Overview of Gene Therapy in Spinal Muscular Atrophy and Duchenne
Muscular Dystrophy
Abstract
Both 5q-linked spinal muscular atrophy (SMA) and Duchenne muscular
dystrophy (DMD) are fatal monogenic neuromuscular disorders caused by
loss-of-function mutations. SMA is an autosomal recessive disorder
affecting motor neurons that is typically caused by homozygous
whole-gene deletions of SMN1. DMD is an X-linked recessive muscle
disease most often due to exon deletions, but also duplications and
smaller sized variants within the DMD gene. Gene replacement therapy
offers the opportunity to correct the underlying genetic defect by the
introduction of a functional gene. We review the transformative work
from clinical trials to United States Food and Drug Administration
approval of onasemnogene abeparvovec-xioi in SMA and its application in
clinical practice and the early results of microdystrophin delivery in
DMD. We also review the introduction of antisense oligonucleotides to
alter pre-mRNA splicing to promote exon inclusion (as in nusinersen in
SMA) or exclusion (as in eteplirsen in DMD) into neuromuscular
therapeutics. There are multiple promising novel genetically mediated
therapies on the horizon, which in aggregate point towards a hopeful
future for individuals with SMA and DMD.