Advanced Gene-Targeting Therapies for Motor Neuron Diseases and Muscular Dystrophies

Abstract

Gene therapy is a revolutionary, cutting-edge approach to permanently ameliorate or amend many neuromuscular diseases by targeting their genetic origins. Motor neuron diseases and muscular dystrophies, whose genetic causes are well known, are the frontiers of this research revolution. Several genetic treatments, with diverse mechanisms of action and delivery methods, have been approved during the past decade and have demonstrated remarkable results. However, despite the high number of genetic treatments studied preclinically, those that have been advanced to clinical trials are significantly fewer. The most clinically advanced treatments include adeno-associated virus gene replacement therapy, antisense oligonucleotides, and RNA interference. This review provides a comprehensive overview of the advanced gene therapies for motor neuron diseases (i.e., amyotrophic lateral sclerosis and spinal muscular atrophy) and muscular dystrophies (i.e., Duchenne muscular dystrophy, limb-girdle muscular dystrophy, and myotonic dystrophy) tested in clinical trials. Emphasis has been placed on those methods that are a few steps away from their authoritative approval.

Keywords: gene-targeting therapy; motor neuron disorders; muscular dystrophies.

Figure 1

Status of the most advanced gene therapies for motor neuron diseases and muscular dystrophies. In ALS, in which the pathology is located both in upper and lower motor neurons, the most advanced GRT has reached phase 2, the most advanced ASO has reached phase 3, and the most advanced RNAi drug has reached phase 1. In SMA, a disease of the lower motor neurons, both a GRT and an ASO, have gained FDA approval and are currently tested in phase 4 clinical trials. In DMD, a disorder that targets the muscles, GRTs are presently tested in phase 3 clinical trials, whereas ASOs have gained FDA approval. In LGMD, which is also a muscle disorder, GRTs are currently tested in phase 3 clinical trials. In DM, both ASOs and RNAi drugs have reached phase 3 of clinical trials. Abbreviations: ALS, amyotrophic lateral sclerosis; GRT, gene-replacement therapy; ASO, antisense oligonucleotide; RNAi, RNA interference; SMA, spinal muscular atrophy; DMD, Duchenne muscular dystrophy; LGMD, limb-girdle muscular dystrophy; DM, myotonic dystrophy.