Opinion
VIEWPOINT
Peter B. Kang, MD Division of Pediatric Neurology, Department of Pediatrics, University of Florida College of Medicine, Gainesville. Robert C. Griggs, MD Center for Human Experimental Therapeutics, Departments of Neurology, Medicine, Pediatrics, and Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York.
Corresponding Author: Peter B. Kang, MD, Department of Pediatrics, University of Florida College of Medicine, PO Box 100296, Gainesville, FL 32610 (pbkang@ufl .edu).
Advances in Muscular Dystrophies Muscular dystrophy (MD) was originally defined as a single disease in the 19th century. In the 20th century, MD was delineated into the following 6 subcategories: Duchenne MD (DMD)/Becker MD, limb-girdle MD, distal myopathies, congenital MD, facioscapulohumeral MD, and myotonic dystrophy. Since the cloning of dystrophin in 1986, a flood of genetic discoveries has made it apparent that muscular dystrophy actually refers to a superfamily of more than 50 distinct diseases definable by specific genetic mutations. Thus, this term is rapidly becoming an anachronism that is likely to be replaced by specific molecular diagnoses. Adding to the complexity, many causative genes are associated with multiple phenotypes, such as the link between dysferlin and both Miyoshi myopathy and limb-girdle MD 2B. However, specific genotypephenotype associations still provide guidance regarding which genes are likely to harbor pathogenic mutations. Whole-exome sequencing and whole-genome sequencing are becoming widely available diagnostic tools. Moreover, new diseases continue to be identified by whole-exome sequencing and whole-genome sequencing, some of which are exceedingly rare but have important mechanistic and therapeutic connections to other MDs. Diagnosis is further complicated by the clinical overlap between MDs and other inherited myopathies, illustrated by our work on MEGF10 myopathy.1 Whole-exome sequencing, whole-genome sequencing, and sophisticated bioinformatic strategies also promise to identify genes, such as LTBP4 in DMD, that modify the course or treatment responses of these mendelian disorders.2 Current and developing treatments for DMD include pharmacologic therapies that ameliorate the downstream consequences of dystrophin deficiency, molecular therapies that are not mutation specific, and molecular therapies that target specific mutations (Table). Only 1 pharmacologic agent, corticosteroids, is currently known to improve weakness in DMD (Table). Despite clear evidence of its benefits, the use of corticosteroids is not standardized.3 Deflazacort (not available in the United States) is currently being compared with prednisone in a study that aims to define standards of care. Several experimental pharmacologic approaches are under active investigation, such as myostatin inhibition, nitric oxide augmentation, and utrophin upregulation. Despite encouraging animal studies of myostatin inhibition and a study of a human with a myostatin mutation and muscle hypertrophy, human clinical trial results of this approach have been negative. Animal studies of phosphodiesterase inhibitors suggest that they may alleviate symptoms of DMD via augmentation of nitric oxide activity. Utrophin is a homologue of dystrophin, the protein associated with DMD and Becker MD.
Pharmacologic strategies to upregulate utrophin are in human clinical trials. Two molecular approaches promise to correct dystrophin deficiency in DMD, regardless of the specific mutation (Table). One is gene therapy, which has become increasingly sophisticated during the years and has now entered human clinical trials. The other is stem cell therapy, which showed inadequate results in the early 1990s. After some retrenchment and more detailed animal studies, various cell-based approaches are now being considered for human clinical trials. Other molecular approaches to DMD target specific mutations, highlighting the importance of confirming genetic diagnoses. Antisense oligonucleotides used to manipulate gene expression and splicing have been designed to induce the skipping of specific exons in dystrophin, restoring the reading frame and resulting in a partially functional dystrophin that converts a DMD phenotype into a milder Becker MD phenotype. A clinical trial has shown promising results.4 Specific pharmacologic compounds (eg, Ataluren) induce readthrough of specific pathogenic stop codons and have been investigated in boys with DMD, with some evidence for efficacy. One or more novel therapies for DMD will be approved for use by the US Food and Drug Administration in the next few years. However, no current treatment is expected to restore a completely normal phenotype and many treatments only target selected mutations that affect subsets of disease populations. Muscular dystrophy research has expanded in many directions, encompassing studies of pathogenesis and treatment for all major subcategories. Almost all limbgirdle MDs will soon be the focus of novel treatment approaches. One example involves dysferlinopathy, which manifests as limb-girdle MD 2B and Miyoshi myopathy (a distal myopathy). Dysferlin appears to be important in membrane repair and there is evidence that mutant dysferlin is degraded by cells but might be functional if it is not degraded. Proteasome inhibition has restored dysferlin expression to muscle cells (and monocytes, another target tissue in the diseases), suggesting a possible treatment strategy for this specific disease.5 Facioscapulohumeral MD, long considered a single disease, has been discovered to be caused by mutations of 2 different loci that may result in muscle damage by the same mechanism. These mutations permit the abnormal expression of the fetal protein DUX4 (double homeobox 4), which appears toxic to adult skeletal muscle. Strategies to reduce DUX4 expression are being actively investigated.6 Myotonic dystrophy type 1 is caused by a trinucleotide repeat expansion mutation in the 3′ untranslated region of the gene. This expansion results in the production of abnormal ribonucleic acid, which is sequestered (and visible) in the nuclei of muscle and other involved
jamaneurology.com
(Reprinted) JAMA Neurology Published online May 18, 2015
Copyright 2015 American Medical Association. All rights reserved.
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E1
Opinion Viewpoint
Table. Treatment Strategies for DMD/Becker MD Strategy
Mechanism
Restores Dystrophin Target Population
Status
Corticosteroids
Inhibition of muscle proteolysis
No
All patients with DMD
Off label, widespread use
Myostatin inhibition
Myostatin inhibition should augment muscle growth
No
All patients with DMD and other patients with muscle disease
Human clinical trials
Nitric oxide augmentation (Sildenafil, Tadalafil)
Phosphodiesterase inhibition reduces functional ischemia of muscle
No
All patients with DMD
Human clinical trials
Utrophin upregulation (SMT C1100)
Compensation of dystrophin No deficiency by utrophin, a close homologue
All patients with DMD
Human clinical trials
Gene therapy (delivery of μ-dystrophin via AAV)
Viral vector-based delivery of dystrophin
Yes, truncated μ-dystrophin fits in AAV
All patients with DMD
Human clinical trials
Stem cell therapy
Cell-based delivery of dystrophin
Yes
All patients with DMD
Preclinical studies
ASO therapy (Eteplirsen, Drisapersen)
ASO-induced exon skipping restores reading frame of dystrophin
Yes, with certain exons missing
Currently approximately 13% of DMD population amenable to exon 51 skipping; other ASOs under development
Human clinical trials
Approximately 13% of DMD population with nonsense mutations
Human clinical trials
Stop codon readthrough (Ataluren)
Biochemically induced readthrough of pathogenic stop codons
Yes
organs. This ribonucleic acid seems toxic and binds other proteins (eg, muscle blind). A mouse model of myotonic dystrophy type 1 that reproduced both the neuromuscular phenotype and the molecular pathology has been reversed by treatment with antisense oligonucleotide.7 A phase I trial of antisense oligonucleotide therapy for DM-1 has begun in humans. Among the therapies discussed, only corticosteroids are available for routine clinical use in DMD and a handful of other medications are known to ameliorate its cardiac complications. The positive effect of currently available interventions, such as noninvasive respiratory support and spinal fusion surgery, is sometimes underappreciated. Both pharmacologic and nonpharmacologic theraARTICLE INFORMATION Published Online: May 18, 2015. doi:10.1001/jamaneurol.2014.4621. Conflict of Interest Disclosures: Dr Kang has received consulting fees from Sarepta Therapeutics and C1 Consulting and participates in multicenter clinical trials sponsored by Sarepta Therapeutics, Pfizer, and Catabasis; has received honoraria for continuing medical education lectures from the American Academy of Neurology, American Academy of Pediatrics, American College of Medical Genetics, and HealthmattersCME; and has received research support from the National Institute of Neurological Diseases and Stroke of the National Institutes of Health and the Muscular Dystrophy Association. Dr Griggs receives support for service on data safety monitoring boards from Novartis, PTC Therapeutics, and Viromed; consults for Sarepta Therapeutics; consults for and has received research support from Marathon Pharmaceuticals and Taro Pharmaceuticals; receives royalties from Elsevier for Cecil Textbook of Medicine and Cecil
E2
Abbreviations: AAV, adenoassociated virus; ASO, antisense oligonucleotide; DMD, Duchenne muscular dystrophy; MD, muscular dystrophy.
pies should be standardized further. The widening pipeline of potent therapeutic tools will transform the care of MD in the years to follow and may tempt stakeholders to focus the bulk of scientific efforts and funding on these novel therapies. However, molecular diagnosis and molecular therapy are becoming increasingly intertwined and genetic epidemiology is a new frontier that will become increasingly important. Thus, there is a pressing need to refine the interpretation of genomic data for individuals and populations, not only to link individual patients to therapies, but to facilitate a broader understanding of muscle biology, pathogenesis, and population dynamics for the benefit of all individuals who are affected by these diseases.
Essentials of Medicine and from Oxford University Press for Evaluation and Treatment of Myopathies (Second Edition); receives a stipend from the American Academy of Neurology for editorial work; has received grants from the National Institute of Neurological Diseases and Stroke/National Institutes of Health, the Muscular Dystrophy Association, and Parent Project Muscular Dystrophy; and chairs the executive committee of the Muscle Study Group, which receives support from numerous pharmaceutical companies.
3. Griggs RC, Herr BE, Reha A, et al. Corticosteroids in Duchenne muscular dystrophy: major variations in practice. Muscle Nerve. 2013;48(1):27-31.
REFERENCES
6. Yao Z, Snider L, Balog J, et al. DUX4-induced gene expression is the major molecular signature in FSHD skeletal muscle. Hum Mol Genet. 2014;23 (20):5342-5352.
1. Boyden SE, Mahoney LJ, Kawahara G, et al. Mutations in the satellite cell gene MEGF10 cause a recessive congenital myopathy with minicores. Neurogenetics. 2012;13(2):115-124. 2. Flanigan KM, Ceco E, Lamar KM, et al; United Dystrophinopathy Project. LTBP4 genotype predicts age of ambulatory loss in Duchenne muscular dystrophy. Ann Neurol. 2013;73(4):481-488.
4. Mendell JR, Rodino-Klapac LR, Sahenk Z, et al; Eteplirsen Study Group. Eteplirsen for the treatment of Duchenne muscular dystrophy. Ann Neurol. 2013;74(5):637-647. 5. Azakir BA, Erne B, Di Fulvio S, Stirnimann G, Sinnreich M. Proteasome inhibitors increase missense mutated dysferlin in patients with muscular dystrophy. Sci Transl Med. 2014;6(250):250ra112.
7. Wheeler TM, Leger AJ, Pandey SK, et al. Targeting nuclear RNA for in vivo correction of myotonic dystrophy. Nature. 2012;488(7409):111-115.
JAMA Neurology Published online May 18, 2015 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a New York University User on 05/19/2015
jamaneurology.com
VIEWPOINT
Peter B. Kang, MD Division of Pediatric Neurology, Department of Pediatrics, University of Florida College of Medicine, Gainesville. Robert C. Griggs, MD Center for Human Experimental Therapeutics, Departments of Neurology, Medicine, Pediatrics, and Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York.
Corresponding Author: Peter B. Kang, MD, Department of Pediatrics, University of Florida College of Medicine, PO Box 100296, Gainesville, FL 32610 (pbkang@ufl .edu).
Advances in Muscular Dystrophies Muscular dystrophy (MD) was originally defined as a single disease in the 19th century. In the 20th century, MD was delineated into the following 6 subcategories: Duchenne MD (DMD)/Becker MD, limb-girdle MD, distal myopathies, congenital MD, facioscapulohumeral MD, and myotonic dystrophy. Since the cloning of dystrophin in 1986, a flood of genetic discoveries has made it apparent that muscular dystrophy actually refers to a superfamily of more than 50 distinct diseases definable by specific genetic mutations. Thus, this term is rapidly becoming an anachronism that is likely to be replaced by specific molecular diagnoses. Adding to the complexity, many causative genes are associated with multiple phenotypes, such as the link between dysferlin and both Miyoshi myopathy and limb-girdle MD 2B. However, specific genotypephenotype associations still provide guidance regarding which genes are likely to harbor pathogenic mutations. Whole-exome sequencing and whole-genome sequencing are becoming widely available diagnostic tools. Moreover, new diseases continue to be identified by whole-exome sequencing and whole-genome sequencing, some of which are exceedingly rare but have important mechanistic and therapeutic connections to other MDs. Diagnosis is further complicated by the clinical overlap between MDs and other inherited myopathies, illustrated by our work on MEGF10 myopathy.1 Whole-exome sequencing, whole-genome sequencing, and sophisticated bioinformatic strategies also promise to identify genes, such as LTBP4 in DMD, that modify the course or treatment responses of these mendelian disorders.2 Current and developing treatments for DMD include pharmacologic therapies that ameliorate the downstream consequences of dystrophin deficiency, molecular therapies that are not mutation specific, and molecular therapies that target specific mutations (Table). Only 1 pharmacologic agent, corticosteroids, is currently known to improve weakness in DMD (Table). Despite clear evidence of its benefits, the use of corticosteroids is not standardized.3 Deflazacort (not available in the United States) is currently being compared with prednisone in a study that aims to define standards of care. Several experimental pharmacologic approaches are under active investigation, such as myostatin inhibition, nitric oxide augmentation, and utrophin upregulation. Despite encouraging animal studies of myostatin inhibition and a study of a human with a myostatin mutation and muscle hypertrophy, human clinical trial results of this approach have been negative. Animal studies of phosphodiesterase inhibitors suggest that they may alleviate symptoms of DMD via augmentation of nitric oxide activity. Utrophin is a homologue of dystrophin, the protein associated with DMD and Becker MD.
Pharmacologic strategies to upregulate utrophin are in human clinical trials. Two molecular approaches promise to correct dystrophin deficiency in DMD, regardless of the specific mutation (Table). One is gene therapy, which has become increasingly sophisticated during the years and has now entered human clinical trials. The other is stem cell therapy, which showed inadequate results in the early 1990s. After some retrenchment and more detailed animal studies, various cell-based approaches are now being considered for human clinical trials. Other molecular approaches to DMD target specific mutations, highlighting the importance of confirming genetic diagnoses. Antisense oligonucleotides used to manipulate gene expression and splicing have been designed to induce the skipping of specific exons in dystrophin, restoring the reading frame and resulting in a partially functional dystrophin that converts a DMD phenotype into a milder Becker MD phenotype. A clinical trial has shown promising results.4 Specific pharmacologic compounds (eg, Ataluren) induce readthrough of specific pathogenic stop codons and have been investigated in boys with DMD, with some evidence for efficacy. One or more novel therapies for DMD will be approved for use by the US Food and Drug Administration in the next few years. However, no current treatment is expected to restore a completely normal phenotype and many treatments only target selected mutations that affect subsets of disease populations. Muscular dystrophy research has expanded in many directions, encompassing studies of pathogenesis and treatment for all major subcategories. Almost all limbgirdle MDs will soon be the focus of novel treatment approaches. One example involves dysferlinopathy, which manifests as limb-girdle MD 2B and Miyoshi myopathy (a distal myopathy). Dysferlin appears to be important in membrane repair and there is evidence that mutant dysferlin is degraded by cells but might be functional if it is not degraded. Proteasome inhibition has restored dysferlin expression to muscle cells (and monocytes, another target tissue in the diseases), suggesting a possible treatment strategy for this specific disease.5 Facioscapulohumeral MD, long considered a single disease, has been discovered to be caused by mutations of 2 different loci that may result in muscle damage by the same mechanism. These mutations permit the abnormal expression of the fetal protein DUX4 (double homeobox 4), which appears toxic to adult skeletal muscle. Strategies to reduce DUX4 expression are being actively investigated.6 Myotonic dystrophy type 1 is caused by a trinucleotide repeat expansion mutation in the 3′ untranslated region of the gene. This expansion results in the production of abnormal ribonucleic acid, which is sequestered (and visible) in the nuclei of muscle and other involved
jamaneurology.com
(Reprinted) JAMA Neurology Published online May 18, 2015
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a New York University User on 05/19/2015
E1
Opinion Viewpoint
Table. Treatment Strategies for DMD/Becker MD Strategy
Mechanism
Restores Dystrophin Target Population
Status
Corticosteroids
Inhibition of muscle proteolysis
No
All patients with DMD
Off label, widespread use
Myostatin inhibition
Myostatin inhibition should augment muscle growth
No
All patients with DMD and other patients with muscle disease
Human clinical trials
Nitric oxide augmentation (Sildenafil, Tadalafil)
Phosphodiesterase inhibition reduces functional ischemia of muscle
No
All patients with DMD
Human clinical trials
Utrophin upregulation (SMT C1100)
Compensation of dystrophin No deficiency by utrophin, a close homologue
All patients with DMD
Human clinical trials
Gene therapy (delivery of μ-dystrophin via AAV)
Viral vector-based delivery of dystrophin
Yes, truncated μ-dystrophin fits in AAV
All patients with DMD
Human clinical trials
Stem cell therapy
Cell-based delivery of dystrophin
Yes
All patients with DMD
Preclinical studies
ASO therapy (Eteplirsen, Drisapersen)
ASO-induced exon skipping restores reading frame of dystrophin
Yes, with certain exons missing
Currently approximately 13% of DMD population amenable to exon 51 skipping; other ASOs under development
Human clinical trials
Approximately 13% of DMD population with nonsense mutations
Human clinical trials
Stop codon readthrough (Ataluren)
Biochemically induced readthrough of pathogenic stop codons
Yes
organs. This ribonucleic acid seems toxic and binds other proteins (eg, muscle blind). A mouse model of myotonic dystrophy type 1 that reproduced both the neuromuscular phenotype and the molecular pathology has been reversed by treatment with antisense oligonucleotide.7 A phase I trial of antisense oligonucleotide therapy for DM-1 has begun in humans. Among the therapies discussed, only corticosteroids are available for routine clinical use in DMD and a handful of other medications are known to ameliorate its cardiac complications. The positive effect of currently available interventions, such as noninvasive respiratory support and spinal fusion surgery, is sometimes underappreciated. Both pharmacologic and nonpharmacologic theraARTICLE INFORMATION Published Online: May 18, 2015. doi:10.1001/jamaneurol.2014.4621. Conflict of Interest Disclosures: Dr Kang has received consulting fees from Sarepta Therapeutics and C1 Consulting and participates in multicenter clinical trials sponsored by Sarepta Therapeutics, Pfizer, and Catabasis; has received honoraria for continuing medical education lectures from the American Academy of Neurology, American Academy of Pediatrics, American College of Medical Genetics, and HealthmattersCME; and has received research support from the National Institute of Neurological Diseases and Stroke of the National Institutes of Health and the Muscular Dystrophy Association. Dr Griggs receives support for service on data safety monitoring boards from Novartis, PTC Therapeutics, and Viromed; consults for Sarepta Therapeutics; consults for and has received research support from Marathon Pharmaceuticals and Taro Pharmaceuticals; receives royalties from Elsevier for Cecil Textbook of Medicine and Cecil
E2
Abbreviations: AAV, adenoassociated virus; ASO, antisense oligonucleotide; DMD, Duchenne muscular dystrophy; MD, muscular dystrophy.
pies should be standardized further. The widening pipeline of potent therapeutic tools will transform the care of MD in the years to follow and may tempt stakeholders to focus the bulk of scientific efforts and funding on these novel therapies. However, molecular diagnosis and molecular therapy are becoming increasingly intertwined and genetic epidemiology is a new frontier that will become increasingly important. Thus, there is a pressing need to refine the interpretation of genomic data for individuals and populations, not only to link individual patients to therapies, but to facilitate a broader understanding of muscle biology, pathogenesis, and population dynamics for the benefit of all individuals who are affected by these diseases.
Essentials of Medicine and from Oxford University Press for Evaluation and Treatment of Myopathies (Second Edition); receives a stipend from the American Academy of Neurology for editorial work; has received grants from the National Institute of Neurological Diseases and Stroke/National Institutes of Health, the Muscular Dystrophy Association, and Parent Project Muscular Dystrophy; and chairs the executive committee of the Muscle Study Group, which receives support from numerous pharmaceutical companies.
3. Griggs RC, Herr BE, Reha A, et al. Corticosteroids in Duchenne muscular dystrophy: major variations in practice. Muscle Nerve. 2013;48(1):27-31.
REFERENCES
6. Yao Z, Snider L, Balog J, et al. DUX4-induced gene expression is the major molecular signature in FSHD skeletal muscle. Hum Mol Genet. 2014;23 (20):5342-5352.
1. Boyden SE, Mahoney LJ, Kawahara G, et al. Mutations in the satellite cell gene MEGF10 cause a recessive congenital myopathy with minicores. Neurogenetics. 2012;13(2):115-124. 2. Flanigan KM, Ceco E, Lamar KM, et al; United Dystrophinopathy Project. LTBP4 genotype predicts age of ambulatory loss in Duchenne muscular dystrophy. Ann Neurol. 2013;73(4):481-488.
4. Mendell JR, Rodino-Klapac LR, Sahenk Z, et al; Eteplirsen Study Group. Eteplirsen for the treatment of Duchenne muscular dystrophy. Ann Neurol. 2013;74(5):637-647. 5. Azakir BA, Erne B, Di Fulvio S, Stirnimann G, Sinnreich M. Proteasome inhibitors increase missense mutated dysferlin in patients with muscular dystrophy. Sci Transl Med. 2014;6(250):250ra112.
7. Wheeler TM, Leger AJ, Pandey SK, et al. Targeting nuclear RNA for in vivo correction of myotonic dystrophy. Nature. 2012;488(7409):111-115.
JAMA Neurology Published online May 18, 2015 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a New York University User on 05/19/2015
jamaneurology.com
