human AChE and BChE, we conducted in vitro kinetic studies with the active metabolite of insecticide parathion, paraoxon, and the warfare nerve agents sarin, cyclosarin, tabun, and VX. Our results showed that both enzymes possessed a binding affinity for olesoxime in the mid-micromolar range, higher than the antidotes in use (i.e., 2-PAM, HI-6, etc.). While olesoxime showed a weak ability to reactivate AChE, cyclosarin-inhibited BChE was reactivated with an overall reactivation rate constant comparable to that of standard oxime HI-6. Moreover, in combination with the oxime 2-PAM, the reactivation maximum increased by 10-30% for cyclosarin- and sarin-inhibited BChE. Molecular modeling revealed productive interactions between olesoxime and BChE, highlighting olesoxime as a potentially BChE-targeted therapy. Moreover, it might be added to OP poisoning treatment to increase the efficacy of BChE reactivation, and its cholesterol scaffold could provide a basis for the development of novel oxime antidotes.
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Affiliation(s)
- Dora Kolić
- Division of Toxicology, Institute for Medical Research and Occupational Health, 10001 Zagreb, Croatia; (D.K.); (G.Š.)
| | - Goran Šinko
- Division of Toxicology, Institute for Medical Research and Occupational Health, 10001 Zagreb, Croatia; (D.K.); (G.Š.)
| | - Ludovic Jean
- Université Paris Cité, CNRS, Inserm, CiTCoM, F-75006 Paris, France;
| | - Mourad Chioua
- Institute of General Organic Chemistry (CSIC), 28006 Madrid, Spain; (M.C.); (J.M.-C.)
| | - José Dias
- Institut de Recherche Biomédicale des Armées, 91220 Brétigny-sur-Orge, Paris, France;
| | - José Marco-Contelles
- Institute of General Organic Chemistry (CSIC), 28006 Madrid, Spain; (M.C.); (J.M.-C.)
| | - Zrinka Kovarik
- Division of Toxicology, Institute for Medical Research and Occupational Health, 10001 Zagreb, Croatia; (D.K.); (G.Š.)
- Faculty of Science, University of Zagreb, 10000 Zagreb, Croatia
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5
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Ponomarev AS, Chulpanova DS, Yanygina LM, Solovyeva VV, Rizvanov AA. Emerging Gene Therapy Approaches in the Management of Spinal Muscular Atrophy (SMA): An Overview of Clinical Trials and Patent Landscape. Int J Mol Sci 2023; 24:13743. [PMID: 37762045 PMCID: PMC10530942 DOI: 10.3390/ijms241813743] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/30/2023] [Revised: 08/28/2023] [Accepted: 08/29/2023] [Indexed: 09/29/2023] Open
Abstract
Spinal muscular atrophy (SMA) is a rare autosomal recessive neuromuscular disease that is characterized by progressive muscle atrophy (degeneration), including skeletal muscles in charge of the ability to move. SMA is caused by defects in the SMN1 gene (Survival of Motor Neuron 1) which encodes a protein crucial for the survival and functionality of neuron cells called motor neurons. Decreased level of functioning SMN protein leads to progressive degeneration of alpha-motor neurons performing muscular motility. Over the past decade, many strategies directed for SMN-level-restoration emerged, such as gene replacement therapy (GRT), CRISPR/Cas9-based gene editing, usage of antisense oligonucleotides and small-molecule modulators, and all have been showing their perspectives in SMA therapy. In this review, modern SMA therapy strategies are described, making it a valuable resource for researchers, clinicians and everyone interested in the progress of therapy of this serious disorder.
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Affiliation(s)
| | | | | | | | - Albert A. Rizvanov
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia; (A.S.P.); (D.S.C.); (L.M.Y.); (V.V.S.)
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Li Q, Kang C. Targeting RNA-binding proteins with small molecules: Perspectives, pitfalls and bifunctional molecules. FEBS Lett 2023; 597:2031-2047. [PMID: 37519019 DOI: 10.1002/1873-3468.14710] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/01/2023] [Revised: 06/26/2023] [Accepted: 06/28/2023] [Indexed: 08/01/2023]
Abstract
RNA-binding proteins (RBPs) play vital roles in organisms through binding with RNAs to regulate their functions. Small molecules affecting the function of RBPs have been developed, providing new avenues for drug discovery. Herein, we describe the perspectives on developing small molecule regulators of RBPs. The following types of small molecule modulators are of great interest in drug discovery: small molecules binding to RBPs to affect interactions with RNA molecules, bifunctional molecules binding to RNA or RBP to influence their interactions, and other types of molecules that affect the stability of RNA or RBPs. Moreover, we emphasize that the bifunctional molecules may play important roles in small molecule development to overcome the challenges encountered in the process of drug discovery.
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Affiliation(s)
- Qingxin Li
- Guangdong Provincial Engineering Laboratory of Biomass High Value Utilization, Institute of Biological and Medical Engineering, Guangdong Academy of Sciences, Guangzhou, China
| | - Congbao Kang
- Experimental Drug Development Centre, Agency for Science, Technology and Research, Singapore, Singapore
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7
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Meanwell NA. The pyridazine heterocycle in molecular recognition and drug discovery. Med Chem Res 2023; 32:1-69. [PMID: 37362319 PMCID: PMC10015555 DOI: 10.1007/s00044-023-03035-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/07/2023] [Accepted: 02/06/2023] [Indexed: 03/17/2023]
Abstract
The pyridazine ring is endowed with unique physicochemical properties, characterized by weak basicity, a high dipole moment that subtends π-π stacking interactions and robust, dual hydrogen-bonding capacity that can be of importance in drug-target interactions. These properties contribute to unique applications in molecular recognition while the inherent polarity, low cytochrome P450 inhibitory effects and potential to reduce interaction of a molecule with the cardiac hERG potassium channel add additional value in drug discovery and development. The recent approvals of the gonadotropin-releasing hormone receptor antagonist relugolix (24) and the allosteric tyrosine kinase 2 inhibitor deucravacitinib (25) represent the first examples of FDA-approved drugs that incorporate a pyridazine ring. In this review, the properties of the pyridazine ring are summarized in comparison to the other azines and its potential in drug discovery is illustrated through vignettes that explore applications that take advantage of the inherent physicochemical properties as an approach to solving challenges associated with candidate optimization. Graphical Abstract
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Sabuncu Gürses G, Erdem SS, Saçan MT. A QSAR study to predict the survival motor neuron promoter activity of candidate diaminoquinazoline derivatives for the potential treatment of spinal muscular atrophy. SAR AND QSAR IN ENVIRONMENTAL RESEARCH 2023; 34:247-266. [PMID: 37125536 DOI: 10.1080/1062936x.2023.2200975] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Academic Contribution Register] [Indexed: 05/03/2023]
Abstract
Spinal Muscular Atrophy is a genetic neuromuscular disease that leads to muscle weakness and atrophy and it is characterized by the loss of α-motor neurons in the spinal cord's anterior horn cells. The disease appears due to low levels of the survival motor neuron protein. There are continuing clinical trials for the treatment of Spinal Muscular Atrophy. Quinazoline-based compounds are promising since they were tested on fibroblasts derived from the patients and found to increase the survival motor neuron protein levels. In this study, using multiple linear regression, we generated robust and valid quantitative structure- activity relationship models to predict the survival motor neuron-2 promoter activity of the new candidate compounds using the experimental survival motor neuron-2 promoter activity values of 2,4-diaminoquinazoline derivatives taken from the literature. The novel compounds designed by combining the pyrido[1,2-α]pyrimidin-4-one moeity of the known drug Risdiplam with that of 2,4 - diaminoquinazoline scaffold were predicted to exhibit strong promoter activities.
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Affiliation(s)
- G Sabuncu Gürses
- Chemistry Department, Faculty of Science, Marmara University, Istanbul, Turkey
| | - S S Erdem
- Chemistry Department, Faculty of Science, Marmara University, Istanbul, Turkey
| | - M T Saçan
- Institute of Environmental Sciences, Bogaziçi University, Istanbul, Turkey
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9
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Lejman J, Panuciak K, Nowicka E, Mastalerczyk A, Wojciechowska K, Lejman M. Gene Therapy in ALS and SMA: Advances, Challenges and Perspectives. Int J Mol Sci 2023; 24:ijms24021130. [PMID: 36674643 PMCID: PMC9860634 DOI: 10.3390/ijms24021130] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/28/2022] [Revised: 12/31/2022] [Accepted: 01/04/2023] [Indexed: 01/11/2023] Open
Abstract
Gene therapy is defined as the administration of genetic material to modify, manipulate gene expression or alter the properties of living cells for therapeutic purposes. Recent advances and improvements in this field have led to many breakthroughs in the treatment of various diseases. As a result, there has been an increasing interest in the use of these therapies to treat motor neuron diseases (MNDs), for which many potential molecular targets have been discovered. MNDs are neurodegenerative disorders that, in their most severe forms, can lead to respiratory failure and death, for instance, spinal muscular atrophy (SMA) or amyotrophic lateral sclerosis (ALS). Despite the fact that SMA has been known for many years, it is still one of the most common genetic diseases causing infant mortality. The introduction of drugs based on ASOs-nusinersen; small molecules-risdiplam; and replacement therapy (GRT)-Zolgensma has shown a significant improvement in both event-free survival and the quality of life of patients after using these therapies in the available trial results. Although there is still no drug that would effectively alleviate the course of the disease in ALS, the experience gained from SMA gene therapy gives hope for a positive outcome of the efforts to produce an effective and safe drug. The aim of this review is to present current progress and prospects for the use of gene therapy in the treatment of both SMA and ALS.
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Affiliation(s)
- Jan Lejman
- Student Scientific Society, Independent Laboratory of Genetic Diagnostics, Medical University of Lublin, 20-093 Lublin, Poland
- Correspondence:
| | - Kinga Panuciak
- Student Scientific Society, Independent Laboratory of Genetic Diagnostics, Medical University of Lublin, 20-093 Lublin, Poland
| | - Emilia Nowicka
- Student Scientific Society, Independent Laboratory of Genetic Diagnostics, Medical University of Lublin, 20-093 Lublin, Poland
| | - Angelika Mastalerczyk
- Student Scientific Society, Independent Laboratory of Genetic Diagnostics, Medical University of Lublin, 20-093 Lublin, Poland
| | - Katarzyna Wojciechowska
- Independent Laboratory of Genetic Diagnostics, Medical University of Lublin, 20-093 Lublin, Poland
| | - Monika Lejman
- Independent Laboratory of Genetic Diagnostics, Medical University of Lublin, 20-093 Lublin, Poland
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Morelli C, Ingrasciotta G, Jacoby D, Masri A, Olivotto I. Sarcomere protein modulation: The new frontier in cardiovascular medicine and beyond. Eur J Intern Med 2022; 102:1-7. [PMID: 35534374 DOI: 10.1016/j.ejim.2022.04.020] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 02/15/2022] [Revised: 04/14/2022] [Accepted: 04/17/2022] [Indexed: 01/10/2023]
Abstract
Over the past decade, the constant progress in science and technologies has provided innovative drug molecules that address specific disease mechanisms thus opening the era of drugs targeting the underlying pathophysiology of the disease. In this scenario, a new paradigm of modulation has emerged, following the development of small molecules capable of interfering with sarcomere contractile proteins. Potential applications include heart muscle disease and various forms of heart failure, although promising targets also include conditions affecting the skeletal muscle, such as degenerative neuromuscular diseases. In cardiac patients, a cardiac myosin stimulator, omecamtiv mecarbil, has shown efficacy in heart failure with reduced systolic function, lowering heart failure related events or cardiovascular death, while two inhibitors, mavacamten and aficamten, in randomized trials targeting hypertrophic cardiomyopathy, have been shown to reduce hypercontractility and left ventricular outflow obstruction improving functional capacity. Based on years of intensive basic and translational research, these agents are the prototypes of active pipelines promising to deliver an array of molecules in the near future. We here review the available evidence and future perspectives of myosin modulation in cardiovascular medicine.
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Affiliation(s)
- Cristina Morelli
- Azienda Ospedaliera Universitaria Careggi and University of Florence, Florence, Italy
| | - Gessica Ingrasciotta
- Azienda Ospedaliera Universitaria Careggi and University of Florence, Florence, Italy
| | - Daniel Jacoby
- Department of Internal Medicine, Section of Cardiovascular Medicine, Yale University, New Haven, CT, USA
| | - Ahmad Masri
- Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR, USA
| | - Iacopo Olivotto
- Azienda Ospedaliera Universitaria Careggi and University of Florence, Florence, Italy.
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Kanda S, Moulton E, Butchbach MER. Effects of Inhibitors of SLC9A-Type Sodium-Proton Exchangers on Survival Motor Neuron 2 ( SMN2) mRNA Splicing and Expression. Mol Pharmacol 2022; 102:92-105. [PMID: 35667685 PMCID: PMC9341265 DOI: 10.1124/molpharm.122.000529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/15/2022] [Accepted: 05/09/2022] [Indexed: 11/22/2022] Open
Abstract
Spinal muscular atrophy (SMA) is an autosomal recessive, pediatric-onset disorder caused by the loss of spinal motor neurons, thereby leading to muscle atrophy. SMA is caused by the loss of or mutations in the survival motor neuron 1 (SMN1) gene. SMN1 is duplicated in humans to give rise to the paralogous survival motor neuron 2 (SMN2) gene. This paralog is nearly identical except for a cytosine to thymine transition within an exonic splicing enhancer element within exon 7. As a result, the majority of SMN2 transcripts lack exon 7 (SMNΔ7), which produces a truncated and unstable SMN protein. Since SMN2 copy number is inversely related to disease severity, it is a well established target for SMA therapeutics development. 5-(N-ethyl-N-isopropyl)amiloride (EIPA), an inhibitor of sodium/proton exchangers (NHEs), has previously been shown to increase exon 7 inclusion and SMN protein levels in SMA cells. In this study, NHE inhibitors were evaluated for their ability to modulate SMN2 expression. EIPA as well as 5-(N,N-hexamethylene)amiloride (HMA) increase exon 7 inclusion in SMN2 splicing reporter lines as well as in SMA fibroblasts. The EIPA-induced exon 7 inclusion occurs via a unique mechanism that does not involve previously identified splicing factors. Transcriptome analysis identified novel targets, including TIA1 and FABP3, for further characterization. EIPA and HMA are more selective at inhibiting the NHE5 isoform, which is expressed in fibroblasts as well as in neuronal cells. These results show that NHE5 inhibition increases SMN2 expression and may be a novel target for therapeutics development. SIGNIFICANCE STATEMENT: This study demonstrates a molecular mechanism by which inhibitors of the sodium-protein exchanger increase the alternative splicing of SMN2 in spinal muscular atrophy cells. NHE5 selective inhibitors increase the inclusion of full-length SMN2 mRNAs by targeting TIA1 and FABP3 expression, which is distinct from other small molecule regulators of SMN2 alternative splicing. This study provides a novel means to increase full-length SMN2 expression and a novel target for therapeutics development.
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Affiliation(s)
- Sambee Kanda
- Division of Neurology, Nemours Children's Hospital Delaware, Wilmington, Delaware (S.K., E.M., M.E.R.B.); Department of Biological Sciences, University of Delaware, Newark, Delaware (S.K., M.E.R.B.); Center for Pediatric Research, Nemours Biomedical Research, Nemours Children's Hospital Delaware, Wilmington, Delaware (M.E.R.B.); and Department of Pediatrics, Thomas Jefferson University, Philadelphia, Pennsylvania (M.E.R.B.)
| | - Emily Moulton
- Division of Neurology, Nemours Children's Hospital Delaware, Wilmington, Delaware (S.K., E.M., M.E.R.B.); Department of Biological Sciences, University of Delaware, Newark, Delaware (S.K., M.E.R.B.); Center for Pediatric Research, Nemours Biomedical Research, Nemours Children's Hospital Delaware, Wilmington, Delaware (M.E.R.B.); and Department of Pediatrics, Thomas Jefferson University, Philadelphia, Pennsylvania (M.E.R.B.)
| | - Matthew E R Butchbach
- Division of Neurology, Nemours Children's Hospital Delaware, Wilmington, Delaware (S.K., E.M., M.E.R.B.); Department of Biological Sciences, University of Delaware, Newark, Delaware (S.K., M.E.R.B.); Center for Pediatric Research, Nemours Biomedical Research, Nemours Children's Hospital Delaware, Wilmington, Delaware (M.E.R.B.); and Department of Pediatrics, Thomas Jefferson University, Philadelphia, Pennsylvania (M.E.R.B.)
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12
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Mahmud Z, Tikunova S, Belevych N, Wagg CS, Zhabyeyev P, Liu PB, Rasicci DV, Yengo CM, Oudit GY, Lopaschuk GD, Reiser PJ, Davis JP, Hwang PM. Small Molecule RPI-194 Stabilizes Activated Troponin to Increase the Calcium Sensitivity of Striated Muscle Contraction. Front Physiol 2022; 13:892979. [PMID: 35755445 PMCID: PMC9213791 DOI: 10.3389/fphys.2022.892979] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/09/2022] [Accepted: 05/10/2022] [Indexed: 11/13/2022] Open
Abstract
Small molecule cardiac troponin activators could potentially enhance cardiac muscle contraction in the treatment of systolic heart failure. We designed a small molecule, RPI-194, to bind cardiac/slow skeletal muscle troponin (Cardiac muscle and slow skeletal muscle share a common isoform of the troponin C subunit.) Using solution NMR and stopped flow fluorescence spectroscopy, we determined that RPI-194 binds to cardiac troponin with a dissociation constant KD of 6-24 μM, stabilizing the activated complex between troponin C and the switch region of troponin I. The interaction between RPI-194 and troponin C is weak (KD 311 μM) in the absence of the switch region. RPI-194 acts as a calcium sensitizer, shifting the pCa50 of isometric contraction from 6.28 to 6.99 in mouse slow skeletal muscle fibers and from 5.68 to 5.96 in skinned cardiac trabeculae at 100 μM concentration. There is also some cross-reactivity with fast skeletal muscle fibers (pCa50 increases from 6.27 to 6.52). In the slack test performed on the same skinned skeletal muscle fibers, RPI-194 slowed the velocity of unloaded shortening at saturating calcium concentrations, suggesting that it slows the rate of actin-myosin cross-bridge cycling under these conditions. However, RPI-194 had no effect on the ATPase activity of purified actin-myosin. In isolated unloaded mouse cardiomyocytes, RPI-194 markedly decreased the velocity and amplitude of contractions. In contrast, cardiac function was preserved in mouse isolated perfused working hearts. In summary, the novel troponin activator RPI-194 acts as a calcium sensitizer in all striated muscle types. Surprisingly, it also slows the velocity of unloaded contraction, but the cause and significance of this is uncertain at this time. RPI-194 represents a new class of non-specific troponin activator that could potentially be used either to enhance cardiac muscle contractility in the setting of systolic heart failure or to enhance skeletal muscle contraction in neuromuscular disorders.
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Affiliation(s)
- Zabed Mahmud
- Department of Biochemistry, University of Alberta, Edmonton, AB, Canada
| | - Svetlana Tikunova
- Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH, United States
| | - Natalya Belevych
- Division of Biosciences, College of Dentistry, The Ohio State University, Columbus, OH, United States
| | - Cory S Wagg
- Department of Pediatrics, University of Alberta, Edmonton, AB, Canada
| | - Pavel Zhabyeyev
- Department of Medicine, University of Alberta, Edmonton, AB, Canada
| | - Philip B Liu
- Department of Medicine, University of Alberta, Edmonton, AB, Canada
| | - David V Rasicci
- Department of Cellular and Molecular Physiology, College of Medicine, Pennsylvania State University, University Park, PA, United States
| | - Christopher M Yengo
- Department of Cellular and Molecular Physiology, College of Medicine, Pennsylvania State University, University Park, PA, United States
| | - Gavin Y Oudit
- Department of Medicine, University of Alberta, Edmonton, AB, Canada
| | - Gary D Lopaschuk
- Department of Pediatrics, University of Alberta, Edmonton, AB, Canada
| | - Peter J Reiser
- Division of Biosciences, College of Dentistry, The Ohio State University, Columbus, OH, United States
| | - Jonathan P Davis
- Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH, United States
| | - Peter M Hwang
- Department of Biochemistry, University of Alberta, Edmonton, AB, Canada.,Department of Medicine, University of Alberta, Edmonton, AB, Canada
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杨 东. Recent research on the treatment of spinal muscular atrophy. ZHONGGUO DANG DAI ER KE ZA ZHI = CHINESE JOURNAL OF CONTEMPORARY PEDIATRICS 2022; 24:204-209. [PMID: 35209987 PMCID: PMC8884051 DOI: 10.7499/j.issn.1008-8830.2110041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Academic Contribution Register] [Received: 10/12/2021] [Accepted: 12/20/2021] [Indexed: 01/24/2023]
Abstract
Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease characterized by progressive muscular weakness and atrophy. SMA, as an inherited disease, is the leading cause of death in infants and young children. Rapid progress has been made in the research field of SMA in recent years, and some related treatment drugs have been successfully approved for marketing. This article reviews the recent research advances in the treatment of SMA.
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14
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Aslesh T, Yokota T. Restoring SMN Expression: An Overview of the Therapeutic Developments for the Treatment of Spinal Muscular Atrophy. Cells 2022; 11:417. [PMID: 35159227 PMCID: PMC8834523 DOI: 10.3390/cells11030417] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/20/2021] [Revised: 01/14/2022] [Accepted: 01/24/2022] [Indexed: 02/06/2023] Open
Abstract
Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder and one of the most common genetic causes of infant death. It is characterized by progressive weakness of the muscles, loss of ambulation, and death from respiratory complications. SMA is caused by the homozygous deletion or mutations in the survival of the motor neuron 1 (SMN1) gene. Humans, however, have a nearly identical copy of SMN1 known as the SMN2 gene. The severity of the disease correlates inversely with the number of SMN2 copies present. SMN2 cannot completely compensate for the loss of SMN1 in SMA patients because it can produce only a fraction of functional SMN protein. SMN protein is ubiquitously expressed in the body and has a variety of roles ranging from assembling the spliceosomal machinery, autophagy, RNA metabolism, signal transduction, cellular homeostasis, DNA repair, and recombination. Motor neurons in the anterior horn of the spinal cord are extremely susceptible to the loss of SMN protein, with the reason still being unclear. Due to the ability of the SMN2 gene to produce small amounts of functional SMN, two FDA-approved treatment strategies, including an antisense oligonucleotide (AON) nusinersen and small-molecule risdiplam, target SMN2 to produce more functional SMN. On the other hand, Onasemnogene abeparvovec (brand name Zolgensma) is an FDA-approved adeno-associated vector 9-mediated gene replacement therapy that can deliver a copy of the human SMN1. In this review, we summarize the SMA etiology, the role of SMN, and discuss the challenges of the therapies that are approved for SMA treatment.
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Affiliation(s)
- Tejal Aslesh
- Neuroscience and Mental Health Institute, Faculty of Medicine and Dentistry, University of Alberta, 116 St. and 85 Ave., Edmonton, AB T6G 2E1, Canada;
| | - Toshifumi Yokota
- Neuroscience and Mental Health Institute, Faculty of Medicine and Dentistry, University of Alberta, 116 St. and 85 Ave., Edmonton, AB T6G 2E1, Canada;
- Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, 116 St. and 85 Ave., Edmonton, AB T6G 2E1, Canada
- The Friends of Garret Cumming Research and Muscular Dystrophy Canada HM Toupin Neurological Science Research Chair, 8812 112 St., Edmonton, AB T6G 2H7, Canada
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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] [Academic Contribution 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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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] [Academic Contribution 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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17
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Abstract
![]()
RNA is an emerging
target for drug discovery. However, like for
proteins, not all RNA binding sites are equally suited to be addressed
with conventional drug-like ligands. To this end, we have developed
the structure-based druggability predictor DrugPred_RNA to identify
druggable RNA binding sites. Due to the paucity of annotated RNA binding
sites, the predictor was trained on protein pockets, albeit using
only descriptors that can be calculated for both RNA and protein binding
sites. DrugPred_RNA performed well in discriminating druggable from
less druggable binding sites for the protein set and delivered predictions
for selected RNA binding sites that agreed with manual assignment.
In addition, most drug-like ligands contained in an RNA test set were
found in pockets predicted to be druggable, further adding confidence
to the performance of DrugPred_RNA. The method is robust against conformational
and sequence changes in the binding sites and can contribute to direct
drug discovery efforts for RNA targets.
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Affiliation(s)
- Illimar Hugo Rekand
- Department of Biomedicine, University of Bergen, Jonas Lies Vei, 5020 Bergen, Norway
| | - Ruth Brenk
- Department of Biomedicine, University of Bergen, Jonas Lies Vei, 5020 Bergen, Norway
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18
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Behera B. Nusinersen, an exon 7 inclusion drug for spinal muscular atrophy: A minireview. World J Meta-Anal 2021; 9:277-285. [DOI: 10.13105/wjma.v9.i3.277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 12/03/2020] [Revised: 05/20/2021] [Accepted: 06/17/2021] [Indexed: 02/06/2023] Open
Abstract
Spinal muscular atrophy is an autosomal recessive neuromuscular disease with incidence of 1 in 5000 to 10000 live births and is produced by homozygous deletion of exons 7 and 8 in the SMN1 gene. The SMN1 and SMN2 genes encode the survival motor neuron protein, a crucial protein for the preservation of motor neurons. Use of the newer drug, Nusinersen, from early infancy has shown improvement in clinical outcomes of spinal muscular atrophy patients.
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Affiliation(s)
- Bijaylaxmi Behera
- Department of Neonatology, Chaitanya Hospital, Chandigarh 160044, India
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19
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Axford J, Sung MJ, Manchester J, Chin D, Jain M, Shin Y, Dix I, Hamann LG, Cheung AK, Sivasankaran R, Briner K, Dales NA, Hurley B. Use of Intramolecular 1,5-Sulfur-Oxygen and 1,5-Sulfur-Halogen Interactions in the Design of N-Methyl-5-aryl- N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine SMN2 Splicing Modulators. J Med Chem 2021; 64:4744-4761. [PMID: 33822618 DOI: 10.1021/acs.jmedchem.0c02173] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/17/2022]
Abstract
Spinal muscular atrophy (SMA) is a debilitating neuromuscular disease caused by low levels of functional survival motor neuron protein (SMN) resulting from a deletion or loss of function mutation of the survival motor neuron 1 (SMN1) gene. Branaplam (1) elevates levels of full-length SMN protein in vivo by modulating the splicing of the related gene SMN2 to enhance the exon-7 inclusion and increase levels of the SMN. The intramolecular hydrogen bond present in the 2-hydroxyphenyl pyridazine core of 1 enforces a planar conformation of the biaryl system and is critical for the compound activity. Scaffold morphing revealed that the pyridazine could be replaced by a 1,3,4-thiadiazole, which provided additional opportunities for a conformational constraint of the biaryl through intramolecular 1,5-sulfur-oxygen (S···O) or 1,5-sulfur-halogen (S···X) noncovalent interactions. Compound 26, which incorporates a 2-fluorophenyl thiadiazole motif, demonstrated a greater than 50% increase in production of full-length SMN protein in a mouse model of SMA.
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Affiliation(s)
- Jake Axford
- Novartis Institutes for BioMedical Research, 181 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
| | - Moo Je Sung
- Novartis Institutes for BioMedical Research, 181 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
| | - John Manchester
- Novartis Institutes for BioMedical Research, 181 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
| | - Donovan Chin
- Novartis Institutes for BioMedical Research, 181 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
| | - Monish Jain
- Novartis Institutes for BioMedical Research, 181 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
| | - Youngah Shin
- Novartis Institutes for BioMedical Research, 181 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
| | - Ina Dix
- Novartis Institutes for BioMedical Research, 181 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
| | - Lawrence G Hamann
- Novartis Institutes for BioMedical Research, 181 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
| | - Atwood K Cheung
- Novartis Institutes for BioMedical Research, 181 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
| | - Rajeev Sivasankaran
- Novartis Institutes for BioMedical Research, 181 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
| | - Karin Briner
- Novartis Institutes for BioMedical Research, 181 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
| | - Natalie A Dales
- Novartis Institutes for BioMedical Research, 181 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
| | - Brian Hurley
- Novartis Institutes for BioMedical Research, 181 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
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20
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Menduti G, Rasà DM, Stanga S, Boido M. Drug Screening and Drug Repositioning as Promising Therapeutic Approaches for Spinal Muscular Atrophy Treatment. Front Pharmacol 2020; 11:592234. [PMID: 33281605 PMCID: PMC7689316 DOI: 10.3389/fphar.2020.592234] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/06/2020] [Accepted: 09/29/2020] [Indexed: 12/12/2022] Open
Abstract
Spinal muscular atrophy (SMA) is the most common genetic disease affecting infants and young adults. Due to mutation/deletion of the survival motor neuron (SMN) gene, SMA is characterized by the SMN protein lack, resulting in motor neuron impairment, skeletal muscle atrophy and premature death. Even if the genetic causes of SMA are well known, many aspects of its pathogenesis remain unclear and only three drugs have been recently approved by the Food and Drug Administration (Nusinersen-Spinraza; Onasemnogene abeparvovec or AVXS-101-Zolgensma; Risdiplam-Evrysdi): although assuring remarkable results, the therapies show some important limits including high costs, still unknown long-term effects, side effects and disregarding of SMN-independent targets. Therefore, the research of new therapeutic strategies is still a hot topic in the SMA field and many efforts are spent in drug discovery. In this review, we describe two promising strategies to select effective molecules: drug screening (DS) and drug repositioning (DR). By using compounds libraries of chemical/natural compounds and/or Food and Drug Administration-approved substances, DS aims at identifying new potentially effective compounds, whereas DR at testing drugs originally designed for the treatment of other pathologies. The drastic reduction in risks, costs and time expenditure assured by these strategies make them particularly interesting, especially for those diseases for which the canonical drug discovery process would be long and expensive. Interestingly, among the identified molecules by DS/DR in the context of SMA, besides the modulators of SMN2 transcription, we highlighted a convergence of some targeted molecular cascades contributing to SMA pathology, including cell death related-pathways, mitochondria and cytoskeleton dynamics, neurotransmitter and hormone modulation.
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Affiliation(s)
| | | | | | - Marina Boido
- Department of Neuroscience Rita Levi Montalcini, Neuroscience Institute Cavalieri Ottolenghi, University of Turin, Turin, Italy
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21
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Meyer SM, Williams CC, Akahori Y, Tanaka T, Aikawa H, Tong Y, Childs-Disney JL, Disney MD. Small molecule recognition of disease-relevant RNA structures. Chem Soc Rev 2020; 49:7167-7199. [PMID: 32975549 PMCID: PMC7717589 DOI: 10.1039/d0cs00560f] [Citation(s) in RCA: 102] [Impact Index Per Article: 20.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/14/2022]
Abstract
Targeting RNAs with small molecules represents a new frontier in drug discovery and development. The rich structural diversity of folded RNAs offers a nearly unlimited reservoir of targets for small molecules to bind, similar to small molecule occupancy of protein binding pockets, thus creating the potential to modulate human biology. Although the bacterial ribosome has historically been the most well exploited RNA target, advances in RNA sequencing technologies and a growing understanding of RNA structure have led to an explosion of interest in the direct targeting of human pathological RNAs. This review highlights recent advances in this area, with a focus on the design of small molecule probes that selectively engage structures within disease-causing RNAs, with micromolar to nanomolar affinity. Additionally, we explore emerging RNA-target strategies, such as bleomycin A5 conjugates and ribonuclease targeting chimeras (RIBOTACs), that allow for the targeted degradation of RNAs with impressive potency and selectivity. The compounds discussed in this review have proven efficacious in human cell lines, patient-derived cells, and pre-clinical animal models, with one compound currently undergoing a Phase II clinical trial and another that recently garnerd FDA-approval, indicating a bright future for targeted small molecule therapeutics that affect RNA function.
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Affiliation(s)
- Samantha M Meyer
- Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA.
| | - Christopher C Williams
- Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA.
| | - Yoshihiro Akahori
- Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA.
| | - Toru Tanaka
- Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA.
| | - Haruo Aikawa
- Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA.
| | - Yuquan Tong
- Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA.
| | - Jessica L Childs-Disney
- Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA.
| | - Matthew D Disney
- Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA.
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22
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Masoudi M, Bereshneh AH, Rasoulinezhad M, Ashrafi MR, Garshasbi M, Tavasoli AR. Leukoencephalopathy in Al-Raqad syndrome: Expanding the clinical and neuroimaging features caused by a biallelic novel missense variant in DCPS. Am J Med Genet A 2020; 182:2391-2398. [PMID: 32770650 DOI: 10.1002/ajmg.a.61776] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/26/2019] [Revised: 05/05/2020] [Accepted: 05/07/2020] [Indexed: 11/11/2022]
Abstract
Al-Raqad syndrome (ARS) is a rare autosomal recessive congenital disorder, associated mainly with developmental delay, and intellectual disability. This syndrome is caused by mutations in DCPS, encoding scavenger mRNA decapping enzyme, which plays a role in the 3-prime-end mRNA decay pathway. Whole-exome sequencing was performed on an offspring of a consanguineous family presenting with developmental delay, intellectual disability, growth retardation, mild craniofacial abnormalities, cerebral and cerebellar atrophy, and white matter diffuse hypomyelination pattern. A novel biallelic missense variant, c.918G>C p. (Glu306Asp), in the DCPS gene was identified which was confirmed by sanger sequencing and segregation analysis subsequently. Few cases of ARS have been described up to now, and this study represents a 7-years-old boy presenting with central and peripheral nervous system impaired myelination in addition to ocular and dental manifestation, therefore outstretch both neuroimaging and clinical findings of this ultra-rare syndrome.
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Affiliation(s)
- Maryam Masoudi
- Myelin Disorders Clinic, Pediatric Neurology Division, Children's Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Hosseini Bereshneh
- Prenatal Diagnosis and Genetic Research Center, Dastgheib Hospital, Shiraz University of Medical Sciences, Shiraz, Iran.,Department of Medical Genetics, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Maryam Rasoulinezhad
- Myelin Disorders Clinic, Pediatric Neurology Division, Children's Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahmoud Reza Ashrafi
- Myelin Disorders Clinic, Pediatric Neurology Division, Children's Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran
| | - Masoud Garshasbi
- Faculty of Medical Sciences, Department of Medical Genetics, Tarbiat Modares University, Tehran, Iran
| | - Ali Reza Tavasoli
- Myelin Disorders Clinic, Pediatric Neurology Division, Children's Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran
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23
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Wadman RI, Jansen MD, Stam M, Wijngaarde CA, Curial CAD, Medic J, Sodaar P, Schouten J, Vijzelaar R, Lemmink HH, van den Berg LH, Groen EJN, van der Pol WL. Intragenic and structural variation in the SMN locus and clinical variability in spinal muscular atrophy. Brain Commun 2020; 2:fcaa075. [PMID: 32954327 PMCID: PMC7425299 DOI: 10.1093/braincomms/fcaa075] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/19/2020] [Revised: 04/17/2020] [Accepted: 04/22/2020] [Indexed: 11/15/2022] Open
Abstract
Clinical severity and treatment response vary significantly between patients with spinal muscular atrophy. The approval of therapies and the emergence of neonatal screening programmes urgently require a more detailed understanding of the genetic variants that underlie this clinical heterogeneity. We systematically investigated genetic variation other than SMN2 copy number in the SMN locus. Data were collected through our single-centre, population-based study on spinal muscular atrophy in the Netherlands, including 286 children and adults with spinal muscular atrophy Types 1–4, including 56 patients from 25 families with multiple siblings with spinal muscular atrophy. We combined multiplex ligation-dependent probe amplification, Sanger sequencing, multiplexed targeted resequencing and digital droplet polymerase chain reaction to determine sequence and expression variation in the SMN locus. SMN1, SMN2 and NAIP gene copy number were determined by multiplex ligation-dependent probe amplification. SMN2 gene variant analysis was performed using Sanger sequencing and RNA expression analysis of SMN by droplet digital polymerase chain reaction. We identified SMN1–SMN2 hybrid genes in 10% of spinal muscular atrophy patients, including partial gene deletions, duplications or conversions within SMN1 and SMN2 genes. This indicates that SMN2 copies can vary structurally between patients, implicating an important novel level of genetic variability in spinal muscular atrophy. Sequence analysis revealed six exonic and four intronic SMN2 variants, which were associated with disease severity in individual cases. There are no indications that NAIP1 gene copy number or sequence variants add value in addition to SMN2 copies in predicting the clinical phenotype in individual patients with spinal muscular atrophy. Importantly, 95% of spinal muscular atrophy siblings in our study had equal SMN2 copy numbers and structural changes (e.g. hybrid genes), but 60% presented with a different spinal muscular atrophy type, indicating the likely presence of further inter- and intragenic variabilities inside as well as outside the SMN locus. SMN2 gene copies can be structurally different, resulting in inter- and intra-individual differences in the composition of SMN1 and SMN2 gene copies. This adds another layer of complexity to the genetics that underlie spinal muscular atrophy and should be considered in current genetic diagnosis and counselling practices.
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Affiliation(s)
- Renske I Wadman
- UMC Utrecht Brain Center, Department of Neurology and Neurosurgery, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands
| | - Marc D Jansen
- UMC Utrecht Brain Center, Department of Neurology and Neurosurgery, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands
| | - Marloes Stam
- UMC Utrecht Brain Center, Department of Neurology and Neurosurgery, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands
| | - Camiel A Wijngaarde
- UMC Utrecht Brain Center, Department of Neurology and Neurosurgery, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands
| | - Chantall A D Curial
- UMC Utrecht Brain Center, Department of Neurology and Neurosurgery, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands
| | - Jelena Medic
- UMC Utrecht Brain Center, Department of Neurology and Neurosurgery, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands
| | - Peter Sodaar
- UMC Utrecht Brain Center, Department of Neurology and Neurosurgery, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands
| | - Jan Schouten
- MRC Holland BV, 1057 DL Amsterdam, the Netherlands
| | | | - Henny H Lemmink
- Department of Genetics, University Medical Center Groningen, 9713 GZ Groningen, the Netherlands
| | - Leonard H van den Berg
- UMC Utrecht Brain Center, Department of Neurology and Neurosurgery, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands
| | - Ewout J N Groen
- UMC Utrecht Brain Center, Department of Neurology and Neurosurgery, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands
| | - W Ludo van der Pol
- UMC Utrecht Brain Center, Department of Neurology and Neurosurgery, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands
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24
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New and Developing Therapies in Spinal Muscular Atrophy: From Genotype to Phenotype to Treatment and Where Do We Stand? Int J Mol Sci 2020; 21:ijms21093297. [PMID: 32392694 PMCID: PMC7246502 DOI: 10.3390/ijms21093297] [Citation(s) in RCA: 76] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/12/2020] [Revised: 05/03/2020] [Accepted: 05/04/2020] [Indexed: 02/08/2023] Open
Abstract
Spinal muscular atrophy (SMA) is a congenital neuromuscular disorder characterized by motor neuron loss, resulting in progressive weakness. SMA is notable in the health care community because it accounts for the most common cause of infant death resulting from a genetic defect. SMA is caused by low levels of the survival motor neuron protein (SMN) resulting from SMN1 gene mutations or deletions. However, patients always harbor various copies of SMN2, an almost identical but functionally deficient copy of the gene. A genotype–phenotype correlation suggests that SMN2 is a potent disease modifier for SMA, which also represents the primary target for potential therapies. Increasing comprehension of SMA pathophysiology, including the characterization of SMN1 and SMN2 genes and SMN protein functions, has led to the development of multiple therapeutic approaches. Until the end of 2016, no cure was available for SMA, and management consisted of supportive measures. Two breakthrough SMN-targeted treatments, either using antisense oligonucleotides (ASOs) or virus-mediated gene therapy, have recently been approved. These two novel therapeutics have a common objective: to increase the production of SMN protein in MNs and thereby improve motor function and survival. However, neither therapy currently provides a complete cure. Treating patients with SMA brings new responsibilities and unique dilemmas. As SMA is such a devastating disease, it is reasonable to assume that a unique therapeutic solution may not be sufficient. Current approaches under clinical investigation differ in administration routes, frequency of dosing, intrathecal versus systemic delivery, and mechanisms of action. Besides, emerging clinical trials evaluating the efficacy of either SMN-dependent or SMN-independent approaches are ongoing. This review aims to address the different knowledge gaps between genotype, phenotypes, and potential therapeutics.
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25
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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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RNA-Targeted Therapies and High-Throughput Screening Methods. Int J Mol Sci 2020; 21:ijms21082996. [PMID: 32340368 PMCID: PMC7216119 DOI: 10.3390/ijms21082996] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/31/2020] [Revised: 04/20/2020] [Accepted: 04/21/2020] [Indexed: 02/07/2023] Open
Abstract
RNA-binding proteins (RBPs) are involved in regulating all aspects of RNA metabolism, including processing, transport, translation, and degradation. Dysregulation of RNA metabolism is linked to a plethora of diseases, such as cancer, neurodegenerative diseases, and neuromuscular disorders. Recent years have seen a dramatic shift in the knowledge base, with RNA increasingly being recognised as an attractive target for precision medicine therapies. In this article, we are going to review current RNA-targeted therapies. Furthermore, we will scrutinise a range of drug discoveries targeting protein-RNA interactions. In particular, we will focus on the interplay between Lin28 and let-7, splicing regulatory proteins and survival motor neuron (SMN) pre-mRNA, as well as HuR, Musashi, proteins and their RNA targets. We will highlight the mechanisms RBPs utilise to modulate RNA metabolism and discuss current high-throughput screening strategies. This review provides evidence that we are entering a new era of RNA-targeted medicine.
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27
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Swalley SE. Expanding therapeutic opportunities for neurodegenerative diseases: A perspective on the important role of phenotypic screening. Bioorg Med Chem 2020; 28:115239. [DOI: 10.1016/j.bmc.2019.115239] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/02/2019] [Revised: 11/15/2019] [Accepted: 11/24/2019] [Indexed: 02/08/2023]
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Bozorg Qomi S, Asghari A, Salmaninejad A, Mojarrad M. Spinal Muscular Atrophy and Common Therapeutic Advances. Fetal Pediatr Pathol 2019; 38:226-238. [PMID: 31060440 DOI: 10.1080/15513815.2018.1520374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Indexed: 10/26/2022]
Abstract
BACKGROUND Spinal muscular atrophy (SMA) is an autosomal recessive destructive motor neuron disease which is characterized primarily by the degeneration of α-motor neurons in the ventral gray horn of the spinal cord. It mainly affects children and represents the most common reason of inherited infant mortality. MATERIAL AND METHODS We provide an overview of the recent therapeutic strategies for the treatment of SMA together with available and developing therapeutic strategies. For this purpose, Google Scholar and PubMed databases were searched for literature on SMA, therapy and treatment. Titles were reviewed and 96 were selected and assessed in this paper. RESULT Over the last two decades, different therapeutic strategies have been proposed for SMA. Some methods are in the pre-clinical, others the clinical phase. CONCLUSION By emergence of the new approaches, especially in gene therapy, effective treatment in the close future is probable.
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Affiliation(s)
- Saeed Bozorg Qomi
- a Department of Medical Genetics, School of Medicine, Mashhad University of Medical Sciences , Mashhad , Iran.,b Medical Genetics Research Center, School of Medicine, Mashhad University of Medical Sciences , Mashhad , Iran
| | - Amir Asghari
- c Department of Medical Physiology, School of Medicine, Mashhad University of Medical Sciences , Mashhad , Iran
| | - Arash Salmaninejad
- d Drug Applied Research Center, Student Research Committee, Tabriz University of Medical Sciences , Tabriz , Iran
| | - Majid Mojarrad
- a Department of Medical Genetics, School of Medicine, Mashhad University of Medical Sciences , Mashhad , Iran.,b Medical Genetics Research Center, School of Medicine, Mashhad University of Medical Sciences , Mashhad , Iran
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Unveiling the druggable RNA targets and small molecule therapeutics. Bioorg Med Chem 2019; 27:2149-2165. [PMID: 30981606 PMCID: PMC7126819 DOI: 10.1016/j.bmc.2019.03.057] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/17/2018] [Revised: 03/25/2019] [Accepted: 03/29/2019] [Indexed: 12/15/2022]
Abstract
The increasing appreciation for the crucial roles of RNAs in infectious and non-infectious human diseases makes them attractive therapeutic targets. Coding and non-coding RNAs frequently fold into complex conformations which, if effectively targeted, offer opportunities to therapeutically modulate numerous cellular processes, including those linked to undruggable protein targets. Despite the considerable skepticism as to whether RNAs can be targeted with small molecule therapeutics, overwhelming evidence suggests the challenges we are currently facing are not outside the realm of possibility. In this review, we highlight the most recent advances in molecular techniques that have sparked a revolution in understanding the RNA structure-to-function relationship. We bring attention to the application of these modern techniques to identify druggable RNA targets and to assess small molecule binding specificity. Finally, we discuss novel screening methodologies that support RNA drug discovery and present examples of therapeutically valuable RNA targets.
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30
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Long KK, O’Shea KM, Khairallah RJ, Howell K, Paushkin S, Chen KS, Cote SM, Webster MT, Stains JP, Treece E, Buckler A, Donovan A. Specific inhibition of myostatin activation is beneficial in mouse models of SMA therapy. Hum Mol Genet 2019; 28:1076-1089. [PMID: 30481286 PMCID: PMC6423420 DOI: 10.1093/hmg/ddy382] [Citation(s) in RCA: 79] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/29/2018] [Revised: 10/29/2018] [Accepted: 10/31/2018] [Indexed: 12/22/2022] Open
Abstract
Spinal muscular atrophy (SMA) is a neuromuscular disease characterized by loss of α-motor neurons, leading to profound skeletal muscle atrophy. Patients also suffer from decreased bone mineral density and increased fracture risk. The majority of treatments for SMA, approved or in clinic trials, focus on addressing the underlying cause of disease, insufficient production of full-length SMN protein. While restoration of SMN has resulted in improvements in functional measures, significant deficits remain in both mice and SMA patients following treatment. Motor function in SMA patients may be additionally improved by targeting skeletal muscle to reduce atrophy and improve muscle strength. Inhibition of myostatin, a negative regulator of muscle mass, offers a promising approach to increase muscle function in SMA patients. Here we demonstrate that muSRK-015P, a monoclonal antibody which specifically inhibits myostatin activation, effectively increases muscle mass and function in two variants of the pharmacological mouse model of SMA in which pharmacologic restoration of SMN has taken place either 1 or 24 days after birth to reflect early or later therapeutic intervention. Additionally, muSRK-015P treatment improves the cortical and trabecular bone phenotypes in these mice. These data indicate that preventing myostatin activation has therapeutic potential in addressing muscle and bone deficiencies in SMA patients. An optimized variant of SRK-015P, SRK-015, is currently in clinical development for treatment of SMA.
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Affiliation(s)
| | | | | | - Kelly Howell
- SMA Foundation, 888 7th Avenue #400, New York, NY
| | | | - Karen S Chen
- SMA Foundation, 888 7th Avenue #400, New York, NY
| | - Shaun M Cote
- Scholar Rock Inc., 620 Memorial Drive, Cambridge, MA
| | | | - Joseph P Stains
- Department of Orthopedics, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Erin Treece
- Scholar Rock Inc., 620 Memorial Drive, Cambridge, MA
| | - Alan Buckler
- Scholar Rock Inc., 620 Memorial Drive, Cambridge, MA
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Intraperitoneal delivery of a novel drug-like compound improves disease severity in severe and intermediate mouse models of Spinal Muscular Atrophy. Sci Rep 2019; 9:1633. [PMID: 30733501 PMCID: PMC6367425 DOI: 10.1038/s41598-018-38208-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/25/2018] [Accepted: 12/20/2018] [Indexed: 01/08/2023] Open
Abstract
Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder that causes progressive muscle weakness and is the leading genetic cause of infant mortality worldwide. SMA is caused by the loss of survival motor neuron 1 (SMN1). In humans, a nearly identical copy gene is present, called SMN2. Although SMN2 maintains the same coding sequence, this gene cannot compensate for the loss of SMN1 because of a single silent nucleotide difference in SMN2 exon 7. SMN2 primarily produces an alternatively spliced isoform lacking exon 7, which is critical for protein function. SMN2 is an important disease modifier that makes for an excellent target for therapeutic intervention because all SMA patients retain SMN2. Therefore, compounds and small molecules that can increase SMN2 exon 7 inclusion, transcription and SMN protein stability have great potential for SMA therapeutics. Previously, we performed a high throughput screen and established a class of compounds that increase SMN protein in various cellular contexts. In this study, a novel compound was identified that increased SMN protein levels in vivo and ameliorated the disease phenotype in severe and intermediate mouse models of SMA.
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Ratni H, Mueller L, Ebeling M. Rewriting the (tran)script: Application to spinal muscular atrophy. PROGRESS IN MEDICINAL CHEMISTRY 2019; 58:119-156. [PMID: 30879473 DOI: 10.1016/bs.pmch.2018.12.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Academic Contribution Register] [Indexed: 06/09/2023]
Abstract
Targeting RNA drastically expands our target space to therapeutically modulate numerous cellular processes implicated in human diseases. Of particular interest, drugging pre-mRNA splicing appears a very viable strategy; to control levels of splicing product by promoting the inclusion or exclusion of exons. After describing the concept of "splicing modulation", this chapter will cover the outstanding progress achieved in this field, by highlighting the breakthrough accomplished recently for the treatment of spinal muscular atrophy using two therapeutic modalities: splice switching oligonucleotides and small molecules. This review discusses the vital but feasible requirement for such drugs to deliver selectivity, and critical safety aspects are highlighted. Transformational medicines such as those developed to treat SMA are likely just the beginning of this story.
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Affiliation(s)
- Hasane Ratni
- F. Hoffmann-La Roche Ltd., pRED, Pharma Research & Early Development, Roche Innovation Center Basel, Basel, Switzerland.
| | - Lutz Mueller
- F. Hoffmann-La Roche Ltd., pRED, Pharma Research & Early Development, Roche Innovation Center Basel, Basel, Switzerland
| | - Martin Ebeling
- F. Hoffmann-La Roche Ltd., pRED, Pharma Research & Early Development, Roche Innovation Center Basel, Basel, Switzerland
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Abstract
Recent studies have indicated the potential to develop small-molecule drugs that act on RNA targets, leading to burgeoning interest in the field. This article discusses general principles for discovering small-molecule drugs that target RNA and argues that the overarching challenge is to identify appropriate target structures in disease-causing RNAs that have high information content and, consequently, appropriate ligand-binding pockets. RNA molecules are essential for cellular information transfer and gene regulation, and RNAs have been implicated in many human diseases. Messenger and non-coding RNAs contain highly structured elements, and evidence suggests that many of these structures are important for function. Targeting these RNAs with small molecules offers opportunities to therapeutically modulate numerous cellular processes, including those linked to 'undruggable' protein targets. Despite this promise, there is currently only a single class of human-designed small molecules that target RNA used clinically — the linezolid antibiotics. However, a growing number of small-molecule RNA ligands are being identified, leading to burgeoning interest in the field. Here, we discuss principles for discovering small-molecule drugs that target RNA and argue that the overarching challenge is to identify appropriate target structures — namely, in disease-causing RNAs that have high information content and, consequently, appropriate ligand-binding pockets. If focus is placed on such druggable binding sites in RNA, extensive knowledge of the typical physicochemical properties of drug-like small molecules could then enable small-molecule drug discovery for RNA targets to become (only) roughly as difficult as for protein targets.
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Affiliation(s)
| | | | - Kevin M Weeks
- Department of Chemistry, University of North Carolina, Chapel Hill, NC, USA
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Abstract
The genetic determinants of many diseases, including monogenic diseases and cancers, have been identified; nevertheless, targeted therapy remains elusive for most. High-throughput screening (HTS) of small molecules, including high-content analysis (HCA), has been an important technology for the discovery of molecular tools and new therapeutics. HTS can be based on modulation of a known disease target (called reverse chemical genetics) or modulation of a disease-associated mechanism or phenotype (forward chemical genetics). Prominent target-based successes include modulators of transthyretin, used to treat transthyretin amyloidoses, and the BCR-ABL kinase inhibitor Gleevec, used to treat chronic myelogenous leukemia. Phenotypic screening successes include modulators of cystic fibrosis transmembrane conductance regulator, splicing correctors for spinal muscular atrophy, and histone deacetylase inhibitors for cancer. Synthetic lethal screening, in which chemotherapeutics are screened for efficacy against specific genetic backgrounds, is a promising approach that merges phenotype and target. In this article, we introduce HTS technology and highlight its contributions to the discovery of drugs and probes for monogenic diseases and cancer.
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Affiliation(s)
- Sarine Markossian
- Small Molecule Discovery Center and Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94143, USA; , , ,
| | - Kenny K Ang
- Small Molecule Discovery Center and Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94143, USA; , , ,
| | - Christopher G Wilson
- Small Molecule Discovery Center and Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94143, USA; , , ,
| | - Michelle R Arkin
- Small Molecule Discovery Center and Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94143, USA; , , ,
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35
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Osman EY, Washington CW, Simon ME, Megiddo D, Greif H, Lorson CL. Analysis of Azithromycin Monohydrate as a Single or a Combinatorial Therapy in a Mouse Model of Severe Spinal Muscular Atrophy. J Neuromuscul Dis 2018; 4:237-249. [PMID: 28598854 DOI: 10.3233/jnd-170230] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Spinal muscular atrophy (SMA) is a neurodegenerative autosomal recessive disorder characterized by the loss of α-motor neurons. A variety of molecular pathways are being investigated to elevate SMN protein expression in SMA models and in the clinic. One of these approaches involves stabilizing the SMNΔ7 protein by inducing translational read-through. Previous studies have demonstrated that functionality and stability are partially restored to the otherwise unstable SMNΔ7 by the addition of non-specific C-terminal peptide sequences, or by inducing a similar molecular event through the use of read-through inducing compounds such as aminoglycosides. OBJECTIVE The objective was to determine the efficacy of the macrolide Azithromycin (AZM), an FDA approved read-through-inducing compound, in the well-established severe mouse model of SMA. METHODS Initially, dosing regimen following ICV administrations of AZM at different post-natal days and concentrations was determined by their impact on SMN levels in disease-relevant tissues. Selected dose was then tested for phenotypic parameters changes as compared to the appropriate controls and in conjugation to another therapy. RESULTS AZM increases SMN protein in disease relevant tissues, however, this did not translate into similar improvements in the SMA phenotype in a severe mouse model of SMA. Co-administration of AZM and a previously developed antisense oligonucleotide that increases SMN2 splicing, resulted in an improvement in the SMA phenotype beyond either AZM or ASO alone, including a highly significant extension in survival with improvement in body weight and movement. CONCLUSIONS It is important to explore various approaches for SMA therapeutics, hence compounds that specifically induce SMNΔ7 read-through, without having prohibitive toxicity, may provide an alternative platform for a combinatorial treatment. Here we established that AZM activity at a low dose can increase SMN protein in disease-relevant animal model and can impact disease severity.
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Affiliation(s)
- Erkan Y Osman
- Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO, USA.,Bond Life Sciences Center, University of Missouri, Columbia, MO, USA
| | - Charles W Washington
- Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO, USA.,Bond Life Sciences Center, University of Missouri, Columbia, MO, USA
| | - Madeline E Simon
- Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO, USA.,Bond Life Sciences Center, University of Missouri, Columbia, MO, USA
| | | | | | - Christian L Lorson
- Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO, USA.,Bond Life Sciences Center, University of Missouri, Columbia, MO, USA
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36
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Edwards JD, Butchbach MER. Effect of the Butyrate Prodrug Pivaloyloxymethyl Butyrate (AN9) on a Mouse Model for Spinal Muscular Atrophy. J Neuromuscul Dis 2018; 3:511-515. [PMID: 27911337 DOI: 10.3233/jnd-160187] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 01/07/2023]
Abstract
Spinal muscular atrophy (SMA) is an early-onset motor neuron disease that leads to loss of muscle function. Butyrate (BA)-based compounds markedly improve the survival and motor phenotype of SMA mice. In this study, we examine the protective effects of the BA prodrug pivaloyloxymethyl butyrate (AN9) on the survival of SMNΔ7 SMA mice. Oral administration of AN9 beginning at PND04 almost doubled the average lifespan of SMNΔ7 SMA mice. AN9 treatment also increased the growth rate of SMNΔ7 SMA mice when compared to vehicle-treated SMNΔ7 SMA mice. In conclusion, BA prodrugs like AN9 have ameliorative effects on SMNΔ7 SMA mice.
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Affiliation(s)
- Jonathan D Edwards
- Department of Biological Chemistry and Pharmacology, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Matthew E R Butchbach
- Department of Biological Chemistry and Pharmacology, The Ohio State University Wexner Medical Center, Columbus, OH, USA.,Center for Applied Clinical Genomics, Nemours Biomedical Research, Nemours Alfred I. duPont Hospital for Children, Wilmington, DE, USA.,Center for Pediatric Research, Nemours Biomedical Research, Nemours Alfred I. duPont Hospital for Children, Wilmington, DE, USA.,Department of Pediatrics, Thomas Jefferson University, Philadelphia, PA, USA.,Department of Biological Sciences, University of Delaware, Newark, DE, USA
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37
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Abstract
Alternative splicing is a well-studied gene regulatory mechanism that produces biological diversity by allowing the production of multiple protein isoforms from a single gene. An involvement of alternative splicing in the key biological signalling Hippo pathway is emerging and offers new therapeutic avenues. This review discusses examples of alternative splicing in the Hippo pathway, how deregulation of these processes may contribute to disease and whether these processes offer new potential therapeutic targets.
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38
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Parente V, Corti S. Advances in spinal muscular atrophy therapeutics. Ther Adv Neurol Disord 2018; 11:1756285618754501. [PMID: 29434670 PMCID: PMC5802612 DOI: 10.1177/1756285618754501] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/21/2017] [Accepted: 10/24/2017] [Indexed: 11/17/2022] Open
Abstract
Spinal muscular atrophy (SMA) is a progressive, recessively inherited neuromuscular disease, characterized by the degeneration of lower motor neurons in the spinal cord and brainstem, which leads to weakness and muscle atrophy. SMA currently represents the most common genetic cause of infant death. SMA is caused by the lack of survival motor neuron (SMN) protein due to mutations, which are often deletions, in the SMN1 gene. In the absence of treatments able to modify the disease course, a considerable burden falls on patients and their families. Greater knowledge of the molecular basis of SMA pathogenesis has fuelled the development of potential therapeutic approaches, which are illustrated here. Nusinersen, a modified antisense oligonucleotide that modulates the splicing of the SMN2 mRNA transcript, is the first approved drug for all types of SMA. Moreover, the first gene therapy clinical trial using adeno-associated virus (AAV) vectors encoding SMN reported positive results in survival and motor milestones achievement. In addition, other strategies are in the pipeline, including modulation of SMN2 transcripts, neuroprotection, and targeting an increasing number of other peripheral targets, including the skeletal muscle. Based on this premise, it is reasonable to expect that therapeutic approaches aimed at treating SMA will soon be changed, and improved, in a meaningful way. We discuss the challenges with regard to the development of novel treatments for patients with SMA, and depict the current and future scenarios as the field enters into a new era of promising effective treatments.
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Affiliation(s)
- Valeria Parente
- Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan, Neurology Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Stefania Corti
- Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan, Neurology Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122 Milan, Italy
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Small-molecule flunarizine increases SMN protein in nuclear Cajal bodies and motor function in a mouse model of spinal muscular atrophy. Sci Rep 2018; 8:2075. [PMID: 29391529 PMCID: PMC5794986 DOI: 10.1038/s41598-018-20219-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/06/2017] [Accepted: 01/16/2018] [Indexed: 02/07/2023] Open
Abstract
The hereditary neurodegenerative disorder spinal muscular atrophy (SMA) is characterized by the loss of spinal cord motor neurons and skeletal muscle atrophy. SMA is caused by mutations of the survival motor neuron (SMN) gene leading to a decrease in SMN protein levels. The SMN deficiency alters nuclear body formation and whether it can contribute to the disease remains unclear. Here we screen a series of small-molecules on SMA patient fibroblasts and identify flunarizine that accumulates SMN into Cajal bodies, the nuclear bodies important for the spliceosomal small nuclear RNA (snRNA)-ribonucleoprotein biogenesis. Using histochemistry, real-time RT-PCR and behavioural analyses in a mouse model of SMA, we show that along with the accumulation of SMN into Cajal bodies of spinal cord motor neurons, flunarizine treatment modulates the relative abundance of specific spliceosomal snRNAs in a tissue-dependent manner and can improve the synaptic connections and survival of spinal cord motor neurons. The treatment also protects skeletal muscles from cell death and atrophy, raises the neuromuscular junction maturation and prolongs life span by as much as 40 percent (p < 0.001). Our findings provide a functional link between flunarizine and SMA pathology, highlighting the potential benefits of flunarizine in a novel therapeutic perspective against neurodegenerative diseases.
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40
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Khadilkar SV, Yadav RS, Patel BA. Spinal Muscular Atrophy. Neuromuscul Disord 2018. [DOI: 10.1007/978-981-10-5361-0_10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 10/18/2022]
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41
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Choi S, Calder AN, Miller EH, Anderson KP, Fiejtek DK, Rietz A, Li H, Cherry JJ, Quist KM, Xing X, Glicksman MA, Cuny GD, Lorson CL, Androphy EA, Hodgetts KJ. Optimization of a series of heterocycles as survival motor neuron gene transcription enhancers. Bioorg Med Chem Lett 2017; 27:5144-5148. [PMID: 29103974 PMCID: PMC5701662 DOI: 10.1016/j.bmcl.2017.10.066] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/02/2017] [Revised: 10/22/2017] [Accepted: 10/24/2017] [Indexed: 12/24/2022]
Abstract
Spinal muscular atrophy (SMA) is a neurodegenerative disorder that results from mutations in the SMN1 gene, leading to survival motor neuron (SMN) protein deficiency. One therapeutic strategy for SMA is to identify compounds that enhance the expression of the SMN2 gene, which normally only is a minor contributor to functional SMN protein production, but which is unaffected in SMA. A recent high-throughput screening campaign identified a 3,4-dihydro-4-phenyl-2(1H)-quinolinone derivative (2) that increases the expression of SMN2 by 2-fold with an EC50 = 8.3 µM. A structure-activity relationship (SAR) study revealed that the array of tolerated substituents, on either the benzo portion of the quinolinone or the 4-phenyl, was very narrow. However, the lactam ring of the quinolinone was more amenable to modifications. For example, the quinazolinone (9a) and the benzoxazepin-2(3H)-one (19) demonstrated improved potency and efficacy for increase in SMN2 expression as compared to 2.
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Affiliation(s)
- Sungwoon Choi
- Laboratory for Drug Discovery in Neurodegeneration, Brigham and Women's Hospital and Harvard Medical School, 65 Landsdowne Street, Cambridge, MA, USA
| | - Alyssa N Calder
- Laboratory for Drug Discovery in Neurodegeneration, Brigham and Women's Hospital and Harvard Medical School, 65 Landsdowne Street, Cambridge, MA, USA
| | - Eliza H Miller
- Laboratory for Drug Discovery in Neurodegeneration, Brigham and Women's Hospital and Harvard Medical School, 65 Landsdowne Street, Cambridge, MA, USA
| | - Kierstyn P Anderson
- Laboratory for Drug Discovery in Neurodegeneration, Brigham and Women's Hospital and Harvard Medical School, 65 Landsdowne Street, Cambridge, MA, USA
| | - Dawid K Fiejtek
- Laboratory for Drug Discovery in Neurodegeneration, Brigham and Women's Hospital and Harvard Medical School, 65 Landsdowne Street, Cambridge, MA, USA
| | - Anne Rietz
- Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Hongxia Li
- Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Jonathan J Cherry
- Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Kevin M Quist
- Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Xuechao Xing
- Laboratory for Drug Discovery in Neurodegeneration, Brigham and Women's Hospital and Harvard Medical School, 65 Landsdowne Street, Cambridge, MA, USA
| | - Marcie A Glicksman
- Laboratory for Drug Discovery in Neurodegeneration, Brigham and Women's Hospital and Harvard Medical School, 65 Landsdowne Street, Cambridge, MA, USA
| | - Gregory D Cuny
- Laboratory for Drug Discovery in Neurodegeneration, Brigham and Women's Hospital and Harvard Medical School, 65 Landsdowne Street, Cambridge, MA, USA
| | - Christian L Lorson
- Department of Veterinary Pathobiology, Bond Life Sciences Center, University of Missouri, Columbia, MO, USA
| | - Elliot A Androphy
- Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Kevin J Hodgetts
- Laboratory for Drug Discovery in Neurodegeneration, Brigham and Women's Hospital and Harvard Medical School, 65 Landsdowne Street, Cambridge, MA, USA.
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RNA as a small molecule druggable target. Bioorg Med Chem Lett 2017; 27:5083-5088. [PMID: 29097169 DOI: 10.1016/j.bmcl.2017.10.052] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/11/2017] [Revised: 10/11/2017] [Accepted: 10/22/2017] [Indexed: 12/20/2022]
Abstract
Small molecule drugs have readily been developed against many proteins in the human proteome, but RNA has remained an elusive target for drug discovery. Increasingly, we see that RNA, and to a lesser extent DNA elements, show a persistent tertiary structure responsible for many diverse and complex cellular functions. In this digest, we have summarized recent advances in screening approaches for RNA targets and outlined the discovery of novel, drug-like small molecules against RNA targets from various classes and therapeutic areas. The link of structure, function, and small-molecule Druggability validates now for the first time that RNA can be the targets of therapeutic agents.
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Abstract
PURPOSE OF REVIEW Spinal muscular atrophy (SMA) is a genetic disorder of motor neurons in the anterior horns of the spinal cord and brainstem that results in muscle atrophy and weakness. SMA is an autosomal recessive disease linked to deletions of the SMN1 gene on chromosome 5q. Humans have a duplicate gene (SMN2) whose product can mitigate disease severity, leading to the variability in severity and age of onset of disease, and is therefore a target for drug development. RECENT FINDINGS Advances in preclinical and clinical trials have paved the way for novel therapeutic options for SMA patients, including many currently in clinical trials. In 2016, the first treatment for SMA has been approved in the USA, an antisense oligonucleotide that increases full-length protein product derived from SMN2. The approval of a first treatment for SMA and the rapid advances in clinical trials provide the prospect for multiple approaches to disease modification. There are several other promising therapeutics in different stages of development, based on approaches such as neuroprotection, or gene therapy.
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Affiliation(s)
- Diana Bharucha-Goebel
- Department of Neurology, Children's National Medical Center, Washington, DC, USA.
- Neuromuscular and Neurogenetic Disorders of Childhoood Section (NNDCS)/NINDS/NIH, Bethesda, MD, USA.
| | - Petra Kaufmann
- National Center for Advancing Translational Sciences (NCATS)/NIH, Bethesda, MD, USA
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44
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Vauthier V, Housset C, Falguières T. Targeted pharmacotherapies for defective ABC transporters. Biochem Pharmacol 2017; 136:1-11. [DOI: 10.1016/j.bcp.2017.02.020] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/24/2017] [Accepted: 02/23/2017] [Indexed: 02/07/2023]
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45
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Therapeutic approaches for spinal muscular atrophy (SMA). Gene Ther 2017; 24:514-519. [DOI: 10.1038/gt.2017.45] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/08/2017] [Accepted: 05/09/2017] [Indexed: 12/13/2022]
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Salameh A, Keller M, Dähnert I, Dhein S. Olesoxime Inhibits Cardioplegia-Induced Ischemia/Reperfusion Injury. A Study in Langendorff-Perfused Rabbit Hearts. Front Physiol 2017; 8:324. [PMID: 28579963 PMCID: PMC5437207 DOI: 10.3389/fphys.2017.00324] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/06/2017] [Accepted: 05/05/2017] [Indexed: 12/15/2022] Open
Abstract
Objective: During cardioplegia, which is often used in cardiac surgery, the heart is subjected to global ischemia/reperfusion injury, which can result in a post-operative impairment of cardiac function. Mitochondria permeability transition pores (MPTP) play a key role in cardiomyocyte survival after ischemia/reperfusion injury. It was shown in clinical settings that blockers of MPTP like cyclosporine might have a positive influence on cardiac function after cardioplegic arrest. Olesoxime, which is a new drug with MPTP blocking activity, has been introduced as a neuroprotective therapeutic agent. This drug has not been investigated on a possible positive effect in ischemia/reperfusion injury in hearts. Therefore, the aim of our study was to investigate possible effects of olesoxime on cardiac recovery after cardioplegic arrest. Methods: We evaluated 14 mature Chinchilla bastard rabbits of 1,500–2,000 g. Rabbit hearts were isolated and perfused with constant pressure according to Langendorff. After induction of cardioplegic arrest (30 ml 4°C cold Custodiol cardioplegia without and with 5 μmol/L olesoxime, n = 7 each) the hearts maintained arrested for 90-min. Thereafter, the hearts were re-perfused for 60 min. At the end of each experiment left ventricular samples were frozen in liquid nitrogen for ATP measurements. Furthermore, heart slices were embedded in paraffin for histological analysis. During the entire experiment hemodynamic and functional data such as left ventricular pressure (LVP), dp/dt(max) and (min), pressure rate product (PRP), coronary flow, pO2, and pCO2 were also assessed. Results: Histological analysis revealed that despite the same ischemic burden for both groups markers of nitrosative and oxidative stress were significantly lower in the olesoxime group. Moreover, hearts of the olesoxime-group showed a significantly faster and better hemodynamic recovery during reperfusion. In addition, tissue ATP-levels were significantly higher in the olesoxime treated hearts. Conclusions: Olesoxime significantly protected the cardiac muscle from ischemia/reperfusion injury.
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Affiliation(s)
- Aida Salameh
- Clinic for Pediatric Cardiology, Heart Centre, University of LeipzigLeipzig, Germany
| | - Maren Keller
- Clinic for Pediatric Cardiology, Heart Centre, University of LeipzigLeipzig, Germany
| | - Ingo Dähnert
- Clinic for Pediatric Cardiology, Heart Centre, University of LeipzigLeipzig, Germany
| | - Stefan Dhein
- Rudolf-Boehm-Institute for Pharmacology and Toxicology, University of LeipzigLeipzig, Germany
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47
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Rietz A, Li H, Quist KM, Cherry JJ, Lorson CL, Burnett BG, Kern NL, Calder AN, Fritsche M, Lusic H, Boaler PJ, Choi S, Xing X, Glicksman MA, Cuny GD, Androphy EJ, Hodgetts KJ. Discovery of a Small Molecule Probe That Post-Translationally Stabilizes the Survival Motor Neuron Protein for the Treatment of Spinal Muscular Atrophy. J Med Chem 2017; 60:4594-4610. [PMID: 28481536 DOI: 10.1021/acs.jmedchem.6b01885] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 01/29/2023]
Abstract
Spinal muscular atrophy (SMA) is the leading genetic cause of infant death. We previously developed a high-throughput assay that employs an SMN2-luciferase reporter allowing identification of compounds that act transcriptionally, enhance exon recognition, or stabilize the SMN protein. We describe optimization and characterization of an analog suitable for in vivo testing. Initially, we identified analog 4m that had good in vitro properties but low plasma and brain exposure in a mouse PK experiment due to short plasma stability; this was overcome by reversing the amide bond and changing the heterocycle. Thiazole 27 showed excellent in vitro properties and a promising mouse PK profile, making it suitable for in vivo testing. This series post-translationally stabilizes the SMN protein, unrelated to global proteasome or autophagy inhibition, revealing a novel therapeutic mechanism that should complement other modalities for treatment of SMA.
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Affiliation(s)
- Anne Rietz
- Department of Dermatology, Indiana University School of Medicine , Indianapolis, Indiana 46202, United States
| | - Hongxia Li
- Department of Dermatology, Indiana University School of Medicine , Indianapolis, Indiana 46202, United States
| | - Kevin M Quist
- Department of Dermatology, Indiana University School of Medicine , Indianapolis, Indiana 46202, United States
| | - Jonathan J Cherry
- Department of Dermatology, Indiana University School of Medicine , Indianapolis, Indiana 46202, United States
| | - Christian L Lorson
- Department of Veterinary Pathobiology, Bond Life Sciences Center, University of Missouri , Columbia, Missouri 65201, United States
| | - Barrington G Burnett
- Department of Anatomy, Physiology and Genetics, F. Edward Hebert School of Medicine, Uniformed Services University of the Health Sciences , Bethesda, Maryland 20814, United States
| | - Nicholas L Kern
- Laboratory for Drug Discovery in Neurodegeneration, Brigham & Women's Hospital and Harvard Medical School , 65 Landsdowne Street, Cambridge, Massachusetts 02139, United States
| | - Alyssa N Calder
- Laboratory for Drug Discovery in Neurodegeneration, Brigham & Women's Hospital and Harvard Medical School , 65 Landsdowne Street, Cambridge, Massachusetts 02139, United States
| | - Melanie Fritsche
- Laboratory for Drug Discovery in Neurodegeneration, Brigham & Women's Hospital and Harvard Medical School , 65 Landsdowne Street, Cambridge, Massachusetts 02139, United States
| | - Hrvoje Lusic
- Laboratory for Drug Discovery in Neurodegeneration, Brigham & Women's Hospital and Harvard Medical School , 65 Landsdowne Street, Cambridge, Massachusetts 02139, United States
| | - Patrick J Boaler
- Laboratory for Drug Discovery in Neurodegeneration, Brigham & Women's Hospital and Harvard Medical School , 65 Landsdowne Street, Cambridge, Massachusetts 02139, United States
| | - Sungwoon Choi
- Laboratory for Drug Discovery in Neurodegeneration, Brigham & Women's Hospital and Harvard Medical School , 65 Landsdowne Street, Cambridge, Massachusetts 02139, United States
| | - Xuechao Xing
- Laboratory for Drug Discovery in Neurodegeneration, Brigham & Women's Hospital and Harvard Medical School , 65 Landsdowne Street, Cambridge, Massachusetts 02139, United States
| | - Marcie A Glicksman
- Laboratory for Drug Discovery in Neurodegeneration, Brigham & Women's Hospital and Harvard Medical School , 65 Landsdowne Street, Cambridge, Massachusetts 02139, United States
| | - Gregory D Cuny
- Laboratory for Drug Discovery in Neurodegeneration, Brigham & Women's Hospital and Harvard Medical School , 65 Landsdowne Street, Cambridge, Massachusetts 02139, United States
| | - Elliot J Androphy
- Department of Dermatology, Indiana University School of Medicine , Indianapolis, Indiana 46202, United States
| | - Kevin J Hodgetts
- Laboratory for Drug Discovery in Neurodegeneration, Brigham & Women's Hospital and Harvard Medical School , 65 Landsdowne Street, Cambridge, Massachusetts 02139, United States
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48
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Pinard E, Green L, Reutlinger M, Weetall M, Naryshkin NA, Baird J, Chen KS, Paushkin SV, Metzger F, Ratni H. Discovery of a Novel Class of Survival Motor Neuron 2 Splicing Modifiers for the Treatment of Spinal Muscular Atrophy. J Med Chem 2017; 60:4444-4457. [DOI: 10.1021/acs.jmedchem.7b00406] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 01/24/2023]
Affiliation(s)
- Emmanuel Pinard
- F. Hoffmann-La Roche Ltd., pRED, Pharma Research & Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070 Basel, Switzerland
| | - Luke Green
- F. Hoffmann-La Roche Ltd., pRED, Pharma Research & Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070 Basel, Switzerland
| | - Michael Reutlinger
- F. Hoffmann-La Roche Ltd., pRED, Pharma Research & Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070 Basel, Switzerland
| | - Marla Weetall
- PTC Therapeutics, Inc., 100
Corporate Court, South Plainfield, New Jersey 07080, United States
| | - Nikolai A. Naryshkin
- PTC Therapeutics, Inc., 100
Corporate Court, South Plainfield, New Jersey 07080, United States
| | - John Baird
- PTC Therapeutics, Inc., 100
Corporate Court, South Plainfield, New Jersey 07080, United States
| | - Karen S. Chen
- SMA Foundation, 888 Seventh
Avenue, Suite 400, New York, New York 10019, United States
| | - Sergey V. Paushkin
- SMA Foundation, 888 Seventh
Avenue, Suite 400, New York, New York 10019, United States
| | - Friedrich Metzger
- F. Hoffmann-La Roche Ltd., pRED, Pharma Research & Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070 Basel, Switzerland
| | - Hasane Ratni
- F. Hoffmann-La Roche Ltd., pRED, Pharma Research & Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070 Basel, Switzerland
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49
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Farrelly-Rosch A, Lau CL, Patil N, Turner BJ, Shabanpoor F. Combination of valproic acid and morpholino splice-switching oligonucleotide produces improved outcomes in spinal muscular atrophy patient-derived fibroblasts. Neurochem Int 2017; 108:213-221. [PMID: 28389270 DOI: 10.1016/j.neuint.2017.02.016] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/23/2017] [Revised: 02/22/2017] [Accepted: 02/24/2017] [Indexed: 12/16/2022]
Abstract
Spinal muscular atrophy (SMA), the leading genetic cause of infant mortality worldwide, is characterised by the homozygous loss of the survival motor neuron 1 (SMN1) gene. The consequent degeneration of spinal motor neurons and progressive atrophy of voluntary muscle groups results in paralysis and eventually premature infantile death. Humans possess a second nearly identical copy of SMN1, known as SMN2. However, SMN2 produces only 10-20% functional SMN protein due to aberrant splicing of its pre-mRNA that leads to the exclusion of exon 7. This level of SMN is insufficient to rescue the phenotype. Recently developed splice-switching antisense oligonuclotides (SSO) have shown great promise in correcting the aberrant splicing of SMN2 towards producing functional SMN protein. Several FDA approved drugs are being repurposed for SMA treatment including valproic acid (VPA), a histone deacetylase inhibitor, which has been shown to increase overall SMN2 expression. In this study, we have characterised the effects of single and combined treatment of VPA and a SSO based on phosphorodiamidate morpholino oligomer (PMO) chemistry. We conjugated both VPA and PMO to a single cell-penetrating peptide (Apolipoprotein E (ApoE)) for their simultaneous intracellular delivery. Treatment of SMA Type I patient-derived fibroblasts with the conjugates showed no additive increase in the level of full-length SMN2 mRNA expression over both 4 and 16 h treatments indicating that conjugation of VPA to ApoE-PMO has limited benefit. However, treatment with a combination of VPA and ApoE-PMO induced more favourable splice switching activity than either agent alone, promoting exon 7 inclusion in SMN2 transcripts. Our results suggest that combination therapy of VPA and ApoE-PMO is superior in upregulating SMN2 production in vitro, as compared to singular treatment of each compound at both transcriptional and protein levels. This study provides the first indication of a novel dual therapy approach for the potential treatment of SMA.
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Affiliation(s)
- Anna Farrelly-Rosch
- The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Victoria 3052, Australia
| | - Chew Ling Lau
- The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Victoria 3052, Australia
| | - Nitin Patil
- The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Victoria 3052, Australia
| | - Bradley J Turner
- The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Victoria 3052, Australia
| | - Fazel Shabanpoor
- The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Victoria 3052, Australia; School of Chemistry, University of Melbourne, Victoria 3052, Australia.
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50
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Gopalsamy A, Narayanan A, Liu S, Parikh MD, Kyne RE, Fadeyi O, Tones MA, Cherry JJ, Nabhan JF, LaRosa G, Petersen DN, Menard C, Foley TL, Noell S, Ren Y, Loria PM, Maglich-Goodwin J, Rong H, Jones LH. Design of Potent mRNA Decapping Scavenger Enzyme (DcpS) Inhibitors with Improved Physicochemical Properties To Investigate the Mechanism of Therapeutic Benefit in Spinal Muscular Atrophy (SMA). J Med Chem 2017; 60:3094-3108. [DOI: 10.1021/acs.jmedchem.7b00124] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 01/27/2023]
Affiliation(s)
- Ariamala Gopalsamy
- Medicine
Design and ‡Rare Disease Research Unit, #Pharmacokinetics and Drug Metabolism, Pfizer, 610 Main Street, Cambridge, Massachusetts 02139, United States
- Medicine Design and †Primary Pharmacology Group, Pfizer, Eastern Point Road, Groton, Connecticut 06340, United States
| | - Arjun Narayanan
- Medicine
Design and ‡Rare Disease Research Unit, #Pharmacokinetics and Drug Metabolism, Pfizer, 610 Main Street, Cambridge, Massachusetts 02139, United States
- Medicine Design and †Primary Pharmacology Group, Pfizer, Eastern Point Road, Groton, Connecticut 06340, United States
| | - Shenping Liu
- Medicine
Design and ‡Rare Disease Research Unit, #Pharmacokinetics and Drug Metabolism, Pfizer, 610 Main Street, Cambridge, Massachusetts 02139, United States
- Medicine Design and †Primary Pharmacology Group, Pfizer, Eastern Point Road, Groton, Connecticut 06340, United States
| | - Mihir D. Parikh
- Medicine
Design and ‡Rare Disease Research Unit, #Pharmacokinetics and Drug Metabolism, Pfizer, 610 Main Street, Cambridge, Massachusetts 02139, United States
- Medicine Design and †Primary Pharmacology Group, Pfizer, Eastern Point Road, Groton, Connecticut 06340, United States
| | - Robert E. Kyne
- Medicine
Design and ‡Rare Disease Research Unit, #Pharmacokinetics and Drug Metabolism, Pfizer, 610 Main Street, Cambridge, Massachusetts 02139, United States
- Medicine Design and †Primary Pharmacology Group, Pfizer, Eastern Point Road, Groton, Connecticut 06340, United States
| | - Olugbeminiyi Fadeyi
- Medicine
Design and ‡Rare Disease Research Unit, #Pharmacokinetics and Drug Metabolism, Pfizer, 610 Main Street, Cambridge, Massachusetts 02139, United States
- Medicine Design and †Primary Pharmacology Group, Pfizer, Eastern Point Road, Groton, Connecticut 06340, United States
| | - Michael A. Tones
- Medicine
Design and ‡Rare Disease Research Unit, #Pharmacokinetics and Drug Metabolism, Pfizer, 610 Main Street, Cambridge, Massachusetts 02139, United States
- Medicine Design and †Primary Pharmacology Group, Pfizer, Eastern Point Road, Groton, Connecticut 06340, United States
| | - Jonathan J. Cherry
- Medicine
Design and ‡Rare Disease Research Unit, #Pharmacokinetics and Drug Metabolism, Pfizer, 610 Main Street, Cambridge, Massachusetts 02139, United States
- Medicine Design and †Primary Pharmacology Group, Pfizer, Eastern Point Road, Groton, Connecticut 06340, United States
| | - Joseph F. Nabhan
- Medicine
Design and ‡Rare Disease Research Unit, #Pharmacokinetics and Drug Metabolism, Pfizer, 610 Main Street, Cambridge, Massachusetts 02139, United States
- Medicine Design and †Primary Pharmacology Group, Pfizer, Eastern Point Road, Groton, Connecticut 06340, United States
| | - Gregory LaRosa
- Medicine
Design and ‡Rare Disease Research Unit, #Pharmacokinetics and Drug Metabolism, Pfizer, 610 Main Street, Cambridge, Massachusetts 02139, United States
- Medicine Design and †Primary Pharmacology Group, Pfizer, Eastern Point Road, Groton, Connecticut 06340, United States
| | - Donna N. Petersen
- Medicine
Design and ‡Rare Disease Research Unit, #Pharmacokinetics and Drug Metabolism, Pfizer, 610 Main Street, Cambridge, Massachusetts 02139, United States
- Medicine Design and †Primary Pharmacology Group, Pfizer, Eastern Point Road, Groton, Connecticut 06340, United States
| | - Carol Menard
- Medicine
Design and ‡Rare Disease Research Unit, #Pharmacokinetics and Drug Metabolism, Pfizer, 610 Main Street, Cambridge, Massachusetts 02139, United States
- Medicine Design and †Primary Pharmacology Group, Pfizer, Eastern Point Road, Groton, Connecticut 06340, United States
| | - Timothy L. Foley
- Medicine
Design and ‡Rare Disease Research Unit, #Pharmacokinetics and Drug Metabolism, Pfizer, 610 Main Street, Cambridge, Massachusetts 02139, United States
- Medicine Design and †Primary Pharmacology Group, Pfizer, Eastern Point Road, Groton, Connecticut 06340, United States
| | - Stephen Noell
- Medicine
Design and ‡Rare Disease Research Unit, #Pharmacokinetics and Drug Metabolism, Pfizer, 610 Main Street, Cambridge, Massachusetts 02139, United States
- Medicine Design and †Primary Pharmacology Group, Pfizer, Eastern Point Road, Groton, Connecticut 06340, United States
| | - Yong Ren
- Medicine
Design and ‡Rare Disease Research Unit, #Pharmacokinetics and Drug Metabolism, Pfizer, 610 Main Street, Cambridge, Massachusetts 02139, United States
- Medicine Design and †Primary Pharmacology Group, Pfizer, Eastern Point Road, Groton, Connecticut 06340, United States
| | - Paula M. Loria
- Medicine
Design and ‡Rare Disease Research Unit, #Pharmacokinetics and Drug Metabolism, Pfizer, 610 Main Street, Cambridge, Massachusetts 02139, United States
- Medicine Design and †Primary Pharmacology Group, Pfizer, Eastern Point Road, Groton, Connecticut 06340, United States
| | - Jodi Maglich-Goodwin
- Medicine
Design and ‡Rare Disease Research Unit, #Pharmacokinetics and Drug Metabolism, Pfizer, 610 Main Street, Cambridge, Massachusetts 02139, United States
- Medicine Design and †Primary Pharmacology Group, Pfizer, Eastern Point Road, Groton, Connecticut 06340, United States
| | - Haojing Rong
- Medicine
Design and ‡Rare Disease Research Unit, #Pharmacokinetics and Drug Metabolism, Pfizer, 610 Main Street, Cambridge, Massachusetts 02139, United States
- Medicine Design and †Primary Pharmacology Group, Pfizer, Eastern Point Road, Groton, Connecticut 06340, United States
| | - Lyn H. Jones
- Medicine
Design and ‡Rare Disease Research Unit, #Pharmacokinetics and Drug Metabolism, Pfizer, 610 Main Street, Cambridge, Massachusetts 02139, United States
- Medicine Design and †Primary Pharmacology Group, Pfizer, Eastern Point Road, Groton, Connecticut 06340, United States
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