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.

Gene Therapy in Pediatric Orthopedics

“…Corrective material in these cases can be delivered via viral/non-viral delivery systems. In DMD, GRT is not aimed at correcting specific mutations but rather restoring muscle function via the injection of truncated or muscle-protective enzymes [4]. To this avail, many gene replacement therapies/treatments aimed at perfecting truncated/muscleprotective enzymes to be used in DMD treatment are currently ongoing.…”

“…Micro-dystrophin targeting trials range from phase 1 to phase 3 and have expected finish dates from 2023 to 2028. Currently, three drugs are being developed for GRT targeting microdystrophin in DMD: SRP-9001 by Sarepta Therapeutics, PF-06939926 by Pfizer and SGT-001 by Solid Biosciences [4]. SRP-9001 is transmitted using vector rAAVrh74 and uses promoter MHCK7 to enhance cardiac dystrophin expression [4].…”

“…Currently, three drugs are being developed for GRT targeting microdystrophin in DMD: SRP-9001 by Sarepta Therapeutics, PF-06939926 by Pfizer and SGT-001 by Solid Biosciences [4]. SRP-9001 is transmitted using vector rAAVrh74 and uses promoter MHCK7 to enhance cardiac dystrophin expression [4]. SRP-9001 first showed promise in Study 102, a two-part phase 2 placebo-controlled trial.…”

A new era: Speckle tracking echocardiography and cardiomyopathies

“…Arrhythmias and conduction disease can be associated with the development of cardiomyopathy. 1,2 Limb-girdle muscular dystrophy (LGMD) is first defined in 1954 as a new entity, distinct from the other dystrophies. It is classified as autosomal dominant LGMD (LGMD1 or AD-LGMD) and autosomalrecessive LGMD (LGMD2 or AR-LGMD).…”

“…Limb‐girdle muscular dystrophy (LGMD) is a heterogeneous inherited disorder affecting the skeletal muscle and frequently also involve the heart and in LGMD; development of dilated cardiomyopathy is common and usually the predominant feature. Arrhythmias and conduction disease can be associated with the development of cardiomyopathy 1,2 …”