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Spinal Muscular Atrophy - 1st Edition - ISBN: 9780128036853, 9780128036860

Spinal Muscular Atrophy

1st Edition

Disease Mechanisms and Therapy

Editors: Charlotte Sumner Sergey Paushkin Chien-Ping Ko
Hardcover ISBN: 9780128036853
eBook ISBN: 9780128036860
Imprint: Academic Press
Published Date: 4th November 2016
Page Count: 506
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Spinal Muscular Atrophy: Disease Mechanisms and Therapy provides the latest information on a condition that is characterized by motoneuron loss and muscle atrophy, and is the leading genetic cause of infant mortality. Since the identification of the gene responsible for SMA in 1995, there have been important advances in the basic understanding of disease mechanisms, and in therapeutic development.

This book provides a comprehensive accounting of recent advances in basic and clinical research that covers SMA clinical features and standards of care, multifaceted aspects of SMN protein functions and SMA disease pathology, various animal models, and biomarkers, as well as current therapeutic development.

This title is ideal for graduate students/postdocs and principal investigators who are already in the SMA field and need to keep updated on recent findings and approaches, and for those who are new to, or would like to join, the field. Likewise, users will find an excellent source of reading for biotech/pharma scientists, clinical researchers, and practitioners, regulators, and patients and their advocacy organizations. Furthermore, this book is a handy reference for researchers and clinicians who may want to apply the research strategies and therapeutic approaches in SMA to other rare diseases.

Key Features

  • Provides comprehensive, up-to-date reviews by leading investigators on diverse topics of SMA, including clinical features and patient care, SMN genetics and protein functions, animal models, disease pathology and mechanisms, biomarkers, current therapeutic development, and the role of non-profit organizations in therapeutic development
  • Written to bridge multiple disciplines and promote better communications among basic scientists, clinical researchers, and health care providers on the latest developments in SMA
  • Includes outstanding questions and perspectives for future investigations and key references for additional detailed study


Neuroscientists, biomedical researchers, grad students, postdocs, academic/biotech researchers, clinicians

Table of Contents

List of Contributors



Sixty Years of Spinal Muscular Atrophy: A Personal Odyssey

Advances in Spinal Muscular Atrophy Research

From Mapping Survival Motor Neuron to Treatment of Spinal Muscular Atrophy

The Path to Therapeutics Development for Spinal Muscular Atrophy

Section I. Clinical Features and Diagnosis of SMA

  • Chapter 1. Spinal Muscular Atrophy: 125 Years Later and on the Verge of a Cure
    • Introduction
    • The First 100 Years: Understanding the Spinal Muscular Atrophy Clinical Spectrum
    • The Mapping of the SMA Gene and Creation of Animal Models
    • Case Example: Spinal Muscular Atrophy, Type III
    • Spinal Muscular Atrophy Clinical Trials and the Development of Outcome Measures
    • Conclusion and Future Directions
  • Chapter 2. Developmental Aspects and Pathological Findings in Spinal Muscular Atrophy
    • Introduction
    • Development of the Neuromuscular System
    • Neuropathological Aspects of Spinal Muscular Atrophy
    • Ultrasound Assessments of Fetal Spinal Muscular Atrophy Patients
    • Conclusions
  • Chapter 3. Standard of Care for Spinal Muscular Atrophy
    • Introduction
    • Respiratory Management
    • Nutritional Support
    • Endocrine Concerns and Intermediary Metabolism
    • Orthopedics
    • Acute Illness, Anesthesia, and Postoperative Care
    • Obstetrics
    • Physical Therapy and Assistive Devices
    • Conclusion
  • Chapter 4. Strategy for the Molecular Testing of Spinal Muscular Atrophy
    • Diagnostic Testing
    • Newborn Screening
    • Carrier Testing
    • SMN2 Testing
    • Conclusion

Section II. Cellular and Molecular Mechanisms of the Disease

  • Chapter 5. Transcriptional and Splicing Regulation of Spinal Muscular Atrophy Genes
    • Introduction
    • Organization of Survival Motor Neuron Gene
    • Role of Exonic Regulatory Elements in Survival Motor Neuron Exon 7 Splicing
    • In Vivo Selection of Exon 7 Revealed Additional Regulatory Elements
    • Role of Negative Intronic Regulatory Elements
    • Role of Positive Intronic Regulatory Elements
    • Role of RNA Structure and Long-Distance Interactions in Survival Motor Neuron Exon 7 Splicing
    • Role of Other Splicing Factors
    • Transcription and Transcription-Coupled Splicing Regulation
    • Concluding Remarks
  • Chapter 6. The Function of Survival Motor Neuron Complex and Its Role in Spinal Muscular Atrophy Pathogenesis
    • Early Studies on the Biochemistry of Survival Motor Neurons
    • Biogenesis of Spliceosomal Small Nuclear Ribonucleoproteins
    • The Survival Motor Neuron Complex As a Chaperone for Small Nuclear Ribonucleoproteins Assembly
    • Survival Motor Neuron
    • Gemin2
    • Gemins 3 and 4
    • Gemin5
    • Gemins 6 and 7
    • Gemin8
    • Unrip
    • The Methylosome/PRMT5 Complex
    • Survival Motor Neuron Complex Subunits and Intermediates in a Stepwise Sm Core Assembly Pathway
    • Regulation of Survival Motor Neuron Complex Activity
    • Survival Motor Neuron As a Redox Sensitive Machine
    • Why Does Survival Motor Neuron Loss of Function Cause Spinal Muscular Atrophy?
    • Potential Role for the Survival Motor Neuron Complex in Other Neurodegenerative Diseases
  • Chapter 7. RNA-Processing Dysfunction in Spinal Muscular Atrophy
    • The SMN Complex: An Assembly Machine for Ribonucleoprotein Complexes
    • Ribonucleoprotein Assembly Defects in Spinal Muscular Atrophy
    • Disease-Relevant SMN Functions: Lessons From Spinal Muscular Atrophy–Linked Mutations of SMN
    • SMN–Mediated Small Nuclear Ribonucleoprotein Assembly and Its Requirement in Time and Space
    • RNA-Processing Defects in Spinal Muscular Atrophy
    • SMN–Dependent RNA-Processing Events Linked to Spinal Muscular Atrophy
    • Outstanding Questions and Perspectives for Future Investigation
  • Chapter 8. Axonal and Neuromuscular Junction Pathology in Spinal Muscular Atrophy
    • Structure, Development, and Function of the Mammalian Neuromuscular Junction
    • Structural and Functional Neuromuscular Junction Pathology in Animal Models of Spinal Muscular Atrophy
    • Delayed Maturation of the Neuromuscular Junction in Animal Models of Spinal Muscular Atrophy
    • Cellular Components of the Neuromuscular Junction and Their Distinct Contribution to Neuromuscular Pathology in Spinal Muscular Atrophy
    • Evidence for Neuromuscular Junction Pathology in Human Spinal Muscular Atrophy Patients
    • Utilizing Neuromuscular Junction Pathology as a Readout in Preclinical Studies
    • Dysregulation of Developmental Pathways and Their Contribution to Neuromuscular Pathology in Spinal Muscular Atrophy
    • Selective Vulnerability of Different Motor Neuron Pools and Neuromuscular Junction Populations in Spinal Muscular Atrophy
    • Potential Cellular and Molecular Mechanisms Underlying Neuromuscular Junction Pathology in Spinal Muscular Atrophy
    • Future Perspectives and Conclusion
  • Chapter 9. Motor Circuit Dysfunction in Spinal Muscular Atrophy
    • Introduction
    • Plasticity of the Central Nervous System
    • Spinal Muscular Atrophy
    • The Role of Proprioception in Spinal Muscular Atrophy
    • Insights From Studies Using Animal Models
    • Glutamate Mishandling in Spinal Muscular Atrophy
    • Summary
  • Chapter 10. Contributions of Different Cell Types to Spinal Muscular Atrophy Pathogenesis
    • Introduction
    • Role of Astrocytes in Central Nervous System Disorders
    • Transgenic Models Provide Insight Into Tissue-Specific Function
    • Spinal Muscular Atrophy Astrocyte Pathology
    • Muscle Contribution to Spinal Muscular Atrophy Pathogenesis
    • Muscles Versus Motor Neurons: Delineating the Interactions of the Motor Unit and the Contribution of Muscle to Spinal Muscular Atrophy Pathogenesis
    • Myogenesis and Muscle Stem Cell Defects in Spinal Muscular Atrophy
    • Anabolism and Catabolism in Spinal Muscular Atrophy
    • Cytoskeletal Dynamic and Force Production in Muscles From Spinal Muscular Atrophy Mice
    • Cardiac Defects in Spinal Muscular Atrophy
    • Could Altered Metabolism Be Involved in Spinal Muscular Atrophy Pathogenesis?
    • Liver Defects in Spinal Muscular Atrophy
    • Pancreatic Defects in Spinal Muscular Atrophy
    • Perspective and Therapeutic Implications
  • Chapter 11. Temporal Requirements for the Survival Motor Neuron Protein
    • Introduction
    • Temporal Requirements for the Survival Motor Neuron Protein: Lessons From Model Organisms
    • Conclusions and Future Directions
  • Chapter 12. Spinal Muscular Atrophy Disease Modifiers
    • Survival Motor Neuron–Dependent Modifiers
    • Survival Motor Neuron‒Independent Modifiers
    • Conclusion

Section III. Cell and Animal SMA Models

  • Chapter 13. Cell Culture Models of Spinal Muscular Atrophy
    • Introduction
    • Probing Survival Motor Neuron Biology in Non–Motor Neuron Cultures
    • Two Sources of Pluripotent Stem Cells for Disease Modeling—Embryonic Stem Cells and Induced Pluripotent Stem Cells
    • Disease Modeling Using Patient Induced Pluripotent Stem Cells–Derived Motor Neurons
    • How to Better Model Spinal Muscular Atrophy—Looking at Non–Motor Neuron Aspects of the Disease
    • Concluding Remarks
  • Chapter 14. Nonmammalian Animal Models of Spinal Muscular Atrophy
    • A Brief History of Drosophila, Caenorhabditis elegans, and Zebrafish Model Systems
    • Survival of Motor Neuron Gene Conservation
    • Modeling Spinal Muscular Atrophy in the Fly
    • Modeling Spinal Muscular Atrophy in Caenorhabditis elegans
    • Modeling Spinal Muscular Atrophy in Zebrafish
    • Impact on the Spinal Muscular Atrophy Field
  • Chapter 15. Mammalian Models of Spinal Muscular Atrophy
    • Introduction
    • Mouse Models of Spinal Muscular Atrophy
    • Severe Spinal Muscular Atrophy Mouse Models
    • The Use of Severe Spinal Muscular Atrophy Mouse Models to Determine Where High Survival Motor Neuron Expression Is Required
    • The Use of Severe Spinal Muscular Atrophy Mouse Models to Determine When High Survival Motor Neuron Expression Is Required
    • Mild Spinal Muscular Atrophy Mouse Models
    • How Does Mouse Pathology Relate to Spinal Muscular Atrophy Patients?
    • Electrophysiological Measures in Mouse Models
    • Genetic Missense Mutations of Survival Motor Neuron
    • Genetic Background Check
    • Mouse Models Use in Therapeutic Testing and Large Mammalian Models of Spinal Muscular Atrophy
    • Conclusions

Section IV. Therapeutic Development

  • Chapter 16. Spinal Muscular Atrophy Therapeutics Development
    • Upregulation of Survival Motor Neuron Protein
    • Neuroprotection
    • Stem Cell Therapy
    • Enhancement of Muscle
    • Targeting Modifiers
    • Lessons Learned
    • Conclusions
  • Chapter 17. Small Molecule Approaches to Upregulate SMN Expression From the SMN2 Locus
    • Introduction
    • Discussion
  • Chapter 18. Antisense-Oligonucleotide Modulation of SMN2 Pre-mRNA Splicing
    • Introduction
    • Antisense Technology
    • Early Strategies in the Design of Antisense Oligonucleotides to Promote SMN2 Exon 7 Inclusion
    • Simultaneous Identification of Splicing Silencers and Lead Antisense Oligonucleotides by Antisense Oligonucleotide Walks
    • Mechanism of Action of ASO10-27
    • Preclinical Studies of ASO10-27
    • Ongoing Clinical Trials of Nusinersen
    • Concluding Remarks and Future Perspectives
  • Chapter 19. Gene Transfer in Spinal Muscular Atrophy
    • Rationale for Gene Therapy in Spinal Muscular Atrophy
    • SMNΔ7 Mouse Model
    • In Vivo Gene Therapy and Spinal Muscular Atrophy
    • Beyond Retrograde Transport
    • The Advent of Blood–Brain Barrier Penetrating Viral Vectors
    • Systemic Gene Delivery for Spinal Muscular Atrophy
    • Gene Delivery to Cerebrospinal Fluid for Spinal Muscular Atrophy
    • Gene Therapy Trial in Spinal Muscular Atrophy Type 1
    • Concluding Remarks and Perspectives
  • Chapter 20. Neuroprotection As a Therapeutic Approach for Spinal Muscular Atrophy
    • Introduction
    • What Is Neuroprotection?
    • How Do Survival Motor Neuron Deficits Cause Neurodegeneration?
    • Neuroprotection: Intervening in a Constant Battle Between Life and Death Targeting Mitochondria
    • Therapeutic Approaches to Providing Neuroprotection
    • Discussion
  • Chapter 21. Skeletal Muscle in Spinal Muscular Atrophy As an Opportunity for Therapeutic Intervention
    • Skeletal Muscle Physiology
    • Mechanisms Regulating Skeletal Muscle Mass
    • Muscle Pathology in Spinal Muscular Atrophy
    • The Role of Survival Motor Neuron Protein in Skeletal Muscle: Implications for Therapeutic Development for Spinal Muscular Atrophy
    • Spinal Muscular Atrophy Muscle As an Opportunity for Therapeutic Intervention
    • Conclusion
  • Chapter 22. Addressing Cell Therapy for Spinal Muscular Atrophy: Open Issues and Future Perspectives
    • Introduction
    • Why Stem Cell Therapy for Spinal Muscular Atrophy?
    • Motor Neuron Precursor Transplantation
    • Neural Stem Cell Transplantation
    • Other Strategies: Targeting Nonneuronal Cell Populations and In Vivo Reprogramming
    • Open Issues
    • Conclusions

Section V. Clinical Research

  • Chapter 23. Spinal Muscular Atrophy Motor Functional Scales and Measures of Pulmonary Function
    • Introduction
    • Part 1: Functional Motor Scales As Clinical Tools
    • Part 2: Pulmonary Function
    • Part 3: Selecting Outcome Measures for Natural History Studies and Clinical Trials
  • Chapter 24. Development and Testing of Biomarkers in Spinal Muscular Atrophy
    • Introduction
    • Overview of Types of Biomarkers
    • Biomarkers in Spinal Muscular Atrophy
    • Survival Motor Neuron–Related Biomarkers
    • Non-Survival Motor Neuron–Related Biomarkers
    • Physiological and Imaging Biomarkers
    • Conclusions
  • Chapter 25. Natural History of Spinal Muscular Atrophy
    • Introduction
    • Natural History Studies in Spinal Muscular Atrophy Type I Patients
    • Natural History Studies in Spinal Muscular Atrophy Type II/III Patients
    • Trends and Insights
    • Conclusions
  • Chapter 26. Spinal Muscular Atrophy Clinical Trials: Lessons Learned
    • Introduction
    • Inclusion Criteria
    • Enrollment
    • Impact of Clinical Networks and Databases
    • Retention
    • Stratification
    • Outcome Measures and Personnel Support/Cost
    • Conclusion

Appendix 1. SMA Types, Summary

Appendix 2. SMN1 and SMN2 Copy Numbers of Commercially Available Spinal Muscular Atrophy Fibroblast and Lymphoblastoid Cell Lines

Appendix 3. Transacting Factors and cis-Elements Involved in Modulation of SMN2 Exon 7 Alternative Splicing

Appendix 4. Sequence Alignment of the SMN Proteins From Diverse Organisms and List of SMN1 Mutations Identified in Humans

Appendix 5. SMN Role in the snRNP Assembly

Appendix 6. Select SMN-Dependent and SMN-Independent Modifiers

Appendix 7. Mouse Models of SMA and Mice Used in SMA Research

Appendix 8. SMA Strains for Testing Site-Specific Smn Expression

Appendix 9. Functional Scales Used in SMA

Appendix 10. Select SMA Organizations Around the World



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© Academic Press 2017
4th November 2016
Academic Press
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About the Editors

Charlotte Sumner

Charlotte Sumner

Dr. Charlotte J. Sumner is an Associate Professor of Neurology and Neuroscience at Johns Hopkins University School of Medicine. She received her B.A. from Princeton University and her M.D. from the University of Pennsylvania School of Medicine. She completed internal medicine internship and neurology residency at the University of California San Francisco and neuromuscular fellowship at Johns Hopkins University School of Medicine. Her scientific training included Neurogenetics fellowship at the National Institute of Neurological Disorders and Stroke. Dr. Sumner cares for patients with inherited diseases of motor neurons and peripheral nerves such as spinal muscular atrophy (SMA) and Charcot-Marie-Tooth (CMT) disease and co-directs the Johns Hopkins CMT clinic. Dr. Sumner’s research focuses on the genetic and cellular pathogenesis of SMAs with particular attention to therapeutics development for these disorders utilizing cell and mouse models and human tissues. This work has included identification of novel genetic causes of these disorders, characterization of molecular and cellular mechanisms underlying disease pathogenesis, and preclinical development of therapeutics now advancing to clinical trials in SMA patients. Dr. Sumner’s laboratory research has been funded by the National Institute of Neurological Disorders and Stroke, Muscular Dystrophy Association, Cure SMA, the Spinal Muscular Atrophy Foundation, Spinal Muscular Atrophy Research Team, Ujala Foundation, and the Howard Hughes Medical Institute. She is an Associate Editor of the journal Experimental Neurology and advisor to several companies developing treatments for SMA as well as nonprofit foundations including the Packard Center for ALS research, ALS Association, Cure SMA, and the SMA Foundation.

Affiliations and Expertise

Neurology and Neuroscience, Johns Hopkins University School of Medicine, USA

Sergey Paushkin

Sergey Paushkin

Dr. Sergey Paushkin is Director of Research at the Spinal Muscular Atrophy (SMA) Foundation. He is responsible for coordinating research efforts of pharmaceutical, biotech, academic, and contract research organizations with the goal of bringing therapeutics to patients with SMA. Dr. Paushkin has more than 20 years of experience in biomedical research related to rare diseases and has been working in the SMA field since 1998. His work on SMA started during postdoctoral training at the Howard Hughes Medical Institute (University of Pennsylvania), where he studied molecular mechanisms of the disease, including the organization and function of the SMN complex. Dr. Paushkin continued working on SMA at PTC Therapeutics, where he established the SMA program and led drug discovery efforts, prior to moving to the SMA Foundation. Dr. Paushkin’s expertise in SMA extends from molecular mechanisms of disease pathogenesis to drug discovery and development of therapeutics. Dr. Paushkin’s work is focused on implementing strategies to overcome translational barriers in preclinical and clinical research by establishing and leading collaborations between industry, academic institutions and CROs, as well as developing strong relationship with the SMA community.

Dr. Paushkin received his MD from the Russian State Medical University and PhD in Biochemistry from the Cardiology Research Center, Moscow. His undergraduate research was focused on the molecular basis of prion diseases, including prion protein conversion.

Affiliations and Expertise

Research, Spinal Muscular Atrophy (SMA) Foundation, USA

Chien-Ping Ko

Chien-Ping Ko

Dr. Chien-Ping Ko is a Professor of Neurobiology at University of Southern California Dornsife College of Letters, Arts and Sciences. Dr. Ko received his B.S. from National Taiwan University in Taipei, Taiwan, and Ph.D. from Washington University in St. Louis. Dr. Ko completed his postdoctoral training at University of Colorado Medical Center in Denver, and at the National Institute of Neurological Disorders and Stroke, NIH, in Bethesda. He served on the editorial board of the Journal of Neurocytology and Neuron Glia Biology and edited a special issue on the Neuromuscular Junction (NMJ) for the Journal of Neurocytology in 2003. Dr. Ko received an NIH Research Career Development Award and grants including past/current supports from NIH, NSF, Muscular Dystrophy Association, the ALS Association, Cure SMA, the Dhont Family Foundation, and the SMA Foundation. Dr. Ko is interested in the NMJ as a model synapse to better understand synaptic structure, function, formation, repair, and maintenance, as well as synapse-glia interactions. His current research focuses on the cellular and molecular mechanisms of the pathogenesis of spinal muscular atrophy (SMA), particularly the possible contribution of motor circuit defects to the pathogenesis of SMA, as well as the role of different cell types in SMA disease mechanisms and potential therapy. In addition, his lab pursues translational research by testing molecules that could potentially be used to treat SMA. Dr. Ko collaborates with many SMA researchers, both in academia and industry, with the hope to develop a novel concept of SMA disease mechanisms and potential therapy for this devastating disease.

Affiliations and Expertise

Neurobiology, Department of Biological Sciences, University of Southern California, USA


"This comprehensive, state-of-the-art textbook, covering all aspects of SMA, is very timely and should provide a springboard for further efforts and advances in the future." --Victor Dubowitz, M.D., Ph.D., Emeritus Professor of Paediatrics, University of London, London, UK

"This book is written by experts who contribute to major progress in the fields of SMA from the clinical features, molecular mechanisms, animal models, therapeutic developments to clinical trials. I have no doubt that this book will become an indispensable resource for clinicians and scientists having the goal to cure SMA." -- Judith Melki, M.D., Ph.D., Professor of Medical Genetics, Medicine Faculty, University of Paris 11; Inserm and University of Paris 11, U-788, Kremlin-Bicetre Hospital, Paris, France

"Now there is an important book which chronicles the many paths and diverse approaches taken to understand SMA and develop therapies, a clear strength of the SMA field has been the extensive sharing of data that has advanced the field rapidly." --Arthur H.M. Burghes, Ph.D., Professor, Department of Biological Chemistry and Pharmacology, College of Medicine, The Ohio State University, Columbus, OH, USA

"We have come a long way on the path to therapeutics development for SMA, and safe and effective treatment is now within reach. This book comes at an opportune time to take stock of where we are on this path and to see what the future holds." -- Kenneth H. Fischbeck, M.D., NIH Distinguished Investigator, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA

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