Department of Neurology, Dongguk University Gyeongju Hospital, Dongguk University College of Medicine, Gyeongju, Korea
Correspondence to Jin-Mo Park Department of Neurology, Dongguk University Gyeongju Hospital, Dongguk University College of Medicine, 87 Dongdae-ro, Gyeongju 38067, Korea Tel: +82-54-770-8215 Fax: +82-54-770-8503 E-mail: neuropjm@gmail.com
• Received: February 15, 2026 • Revised: May 11, 2026 • Accepted: May 12, 2026
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Charcot-Marie-Tooth disease (CMT) comprises a genetically and clinically heterogeneous group of inherited peripheral neuropathies and remains a major indication for gene-based diagnostic evaluations in neuromuscular practice. Although supportive management has traditionally been applied across most subtypes, there has recently been a notable expansion of disease-modifying approaches due to advances in molecular diagnostics and accumulating preclinical and early clinical evidence. Improved genetic classification, including the recognition of metabolically defined and potentially treatable subtypes, has increased diagnostic precision and the development of subtype-specific therapeutics, with an increasing emphasis on mechanism-based stratification. This review summarizes recent progress in inherited neuropathies from a clinical perspective. We describe ongoing developments in clinical interventions, including combination pharmacotherapy for Charcot-Marie-Tooth disease type 1A (CMT1A), pathway-targeted therapy for CMT associated with sorbitol dehydrogenase deficiency and related metabolic neuropathies, and early biological and gene-based approaches that are being applied in selected subtypes. We also review the evolving preclinical approaches aimed at normalizing the peripheral myelin protein 22 dosage in CMT1A and gene-replacement and other precision therapies for loss-of-function and dominant-negative conditions. Because many subtypes of CMT progress slowly and conventional clinical scales have low sensitivity, we further discuss recent advances in the approaches used in clinical trials, including the refinement of clinical outcome assessments and the identification of candidate biomarkers such as the magnetic resonance imaging-based muscle fat fraction and the circulating level of neurofilament light chain. Collectively these developments are making subtype-specific therapeutic approaches increasingly feasible, although continued progress will depend on aligning disease biology, therapeutic approaches, and outcome measurements.
Charcot-Marie-Tooth disease (CMT) refers to a heterogeneous group of inherited peripheral neuropathies characterized by length-dependent motor and sensory impairments that are frequently accompanied by foot deformities and gait disturbance. The clinical presentation varies widely with in terms of the age at onset, progression rate, and severity, which reflects substantial underlying biological diversity. Although the traditional distinction between demyelinating and axonal neuropathy remains useful in initial clinical evaluations, this distinction has become increasingly inadequate for therapy development since disease mechanisms and treatment approaches are often determined at the gene-and variant-specific level rather than by the electrophysiological category alone.1
Advances in genetic testing over the past decade have substantially improved diagnostic outcomes in CMT. The widespread use of copy-number analysis, next-generation sequencing panels, and exome or genome sequencing has increased the diagnostic yield and enabled more-precise molecular stratification. This progress has had direct implications for the development of new therapies by clarifying disease mechanisms and identifying subtypes with distinct therapeutic vulnerabilities. For example, peripheral myelin protein 22 (PMP22) overexpression causes CMT1A via gene duplication, which makes dosage normalization a rational therapeutic objective, whereas many autosomal recessive subtypes represent loss-of-function states that may be more amenable to gene-replacement approaches.2 In dominant axonal subtypes, pathogenic mechanisms may involve dominant-negative or toxic gain-of-function effects that necessitate more-precise therapeutic approaches.3
The therapeutic inventions for CMT have widened in parallel with these diagnostic advances. Clinical interventions now include combination pharmacotherapy for CMT1A, pathway-directed treatment for metabolically defined neuropathies such as CMT-SORD, and early biological and gene-based interventions in selected subtypes.2 At the same time, limitations of traditional clinical outcome measures in slowly progressive neuropathies have highlighted the importance of trial readiness, including refinement of clinical outcome assessments and development of responsive biomarkers.4 In addition to traditional classification approaches, emerging frameworks increasingly emphasize the mechanism-based categorization of CMT, including gene-dosage abnormalities, loss-of-function conditions, dominant-negative or toxic gain-of-function mechanisms, and metabolically defined neuropathies. This framework is directly relevant to therapeutic development, as each category aligns with distinct therapeutic strategies.
The purpose of this review is to provide a clinical synthesis of recent developments in therapeutic interventions for inherited neuropathies, with a focus on subtype-specific therapeutic interventions and the evolving infrastructure required to support effective clinical trials.
GENETIC DIAGNOSIS AND CLASSIFICATION RELEVANT TO THE STRATIFICATION OF THERAPEUTIC INTERVENTIONS
Clinical evaluations of suspected inherited neuropathies traditionally integrate phenotype, family history, neurophysiology, and targeted laboratory testing; this is followed by genetic confirmation, for which there have been substantial developments. Detecting copy-number variations remains essential for common dosage disorders such as PMP22 duplication in CMT1A and PMP22 deletion in hereditary neuropathy with liability to pressure palsies. Next-generation sequencing panels as well as exome and genome sequencing are now routinely used to cover the large genetic heterogeneity. Diagnostic refinement increasingly depends on careful variant interpretation in the context of the phenotype and inheritance, as well as awareness of metabolic and potentially treatable subtypes.2,5
From a therapeutic perspective, subtype classification increasingly aligns with practical mechanistic categories. The overexpression of PMP22 in CMT1A suggests that reducing transcript or protein levels toward physiological ranges can be disease-modifying. In contrast, many autosomal recessive CMT4 subtypes reflect loss-of-function states, making gene replacement conceptually suitable, although challenges related to tissue targeting, dose constraints, and safety remain.3 In dominant axonal subtypes such as CMT2A and CMT2D, pathogenic mechanisms may involve dominant-negative or toxic gain-of-function effects. These mechanisms have prompted interest in allele-specific silencing, combined knockdown-and-replacement approaches, and other precision approaches rather than straightforward gene addition.6-8
The identification of CMT-SORD as a relatively frequent, genetically defined metabolic neuropathy supports the therapeutic importance of a genetic diagnosis. This subtype was initially identified in large cohorts and subsequently confirmed in diverse populations and has reinforced the principle that molecular diagnosis can reveal metabolic vulnerabilities that are amenable to pharmacological interventions.9
DEVELOPMENTS IN CLINICAL INTERVENTIONS
While no disease-modifying therapies are currently approved for CMT, multiple candidates are undergoing clinical evaluations. Clinical interventions are heterogeneous and include the use of repurposed and pathway-directed small molecules, combination pharmacotherapy, and early biological and gene-based interventions. The inherent delay between when trials are performed and reported means that the evidence base comprises peer-reviewed reports with mechanistic rationales along with recent more-speculative clinical information.2
A summary of representative therapeutic approaches and their supporting evidence is provided in Table 1.
CMT1A COMBINATION PHARMACOTHERAPY AND EARLY BIOLOGICAL APPROACHES
CMT1A has remained a central focus of developments in clinical therapies due to its high prevalence and relatively uniform underlying mechanism. PXT3003 is an oral fixed-dose combination of baclofen, naltrexone, and sorbitol that has progressed through randomized clinical trials, and early phase 2 studies have established its feasibility and potential for therapeutic efficacy.10 The phase 3 placebo-controlled, randomized, double-blind, safety and efficacy study of four arm PXT3003 in CMT1A patients (PLEO-CMT) trial demonstrated a statistically significant benefit in the high-dose group,11 whereas the subsequent confirmatory PXT3003 randomized multicenter international efficacy and safety study in CMT1A research (PREMIER) trial did not meet its primary efficacy endpoint. These findings highlight the challenges of identifying treatment effects in slowly progressive neuropathies and the associated importance of trial design, endpoint sensitivity, and patient selection.
Beyond pharmacological approaches, biological approaches have started for early human evaluations. The intramuscular delivery of adeno-associated virus (AAV) serotype 1 encoding neurotrophin-3 has been explored for improving peripheral nerve regeneration and function and is supported by preclinical and translational data.12 Cell-based approaches have also been investigated in early-phase studies for CMT1A and other subtypes.2
METABOLIC NEUROPATHIES AND ALDOSE REDUCTASE INHIBITION
The identification of SORD deficiency as a relatively frequent inherited neuropathy has increased interest in therapies targeting the polyol pathway. Biallelic SORD variants lead to sorbitol accumulation, which provides a clear biochemical rationale for pharmacological interventions. The development of aldose reductase inhibitors has attracted considerable attention, with govorestat frequently cited as a leading clinical intervention.9 Epalrestat has also been discussed as a potential candidate, although subtype-specific clinical evidence of its efficacy in SORD-related neuropathy remains weak.13-15
GIANT AXONAL NEUROPATHY AND OTHER EMERGING INTERVENTIONS
Giant axonal neuropathy represents an inherited neurodegenerative disorder in which gene therapy has progressed to clinical trials. Early experience with intrathecal AAV-mediated gene delivery has provided valuable insights into delivery routes, safety considerations, and interpretations of early clinical and biomarker signals relevant to the broader inherited neuropathy field.2
There is a diversity of clinical investigations. The transient receptor potential vanilloid 4 (TRPV4)-related neuropathy associated with CMT2C manifestations such as vocal-cord and respiratory involvement has motivated investigations of TRPV4 inhibition as a targeted approach for symptomatic complications.5,16 Histone deacetylase 6 (HDAC6) inhibition has been supported by preclinical data across several neuropathy models and at least one HDAC6 inhibitor is undergoing early-phase clinical evaluations.3 Interventions aimed at improving skeletal muscle excitability have also entered clinical trials and may provide symptomatic benefit independent of the direct modification of nerve pathology.3
PRECLINICAL THERAPEUTIC APPROACHES
The preclinical approaches applied to inherited neuropathies have expanded markedly, with diverse technologies being adapted to peripheral nerve biology. There are three main types: 1) normalization of gene dosage in overexpression disorders, 2) gene replacement in loss-of-function states, and 3) precision approaches for dominant-negative or toxic gain-of-function contexts.3
THERAPEUTIC RATIONALE FOR PMP22 DOSAGE REDUCTION IN CMT1A
CMT1A is mechanistically distinct from many inherited neuropathies in that it arises from gene duplication and the consequent overexpression of PMP22, rather than from a loss of gene function. Experimental and clinical observations have consistently shown that both overexpression and underexpression of PMP22 disrupt myelin homeostasis, indicating that the integrity of peripheral nerves is highly sensitive to the PMP22 dosage. Accordingly, the therapeutic objective in CMT1A is not gene replacement but rather the normalization of PMP22 expression to physiological levels, with an estimated reduction of approximately one-third relative to the duplicated state.17-19
This dosage-sensitive pathogenic mechanism has driven the development of multiple molecular-level therapeutic interventions aimed at reducing PMP22 expression. These interventions include the use of antisense oligonucleotides and small interfering RNA designed to suppress PMP22 transcripts, viral-vector-mediated delivery of short hairpin RNA (shRNA) to achieve sustained knockdown, and emerging genome-editing approaches intended to correct or functionally silence the duplicated allele.20-23 Although there are substantial differences in delivery, durability, and risk profile between these approaches, they share a common mechanistic goal of restoring PMP22 expression to a range compatible with normal myelin function.
PMP22 DOSAGE NORMALIZATION IN PRECLINICAL MODELS
Based on the PMP22 dosage sensitivity in CMT1A, extensive preclinical studies have demonstrated that reducing PMP22 expression to near to physiological levels can reduce disease manifestations. Antisense oligonucleotides targeting PMP22 have reversed CMT1A-like phenotypes in rodent models, providing proof of concept for transcript-lowering approaches.20 Viral delivery approaches have similarly been used to introduce silencing constructs, including AAV2/9-mediated delivery of shRNA targeting PMP22, which prevented the development of pathological features and functional deficits in rat models when expression levels were carefully controlled.21
Genome-editing approaches that directly target regulatory elements controlling PMP22 expression have also been explored. In a CMT1A mouse model, clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9-mediated editing of the PMP22 TATA-box reduced PMP22 overexpression, improved myelination, and ameliorated electrophysiological and histopathological features of demyelinating neuropathy, providing in vivo proof of concept for transcriptional normalization.22 Complementary CRISPR-based approaches utilizing AAV have also been evaluated in human pluripotent stem cell models of Schwann cells, which identified partial reduction of the PMP22 duplication burden and normalization of expression with improvement in downstream cellular phenotypes.22
GENE REPLACEMENT FOR LOSS-OF-FUNCTION NEUROPATHIES
Gene replacement remains an attractive concept for inherited neuropathies caused by loss-of-function mutations. Experience with systemic AAV9 delivery in motor neuron disease has provided a broader technological framework, although peripheral nerve targeting poses distinct challenges.3 Gene-replacement approaches have been applied to several candidate neuropathies, with proof of concept achieved in multiple models; however, clinical translation requires issues related to the delivery route, biodistribution, dose-limiting toxicity, and durability to be addressed.3
PRECISION APPROACHES FOR DOMINANT AXONAL SUBTYPES
Dominant axonal CMT subtypes often involve mechanisms that complicate simple gene addition. TRPV4-related neuropathy is directly linked to pathogenic channel mutations, prompting interest in targeted channel modulation.5,16 Preclinical studies of mitofusin 2 (MFN2)-and glycyl-tRNA synthetase 1 (GARS1)-related neuropathies have explored allele-selective suppression and combined knockdown-and-replacement approaches aimed at reducing toxic alleles while preserving wild-type function.7,8
INVENTIONS AND OUTCOME MEASURES IN CLINICAL TRIALS
Traditional clinical scales often lack sensitivity due to the feasible trial durations being too short and the possibility of nonlinearities and ceiling or floor effects. Recent efforts have therefore focused on refining clinical outcome assessments and identifying objective biomarkers.4
Successive versions of the CMT neuropathy score (CMTNS) and Rasch-optimized disability scales have exhibited improved psychometric performance across age groups.24-26 The magnetic resonance imaging (MRI)-based muscle fat fraction is a sensitive biomarker whose relationship to meaningful functional change remains unclear.27,28 Tissue-based biomarkers such as skin transcriptomic signatures have also been proposed as markers of disease severity and progression in CMT1A.29,30
Blood-based biomarkers such as the circulating level of neurofilament light chain exhibit cross-sectional associations with disease severity in some cohorts.31 Longitudinal studies have found modest or subtype-specific effects and have raised concerns regarding responsiveness in adult CMT.32,33 These findings suggest that neurofilament light chain is useful for diagnostic or stratification purposes but is unlikely to be useful as a standalone progression biomarker in patients with slowly progressive disease.
Assessments of patients with CMT in both clinical practice and clinical trials should utilize a standardized clinical severity scale, most commonly the CMTNS or its examination-based derivatives, together with functional and disability measures such as Rasch-optimized scales (e.g., CMT examination score [CMTES] or overall neuropathy limitations scale [ONLS]). These measures can be used for both baseline characterization and longitudinal follow-up and in research settings and clinical trials they are often complemented by quantitative biomarkers. The MRI-based muscle fat fraction is one of the most sensitive measures of disease burden and progression, while the circulating level of neurofilament light chain is a supportive biomarker for disease stratification. A multimodal approach integrating clinical, functional, and biomarker- based assessments is therefore increasingly utilized to optimize patient selection and to improve the detection of treatment effects.
CONCLUSION
Research in CMT is increasingly guided by subtype-specific therapeutic hypotheses and early interventional studies. Clinical interventions now encompass pharmacological, metabolic, and biological approaches, while preclinical investigations aim at normalizing gene dosages and are based on gene-replacement and precision approaches. Continued progress will depend on advances in clinical trials, including the use of sensitive outcome measures and validated biomarkers. Improvements in genetic diagnoses and trial infrastructures will make subtype-specific therapeutic interventions increasingly feasible when there is appropriate alignment between the therapeutic approach, disease biology, and outcome measurements.
Notes
Conflicts of Interest
The author declares no conflicts of interest relevant to this article.
Table 1.
Clinical and preclinical therapeutic interventions in Charcot-Marie-Tooth disease
Disease subtype
Development stage
Strategy
Therapeutic modality
Key evidence
CMT1A
Clinical-stage
Combination pharmacotherapy
Baclofen + naltrexone + sorbitol (PXT3003)
Phase 2 randomized trial demonstrating feasibility and signal of efficacy;10 phase 3 trial evaluating efficacy and safety11
CMT1A
Preclinical
Neurotrophic support
AAV1-mediated NT-3 delivery
Functional and histological improvement following intramuscular gene delivery12
CMT1A
Phase 1 completed
Cell-based therapy
Mesenchymal stem cell-derived product (EN001)
First-in-human safety and feasibility data in inherited neuropathy2
CMT-SORD
Clinical-stage
Polyol pathway modulation
Aldose reductase inhibitor (govorestat)
Identification of SORD deficiency as a common, treatable neuropathy and translational rationale for sorbitol reduction9
CMT-SORD
Repurposing/exploratory
Polyol pathway modulation
Aldose reductase inhibitor (epalrestat)
Clinical experience with aldose reductase inhibition in peripheral neuropathy13-15
Giant axonal neuropathy
Early clinical
Gene replacement
Intrathecal AAV-mediated gigaxonin delivery
First-in-human intrathecal gene therapy experience with biomarker and clinical signals2
CMT2C
Preclinical/early clinical
Ion channel modulation
TRPV4 inhibition
Pathogenic TRPV4 mutations causing CMT2C and mechanistic channel dysfunction6,16
Axonal CMT
Early clinical
Axonal protection
HDAC6 inhibition
Broad preclinical efficacy across axonal and demyelinating neuropathy models3
CMT
Phase 2 completed
Muscle excitability enhancement
ClC-1 inhibition (NMD670)
Increased skeletal muscle excitability in human proof-of-mechanism studies2
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