RARE DISEASE
Charcot-Marie-Tooth disease type 1A
Charcot-Marie-Tooth disease type 1A
Charcot-Marie-Tooth disease type 1A
Synonyms: CMT1A, Microduplication 17p12
Synonyms: CMT1A, Microduplication 17p12
Synonyms: CMT1A, Microduplication 17p12
Drug discovery
9
drugs
With orphan designations
Overview
Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common inherited neuropathy, caused by a PMP22 gene duplication on chromosome 17, leading to peripheral nerve demyelination. Autosomal dominant inheritance predominates, though 10% result from de novo mutations. Symptoms include distal muscle weakness/atrophy, pes cavus, hammertoes, sensory loss, and slowed nerve conduction velocities. Onset typically occurs in childhood with slow progression, preserved ambulation, and normal life expectancy [1][2][9][17].
Burden
Progressive mobility decline: 95% remain ambulatory, but 40% report frequent falls and balance issues [2][11][19].
Functional impact: Hand weakness, sensory deficits, and fatigue impair daily activities in >70% of patients [11][12].
Psychosocial burden: Chronic pain, disability, and limited treatment options reduce quality of life [11][19].
Therapies
Supportive care: Orthotics, physical therapy, and surgical correction of deformities [3][14].
Experimental agents: PXT3003 (baclofen/naltrexone/sorbitol) shows modest efficacy in trials; ascorbic acid lacks proven benefit [3][7][13].
Emerging therapies: Gene silencing (ASOs, RNAi) and PMP22 expression modulators in preclinical stages [7][16].
Categories: rare developmental anomalies during embryogenesis, rare genetic diseases, rare neurological diseases
Research Papers
675 drug discovery papers about Charcot-Marie-Tooth disease type 1A, with 4 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
675 drug discovery papers about Charcot-Marie-Tooth disease type 1A, with 4 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-22 | PXT3003: Lessons for therapeutic development in Charcot-Marie-Tooth disease type 1A and related neuropathies
Most drug development stories end predictably: promising compounds either succeed or fail. Occasionally, however, a therapy repeatedly returns from apparent extinction. PXT3003 for Charcot-Marie-Tooth disease type 1A (CMT1A) represents one such example. More than a decade after early promise, the program has survived formulation instability, interrupted clinical development, regulatory uncertainty, and controversy surrounding efficacy before re-emerging with renewed evidence of clinical benefit. Yet, as with many therapeutic development programs, interpretation of the available evidence is influenced by the extent to which findings are publicly accessible. In a recent issue of iScience , a phase 3 clinical trial evaluated PXT3003, a combination of baclofen, naltrexone, and D-sorbitol, versus placebo over 15 months in participants aged 16–65 years with mild-to-moderate CMT1A across 25 sites in China. PXT3003 is not simply the story of one drug; it highlights the scientific, methodological, operational, and reporting challenges of developing disease-modifying therapies for slowly progressive inherited neuropathies.
2026-09-04 | REPO-RARE: From Phenotypes to Spatial Disease Modules for Causal Therapy, Precision Medicine and Prevention
Current bioinformatics does not adequately represent disease mechanisms. Protein–protein interactomes often aggregate associations from different assays, cell types, subcellular locations, and biological states, producing networks whose neighbouring proteins may not form a functional unit in the relevant intact cell. Computational proximity alone therefore cannot establish causality, define a patient’s molecular disease state, or indicate how it should be corrected. REPO-RARE defines diseases as context-specific dysfunctional molecular modules rather than primarily by shared phenotypes, organs, or histopathology. Candidate modules generated from interaction data must be resolved in the relevant cell type, subcellular location, molecular state, and disease condition. Validation establishes their composition, causal relevance, and direction of dysfunction. The validated module then connects molecular diagnosis, mechanistic biomarkers, patient stratification, and therapy. Treatment is selected to restore module function by modulating a complementary component rather than suppressing downstream symptoms. Rare diseases are an ideal first application: their comparatively well-defined causal entry points provide a rapid, rigorous setting for testing the framework across multiple conditions. REPO-RARE will establish a reproducible route from causal gene to dysfunctional module, mechanistic biomarker, patient selection, and module-directed drug repurposing. The first RExPO’26 projects test complementary stages of this route. In SYNGAP1-related disorder, comparison of network and co-complex representations begins to resolve the context-specific organisation of the SynGAP protein environment [1]. In Charcot–Marie–Tooth disease type 1A, PMP22 provides the genetic entry point to a membrane-homeostasis module, with KCNN4/KCa3.1 prioritised as a candidate modulatory target [2]. In Duchenne muscular dystrophy, DMD-associated pathology is linked to dysfunction of the NOS–sGC module and a mechanistically directed drug-repurposing combination hypothesis [3]. Projects will be prioritised according to genetic causality, unmet need, therapeutic window, measurable module dysfunction, and repurposing potential. Success will be assessed through reproducible module validation and progression towards biomarker-guided therapeutic testing. By applying this framework across rare diseases, REPO-RARE aims to establish a general foundation for causal therapy, precision medicine, and, where intervention can precede irreversible damage, precision prevention. References Caune H, Hangul C, Kötting J, Casas AI, Schmidt HHHW. Network and co-complex representations identify distinct components of the SynGAP protein environment. RExPO’26 abstract. doi: 10.58647/REXPO26000198.v1. Kötting J, Schmidt HHHW. Network analysis of Charcot–Marie–Tooth disease type 1A prioritises a membrane-homeostasis module and KCNN4 as a candidate drug target. RExPO’26 abstract. doi: 10.58647/REXPO26000197.v1. Hangul C, Schmidt HHHW. Network medicine in Duchenne muscular dystrophy generates a mechanistic NOS–sGC-targeted drug-repurposing combination hypothesis. RExPO’26 abstract. doi: 10.58647/REXPO26000199.v1.
2026-08-27 | Tyrosine Supplementation Rescues a Growth Defect in a Humanized S. cerevisiae Model of YARS1 Associated with CMT-DI.
Dominant pathogenic mutations in tyrosyl-tRNA synthetase (YARS1) are associated with Charcot-Marie-Tooth disease (CMT), a progressive peripheral neuropathy for which no disease-modifying therapies currently exist. While recent advances in amino acid supplementation therapies suggest potential benefit for recessive aminoacyl-tRNA synthetase disorders, their applicability to dominant YARS1-associated neuropathies remains unclear. Here, we investigated the pathogenic mechanisms underlying the dominant YARS1 variants G41R, D81I, and E196Q. Using biochemical and functional analyses, we identified increased structural rigidity for G41R and E196Q proteins, while D81I is more susceptible to tryptic digestion. Furthermore, expression of the YARS1 variants in a humanized yeast model produced a dominant negative growth defect that is exacerbated at elevated temperatures, supporting disruption of canonical YARS1 function as a contributor to disease pathogenesis. Notably, tyrosine supplementation significantly rescued the observed growth defects across variants. These findings demonstrate that impaired tyrosine utilization contributes to the pathogenic effects of dominant YARS1 variants and provide proof-of-concept evidence that tyrosine supplementation may represent a potential therapeutic strategy for patients with YARS1-associated CMT.
2026-08-22 | Network analysis of Charcot-Marie-Tooth Disease Type 1A prioritises a membrane-homeostasis module and KCNN4 as a candidate drug target
Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common inherited demyelinating peripheral neuropathy and is caused by duplication of the peripheral myelin protein 22 (PMP22) gene [1,2]. Despite more than three decades of research, the molecular mechanisms linking PMP22 overexpression to progressive demyelination remain incompletely understood, and no disease-modifying therapy exists.[2,3] We asked whether expanding PMP22 into a protein-protein interaction (PPI) network could integrate fragmented CMT1A biology and generate testable pathomechanistic and drug-repurposing hypotheses. Using PMP22 as the sole seed protein, we generated a first-neighbour PPI network using the Drugst.One DREAM tool [4,5] on the REPO4EU platform alpha version. The resulting network was refined by subnetwork participation degree pruning, community detection, and expert-guided functional annotation to identify biologically coherent modules, formulate mechanistic hypotheses, and predict repurposing candidates. The analysis yielded a 21-protein module centred on membrane biology, including PMP22, MPZ, EMP1, KCNN4, GPR61 and SDC4, and linked it to modules related to endoplasmic-reticulum quality control/proteostasis, lipid synthesis/trafficking and immune/inflammatory processes. This topology-derived representation organised these processes into a mechanistic hypothesis centred on myelin-membrane homeostasis. Within the membrane-centred module, KCNN4 (KCa3.1) emerged as a candidate effector potentially coupling intracellular calcium signals to potassium efflux, membrane potential and cellular homeostasis. KCNN4 is therefore prioritised as a candidate drug target in CMT1A, while pharmacological inhibition of KCa3.1 with the selective inhibitor senicapoc is proposed as a testable drug-repurposing hypothesis [6,7]. Because this prioritisation is topology- and expert-annotation-dependent, it does not establish disease causality or therapeutic efficacy. We propose preclinical validation in relevant models such as patient-specific iPSC-derived Schwann cells or Schwann cell precursors [8], the C3-PMP22 transgenic mouse [9] or the humanised PMP22-C3 mouse [9].
2026-07-15 | PXT3003 in CMT1A Phase III Multicenter Clinical Trial Dataset
This dataset contains the raw data and analysis materials related to the phase III multicenter clinical trial of PXT3003 in CMT1A patients. It includes de - identified individual patient data, statistical analysis files, etc., which can support the conclusions of the relevant paper
proteins
2026-09-21 | Ciliary neurotrophic factor slows axonal transport of signalling endosomes.
Efficient axonal transport is essential for maintaining neuronal function, enabling the bidirectional delivery of diverse cargoes between the cell body and distal compartments. In the neuromuscular system, neurotrophic factors regulate motor neuron survival, function and synaptic connectivity, in part, through retrograde trafficking of activated neurotrophic factor-receptor complexes from the neuromuscular junction to the cell body. We recently demonstrated that brain-derived neurotrophic factor stimulation to muscles selectively enhances retrograde transport of signalling endosomes in fast, but not slow, motor neurons in vivo. Moreover, both axonal endosome transport and its brain-derived neurotrophic factor-mediated regulation are disrupted in mouse models of diseases impacting motor neurons, including amyotrophic lateral sclerosis and Charcot-Marie-Tooth disease. Here, we examined whether additional neurotrophic factors, when applied to distal axon terminals, share this transport-modulating property. Through imaging sciatic nerves in anaesthetised mice, we tracked the in vivo dynamics of signalling endosomes in fast and slow motor neurons via intramuscular injections of a fluorescent atoxic fragment of tetanus neurotoxin. These injections were co-administered with ciliary neurotrophic factor, hepatocyte growth factor, neurturin, or cleavage-resistant pro-brain-derived neurotrophic factor-four growth factors with known effects on motor neurons. Compared to vehicle-treated controls, pro-brain-derived neurotrophic factor, hepatocyte growth factor and neurturin produced no detectable change in transport dynamics. In contrast, ciliary neurotrophic factor markedly reduced endosome speeds in both fast and slow motor neurons, indicating remarkable selectivity of specific neurotrophic factors in the regulation of signalling endosome transport in motor neurons. Understanding this selectivity may aid the development of muscle-targeted neurotrophic factor-based therapeutic strategies aimed at restoring axonal transport in neurodegenerative disease, peripheral neuropathy and nerve injury.
2026-01-01 | Schmidt-Lanterman incisures in the Schwann cell and their role for peripheral nerve regeneration
Schmidt-Lanterman incisures (SLIs) are cytoplasmic channels within compact peripheral myelin, yet their formation and functional relevance in health and disease remain incompletely understood. This study investigates SLI development, their regulation across the lifespan, and their role in neuropathy and nerve regeneration. Using immunofluorescence and high-pressure freezing electron microscopy of developing murine sciatic nerves, we show that SLIs arise early during myelin formation. During development, SLI number increases in parallel with internodal elongation and remains stable in adulthood and aging, indicating an essential role in Schwann cell maturation and myelin maintenance. In mouse models of PMP22-associated neuropathies (CMT1A and HNPP), SLI number is altered in a dosage-dependent manner: increased in PMP22-duplication and transiently reduced during early development in PMP22-deletion. Similarly, sural nerve biopsies from patients with demyelinating neuropathy reveal increased SLI numbers, particularly in short internodes, suggesting a compensatory function in disease. Following sciatic nerve crush injury, mice with reduced SLI numbers (VCLcKO) exhibit delayed motor recovery and fail to upregulate SLIs, in contrast to wildtype controls. These findings support a critical role of SLIs in preserving nerve function and promoting regeneration, potentially by facilitating axo-glial communication and metabolic support. Together, this work identifies SLIs as dynamic and regulated structures essential for peripheral nerve development, maintenance, and repair, highlighting their potential as targets for therapeutic strategies to enhance nerve regeneration.
2025-05-21 | Combining dynamin 2 myopathy and neuropathy mutations rescues both phenotypes.
Mutations within a single gene can lead to diverse human genetic diseases affecting highly specialized tissues. Notably, dominant mutations in the DNM2 gene, encoding the mechanoenzyme dynamin, lead to distinct neuromuscular disorders: centronuclear myopathy (CNM) and Charcot-Marie-Tooth neuropathy (CMT). CNM is characterized by myofiber structural anomalies while CMT presents peripheral nerve defects, both culminating in muscle weakness and atrophy. Despite their shared genetic origin, the mechanisms driving these diseases remain elusive, and no cure is available. Here, we present in vitro assays underlining opposing effects of DNM2 mutations, gain-of-function in CNM and loss-of-function in CMT. In vivo, we explored the potential compensatory effects of CNM and CMT mutations by breeding Dnm2S619L/+ CNM with Dnm2K562E/+ CMT mouse models. Dnm2S619L/K562E offspring exhibit strongly improved motor coordination and muscle strength and mass, compared to single-mutant littermates. Dnm2S619L/K562E mice present normalized muscle structure and nerve fiber organization. This study reveals that two distinct disease-causing mutations within the DNM2 gene compensate each other in vivo, leading to corrections of most individual phenotypes. The inverse modulation of DNM2 activity emerges as a promising therapeutic strategy to address CNM and CMT diseases.
2023-06-01 | Cytokine-Induced Neurogenesis in Charcot-Marie-Tooth neuropathy with Connexin 32 Gene Mutation
Charcot-Marie-Tooth (CMT) neuropathy is one of the most common neuromuscular disorders.Despite the identification of more than 100 causative genes, there are few therapeutic options.We present the case of a 66-year-old man carrying a CMT mutation in the connexin 32 gene with the APOE genotype ε4/ε3 that had exhibited symptoms of slowly progressive muscle weakness and atrophy in the hands and feet and recently developed memory impairment.The muscle weakness, motor dysfunction, and memory impairment symptoms were significantly improved by cytokine-induced neurogenesis combined with physical wave therapy using an arbitrary waveform generator (AWG).Here, we discuss the possible mechanistic basis of how this new treatment ameliorates the symptoms of CMT and propose a novel clinical treatment strategy for CMT.
2023-05-05 | TGFβ4 alleviates the phenotype of Charcot–Marie–Tooth disease type 1A
The duplication of the peripheral myelin protein 22 (PMP22) gene causes a demyelinating type of neuropathy, commonly known as Charcot-Marie-Tooth disease type 1A (CMT1A). Development of effective drugs for CMT1A still remains as an unmet medical need. In the present study, we assessed the role of the transforming growth factor beta 4 (TGFβ4)/Nodal axis in the pathogenesis of CMT1A. First, we identified PMP22 overexpression-induced Nodal expression in Schwann cells, which might be one of the downstream effectors in CMT1A. Administration of Nodal protein at the developmental stage of peripheral nerves induced the demyelinating phenotype in vivo. Second, we further isolated TGFβ4 as an antagonist that could abolish Nodal-induced demyelination. Finally, we developed a recombinant TGFβ4-fragment crystallizable (Fc) fusion protein, CX201, and demonstrated that its application had promyelinating efficacy in Schwann cells. CX201 administration improved the demyelinating phenotypes of CMT1A mouse models at both pre-symptomatic and post-symptomatic stages. These results suggest that the TGFβ4/Nodal axis plays a crucial role in the pathogenesis of CMT1A and might be a potential therapeutic target for CMT1A.
gene therapies
2026-09-17 | Distinct small-fiber dysfunction profiles in CMT1A and RFC1 disease: a multimodal study.
Charcot-Marie-Tooth disease 1A (CMT1A) and Cerebellar Ataxia, Neuropathy, Vestibular Areflexia Syndrome (CANVAS)/Replication Factor Complex subunit 1 (RFC1)-related disease affect large nerve fibers, but small fiber dysfunction may contribute to pain and dysautonomia. We applied a multimodal protocol, including potentials elicited by a micropatterned electrode targeting intraepidermal nerve endings, to characterize small fiber involvement. In this cross-sectional study, healthy controls (HC) and patients with CMT1A or RFC1 disease underwent neurologic examination, autonomic assessment with the composite autonomic symptom score-31 (COMPASS-31) and compound autonomic dysfunction test (CADT), electrochemical skin conductance (ESC), nociceptive evoked potentials (NEPs), pain-related evoked potentials (PREPs), somatosensory evoked potentials (SEPs), and skin biopsy. Twenty-one patients with CMT1A, 16 with RFC1 disease, and 21 HC were included. Neuropathic pain occurred in 33% of CMT1A and 81% of RFC1 patients. Dysautonomia was prominent in RFC1 disease, with abnormal CADT scores in 94%, COMPASS-31 scores of 7-46, and abnormal ESC in 63%, compared with 24% in CMT1A. N40 NEP latencies were prolonged in both patient groups versus HC (p<0.001), with absent responses in 33% and 44%, respectively. PREPs showed prolonged N2 latencies in CMT1A (p=0.003), with absent N2 responses in 57%; in RFC1 disease, N2 responses were absent in 50%. Skin biopsy showed length-dependent intraepidermal nerve fiber density loss in CMT1A and severe non-length-dependent epidermal denervation in RFC1 disease. Multimodal assessment integrating ESC, NEPs, PREPs, and skin biopsy identifies distinct Aδ- and C-fiber dysfunction patterns in CMT1A and RFC1 disease and may support phenotyping and small-fiber biomarker development in peripheral neuropathies.
2026-08-17 | Neuronal Prps is required for synaptic development and motor function in Drosophila melanogaster.
Phosphoribosyl pyrophosphate synthetase (PRPS) produces phosphoribosyl pyrophosphate, which is a key precursor for nucleotide biosynthesis. Mutations in the human PRPS1 gene cause Charcot-Marie-Tooth disease and other neuropathies. However, how PRPS1 dysfunction impairs neuronal and synaptic function remains unclear. In this study, we used Drosophila melanogaster to determine the effects of reduced Prps expression on neurons in vivo. Neuronal knockdown of Prps caused severe locomotor impairment in third instar larvae and in adults, which indicated a critical requirement for Prps in motor output. At the neuromuscular junction, Prpsdepletion led to a reduced number of synaptic boutons accompanied by enlargement of boutons, disrupted presynaptic active zone organization indicated by decreased Bruchpilot puncta, and loss of Futsch-positive microtubule loops. These findings suggested destabilization of cytoskeletal architecture. These phenotypes were consistently observed using independent RNAi lines. Importantly, neuronal expression of Drosophila Prps or human PRPS1 significantly rescued locomotor activity, synaptic growth, active zone organization, and microtubule structure, which are caused by the expression of the Prps short hairpin RNA. The rescue by Drosophila Prps and human PRPS1 highlights evolutionary conservation of PRPS1 function and suggests Drosophila as a model for analyzing PRPS1-associated neuropathies.
2026-07-12 | High-Resolution Ultrasound Evaluation of Nerves and Muscles at Multiple Sites in Charcot-Marie-Tooth Disease.
To characterize nerve cross-sectional area (CSA) and muscle thickness at multiple sites in Charcot-Marie-Tooth disease (CMT) using high-resolution ultrasound (HRUS), with emphasis on CMT1A and comparisons with healthy controls. Fifty-nine genetically confirmed CMT patients (including CMT1A, CMT1B, CMTX1, and CMT2A) and 42 healthy controls underwent HRUS evaluation of 7 nerves (median, ulnar, radial, sciatic, tibial, common peroneal, and vagus) at 20 predefined anatomical sites, along with measurements of peroneus longus and tibialis anterior thickness. In CMT1A, we assessed correlations between CSA and clinical severity (Charcot-Marie-Tooth Examination Score [CMTES]), ankle strength, and 15-month longitudinal changes in CSA. Median thicknesses of peroneus longus and tibialis anterior were reduced across CMT subtypes compared with controls (0.99-1.52 versus 1.70 cm and 0.94-1.95 versus 2.64 cm, respectively; all p < .05). CMT1A showed significantly larger CSA at all 20 sites compared with controls (all p < .001), whereas no significant CSA differences were observed in CMT1B, CMTX1, or CMT2A. In CMT1A, no site-specific CSA correlated significantly with CMTES, muscle thickness, or ankle strength. Over 15 months, small but significant CSA increases were observed at selected nerve sites in CMT1A, with the largest increase (0.07 cm2) at the upper-arm segment of the median nerve (p = .04). Short-axis HRUS at superficial nerve segments revealed a beaded "fusion-separation-refusion" fascicular appearance in 16 of 42 CMT1A patients (38.1%). HRUS demonstrates a diffuse nerve enlargement pattern in CMT1A and muscle atrophy across CMT subtypes. Short-term CSA changes were minimal, suggesting HRUS CSA is more informative for subtype characterization than for short-interval progression monitoring.
2026-06-20 | Autonomic Nervous System Phenotyping Across Chronic Demyelinating Peripheral Neuropathies: A Comparative Study.
This study aimed to systematically phenotype autonomic nervous system (ANS) involvement in patients with chronic inflammatory demyelinating polyneuropathy (CIDP), monoclonal gammopathy of undetermined significance-associated neuropathy (MGUS-PNP), Charcot-Marie-Tooth disease Type 1A (CMT1A), and hereditary neuropathy with liability to pressure palsies (HNPP). Autonomic symptoms were assessed using the SCales for Outcomes in Parkinson's Disease-Autonomic Dysfunction (SCOPA-AUT). Muscle strength and functional disability were evaluated using the Medical Research Council (MRC) scale, the Inflammatory Neuropathy Cause and Treatment (INCAT) disability scale, and the Overall Neuropathy Limitation Scale (ONLS). A total of 343 participants were included: 98 with CIDP (mean age: 59.2 ± 13.2 years), 51 with MGUS-PNP (66.0 ± 11.3 years), 51 with CMT1A (51.2 ± 13.1 years), 18 with HNPP (40.6 ± 15.1 years), and 125 healthy controls (58.2 ± 13.3 years). Compared with healthy controls, patients with CIDP, MGUS-PNP, and CMT1A showed significantly higher total SCOPA-AUT scores (p < 0.01). Distinct, disease-specific ANS symptom patterns were observed across neuropathy subtypes. Overall disability was independently associated with overall autonomic symptom burden in MGUS-PNP (β = 0.42, p < 0.05) and CMT1A (β = 0.68, p < 0.05). In CIDP, patients with active disease showed higher autonomic symptom burden than those with inactive disease (12.7 ± 11.7 vs. 8.6 ± 7.9, p = 0.042). Patients with CIDP, MGUS-PNP, and CMT1A exhibit a substantial autonomic symptom burden with distinct disease-specific ANS patterns. These findings highlight the relevance of autonomic dysfunction in immune-mediated and hereditary neuropathies and warrant further studies to clarify their clinical and prognostic significance.
2026-05-15 | Development of in vitro potency assays for AAV-based gene silencing therapies targeting FSHD and CMT1A.
Adeno-associated viral (AAV) vectors are a cornerstone system for delivering gene therapies for several diseases, including two under development in our lab: Charcot-Marie-Tooth disease type 1A (CMT1A) and facioscapulohumeral muscular dystrophy (FSHD). Although most AAV therapies today involve gene replacement for recessive disorders, CMT1A and FSHD are dominant diseases that would benefit from disease gene silencing, and we have generated extensive pre-clinical safety and efficacy data to support translating gene therapies for both diseases. Here, in anticipation of clinical trials and, optimistically, post-approval, we describe our approach to develop a robust potency assay to assess product strength and stability. To do this, we modified HEK293T cells to increase permissibility to AAV transduction and produce a quantifiable, treatment-responsive readout. Specifically, we created stable cell lines containing (1) the AAV receptor (AAVR) to improve AAV transduction and (2) a Renilla luciferase (rLuc) open reading frame with disease gene sequences in the 3' UTR, to enable disease gene knockdown quantification by luciferase assay. Our study provides a straightforward framework for potency assay development supporting AAV-mediated and non-viral gene silencing programs.
cell therapies
2026-07-29 | A Phase 1 clinical trial to evaluate the safety and tolerability of CLZ-2002 for the treatment of patients with Charcot-Marie-Tooth disease type 1.
Charcot-Marie-Tooth disease type 1 (CMT1) is a rare, genetically diverse condition and represents the most prevalent form of inherited peripheral neuropathy, characterized by Schwann cell dysfunction resulting in progressive demyelination and muscle wasting. CLZ-2002, an allogeneic Schwann cell-like product derived from human tonsillar mesenchymal stem cells, has been developed as a regenerative therapy and investigated in CMT1 patients. A Phase 1, open-label, dose-escalation clinical trial was performed in nine patients with genetically diagnosed CMT1 (five with CMT1A, four with CMT1B). Participants were allocated to three dosing cohorts: 6 million (G1), 12 million (G2), or 24 million cells (G3). CLZ-2002 was delivered as a single intramuscular injection into the lower limbs. The primary objective was to assess safety and tolerability. Exploratory endpoints included Charcot-Marie-Tooth Neuropathy Score version 2 (CMTNSv2), Overall Neuropathy Limitation Score-leg (ONLS-leg), Functional Disability Score (FDS), electrophysiology, MRI, and circulating biomarkers. No drug-related adverse reactions, serious adverse events, or dose-limiting toxicities occurred. Four participants experienced a total of five grade 1-2 treatment-emergent adverse events. By Week 24, improvements relative to baseline were noted in CMTNSv2 and ONLS-leg. Biomarker levels of NCAM1 and GDF15 declined at Week 4 but returned toward baseline by Week 24, reflecting the observed clinical trends. A single intramuscular dose of CLZ-2002 of up to 24 million cells was safe and well-tolerated in CMT1 patients. Exploratory efficacy assessments suggested possible clinical benefit, warranting continued investigation of CLZ-2002 in larger, controlled study populations.
2026-01-20 | Evaluating Cochlear Implantation Outcomes in Charcot-Marie-Tooth Disease: A Case Series Analysis of Genetic Profiles and Intervention Timing.
Charcot-Marie-Tooth disease (CMT) is a hereditary neuropathy that may present with sensorineural hearing loss (SNHL) or auditory neuropathy spectrum disorder (ANSD). Cochlear implants (CIs) have been used to rehabilitate hearing loss in CMT, but their effectiveness remains poorly understood due to the central and peripheral neurological complexities of the disease. Clinical capsule report. Two adult CMT patients and 2 pediatric CMT patients. Cochlear implantation. Preoperative clinical profiles and postoperative auditory performance. Case 1: A 60-year-old woman with bilateral ANSD and comorbid multiple sclerosis (MS) achieved significant speech perception improvement (CNC: 8%-68%, AzBio: 64%) 1 year post-CI. Case 2: A 20-month-old boy with GJB1 -associated CMT1X and developmental delays exhibited rapid auditory gains (MLNT: 100%) following CI. Case 3: A 12-year-old boy with AIFM1 -related ANSD and mitochondrial dysfunction achieved moderate speech recognition (CNC: 56%, AzBio: 75%) but remained limited in noisy environments. Case 4: A 32-year-old man with PRPS1 -associated CMTX5 and profound prelingual SNHL showed improved sound awareness (20-30 dB HL) post-CI but had no speech perception gains due to prolonged auditory deprivation. Cochlear implantation in CMT patients demonstrates variable but meaningfully beneficial auditory outcomes, with early intervention yielding the most favorable results. A personalized approach incorporating genetic profiling, tailored rehabilitation strategies, and setting realistic patient expectations is essential to optimizing outcomes.
2025-08-20 | Modeling of Charcot-Marie-Tooth disease in zebrafish.
Charcot-Marie-Tooth (CMT) disease is one of the most common inherited neuromuscular disorders, characterized by progressive peripheral nerve degeneration, muscle weakness, and sensory loss. To date, no effective therapy has been developed for CMT. The extreme genetic heterogeneity of CMT, encompassing mutations in more than 50 genes and the involvement of diverse pathological mechanisms, continues to pose significant challenges for disease modeling and therapeutic development. To address these challenges and interrogate specific hypotheses with greater experimental control, researchers have increasingly turned to alternative model organisms that offer genetic tractability and in vivo functional readouts. Zebrafish models have been employed to study hallmark features of CMT, including motor deficits, sensory dysfunction, skeletal abnormalities, and auditory neuropathy. Through the use of forward and reverse genetic screening approaches, as well as transgenic lines, zebrafish have yielded some interesting insights into the functional roles of specific genes implicated in CMT and the effects of pathogenic mutations. Moreover, zebrafish serve as a versatile platform for evaluating potential therapeutic interventions, including pharmacological compounds and gene therapy strategies. This review underscores the value of zebrafish as a robust model for advancing our understanding of CMT pathophysiology. It also addresses the ongoing challenges in genetic diagnosis and highlights the therapeutic potential of this model in guiding future treatments for CMT.
2025-02-13 | Addressing myelination disorders: Novel strategies using human 3D peripheral nerve model.
Peripheral myelination disorders encompass a variety of disorders that affect myelin sheaths in the peripheral nervous system. The Charcot-Marie-Tooth disease (CMT), the most common inherited peripheral neuropathy, is one of the most prevalent among them. CMT stems from a wide range of genetic causes that disrupt the nerve conduction, leading to progressive muscle weakness and atrophy, sensory loss, and motor function impairment. Historically, the study of these disorders has relied heavily on animal studies, owing to the challenges in accessing human cells. However, the advent of human induced pluripotent stem cell (hiPSC)-derived neuronal cells has addressed these limitations in the realm of peripheral myelination disorders. Despite this, obtaining myelin in these models remains an expensive, time-consuming, and material-intensive process. This study presents a novel, cost-effective method utilizing hiPSC-derived Schwann cells and motor neurons in a three-dimensional culture system. Our method successfully enabled the acquisition of myelin in a control clone within just four weeks, as confirmed by electron microscopy. Furthermore, the utility of these approaches was validated by studying CMT4C, also named AR-CMTde-SH3TC2, the most common recessive demyelinating form of CMT. This revealed defects in Schwann cell support to motor neuron neurite outgrowth and impaired myelination in disease-specific hiPSC-derived lines. This approach offers valuable insights into the pathogenesis of peripheral myelination disorders and provides a platform for testing potential therapeutic strategies.
2024-11-14 | Synergistic effect of Wharton's jelly-derived mesenchymal stem cells and insulin on Schwann cell proliferation in Charcot-Marie-Tooth disease type 1A treatment.
Charcot-Marie-Tooth disease type 1A (CMT1A) is a demyelinating disease caused by PMP22 duplication and an exceedingly rare hereditary peripheral neuropathy, with an incidence of 1 in 2500. Currently, no cure exists for CMT1A; however, various therapeutic approaches are under development. Considering the known therapeutic effects of mesenchymal stem cells (MSCs) and the relation of blood sugar levels with nerve damage in CMT, this study aimed to confirm the therapeutic effects of MSCs and insulin on CMT, using both in-vitro and in-vivo models. CMT1A in-vitro models were exposed to Wharton's jelly-derived MSCs (WJ-MSCs) or insulin, and the resulting proliferation changes were measured. CMT1A mice were treated with WJ-MSCs or insulin, and their phenotypic changes were observed. We observed improvements in myelination of Schwann cells in vitro and motor function in vivo. Insulin also showed therapeutic efficacy by promoting Schwann cell proliferation. Furthermore, combination therapy using insulin and WJ-MSCs was more effective than WJ-MSCs or insulin alone. Insulin promoted the proliferation of Schwann cells and WJ-MSCs through activation of the ATK and PI3K-MAPK signaling pathways. Overall, this study is the first to confirm the therapeutic efficacy of WJ-MSCs and insulin in CMT1A, and their synergistic effect without causing insulin resistance.
other
2026-05-04 | Identification and Targeted Correction of a Pathogenic PMP22 Deep Intronic Variant.
Pathogenic variants in the PMP22 gene can lead to hereditary peripheral demyelinating neuropathies of varying severity, including hereditary neuropathy with liability to pressure palsies (HNPP), Charcot-Marie-Tooth disease types 1A and 1E (CMT1A, CMT1E), Roussy-Lévy syndrome, and Dejerine-Sottas disease (DSS). This study describes a novel deep intronic variant c.179-2809A>G in the PMP22 gene, identified in two unrelated Avar families from Dagestan republic, Russia. This variant was identified in nine patients. In seven cases, it was detected in a heterozygous state, leading to the development of HNPP. In two cases, this variant was found in a homozygous state, resulting in a more severe CMT1A phenotype (Dejerine-Sottas disease). The performed functional analysis allowed us to characterize the deleterious effect of this variant and propose an approach for personalized antisense therapy. This work demonstrates that, in Avar people with HNPP traits, variant c.179-2809A>G should be considered as disease-causing and included in standard genetic testing.
2026-03-14 | Longitudinal analysis of lipid changes in the sciatic nerve caused by overexpression of PMP22 in murine models of CMT1A.
Charcot-Marie-Tooth type 1A (CMT1A), a prevalent progressive demyelinating peripheral neuropathy is caused by a duplication of the peripheral myelin protein (PMP22) gene. PMP22 is crucial for formation of compact myelin, but the mechanism by which PMP22 overexpression results in CMT1A pathogenesis remains elusive. Emerging evidence points to the role of PMP22 in lipid metabolism as a key modulator of disease progression. Here we show that C3 and C22 mouse models, carrying 5 and 10 additional copies of the human PMP22 gene, have PMP22 dose-dependent lipidomic and transcriptomic alterations. Both models show a decrease in membrane-associated lipids (e.g. phospholipids and sphingolipids) and an increase in neutral lipids (e.g. cholesteryl esters) from three weeks of age. Notably, while cholesteryl ester concentrations are elevated, particularly in C22 mice, total cholesterol levels were significantly reduced, accompanied by the downregulation of key genes involved in cholesterol biosynthesis. Significant decreases were also observed in phospholipids and sphingolipids, including ceramide and sphingomyelin, with a proportional shift towards shorter fatty acid chains in sphingomyelin due to altered ceramide synthase expression. Plasmalogen concentrations decreased with shifts in the proportion of specific plasmalogen species, aligning with impaired synthesis. These lipidomic changes, impacting myelin-associated lipids and fatty acid compositions, underscore their critical role in the dysmyelination observed in CMT1A. Our findings suggest potential avenues for dietary interventions, such as specific fatty acid and plasmalogen supplementation to improve myelination in CMT1A.
2025-11-14 | Characterization of a humanized mouse model of Charcot-Marie-Tooth type 1A for the discovery of human PMP22-targeting drugs.
Charcot-Marie-Tooth type 1A (CMT1A) is the most common inherited demyelinating peripheral neuropathy caused by duplication of the peripheral myelin protein 22 (PMP22) gene. Although there is currently no approved treatment for CMT1A, reducing PMP22 expression has emerged as a promising therapeutic approach. The PMP22-C3 mouse model is a widely used CMT1A model that carries human PMP22 (hPMP22) and mouse Pmp22 (mPmp22) genes, complicating the relationship between reduced PMP22 levels and the recovery of phenotypes by drug candidates targeting only human PMP22. To address this, we developed humanized C3 mouse lines lacking the mPmp22 gene. Here, we characterized these models to confirm their utility as novel disease models for CMT1A. Heterozygous (hetero-humanized) and homozygous (homo-humanized) hPMP22 transgenic mice, with an mPmp22 homozygous knockout background, were investigated using biochemical, electrophysiological, histopathological, and behavioral analyses. Homo-humanized mice exhibited abnormal mRNA expression of myelin-related genes, slow nerve conduction velocity, reduced compound muscle action potential, demyelinated peripheral nerves, higher levels of plasma neurofilament light chain, muscle weakness and motor/balance disabilities, alterations in electrical impedance myography, and muscle fiber atrophy. In contrast, the hetero-humanized mice did not display any of the previously described impairments. Homo-humanized mice reflect various aspects of CMT1A characteristics in an hPMP22 gene dosage-dependent manner. This model will help us better understand the relationship between PMP22 reduction levels and the recovery of CMT1A-related phenotypes, contributing to the translation of preclinical findings into clinically relevant human treatments and dosing strategies.
2025-10-16 | Guillain-Barré Syndrome With Asymmetrical Weakness in a Patient With Charcot-Marie-Tooth Disease Type 1A.
A man in his 60s presented with acute, progressive right lower limb weakness, low back pain, and paraesthesia. Neuroimaging ruled out spinal cord and central pathology. Cerebrospinal fluid analysis revealed albumin-cytological dissociation, and nerve conduction studies confirmed Guillain-Barré syndrome (GBS) superimposed on Charcot-Marie-Tooth disease type 1A (CMT1A). There was no preceding infection or ganglioside antibody positivity. His weakness progressed rapidly, resulting in flaccid paralysis of the right leg. He received intravenous immunoglobulin with marked clinical improvement and regained independent mobility by follow-up. This case is notable for its atypical, asymmetrical presentation of GBS in the context of pre-existing hereditary neuropathy, posing diagnostic challenges. It contributes to the limited literature on overlapping GBS and CMT1A and reinforces the importance of early investigation and immunotherapy in non-classical cases. The case highlights that reflex loss and chronic neuropathy should not preclude consideration of acute treatable causes.
2025-09-25 | Advances and Clues of Nutritional Adjuvant Therapy for Charcot-Marie-Tooth Disease.
Charcot-Marie-Tooth disease (CMT) is an inherited peripheral neuropathy with significant genetic heterogeneity and clinical variability. Currently, there are no specific drugs to cure the disease, and adjuvant therapies are used to alleviate the symptoms. By supporting the functions of nerves, bones, and muscles, as well as systemic metabolism, personalized intakes of energy and nutrients help slow down disease progression, delay CMT onset, relieve the suffering and pain of patients, and improve their quality of life. This review discusses the research progress on energy- and fat-manipulated diets (caloric restriction diet, ketogenic diet, and high-fat diet) and several nutrients (polyunsaturated fatty acids, phospholipids, copper, iron, zinc, selenium, vitamins A/D/E/C, and some vitamin Bs) in the treatment of CMT and related peripheral neuropathies, which is expected to encourage exploration on and application of healthy diets and nutritional intakes from the viewpoint of clinical nutrition to improve the symptoms of CMT.
small molecules
2026-09-22 | PXT3003: Lessons for therapeutic development in Charcot-Marie-Tooth disease type 1A and related neuropathies
Most drug development stories end predictably: promising compounds either succeed or fail. Occasionally, however, a therapy repeatedly returns from apparent extinction. PXT3003 for Charcot-Marie-Tooth disease type 1A (CMT1A) represents one such example. More than a decade after early promise, the program has survived formulation instability, interrupted clinical development, regulatory uncertainty, and controversy surrounding efficacy before re-emerging with renewed evidence of clinical benefit. Yet, as with many therapeutic development programs, interpretation of the available evidence is influenced by the extent to which findings are publicly accessible. In a recent issue of iScience , a phase 3 clinical trial evaluated PXT3003, a combination of baclofen, naltrexone, and D-sorbitol, versus placebo over 15 months in participants aged 16–65 years with mild-to-moderate CMT1A across 25 sites in China. PXT3003 is not simply the story of one drug; it highlights the scientific, methodological, operational, and reporting challenges of developing disease-modifying therapies for slowly progressive inherited neuropathies.
2026-09-04 | REPO-RARE: From Phenotypes to Spatial Disease Modules for Causal Therapy, Precision Medicine and Prevention
Current bioinformatics does not adequately represent disease mechanisms. Protein–protein interactomes often aggregate associations from different assays, cell types, subcellular locations, and biological states, producing networks whose neighbouring proteins may not form a functional unit in the relevant intact cell. Computational proximity alone therefore cannot establish causality, define a patient’s molecular disease state, or indicate how it should be corrected. REPO-RARE defines diseases as context-specific dysfunctional molecular modules rather than primarily by shared phenotypes, organs, or histopathology. Candidate modules generated from interaction data must be resolved in the relevant cell type, subcellular location, molecular state, and disease condition. Validation establishes their composition, causal relevance, and direction of dysfunction. The validated module then connects molecular diagnosis, mechanistic biomarkers, patient stratification, and therapy. Treatment is selected to restore module function by modulating a complementary component rather than suppressing downstream symptoms. Rare diseases are an ideal first application: their comparatively well-defined causal entry points provide a rapid, rigorous setting for testing the framework across multiple conditions. REPO-RARE will establish a reproducible route from causal gene to dysfunctional module, mechanistic biomarker, patient selection, and module-directed drug repurposing. The first RExPO’26 projects test complementary stages of this route. In SYNGAP1-related disorder, comparison of network and co-complex representations begins to resolve the context-specific organisation of the SynGAP protein environment [1]. In Charcot–Marie–Tooth disease type 1A, PMP22 provides the genetic entry point to a membrane-homeostasis module, with KCNN4/KCa3.1 prioritised as a candidate modulatory target [2]. In Duchenne muscular dystrophy, DMD-associated pathology is linked to dysfunction of the NOS–sGC module and a mechanistically directed drug-repurposing combination hypothesis [3]. Projects will be prioritised according to genetic causality, unmet need, therapeutic window, measurable module dysfunction, and repurposing potential. Success will be assessed through reproducible module validation and progression towards biomarker-guided therapeutic testing. By applying this framework across rare diseases, REPO-RARE aims to establish a general foundation for causal therapy, precision medicine, and, where intervention can precede irreversible damage, precision prevention. References Caune H, Hangul C, Kötting J, Casas AI, Schmidt HHHW. Network and co-complex representations identify distinct components of the SynGAP protein environment. RExPO’26 abstract. doi: 10.58647/REXPO26000198.v1. Kötting J, Schmidt HHHW. Network analysis of Charcot–Marie–Tooth disease type 1A prioritises a membrane-homeostasis module and KCNN4 as a candidate drug target. RExPO’26 abstract. doi: 10.58647/REXPO26000197.v1. Hangul C, Schmidt HHHW. Network medicine in Duchenne muscular dystrophy generates a mechanistic NOS–sGC-targeted drug-repurposing combination hypothesis. RExPO’26 abstract. doi: 10.58647/REXPO26000199.v1.
2026-08-27 | Tyrosine Supplementation Rescues a Growth Defect in a Humanized S. cerevisiae Model of YARS1 Associated with CMT-DI.
Dominant pathogenic mutations in tyrosyl-tRNA synthetase (YARS1) are associated with Charcot-Marie-Tooth disease (CMT), a progressive peripheral neuropathy for which no disease-modifying therapies currently exist. While recent advances in amino acid supplementation therapies suggest potential benefit for recessive aminoacyl-tRNA synthetase disorders, their applicability to dominant YARS1-associated neuropathies remains unclear. Here, we investigated the pathogenic mechanisms underlying the dominant YARS1 variants G41R, D81I, and E196Q. Using biochemical and functional analyses, we identified increased structural rigidity for G41R and E196Q proteins, while D81I is more susceptible to tryptic digestion. Furthermore, expression of the YARS1 variants in a humanized yeast model produced a dominant negative growth defect that is exacerbated at elevated temperatures, supporting disruption of canonical YARS1 function as a contributor to disease pathogenesis. Notably, tyrosine supplementation significantly rescued the observed growth defects across variants. These findings demonstrate that impaired tyrosine utilization contributes to the pathogenic effects of dominant YARS1 variants and provide proof-of-concept evidence that tyrosine supplementation may represent a potential therapeutic strategy for patients with YARS1-associated CMT.
2026-08-22 | Network analysis of Charcot-Marie-Tooth Disease Type 1A prioritises a membrane-homeostasis module and KCNN4 as a candidate drug target
Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common inherited demyelinating peripheral neuropathy and is caused by duplication of the peripheral myelin protein 22 (PMP22) gene [1,2]. Despite more than three decades of research, the molecular mechanisms linking PMP22 overexpression to progressive demyelination remain incompletely understood, and no disease-modifying therapy exists.[2,3] We asked whether expanding PMP22 into a protein-protein interaction (PPI) network could integrate fragmented CMT1A biology and generate testable pathomechanistic and drug-repurposing hypotheses. Using PMP22 as the sole seed protein, we generated a first-neighbour PPI network using the Drugst.One DREAM tool [4,5] on the REPO4EU platform alpha version. The resulting network was refined by subnetwork participation degree pruning, community detection, and expert-guided functional annotation to identify biologically coherent modules, formulate mechanistic hypotheses, and predict repurposing candidates. The analysis yielded a 21-protein module centred on membrane biology, including PMP22, MPZ, EMP1, KCNN4, GPR61 and SDC4, and linked it to modules related to endoplasmic-reticulum quality control/proteostasis, lipid synthesis/trafficking and immune/inflammatory processes. This topology-derived representation organised these processes into a mechanistic hypothesis centred on myelin-membrane homeostasis. Within the membrane-centred module, KCNN4 (KCa3.1) emerged as a candidate effector potentially coupling intracellular calcium signals to potassium efflux, membrane potential and cellular homeostasis. KCNN4 is therefore prioritised as a candidate drug target in CMT1A, while pharmacological inhibition of KCa3.1 with the selective inhibitor senicapoc is proposed as a testable drug-repurposing hypothesis [6,7]. Because this prioritisation is topology- and expert-annotation-dependent, it does not establish disease causality or therapeutic efficacy. We propose preclinical validation in relevant models such as patient-specific iPSC-derived Schwann cells or Schwann cell precursors [8], the C3-PMP22 transgenic mouse [9] or the humanised PMP22-C3 mouse [9].
2026-07-15 | PXT3003 in CMT1A Phase III Multicenter Clinical Trial Dataset
This dataset contains the raw data and analysis materials related to the phase III multicenter clinical trial of PXT3003 in CMT1A patients. It includes de - identified individual patient data, statistical analysis files, etc., which can support the conclusions of the relevant paper
proteins
2026-09-21 | Ciliary neurotrophic factor slows axonal transport of signalling endosomes.
Efficient axonal transport is essential for maintaining neuronal function, enabling the bidirectional delivery of diverse cargoes between the cell body and distal compartments. In the neuromuscular system, neurotrophic factors regulate motor neuron survival, function and synaptic connectivity, in part, through retrograde trafficking of activated neurotrophic factor-receptor complexes from the neuromuscular junction to the cell body. We recently demonstrated that brain-derived neurotrophic factor stimulation to muscles selectively enhances retrograde transport of signalling endosomes in fast, but not slow, motor neurons in vivo. Moreover, both axonal endosome transport and its brain-derived neurotrophic factor-mediated regulation are disrupted in mouse models of diseases impacting motor neurons, including amyotrophic lateral sclerosis and Charcot-Marie-Tooth disease. Here, we examined whether additional neurotrophic factors, when applied to distal axon terminals, share this transport-modulating property. Through imaging sciatic nerves in anaesthetised mice, we tracked the in vivo dynamics of signalling endosomes in fast and slow motor neurons via intramuscular injections of a fluorescent atoxic fragment of tetanus neurotoxin. These injections were co-administered with ciliary neurotrophic factor, hepatocyte growth factor, neurturin, or cleavage-resistant pro-brain-derived neurotrophic factor-four growth factors with known effects on motor neurons. Compared to vehicle-treated controls, pro-brain-derived neurotrophic factor, hepatocyte growth factor and neurturin produced no detectable change in transport dynamics. In contrast, ciliary neurotrophic factor markedly reduced endosome speeds in both fast and slow motor neurons, indicating remarkable selectivity of specific neurotrophic factors in the regulation of signalling endosome transport in motor neurons. Understanding this selectivity may aid the development of muscle-targeted neurotrophic factor-based therapeutic strategies aimed at restoring axonal transport in neurodegenerative disease, peripheral neuropathy and nerve injury.
2026-01-01 | Schmidt-Lanterman incisures in the Schwann cell and their role for peripheral nerve regeneration
Schmidt-Lanterman incisures (SLIs) are cytoplasmic channels within compact peripheral myelin, yet their formation and functional relevance in health and disease remain incompletely understood. This study investigates SLI development, their regulation across the lifespan, and their role in neuropathy and nerve regeneration. Using immunofluorescence and high-pressure freezing electron microscopy of developing murine sciatic nerves, we show that SLIs arise early during myelin formation. During development, SLI number increases in parallel with internodal elongation and remains stable in adulthood and aging, indicating an essential role in Schwann cell maturation and myelin maintenance. In mouse models of PMP22-associated neuropathies (CMT1A and HNPP), SLI number is altered in a dosage-dependent manner: increased in PMP22-duplication and transiently reduced during early development in PMP22-deletion. Similarly, sural nerve biopsies from patients with demyelinating neuropathy reveal increased SLI numbers, particularly in short internodes, suggesting a compensatory function in disease. Following sciatic nerve crush injury, mice with reduced SLI numbers (VCLcKO) exhibit delayed motor recovery and fail to upregulate SLIs, in contrast to wildtype controls. These findings support a critical role of SLIs in preserving nerve function and promoting regeneration, potentially by facilitating axo-glial communication and metabolic support. Together, this work identifies SLIs as dynamic and regulated structures essential for peripheral nerve development, maintenance, and repair, highlighting their potential as targets for therapeutic strategies to enhance nerve regeneration.
2025-05-21 | Combining dynamin 2 myopathy and neuropathy mutations rescues both phenotypes.
Mutations within a single gene can lead to diverse human genetic diseases affecting highly specialized tissues. Notably, dominant mutations in the DNM2 gene, encoding the mechanoenzyme dynamin, lead to distinct neuromuscular disorders: centronuclear myopathy (CNM) and Charcot-Marie-Tooth neuropathy (CMT). CNM is characterized by myofiber structural anomalies while CMT presents peripheral nerve defects, both culminating in muscle weakness and atrophy. Despite their shared genetic origin, the mechanisms driving these diseases remain elusive, and no cure is available. Here, we present in vitro assays underlining opposing effects of DNM2 mutations, gain-of-function in CNM and loss-of-function in CMT. In vivo, we explored the potential compensatory effects of CNM and CMT mutations by breeding Dnm2S619L/+ CNM with Dnm2K562E/+ CMT mouse models. Dnm2S619L/K562E offspring exhibit strongly improved motor coordination and muscle strength and mass, compared to single-mutant littermates. Dnm2S619L/K562E mice present normalized muscle structure and nerve fiber organization. This study reveals that two distinct disease-causing mutations within the DNM2 gene compensate each other in vivo, leading to corrections of most individual phenotypes. The inverse modulation of DNM2 activity emerges as a promising therapeutic strategy to address CNM and CMT diseases.
2023-06-01 | Cytokine-Induced Neurogenesis in Charcot-Marie-Tooth neuropathy with Connexin 32 Gene Mutation
Charcot-Marie-Tooth (CMT) neuropathy is one of the most common neuromuscular disorders.Despite the identification of more than 100 causative genes, there are few therapeutic options.We present the case of a 66-year-old man carrying a CMT mutation in the connexin 32 gene with the APOE genotype ε4/ε3 that had exhibited symptoms of slowly progressive muscle weakness and atrophy in the hands and feet and recently developed memory impairment.The muscle weakness, motor dysfunction, and memory impairment symptoms were significantly improved by cytokine-induced neurogenesis combined with physical wave therapy using an arbitrary waveform generator (AWG).Here, we discuss the possible mechanistic basis of how this new treatment ameliorates the symptoms of CMT and propose a novel clinical treatment strategy for CMT.
2023-05-05 | TGFβ4 alleviates the phenotype of Charcot–Marie–Tooth disease type 1A
The duplication of the peripheral myelin protein 22 (PMP22) gene causes a demyelinating type of neuropathy, commonly known as Charcot-Marie-Tooth disease type 1A (CMT1A). Development of effective drugs for CMT1A still remains as an unmet medical need. In the present study, we assessed the role of the transforming growth factor beta 4 (TGFβ4)/Nodal axis in the pathogenesis of CMT1A. First, we identified PMP22 overexpression-induced Nodal expression in Schwann cells, which might be one of the downstream effectors in CMT1A. Administration of Nodal protein at the developmental stage of peripheral nerves induced the demyelinating phenotype in vivo. Second, we further isolated TGFβ4 as an antagonist that could abolish Nodal-induced demyelination. Finally, we developed a recombinant TGFβ4-fragment crystallizable (Fc) fusion protein, CX201, and demonstrated that its application had promyelinating efficacy in Schwann cells. CX201 administration improved the demyelinating phenotypes of CMT1A mouse models at both pre-symptomatic and post-symptomatic stages. These results suggest that the TGFβ4/Nodal axis plays a crucial role in the pathogenesis of CMT1A and might be a potential therapeutic target for CMT1A.
gene therapies
2026-09-17 | Distinct small-fiber dysfunction profiles in CMT1A and RFC1 disease: a multimodal study.
Charcot-Marie-Tooth disease 1A (CMT1A) and Cerebellar Ataxia, Neuropathy, Vestibular Areflexia Syndrome (CANVAS)/Replication Factor Complex subunit 1 (RFC1)-related disease affect large nerve fibers, but small fiber dysfunction may contribute to pain and dysautonomia. We applied a multimodal protocol, including potentials elicited by a micropatterned electrode targeting intraepidermal nerve endings, to characterize small fiber involvement. In this cross-sectional study, healthy controls (HC) and patients with CMT1A or RFC1 disease underwent neurologic examination, autonomic assessment with the composite autonomic symptom score-31 (COMPASS-31) and compound autonomic dysfunction test (CADT), electrochemical skin conductance (ESC), nociceptive evoked potentials (NEPs), pain-related evoked potentials (PREPs), somatosensory evoked potentials (SEPs), and skin biopsy. Twenty-one patients with CMT1A, 16 with RFC1 disease, and 21 HC were included. Neuropathic pain occurred in 33% of CMT1A and 81% of RFC1 patients. Dysautonomia was prominent in RFC1 disease, with abnormal CADT scores in 94%, COMPASS-31 scores of 7-46, and abnormal ESC in 63%, compared with 24% in CMT1A. N40 NEP latencies were prolonged in both patient groups versus HC (p<0.001), with absent responses in 33% and 44%, respectively. PREPs showed prolonged N2 latencies in CMT1A (p=0.003), with absent N2 responses in 57%; in RFC1 disease, N2 responses were absent in 50%. Skin biopsy showed length-dependent intraepidermal nerve fiber density loss in CMT1A and severe non-length-dependent epidermal denervation in RFC1 disease. Multimodal assessment integrating ESC, NEPs, PREPs, and skin biopsy identifies distinct Aδ- and C-fiber dysfunction patterns in CMT1A and RFC1 disease and may support phenotyping and small-fiber biomarker development in peripheral neuropathies.
2026-08-17 | Neuronal Prps is required for synaptic development and motor function in Drosophila melanogaster.
Phosphoribosyl pyrophosphate synthetase (PRPS) produces phosphoribosyl pyrophosphate, which is a key precursor for nucleotide biosynthesis. Mutations in the human PRPS1 gene cause Charcot-Marie-Tooth disease and other neuropathies. However, how PRPS1 dysfunction impairs neuronal and synaptic function remains unclear. In this study, we used Drosophila melanogaster to determine the effects of reduced Prps expression on neurons in vivo. Neuronal knockdown of Prps caused severe locomotor impairment in third instar larvae and in adults, which indicated a critical requirement for Prps in motor output. At the neuromuscular junction, Prpsdepletion led to a reduced number of synaptic boutons accompanied by enlargement of boutons, disrupted presynaptic active zone organization indicated by decreased Bruchpilot puncta, and loss of Futsch-positive microtubule loops. These findings suggested destabilization of cytoskeletal architecture. These phenotypes were consistently observed using independent RNAi lines. Importantly, neuronal expression of Drosophila Prps or human PRPS1 significantly rescued locomotor activity, synaptic growth, active zone organization, and microtubule structure, which are caused by the expression of the Prps short hairpin RNA. The rescue by Drosophila Prps and human PRPS1 highlights evolutionary conservation of PRPS1 function and suggests Drosophila as a model for analyzing PRPS1-associated neuropathies.
2026-07-12 | High-Resolution Ultrasound Evaluation of Nerves and Muscles at Multiple Sites in Charcot-Marie-Tooth Disease.
To characterize nerve cross-sectional area (CSA) and muscle thickness at multiple sites in Charcot-Marie-Tooth disease (CMT) using high-resolution ultrasound (HRUS), with emphasis on CMT1A and comparisons with healthy controls. Fifty-nine genetically confirmed CMT patients (including CMT1A, CMT1B, CMTX1, and CMT2A) and 42 healthy controls underwent HRUS evaluation of 7 nerves (median, ulnar, radial, sciatic, tibial, common peroneal, and vagus) at 20 predefined anatomical sites, along with measurements of peroneus longus and tibialis anterior thickness. In CMT1A, we assessed correlations between CSA and clinical severity (Charcot-Marie-Tooth Examination Score [CMTES]), ankle strength, and 15-month longitudinal changes in CSA. Median thicknesses of peroneus longus and tibialis anterior were reduced across CMT subtypes compared with controls (0.99-1.52 versus 1.70 cm and 0.94-1.95 versus 2.64 cm, respectively; all p < .05). CMT1A showed significantly larger CSA at all 20 sites compared with controls (all p < .001), whereas no significant CSA differences were observed in CMT1B, CMTX1, or CMT2A. In CMT1A, no site-specific CSA correlated significantly with CMTES, muscle thickness, or ankle strength. Over 15 months, small but significant CSA increases were observed at selected nerve sites in CMT1A, with the largest increase (0.07 cm2) at the upper-arm segment of the median nerve (p = .04). Short-axis HRUS at superficial nerve segments revealed a beaded "fusion-separation-refusion" fascicular appearance in 16 of 42 CMT1A patients (38.1%). HRUS demonstrates a diffuse nerve enlargement pattern in CMT1A and muscle atrophy across CMT subtypes. Short-term CSA changes were minimal, suggesting HRUS CSA is more informative for subtype characterization than for short-interval progression monitoring.
2026-06-20 | Autonomic Nervous System Phenotyping Across Chronic Demyelinating Peripheral Neuropathies: A Comparative Study.
This study aimed to systematically phenotype autonomic nervous system (ANS) involvement in patients with chronic inflammatory demyelinating polyneuropathy (CIDP), monoclonal gammopathy of undetermined significance-associated neuropathy (MGUS-PNP), Charcot-Marie-Tooth disease Type 1A (CMT1A), and hereditary neuropathy with liability to pressure palsies (HNPP). Autonomic symptoms were assessed using the SCales for Outcomes in Parkinson's Disease-Autonomic Dysfunction (SCOPA-AUT). Muscle strength and functional disability were evaluated using the Medical Research Council (MRC) scale, the Inflammatory Neuropathy Cause and Treatment (INCAT) disability scale, and the Overall Neuropathy Limitation Scale (ONLS). A total of 343 participants were included: 98 with CIDP (mean age: 59.2 ± 13.2 years), 51 with MGUS-PNP (66.0 ± 11.3 years), 51 with CMT1A (51.2 ± 13.1 years), 18 with HNPP (40.6 ± 15.1 years), and 125 healthy controls (58.2 ± 13.3 years). Compared with healthy controls, patients with CIDP, MGUS-PNP, and CMT1A showed significantly higher total SCOPA-AUT scores (p < 0.01). Distinct, disease-specific ANS symptom patterns were observed across neuropathy subtypes. Overall disability was independently associated with overall autonomic symptom burden in MGUS-PNP (β = 0.42, p < 0.05) and CMT1A (β = 0.68, p < 0.05). In CIDP, patients with active disease showed higher autonomic symptom burden than those with inactive disease (12.7 ± 11.7 vs. 8.6 ± 7.9, p = 0.042). Patients with CIDP, MGUS-PNP, and CMT1A exhibit a substantial autonomic symptom burden with distinct disease-specific ANS patterns. These findings highlight the relevance of autonomic dysfunction in immune-mediated and hereditary neuropathies and warrant further studies to clarify their clinical and prognostic significance.
2026-05-15 | Development of in vitro potency assays for AAV-based gene silencing therapies targeting FSHD and CMT1A.
Adeno-associated viral (AAV) vectors are a cornerstone system for delivering gene therapies for several diseases, including two under development in our lab: Charcot-Marie-Tooth disease type 1A (CMT1A) and facioscapulohumeral muscular dystrophy (FSHD). Although most AAV therapies today involve gene replacement for recessive disorders, CMT1A and FSHD are dominant diseases that would benefit from disease gene silencing, and we have generated extensive pre-clinical safety and efficacy data to support translating gene therapies for both diseases. Here, in anticipation of clinical trials and, optimistically, post-approval, we describe our approach to develop a robust potency assay to assess product strength and stability. To do this, we modified HEK293T cells to increase permissibility to AAV transduction and produce a quantifiable, treatment-responsive readout. Specifically, we created stable cell lines containing (1) the AAV receptor (AAVR) to improve AAV transduction and (2) a Renilla luciferase (rLuc) open reading frame with disease gene sequences in the 3' UTR, to enable disease gene knockdown quantification by luciferase assay. Our study provides a straightforward framework for potency assay development supporting AAV-mediated and non-viral gene silencing programs.
cell therapies
2026-07-29 | A Phase 1 clinical trial to evaluate the safety and tolerability of CLZ-2002 for the treatment of patients with Charcot-Marie-Tooth disease type 1.
Charcot-Marie-Tooth disease type 1 (CMT1) is a rare, genetically diverse condition and represents the most prevalent form of inherited peripheral neuropathy, characterized by Schwann cell dysfunction resulting in progressive demyelination and muscle wasting. CLZ-2002, an allogeneic Schwann cell-like product derived from human tonsillar mesenchymal stem cells, has been developed as a regenerative therapy and investigated in CMT1 patients. A Phase 1, open-label, dose-escalation clinical trial was performed in nine patients with genetically diagnosed CMT1 (five with CMT1A, four with CMT1B). Participants were allocated to three dosing cohorts: 6 million (G1), 12 million (G2), or 24 million cells (G3). CLZ-2002 was delivered as a single intramuscular injection into the lower limbs. The primary objective was to assess safety and tolerability. Exploratory endpoints included Charcot-Marie-Tooth Neuropathy Score version 2 (CMTNSv2), Overall Neuropathy Limitation Score-leg (ONLS-leg), Functional Disability Score (FDS), electrophysiology, MRI, and circulating biomarkers. No drug-related adverse reactions, serious adverse events, or dose-limiting toxicities occurred. Four participants experienced a total of five grade 1-2 treatment-emergent adverse events. By Week 24, improvements relative to baseline were noted in CMTNSv2 and ONLS-leg. Biomarker levels of NCAM1 and GDF15 declined at Week 4 but returned toward baseline by Week 24, reflecting the observed clinical trends. A single intramuscular dose of CLZ-2002 of up to 24 million cells was safe and well-tolerated in CMT1 patients. Exploratory efficacy assessments suggested possible clinical benefit, warranting continued investigation of CLZ-2002 in larger, controlled study populations.
2026-01-20 | Evaluating Cochlear Implantation Outcomes in Charcot-Marie-Tooth Disease: A Case Series Analysis of Genetic Profiles and Intervention Timing.
Charcot-Marie-Tooth disease (CMT) is a hereditary neuropathy that may present with sensorineural hearing loss (SNHL) or auditory neuropathy spectrum disorder (ANSD). Cochlear implants (CIs) have been used to rehabilitate hearing loss in CMT, but their effectiveness remains poorly understood due to the central and peripheral neurological complexities of the disease. Clinical capsule report. Two adult CMT patients and 2 pediatric CMT patients. Cochlear implantation. Preoperative clinical profiles and postoperative auditory performance. Case 1: A 60-year-old woman with bilateral ANSD and comorbid multiple sclerosis (MS) achieved significant speech perception improvement (CNC: 8%-68%, AzBio: 64%) 1 year post-CI. Case 2: A 20-month-old boy with GJB1 -associated CMT1X and developmental delays exhibited rapid auditory gains (MLNT: 100%) following CI. Case 3: A 12-year-old boy with AIFM1 -related ANSD and mitochondrial dysfunction achieved moderate speech recognition (CNC: 56%, AzBio: 75%) but remained limited in noisy environments. Case 4: A 32-year-old man with PRPS1 -associated CMTX5 and profound prelingual SNHL showed improved sound awareness (20-30 dB HL) post-CI but had no speech perception gains due to prolonged auditory deprivation. Cochlear implantation in CMT patients demonstrates variable but meaningfully beneficial auditory outcomes, with early intervention yielding the most favorable results. A personalized approach incorporating genetic profiling, tailored rehabilitation strategies, and setting realistic patient expectations is essential to optimizing outcomes.
2025-08-20 | Modeling of Charcot-Marie-Tooth disease in zebrafish.
Charcot-Marie-Tooth (CMT) disease is one of the most common inherited neuromuscular disorders, characterized by progressive peripheral nerve degeneration, muscle weakness, and sensory loss. To date, no effective therapy has been developed for CMT. The extreme genetic heterogeneity of CMT, encompassing mutations in more than 50 genes and the involvement of diverse pathological mechanisms, continues to pose significant challenges for disease modeling and therapeutic development. To address these challenges and interrogate specific hypotheses with greater experimental control, researchers have increasingly turned to alternative model organisms that offer genetic tractability and in vivo functional readouts. Zebrafish models have been employed to study hallmark features of CMT, including motor deficits, sensory dysfunction, skeletal abnormalities, and auditory neuropathy. Through the use of forward and reverse genetic screening approaches, as well as transgenic lines, zebrafish have yielded some interesting insights into the functional roles of specific genes implicated in CMT and the effects of pathogenic mutations. Moreover, zebrafish serve as a versatile platform for evaluating potential therapeutic interventions, including pharmacological compounds and gene therapy strategies. This review underscores the value of zebrafish as a robust model for advancing our understanding of CMT pathophysiology. It also addresses the ongoing challenges in genetic diagnosis and highlights the therapeutic potential of this model in guiding future treatments for CMT.
2025-02-13 | Addressing myelination disorders: Novel strategies using human 3D peripheral nerve model.
Peripheral myelination disorders encompass a variety of disorders that affect myelin sheaths in the peripheral nervous system. The Charcot-Marie-Tooth disease (CMT), the most common inherited peripheral neuropathy, is one of the most prevalent among them. CMT stems from a wide range of genetic causes that disrupt the nerve conduction, leading to progressive muscle weakness and atrophy, sensory loss, and motor function impairment. Historically, the study of these disorders has relied heavily on animal studies, owing to the challenges in accessing human cells. However, the advent of human induced pluripotent stem cell (hiPSC)-derived neuronal cells has addressed these limitations in the realm of peripheral myelination disorders. Despite this, obtaining myelin in these models remains an expensive, time-consuming, and material-intensive process. This study presents a novel, cost-effective method utilizing hiPSC-derived Schwann cells and motor neurons in a three-dimensional culture system. Our method successfully enabled the acquisition of myelin in a control clone within just four weeks, as confirmed by electron microscopy. Furthermore, the utility of these approaches was validated by studying CMT4C, also named AR-CMTde-SH3TC2, the most common recessive demyelinating form of CMT. This revealed defects in Schwann cell support to motor neuron neurite outgrowth and impaired myelination in disease-specific hiPSC-derived lines. This approach offers valuable insights into the pathogenesis of peripheral myelination disorders and provides a platform for testing potential therapeutic strategies.
2024-11-14 | Synergistic effect of Wharton's jelly-derived mesenchymal stem cells and insulin on Schwann cell proliferation in Charcot-Marie-Tooth disease type 1A treatment.
Charcot-Marie-Tooth disease type 1A (CMT1A) is a demyelinating disease caused by PMP22 duplication and an exceedingly rare hereditary peripheral neuropathy, with an incidence of 1 in 2500. Currently, no cure exists for CMT1A; however, various therapeutic approaches are under development. Considering the known therapeutic effects of mesenchymal stem cells (MSCs) and the relation of blood sugar levels with nerve damage in CMT, this study aimed to confirm the therapeutic effects of MSCs and insulin on CMT, using both in-vitro and in-vivo models. CMT1A in-vitro models were exposed to Wharton's jelly-derived MSCs (WJ-MSCs) or insulin, and the resulting proliferation changes were measured. CMT1A mice were treated with WJ-MSCs or insulin, and their phenotypic changes were observed. We observed improvements in myelination of Schwann cells in vitro and motor function in vivo. Insulin also showed therapeutic efficacy by promoting Schwann cell proliferation. Furthermore, combination therapy using insulin and WJ-MSCs was more effective than WJ-MSCs or insulin alone. Insulin promoted the proliferation of Schwann cells and WJ-MSCs through activation of the ATK and PI3K-MAPK signaling pathways. Overall, this study is the first to confirm the therapeutic efficacy of WJ-MSCs and insulin in CMT1A, and their synergistic effect without causing insulin resistance.
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2026-05-04 | Identification and Targeted Correction of a Pathogenic PMP22 Deep Intronic Variant.
Pathogenic variants in the PMP22 gene can lead to hereditary peripheral demyelinating neuropathies of varying severity, including hereditary neuropathy with liability to pressure palsies (HNPP), Charcot-Marie-Tooth disease types 1A and 1E (CMT1A, CMT1E), Roussy-Lévy syndrome, and Dejerine-Sottas disease (DSS). This study describes a novel deep intronic variant c.179-2809A>G in the PMP22 gene, identified in two unrelated Avar families from Dagestan republic, Russia. This variant was identified in nine patients. In seven cases, it was detected in a heterozygous state, leading to the development of HNPP. In two cases, this variant was found in a homozygous state, resulting in a more severe CMT1A phenotype (Dejerine-Sottas disease). The performed functional analysis allowed us to characterize the deleterious effect of this variant and propose an approach for personalized antisense therapy. This work demonstrates that, in Avar people with HNPP traits, variant c.179-2809A>G should be considered as disease-causing and included in standard genetic testing.
2026-03-14 | Longitudinal analysis of lipid changes in the sciatic nerve caused by overexpression of PMP22 in murine models of CMT1A.
Charcot-Marie-Tooth type 1A (CMT1A), a prevalent progressive demyelinating peripheral neuropathy is caused by a duplication of the peripheral myelin protein (PMP22) gene. PMP22 is crucial for formation of compact myelin, but the mechanism by which PMP22 overexpression results in CMT1A pathogenesis remains elusive. Emerging evidence points to the role of PMP22 in lipid metabolism as a key modulator of disease progression. Here we show that C3 and C22 mouse models, carrying 5 and 10 additional copies of the human PMP22 gene, have PMP22 dose-dependent lipidomic and transcriptomic alterations. Both models show a decrease in membrane-associated lipids (e.g. phospholipids and sphingolipids) and an increase in neutral lipids (e.g. cholesteryl esters) from three weeks of age. Notably, while cholesteryl ester concentrations are elevated, particularly in C22 mice, total cholesterol levels were significantly reduced, accompanied by the downregulation of key genes involved in cholesterol biosynthesis. Significant decreases were also observed in phospholipids and sphingolipids, including ceramide and sphingomyelin, with a proportional shift towards shorter fatty acid chains in sphingomyelin due to altered ceramide synthase expression. Plasmalogen concentrations decreased with shifts in the proportion of specific plasmalogen species, aligning with impaired synthesis. These lipidomic changes, impacting myelin-associated lipids and fatty acid compositions, underscore their critical role in the dysmyelination observed in CMT1A. Our findings suggest potential avenues for dietary interventions, such as specific fatty acid and plasmalogen supplementation to improve myelination in CMT1A.
2025-11-14 | Characterization of a humanized mouse model of Charcot-Marie-Tooth type 1A for the discovery of human PMP22-targeting drugs.
Charcot-Marie-Tooth type 1A (CMT1A) is the most common inherited demyelinating peripheral neuropathy caused by duplication of the peripheral myelin protein 22 (PMP22) gene. Although there is currently no approved treatment for CMT1A, reducing PMP22 expression has emerged as a promising therapeutic approach. The PMP22-C3 mouse model is a widely used CMT1A model that carries human PMP22 (hPMP22) and mouse Pmp22 (mPmp22) genes, complicating the relationship between reduced PMP22 levels and the recovery of phenotypes by drug candidates targeting only human PMP22. To address this, we developed humanized C3 mouse lines lacking the mPmp22 gene. Here, we characterized these models to confirm their utility as novel disease models for CMT1A. Heterozygous (hetero-humanized) and homozygous (homo-humanized) hPMP22 transgenic mice, with an mPmp22 homozygous knockout background, were investigated using biochemical, electrophysiological, histopathological, and behavioral analyses. Homo-humanized mice exhibited abnormal mRNA expression of myelin-related genes, slow nerve conduction velocity, reduced compound muscle action potential, demyelinated peripheral nerves, higher levels of plasma neurofilament light chain, muscle weakness and motor/balance disabilities, alterations in electrical impedance myography, and muscle fiber atrophy. In contrast, the hetero-humanized mice did not display any of the previously described impairments. Homo-humanized mice reflect various aspects of CMT1A characteristics in an hPMP22 gene dosage-dependent manner. This model will help us better understand the relationship between PMP22 reduction levels and the recovery of CMT1A-related phenotypes, contributing to the translation of preclinical findings into clinically relevant human treatments and dosing strategies.
2025-10-16 | Guillain-Barré Syndrome With Asymmetrical Weakness in a Patient With Charcot-Marie-Tooth Disease Type 1A.
A man in his 60s presented with acute, progressive right lower limb weakness, low back pain, and paraesthesia. Neuroimaging ruled out spinal cord and central pathology. Cerebrospinal fluid analysis revealed albumin-cytological dissociation, and nerve conduction studies confirmed Guillain-Barré syndrome (GBS) superimposed on Charcot-Marie-Tooth disease type 1A (CMT1A). There was no preceding infection or ganglioside antibody positivity. His weakness progressed rapidly, resulting in flaccid paralysis of the right leg. He received intravenous immunoglobulin with marked clinical improvement and regained independent mobility by follow-up. This case is notable for its atypical, asymmetrical presentation of GBS in the context of pre-existing hereditary neuropathy, posing diagnostic challenges. It contributes to the limited literature on overlapping GBS and CMT1A and reinforces the importance of early investigation and immunotherapy in non-classical cases. The case highlights that reflex loss and chronic neuropathy should not preclude consideration of acute treatable causes.
2025-09-25 | Advances and Clues of Nutritional Adjuvant Therapy for Charcot-Marie-Tooth Disease.
Charcot-Marie-Tooth disease (CMT) is an inherited peripheral neuropathy with significant genetic heterogeneity and clinical variability. Currently, there are no specific drugs to cure the disease, and adjuvant therapies are used to alleviate the symptoms. By supporting the functions of nerves, bones, and muscles, as well as systemic metabolism, personalized intakes of energy and nutrients help slow down disease progression, delay CMT onset, relieve the suffering and pain of patients, and improve their quality of life. This review discusses the research progress on energy- and fat-manipulated diets (caloric restriction diet, ketogenic diet, and high-fat diet) and several nutrients (polyunsaturated fatty acids, phospholipids, copper, iron, zinc, selenium, vitamins A/D/E/C, and some vitamin Bs) in the treatment of CMT and related peripheral neuropathies, which is expected to encourage exploration on and application of healthy diets and nutritional intakes from the viewpoint of clinical nutrition to improve the symptoms of CMT.
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Drug Discovery Landscape
9 orphan drug designations for Charcot-Marie-Tooth disease type 1A.
9 orphan drug designations for Charcot-Marie-Tooth disease type 1A.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
synthetic double strand oligonucleotide encoding PMP22 siRNA with the sense strand modified by a DBCO residue at the 5¿-end, conjugated with a triazole SQ | RNAs | FDA | — | MAAsiRNA |
3-Methyl-1-phenylpyrazolo-1,2-naphthoquinone | small molecules | FDA | — | Lmito Therapeutics Inc. |
a non-replicating recombinant adeno- associated virus serotype 9 (AAV9) based gene therapy vector containing the DNA of Streptococcus pyogenes Cas9 (SpCas9) protein and single guide RNA (sgRNA) designed to target the TATA-box of the PMP22 P1 promoter | gene therapies | FDA | — | ToolGen, Inc. |
AAV-based engineered microRNA targeting conserved regions on the human PMP22 transcript | gene therapies | FDA | — | Armatus Bio |
Double-stranded small-interfering ribonucleic acid (siRNA) comprised of an antisense strand complementary to a targeted sequence within human PMP22 messenger RNA and a nucleotide sense strand linked to a fatty acid motif | RNAs | FDA | Novartis Pharmaceuticals Corporation | |
Fixed-dose combination of (R-S) baclofen, naltrexone hydrochloride and D-sorbitol | small molecules | EMA | Pharnext SA | |
(RS)-baclofen, naltrexone and D-sorbitol | small molecules | FDA | Pharnext SA | |
ascorbic acid | small molecules | FDA | Murigenetics SAS | |
ascorbic acid | small molecules | EMA | Murigenetics SAS |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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