Restoring Protein Expression in Neuromuscular Conditions: A Review Assessing the Current State of Exon Skipping/Inclusion and Gene Therapies for Duchenne Muscular Dystrophy and Spinal Muscular Atrophy.
Abstract
The debilitating neuromuscular disorders Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA), which harm 1 in 5000 newborn males and 1 in 11,000 newborns, respectively, are marked by progressive muscle wasting among other complications. While DMD causes generalized muscle weakness due to the absence of the dystrophin protein, SMA patients generally face motor neuron degeneration because of the lack of the survival motor neuron (SMN) protein. Many of the most promising therapies for both conditions restore the absent proteins dystrophin and SMN. Antisense oligonucleotide-mediated exon skipping and inclusion therapies are advancing clinically with the approved DMD therapies casimersen, eteplirsen, golodirsen, and viltolarsen, and the SMA therapy nusinersen. Existing antisense therapies focus on skeletal muscle for DMD and motor neurons for SMA, respectively. Through innovative techniques, such as peptide conjugation and multi-exon skipping, these therapies could be optimized for efficacy and applicability. By contrast, gene replacement therapy is administered only once to patients during treatment. Currently, only onasemnogene abeparvovec for SMA has been approved. Safety shortcomings remain a major challenge for ...Continue Reading
References
Rescue of the spinal muscular atrophy phenotype in a mouse model by early postnatal delivery of SMN.
The TREAT-NMD DMD Global Database: analysis of more than 7,000 Duchenne muscular dystrophy mutations
Long-term microdystrophin gene therapy is effective in a canine model of Duchenne muscular dystrophy
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