Gene therapy in neuromuscular disorders

Abstract

Monogenic neuromuscular disorders are potentially treatable through gene therapy. Using viral vectors, a therapeutic transgene aims to restore normal levels of a protein not produced by the defective gene, or to silence a gene whose expression leads to toxic effects. Spinal Muscular Atrophy (SMA) is a good example of a monogenic disease that currently has an AAV9-based vector gene therapy as a therapeutic option. In this review, we intend to discuss the viral vectors and their mechanisms of action, in addition to reviewing the clinical trials that supported the approval of gene therapy (AVXS-101) for SMA as well as neuromuscular diseases that are potentially treatable with gene replacement therapy.

Figure 1.. Main components of a gene therapy (in parentheses, AVXS-101 components are specified): Capsid of viral vector (scAAV9); therapeutic transgene (Human SMN1, deliver a copy of the gene encoding the SMN protein); and the “regulatory cassette,” the enhancer or promoter (Hybrid CMV enhancer and chicken beta-actin promoter activate the transgene to allow continuous and sustained expression of the SMN1 protein) and the termination signal or inverted terminal repeats (ITRs) (Self-complementary AAV ITRs increase the rate at which the double-stranded transgene is transcribed and the resulting protein is produced). Figure adapted from Wang D, Gao G. 2014