Charcot–Marie–Toothneuropathies: Current gene therapy advances and the route toward translation

Abstract

Charcot–Marie–Tooth (CMT) neuropathies are a group of genetically and phenotypically heterogeneous disorders that predominantly affect the peripheral nervous system. Unraveling the genetic and molecular mechanisms, as well as the cellular effects of CMT mutations, has facilitated the development of promising gene therapy approaches. Proposed gene therapy treatments for CMTs include virally or non‐virally mediated gene replacement, addition, silencing, modification, and editing of genetic material. For most CMT neuropathies, gene‐ and disease‐ and even mutation‐specific therapy approaches targeting the neuronal axon or myelinating Schwann cells may be needed, due to the diversity of underlying cellular and molecular‐genetic mechanisms. The efficiency of gene therapies to improve the disease phenotype has been tested mostly in vitro and in vivo rodent models that reproduce different molecular and pathological aspects of CMT neuropathies. In the next stage, bigger animal models, in particular non‐human primates, provide important insights into the translatability of the proposed administration and dosing, demonstrating scale‐up potential and safety. The path toward clinical trials is faced with further challenges but is becoming increasingly feasible owing to the progress and knowledge gained from clinical applications of gene therapies for other neurological disorders, as well as the emergence of sensitive outcome measures and biomarkers in patients with CMT neuropathies.

Molecular mechanisms and therapeutic strategies for neuromuscular diseases

“…Gene replacement strategies have been tested at preclinical level for both demyelinating and axonal CMTs, where the genes of interest have been expressed using AAV9 [ 85 , 88 ]. Following systemic delivery or via intracerebroventricular (i.c.v.)…”

Clinical trials in Charcot-Marie-Tooth disorders: a retrospective and preclinical assessment

“…From the PubMed search of animal gene therapy studies in CMT, 27 articles were most recently identified in July 2023 ( 10 ), with the most relevant studies with references listed ( Table 1 ). Targeted gene therapy approaches include utilization of viral delivery by LV ( n = 4), AAV ( n = 9), CRISPR-Cas9 ( n = 2), squalene nanoparticles ( n = 1), and antisense oligonucleotides ( n = 1).…”

AAV-mediated editing of PMP22 rescues Charcot-Marie-Tooth disease type 1A features in patient-derived iPS Schwann cells

“…No therapeutics that directly target CMT1A have proven clinical effects on CMT1A. As summarized in recent reviews 9 , 10 , various therapeutics currently developed include indirect methods to increase viability of Schwann cells and/or neurons and direct approaches to decrease PMP22 protein expression. Preclinical studies in rodent models suggested that soluble neuregulin-1 54 , 55 , AAV1-mediated delivery of neurotrophin-3 (NT3) 56 , P2X7 receptor inhibition 57 , shRNA 15 , AAV-mediated expression of miRNA 16 , and antisense oligonucleotides targeting PMP22 7 could improve CMT1A pathology.…”

“…Presently, no therapeutic interventions are available whose effects are clinically confirmed for CMT or CMT1A 6 , 9 , 10 . Primary management includes physiotherapy and occupational therapy and in some cases non-steroidal anti-inflammatory drugs (NSAIDs) or antidepressants to manage pain 6 – 10 , 12 .…”

“…There are a number of mouse models of CMT1A 9 , 10 , 14 , 17 – 20 to examine the idea. However, they are transgenic mouse or rats overexpressing PMP22, and there is no knock-in animal model possessing PMP22 gene tandem duplication with sufficiently long flanking genome regions.…”