Neuromuscular Disorders

Neuromuscular disorders (NMDs) are a broad and heterogeneous group of diseases affecting the peripheral nervous system and/or muscles. NMDs are largely genetic disorders. Their symptoms may include muscle weakness, contractures, cardiomyopathy, and/or peripheral neuropathy. Overall, they can lead to a shorter life expectancy. NMDs vary in terms of age of onset, severity, and prognosis. They are classified based on the patients and phenotype and genetic background and include, among others, the following diseases: spinal muscular atrophy (SMA), charcot-marie-tooth disease (CMT), amyotrophic lateral sclerosis (ALS), duchenne muscular dystrophy (DMD), and limb-girdle muscular dystrophy (LGMD).

Neuromuscular diseases have high phenotypic variability, with mutations in one gene often leading to different phenotypes. An example of this is individuals affected by a charcot-marie-tooth 1 A disease (CMT1A), carrying a copy of the PMP22 gene.

Genetic Modifiers in NMDs

Modifier genes belong to different pathways and are mainly involved in TGF-β signaling/extracellular matrix remodeling, endoplasmic reticulum metabolism, RNA turnover, nerve formation, growth and myelination, inflammation, and regeneration. There is an emerging concept that shared pathways can link a few modifier genes in the same disease and that shared molecular mechanisms can underlie several NMDs.

Delivery Methods for NMDs

• Cell Therapy

Repopulation of skeletal muscle with myoblasts has been proposed as a potential treatment for severe neuromuscular disorders. Owing to the challenge of obtaining enough human myoblasts, muscle progenitors have been derived from induced pluripotent stem cells (iPSCs) using conditional PAX7 expression. Engraftment of these cells into damaged muscles has been shown to improve muscle contractility in mdx mice. By means of genome engineering, patient-derived cells such as iPSCs can be genetically corrected, then used to repopulate dystrophic muscle and improve the muscle phenotype.

• Viral Gene Delivery

Viral vectors are currently the most likely candidates for systemic gene delivery or highly efficient delivery to cultured patient cells. AAVs are ideal vectors in part because AAV rarely integrates into the host genome and, instead, exists in an episomal state. Another prominent candidate for gene delivery is lentivirus. Adenovirus might also prove to be an effective gene delivery vector, as it has a much larger genome than AAV and remains episomal.

• Non-viral Gene and Protein Delivery.

In skeletal muscle, non-viral delivery approaches have included direct plasmid injection, oligonucleotides for exon skipping, and oligonucleotides for genome editing. Direct delivery of Cas9-gRNA ribonucleoprotein has been demonstrated in primary cells and in local settings in vivo, such as the inner ear, although systemic administration of ribonucleoprotein complexes will be considerably more challenging.

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