I.10 Gene therapy and other novel treatment approaches for CMT

Abstract

There is still no effective drug treatment available for Charcot-Marie-Tooth disease (CMT). Current management relies on rehabilitation therapy, surgery for skeletal deformities, and symptomatic treatment. The challenge is to find disease-modifying therapies. Several approaches, including gene silencing (by means of ASO, siRNA, CRISPR-Cas9 editing) to counteract the <i>PMP22</i> gene overexpression in the most frequent CMT1A type are under investigation. PXT3003 is the compound in the most advanced phase for CMT1A, as a second phase-III trial is ongoing. Gene therapy to substitute defective genes (particularly in recessive forms associated with loss-of-function mutations) or insert novel ones (e.g., <i>NT3</i> gene) are being developed and tested in animal models. Novel treatment approaches are also aimed at developing compounds acting on pathways important for different CMT types. Modulation of the Neuregulin pathway determining myelin thickness is promising for both hypo-demyelinating and hypermyelinating neuropathies; intervention on Unfolded Protein Response seems effective for rescuing misfolded myelin proteins such as P0 in CMT1B. HDAC6 inhibitors improved axonal transport and ameliorated phenotypes in different CMT models. Other potential therapeutic strategies include targeting macrophages, lipid metabolism, and Nav1.8 sodium channel in demyelinating CMT and the P2X7 receptor, which regulates calcium influx into Schwann cells, in CMT1A. Further approaches are aimed at correcting metabolic abnormalities, including the accumulation of sorbitol caused by biallelic mutations in the sorbitol dehydrogenase (SORD) gene and of neurotoxic glycosphingolipids in HSN1.