Genetic-Based Treatment Strategies for Muscular Dystrophy and Congenital Myopathies

PURPOSE OF REVIEW This article discusses the foundational concepts of genetic treatment strategies employed in neuromuscular medicine, as well as the importance of genetic testing as a requirement for applying gene-based therapy.

RECENT FINDINGS Gene therapies have become a reality for several neuromuscular disorders. Exon-skipping and (in Europe) ribosomal read-through approaches are currently available to a subset of patients with Duchenne muscular dystrophy. Microdystrophin gene replacement has shown promise and is nearing the final stages of clinical trials. Numerous gene-based therapies for other muscular dystrophies and congenital myopathies are progressing toward approval as well.

SUMMARY Muscular dystrophies and congenital myopathies are a heterogenous group of hereditary muscle disorders. Confirming a diagnosis with genetic testing is not only critical for guiding management, but also an actual prerequisite for current and future gene therapies. Recessive loss-of-function or dominant haploinsufficiency disorders may be treated with gene replacement strategies, whereas dominant negative and toxic gain-of-function disorders are best addressed with a variety of knockdown approaches. It is important to recognize that many therapeutics are mutation specific and will only benefit a subset of individuals with a specific disease.

Address correspondence to Dr Andrew R. Findlay, 660 S Euclid Ave, Washington University School of Medicine, St. Louis, MO 63110, [email protected].

RELATIONSHIP DISCLOSURE: Dr Findlay has received personal compensation in the range of $500 to $4999 for serving as a consultant for Atheneum, Guidepoint, RiverVest and Triangle Insights Group. The institution of Dr Findlay has received research support from the American Academy of Neurology, the American Society for Gene and Cell Therapy, the Children's Discovery Institute of Washington University and St. Louis Children's Hospital, the LGMD-1D DNAJB6 Foundation and International Registry, and the National Institutes of Health. Dr Weihl has received personal compensation in the range of $500 to $4999 for serving as a consultant or on a scientific advisory or data safety monitoring board for Abata Therapeutics, Acceleron Pharma, Casma Therapeutics, and Sarepta Therapeutics.

UNLABELED USE OF PRODUCTS/INVESTIGATIONAL USE DISCLOSURE: Drs Findlay and Weihl report no disclosure.