Challenges in Treating Charcot-Marie-Tooth Disease and Related Neuropathies: Current Management and Future Perspectives

Abstract

There is still no effective drug treatment available for Charcot-Marie-Tooth neuropathies (CMT). Current management relies on rehabilitation therapy, surgery for skeletal deformities, and symptomatic treatment of pain; fatigue and cramps are frequent complaints that are difficult to treat. The challenge is to find disease-modifying therapies. Several approaches, including gene silencing, to counteract the PMP22 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 or insert novel ones and compounds acting on pathways important for different CMT types are being developed and tested in animal models. 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.

Keywords: CMT; clinical trials; gene silencing; gene therapy; inherited neuropathy; management; therapy.

Figure 1

Partial silencing of PMP22 gene (a–d) and gene therapy against CMT1A and CMTX1 (e,f) in different rodent models. (a) ASOs decrease PMP22 mRNA in affected nerves in two CMT1A mouse models. (b) siRNAs conjugated to squalene nanoparticles normalise Pmp22 protein levels in two CMT1A mouse models. (c) AAV serotype 9 viral vectors expressing shRNA directed against PMP22 mRNA restore wild-type expression levels of PMP22 in CMT1A rats. (d) Liposome encapsulated sgRNAs delete the PMP22 TATA-box by CRISPR-Cas9 editing in a mouse model of CMT1A. (e) AAV1.NT-3 gene therapy in transgenic mouse models (TremblerJ and Cx32 knockout mice) and planned in three CMT1A patients. (f) Gene delivery using lentivirus or AAV9 vectors and a myelin-specific MPZ promoter to target murine Schwann cells (Sh3tc2^−/− and Cx32 knockout mice). For each approach, the route of administration is also indicated in parentheses.

Figure 2

Neuregulin1/ErbB signalling determines myelin sheath thickness. Neuregulin1 type III (Nrg1-III) has an epidermal growth factor-like (EGF-like) domain and contains a cysteine-rich domain (CRD) embedded in the lipid bilayer, which leaves the N-terminal side tethered to the membrane. Nrg1-III, produced by axons, is proteolytically cleaved by proteases of the ADAM family and BACE1. The BACE1 and TACE (also known as ADAM17) secretases are Nrg1-III regulators with opposite actions, the first by enhancing its activity and thus increasing myelin thickness, whereas the latter has an inhibitory effect. Nrg1-III provides the ligand for ErbB3 receptor leading to its heterodimerisation with ErbB2, activation of the tyrosine kinase domain, and phosphorylation of the cytoplasmic region of the ErbB partner. This event causes various adaptors/effectors’ (e.g., Ras-Shc, PI3K) recruitment and activation of multiple intracellular signalling pathways such as the PI3K–Akt and MAPK/Erk pathways in the Schwann cell.