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Hum Mol Genet. 2019 Jun 22. pii: ddz131. doi: 10.1093/hmg/ddz131. [Epub ahead of print]

Genetic approaches to the treatment of inherited neuromuscular diseases.

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Department of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109.
Department of Neurology, University of Michigan Medical School, Ann Arbor, MI 48109.
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109.


Inherited neuromuscular diseases are a heterogeneous group of developmental and degenerative disorders that affect motor unit function. Major challenges toward developing therapies for these diseases include heterogeneity with respect to clinical severity, age of onset, and the primary cell type that is affected (e.g. motor neurons, skeletal muscle, and Schwann cells). Here, we review recent progress toward the establishment of genetic therapies to treat inherited neuromuscular disorders that affect both children and adults with a focus on spinal muscular atrophy, Charcot-Marie-Tooth disease, and spinal and bulbar muscular atrophy. We discuss clinical features, causative mutations, and emerging approaches that are undergoing testing in preclinical models and in patients or that have received recent approval for clinical use. Many of these efforts employ antisense oligonucleotides to alter pre-mRNA splicing or diminish target gene expression and use viral vectors to replace expression of mutant genes. Finally, we discuss remaining challenges for optimizing the delivery and effectiveness of these approaches. In sum, therapeutic strategies for neuromuscular diseases have shown encouraging results, raising hope that recent strides will translate into significant clinical benefits for patients with these disorders. Remarkable progress during the last several decades has defined causative mutations that drive pathogenesis in a large number of inherited neuromuscular diseases. Mechanistic studies have uncovered diverse consequences of disease-causing mutations, including both loss-of-function and toxic gain-of-function effects that often occur concurrently to contribute to pathogenesis. This complexity reverberates as dysfunction in an unexpectedly large number of pathways. As a result, therapeutically targeting any of one of these downstream pathways most often leads to incomplete or inadequate clinical responses. To address this challenge, recent therapeutic efforts for inherited neuromuscular diseases have focused on the mutant protein or gene as the proximal mediator of pathogenesis, often using emerging technologies to drug these targets. We review recent progress in developing genetic therapies for three types of neuromuscular disease. We highlight efforts toward treating disorders that affect children (spinal muscular atrophy [SMA]) and adults (Charcot-Marie-Tooth [CMT] disease and spinal and bulbar muscular atrophy [SBMA]). Foundational work on these disorders is aimed at identifying disease-specific clinical outcome measures that are both sensitive and reliable. These quantitative metrics are essential for evaluating efficacy in the clinic. Additional significant challenges are notable for therapy development. For adult onset diseases, a slowly worsening clinical course can make it difficult to measure rescue of disease progression during clinical trials that may last a year or less. Moreover, experiences in model systems suggest that beneficial effects may be most robust when interventions occur early in disease course. However, this can be challenging to achieve, as treatment of asymptomatic adults is not standard practice yet age of disease onset is often poorly defined. Limitations of current genetic approaches are also important to consider. Poor uptake of therapeutic oligonucleotides and limited accessibility to or durability of viral vectors in critical target cells raise the likelihood of partial treatment responses. Moreover, gene therapy approaches are presumably irreversible, potentially providing sustained benefits but also raising the specter of long-term untoward effects. While these issues present notable hurdles to translating approaches to the clinic, there has also been striking progress. We start by reviewing recent successes in the treatment of SMA, as this progress may provide a framework that is applicable to other neuromuscular diseases.


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