Charcot-Marie-Tooth disease (CMT) is the name for a diverse group of inherited peripheral neuropathies affecting 1 in 2500 people worldwide with over 100 known causative genes. The underlying pathology of CMT is divided into demyelinating forms (CMT1/CMT4), which cause defects in the development and maintenance of the Schwann cell myelin sheath, and axonal forms (CMT2), characterized by primary axonal degeneration, as well as intermediate subtypes with mixed features (CMT-I). All CMT subtypes share a common clinical phenotype of slowly progressive distal muscle weakness and atrophy, sensory loss, hypo-reflexia, and characteristic foot deformities. Current clinical management of CMT is limited to symptomatic care, making the development of disease-modifying treatment a top priority within the field. Decades of research to understand the cellular pathophysiology of individual CMTs have given rise to novel therapeutic strategies, many of which show great promise in preclinical testing and are poised to begin or have just entered first-in-human trials. Clinical translation of CMT therapeutics faces several important challenges: prompt genetic diagnosis, reliable tracking of disease progression, and safe/effective delivery of novel therapies to the human nerves.

Advances in clinical genetics allow for more reliable diagnosis of CMT than ever before. The broad availability and reduced cost of gene panels targeting the commonest CMT genes are now accessible to neuromuscular specialists even outside of major academic centers. More advanced tools, such as whole-exome or whole-genome sequencing, can help solve CMT cases not readily diagnosed with panel testing, though these strategies are less readily available as they require consultation with neurogenetic specialists due to the challenges of interpreting variants of unknown significance. Even with these technical advancements, up to 20% of CMT cases remain genetically unsolved, particularly CMT2. Early and accurate genetic diagnosis is essential to the deployment of novel therapies given the clear benefits of early intervention prior to the accumulation of irreversible axonal loss.

The slow clinical progression of CMT makes it challenging to select well-informed endpoints for clinical trials and necessitates the development of responsive biomarker strategies. Established functional scales (such as the CMT Neuropathy Score [CMTNS] and CMT Examination Score [CMTES]) remain fundamental for assessing patient disability, though they often lack the resolution to capture disease progression on shorter timescales. Blood neurofilament light (NfL) levels, reflecting axonal injury and breakdown, are elevated in CMT and function as a treatment-responsive biomarker in preclinical models but have shown limited correlation with human disease progression over the years. Another promising serum biomarker is Schwann cell protein periaxin, which was recently shown to reliably correlate specifically with demyelinating CMT disease severity, though further work is required to validate its role in monitoring disease progression and treatment response. Finally, quantitative MRI measuring intramuscular fat fraction in the calf and other levels has emerged as a particularly sensitive indicator of disease progression for CMT1A and the next 3 commonest CMT types, reliably detecting changes over 12 months missed by other strategies. Integrating quantitative imaging and serum biomarkers with existing clinical scales should improve the sensitivity of outcome assessment in future trials.

One of the most advanced clinical efforts targeting inherited neuropathy focuses on sorbitol dehydrogenase (SORD) deficiency, a common form of CMT2. Aldose reductase inhibitors (ARIs) are being tested, which prevent the accumulation of sorbitol, a toxic metabolic byproduct believed to cause osmotic injury to myelinated nerves. In an initial trial, the ARI Govorestat significantly reduced sorbitol levels and showed preliminary signs of slowing neuropathy progression. If confirmed, this targeted metabolic therapy could become the first approved disease-modifying treatment for CMT. Another major trial focuses on CMT1A, the commonest CMT form caused by PMP22 gene duplication, using PXT3003, an oral combination of three repurposed drugs designed to downregulate PMP22 expression. In a large Phase III study, PXT3003 achieved modest improvements in functional disability, though this was likely limited by resolution of outcome measures as discussed above.

Advances in genetic medicine offer the most promising path towards the development of disease-modifying treatments for CMT. Strategies under development include gene replacement (adding functional gene copies to replace defective ones), gene silencing (suppressing toxic gene products), and genome editing to correct pathogenic mutations. Proof-of-concept studies have shown success in animal models: for example, AAV-mediated gene delivery showed significant improvements in histopathological, electrophysiologic, and behavioral outcomes in a CMT1X and CMT4C models, and RNA interference (siRNA) targeting PMP22 showed similar efficacy in CMT1A models. Translating these therapies to patients faces major hurdles related to cost, efficiency, and safety. Nevertheless, a first clinical trial of gene silencing approach for CMT1A using fatty acid conjugated RNA interference has been recently launched, creating optimism for more advanced therapies in the near future.

At the moment, commercial manufacturing of these custom genetic treatments is limited and is costly. Treatment success requires widespread and efficient biodistribution into the human nervous peripheral nervous system, necessitating the validation of delivery tools in larger animal models such as non-human primates. Chemical modification of nucleic acids (such as the conjugation of siRNAs to squalene nanoparticles or fatty acids) or intrathecal delivery of viral vectors will likely be required to circumvent the blood-nerve-barrier and to facilitate entry into the nerves. Systemic AAV vectors also pose significant safety risks due to immune responses to the vector or its cargo, as well as end-organ injury from off-target expression, necessitating significant immunosuppression and close clinical monitoring. Finally, gene editing strategies carry an inherent risk of genotoxicity from persistent endonuclease activity in the treated patient. Ongoing advances in vector engineering and delivery strategies are gradually overcoming these barriers, bringing gene therapies closer to clinical reality.

Kleopas Kleopa, MD, PhD
Vice Chair, CMTR

Brendan Zotter, MD, PhD
Junior Representative, CMTR