RARE DISEASE
Charcot-Marie-Tooth disease type 1
Charcot-Marie-Tooth disease type 1
Charcot-Marie-Tooth disease type 1
Synonyms: Autosomal dominant demyelinating Charcot-Marie-Tooth disease, CMT1, Charcot-Marie-Tooth neuropathy type 1, Hereditary motor and sensory neuropathy type 1
Synonyms: Autosomal dominant demyelinating Charcot-Marie-Tooth disease, CMT1, Charcot-Marie-Tooth neuropathy type 1, Hereditary motor and sensory neuropathy type 1
Synonyms: Autosomal dominant demyelinating Charcot-Marie-Tooth disease, CMT1, Charcot-Marie-Tooth neuropathy type 1, Hereditary motor and sensory neuropathy type 1
Drug discovery
1
drug
With orphan designation
Overview
Charcot-Marie-Tooth disease type 1 (CMT1) is an autosomal dominant demyelinating peripheral neuropathy characterized by progressive distal muscle weakness/atrophy, sensory loss, foot deformities (pes cavus), and slowed nerve conduction velocity (<38 m/s). Caused primarily by PMP22 gene duplication (CMT1A, 70% of cases) or mutations in myelin-related genes (MPZ, LITAF, EGR2), it typically manifests in childhood/adolescence with variable severity [1][5][12][13].
Burden
Progressive disability: 25% require mobility aids by adulthood; 93% report chronic pain/fatigue [8][16][17]
Economic/psychosocial impact: Frequent orthopedic interventions, reduced workforce participation, and anxiety/depression in 40% [8][14][17]
Diagnostic challenges: 6.8% remain undiagnosed due to lack of healthcare engagement [2][14]
Therapies
Multidisciplinary management: Ankle-foot orthoses, physical/occupational therapy, and orthopedic surgery for severe deformities [1][15][16]
Experimental therapies: Ascorbic acid trials (myelin modulation), antisense oligonucleotides targeting PMP22 overexpression, and progesterone antagonists under investigation [3][7][17]
Symptom-focused care: Pain management, fall prevention, and adaptive devices [11][16][19]
Categories: rare genetic diseases, rare neurological diseases
Research Papers
720 drug discovery papers about Charcot-Marie-Tooth disease type 1, with 7 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
720 drug discovery papers about Charcot-Marie-Tooth disease type 1, with 7 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
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.
2026-06-29 | GDAP1 orchestrates redox signaling at membrane contact sites to preserve axonal integrity in Charcot-Marie-Tooth disease.
Pathogenic variants in GDAP1 cause Charcot-Marie-Tooth disease (CMT), an inherited peripheral neuropathy characterized by progressive axonal degeneration. Although GDAP1 is an atypical glutathione S-transferase localized to the outer mitochondrial membrane, it has been proposed to function as a redox sensor that likely maintains inter-organelle communication in neurons. However, the mechanisms by which GDAP1 performs these functions remain unclear. To address this question, we here used a robust multi-tier approach that combines high-resolution and live-cell imaging with pH-sensitive probes, membrane contact sites (MCSs) analysis, lipid studies, transcriptomics, and nerve ultrastructural studies in both patient-derived fibroblasts and Gdap1-/- mice. We find that deletion of the GDAP1 gene induces localized pH and redox imbalances at mitochondria-lysosomes contact sites, which propagate to defective mitochondria-peroxisome interactions, impaired peroxisome biogenesis and morphology, leading to altered lipid homeostasis. These defects are accompanied by axonal organelle mislocalization, disruption of nodes of Ranvier, and structural abnormalities in peripheral nerves. Investigations on the potential reversibility of these processes, reveal that restoration of redox balance rescues MCS organization, identifying a therapeutically tractable MCS-peroxisome axis downstream of GDAP1. Together, our findings position GDAP1 as a redox-sensing organizer of mitochondrial membrane contact sites whose dysfunction triggers a cascade of organelle and axonal defects underlying CMT pathogenesis. Thus, this new knowledge should be taken into consideration in the future design of therapeutic interventions that can ameliorate the symptoms of this dismal disease.
2026-05-19 | Neuromuscular junction dysfunction in a subset of Charcot-Marie Tooth and related peripheral neuropathies mouse models.
Charcot-Marie Tooth (CMT) disease is a clinically and genetically heterogeneous inherited peripheral neuropathy for which there is no treatment. CMT patients often present with weakness, fatigue, and muscle atrophy in the distal limbs. Improving function at the neuromuscular junction (NMJ) may improve function in some CMT patients. Using mouse models, we investigated eight CMT subtypes for NMJ phenotypes by morphology and functional deficits assessed by electromyography (EMG). We did not find NMJ abnormalities in mice with mutations in Gjb1Y/Δ2 (CMT1X), or Yars1E196K/E196K (diCMTC). Mice with mutations in Ighmbp2Y918S/Y918S (CMT2S) and Pla2g6M1J/M1J (Infantile Neuroaxonal Dystrophy) have neuromuscular phenotypes that could imply NMJ dysfunction, but we did not find defects in synaptic transmission or anatomy. A transgenic model of PMP22 overexpression (CMT1A) had EMG deficits with high frequency stimulation that are consistent with NMJ involvement. Three models showed indications of altered NMJ morphology and/or function. Gars+/ΔETAQ mice, modeling CMT2D, displayed robust synaptic deficits morphologically and by EMG. Nadk2S330P/S330P mice, modeling an ultrarare neuromuscular disease, had an EMG phenotype coinciding with symptom onset. Nefl+/N98S mice, modeling CMT2E, had normal EMG; but pre-synaptic axon terminals were dysmorphic, with large varicosities, which were more pronounced in proximal muscles. Across multiple models, we found that the extensor digitorum longus was resistant to disease phenotypes based on NMJ innervation status and/or muscle weight and atrophy. Our results indicate that some subtypes of CMT have NMJ deficits, and that assessing neuromuscular disease patients for NMJ dysfunction may reveal a population that could benefit from therapies that enhance transmission.
2026-05-17 | An updated patent review of histone deacetylase 6 inhibitors in neurodegenerative diseases (2020-2025).
Histone deacetylase 6 (HDAC6) inhibitors have been widely explored as potential therapeutic approaches for oncological, autoimmune, cardiovascular, and neurodegenerative disorders. Recent clinical advancements in non-hydroxamate-based HDAC6 inhibitors highlight favorable drug-like properties and improved safety margins, enhancing suitability for long-term treatment. This review updates the clinical status of HDAC6 inhibitors, the evolution of HDAC6 inhibitor pharmacophores, and patent disclosures from 2020 to 2025 identified by SciFinder search and manual confirmation. It also describes pharmacological assessment of new selective HDAC6 inhibitors in in vitro and in vivo models of neurodegenerative diseases. Expanding interest in the development of 2-(difluoromethyl)-1,3,4-oxadiazole (1,3,4-DFMO) derivatives has yielded a diverse set of HDAC6 inhibitors with superior HDAC6 potency and selectivity and enhanced oral pharmacokinetic profiles. These characteristics have facilitated the identification of optimized drug candidates for treating both peripheral and central nervous neurodegenerative diseases. Among the emerging therapeutic applications, Charcot-Marie-Tooth (CMT) disease has become the leading focus in preclinical and early clinical development using HDAC6 inhibitors.
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.
2026-08-17 | 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.
2026-02-12 | Stress-Driven Selective Neuronal Vulnerability in Charcot-Marie-Tooth Disease: From Prodromal Pathology to Therapeutic Implications.
Charcot-Marie-Tooth (CMT) disease represents the most prevalent inherited peripheral neuropathy with a broad range of clinical manifestations, inheritance patterns, and causative genes. The primary pathological hallmark is progressive degeneration, predominantly affecting sensory and motor neurons, leading to prominent sensory deficits and progressive motor impairments. While neuropathy-causing mutations in the ubiquitously expressed small heat shock protein HSPB1 account for a subset of axonal CMT cases, the mechanisms underlying the selective vulnerability of peripheral neurons remain poorly understood. In this review, we synthesize emerging evidence to reframe HSPB1-related CMT as a prototypical gene-environment interaction disorder. The unique anatomical exposure and high metabolic demands of the peripheral nervous system (PNS) render it particularly vulnerable to HSPB1 mutation-mediated homeostatic collapse, which manifests through three interconnected pathological axes: proteostatic disturbance, cytoskeletal dysregulation, and mitochondrial dysfunction. Crucially, these deficits converge to impair the stress adaptability of peripheral neurons, creating a maladaptive feedback loop wherein environmental stressors exacerbate intrinsic vulnerabilities. We further propose a phase-specific therapeutic framework that prioritizes early intervention during the clinically silent yet biologically active prodromal stage, when targeted modulation of the HSPB1 chaperone interactome and remodeling neural homeostasis may forestall neurodegeneration. This therapeutic paradigm shift from symptomatic management to preclinical neuroprotection underscores the imperative for precision medicine approaches in future CMT intervention.
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.
2025-04-17 | The Spectrum of Small Heat Shock Protein B8 (HSPB8)-Associated Neuromuscular Disorders.
The heat shock protein B8 (HSPB8) is one of the small heat shock proteins (sHSP or HSPB) and is a ubiquitous protein in various organisms, including humans. It is highly expressed in skeletal muscle, heart, and neurons. It plays a crucial role in identifying misfolding proteins and participating in chaperone-assisted selective autophagy (CASA) for the removal of misfolded and damaged, potentially cytotoxic proteins. Mutations in HSPB8 can cause distal hereditary motor neuropathy (dHMN), Charcot-Marie-Tooth (CMT) disease type 2L, or myopathy. The disease can manifest from childhood to mid-adulthood. Most missense mutations in the N-terminal and α-crystallin domains of HSPB8 lead to dHMN or CMT2L. Frameshift mutations in the C-terminal domain (CTD), resulting in elongation of the HSPB8 C-terminal, cause myopathy with myofibrillar pathology and rimmed vacuoles. Myopathy and motor neuropathy can coexist. HSPB8 frameshift mutations in the CTD result in HSPB8 mutant aggregation, which weakens the CASA ability to direct misfolded proteins to autophagic degradation. Cellular and animal models indicate that HSPB8 mutations drive pathogenesis through a toxic gain-of-function mechanism. Currently, no cure is available for HSPB8-associated neuromuscular disorders, but numerous therapeutic strategies are under investigation spanning from small molecules to RNA interference to exogenous HSPB8 delivery.
gene therapies
2026-09-27 | Promoter-Targeted CRISPR Correction of PMP22 Gene Dosage Restores Schwann Cell Homeostasis in Charcot-Marie-Tooth Disease Type 1A.
Charcot-Marie-Tooth disease type 1A (CMT1A), the most common inherited peripheral neuropathy, arises from a 1.4 Mb duplication of the Peripheral Myelin Protein 22 (PMP22) gene, causing gene-dosage-dependent toxic overexpression that drives Schwann cell dysfunction and demyelination. We developed a gene-dosage-targeted therapeutic strategy using an sgRNA-mediated bidirectional promoter microdeletion (sgRNA-BPM) approach to selectively suppress pathogenic PMP22 overexpression while preserving physiological expression levels. Clinical evaluation of an index patient (pedigree analysis, muscle MRI, electrophysiological assessment) confirmed an inherited demyelinating neuropathy with distal muscle atrophy. Patient-derived pluripotent stem cells (iPSCs) were used to establish a single-cell-derived clone in which all three PMP22 P1 promoter TATA boxes were disrupted (- 2, - 2, and - 17 bp deletions). This promoter-targeted editing attenuated PMP22 expression during directed differentiation into Schwann cell lineage. Edited cells exhibited partial restoration of Schwann cell maturation-associated, promyelinating-like transcriptional features, accompanied by upregulation of SOX9 and AP2α, attenuation of aberrant PMP22 overexpression, and improvement of Schwann cell morphology. Quantitative imaging revealed ~ 50% reduction (p < 0.01) in PMP22/S100β co-expression index, indicating substantial molecular and structural correction. Despite P1 promoter disruption, basal PMP22 expression was preserved, consistent with transcription driven by the downstream TATA-less P2 promoter. This promoter-level repression of PMP22 was reproducible in mature human primary Schwann cells, where quantitative PCR confirmed reduced PMP22 expression (p < 0.05), supporting translational feasibility of this gene-dosage modulation strategy beyond iPSC-derived systems. Collectively, patient-anchored, promoter-targeted genome editing can potentially correct pathogenic PMP22 dosage while preserving basal expression, establishing a translational iPSC-based framework for treating dosage-sensitive demyelinating neuropathies such as CMT1A.
2026-09-23 | DNM2-Charcot-Marie-Tooth neuropathy stems from disrupted Schwann cell function and shows limited therapeutic reversibility.
Dominant loss-of-function mutations in DNM2 cause Charcot-Marie-Tooth neuropathy characterized by sensory and motor deficits associated with myelin and/or axonal abnormalities and muscle atrophy. Increasing DNM2 activity from embryogenesis has been reported to ameliorate neuromuscular phenotypes in the Dnm2K562E/+ Charcot-Marie-Tooth mouse; however, this model displays predominantly muscle pathology and limited nerve involvement, precluding rigorous evaluation of neuropathic mechanisms and potential therapies. Here, we performed comprehensive behavioural, electrophysiological, histological and molecular analyses to characterize the Dnm2K562E/ SC- mouse, which combines systemic heterozygosity for the common K562E mutation together with Schwann cell-specific deletion of wild-type Dnm2. This model faithfully reproduces key clinical and pathological features of DNM2-Charcot-Marie-Tooth, including motor deficits, reduced general force and coordination, and severe sensory and motor conduction deficits associated with axonal loss, demyelination and inflammation. Mechanistically, we delineate a coherent pathological sequence that explains the profound functional deficits. In particular, a downregulation of the transcription factor EGR2, a master regulator of myelin gene expression, and of the myelin protein MPZ correlates with demyelination. To evaluate the therapeutic potential of DNM2 supplementation, post-symptomatic intrathecal delivery of AAV9-DNM2 driven by the Schwann cell-specific MPZ promoter was performed at 4 weeks. Although DNM2 expression increased in peripheral nerves (∼1.9-fold), no significant improvements were observed across behavioural, electrophysiological, structural or molecular parameters. Together, these findings establish the Dnm2K562E/ SC- mouse as a robust preclinical model, recapitulating key features of DNM2-Charcot-Marie-Tooth, and provide crucial insight into the biological and temporal constraints that must guide future therapeutic strategies for DNM2-Charcot-Marie-Tooth.
2026-09-07 | Tyrosyl-tRNA sequestration triggers tyrosyl-tRNA synthetase-associated peripheral neuropathy.
Mono-allelic mutations in seven cytosolic aminoacyl-tRNA synthetase genes cause Charcot-Marie-Tooth (CMT) peripheral neuropathy. Here, we report that tyrosyl-tRNA (tRNATyr) sequestration by CMT-mutant tyrosyl-tRNA synthetase (TyrRS) is the molecular root cause of CMT-YARS1. tRNATyr sequestration depletes the cellular free tRNATyr pool, leading to insufficient tyrosyl-tRNATyr production and ribosome stalling at tyrosine codons. In three Drosophila CMT-YARS1 models, transgenic overexpression of tRNATyr rescued peripheral neuropathy phenotypes and defective mRNA translation. We provide biochemical evidence for tRNATyr sequestration by the three CMT-TyrRS variants expressed in the Drosophila models and ribosome profiling revealed selective ribosome pausing at the two tyrosine codons. In the Yars1E196K mouse model, adeno-associated virus serotype 9 (AAV9)-mediated overexpression of tRNATyr-but not wild-type TyrRS protein-fully rescued motor performance deficits, reduced nerve conduction velocity and reduced motor axon calibre. Furthermore, AAV9-tRNATyr gene therapy prevented activation of the integrated stress response in spinal motor neurons, indicating resolution of ribosome stalling. Thus, elevating tRNATyr levels constitutes a novel therapeutic approach for CMT-YARS1.
2026-09-06 | A phase III clinical trial of PXT3003 in Chinese patients with Charcot-Marie-Tooth disease type 1A.
Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common inherited peripheral neuropathy and currently lacks disease-modifying therapy. PXT3003, a low-dose oral combination targeting PMP22 overexpression, has shown efficacy in two trials, while one recent confirmatory trial failed to meet its primary efficacy endpoints. In this trial, eligible participants aged 16 to 65 years with genetically confirmed mild-to-moderate CMT1A were randomly assigned to receive oral PXT3003 or placebo twice daily for 15 months. The primary endpoint was the change in the overall neuropathy limitations scale (ONLS) total score from baseline to month 15. At month 15, mean ONLS change from baseline was -0.268 (SD: 0.82) in the PXT3003 group versus 0.013 (SD: 0.65) in the placebo group, with a between-group difference of -0.249 (95% confidence interval [CI]: -0.467 to -0.030; p = 0.0257). Significant improvements were observed in the ONLS leg subscore and ankle-dorsiflexion strength. These findings support PXT3003 as a promising therapeutic option for alleviating limb symptoms in patients with CMT1A.
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.
oligonucleotides
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.
2026-01-28 | Hereditary Polyneuropathies in the Era of Precision Medicine: Genetic Complexity and Emerging Strategies.
Hereditary polyneuropathies represent a genetically and clinically heterogeneous group of disorders affecting the peripheral nervous system, characterized by progressive motor, sensory, and autonomic impairment. Advances in molecular genetics have identified key causative genes, including PMP22, MPZ, MFN2, TTR, EGR2, and CX32 (GJB1), which are implicated in Charcot-Marie-Tooth disease, Dejerine-Sottas syndrome, and related neuropathies. These conditions display substantial allelic and locus heterogeneity. Pathogenetically, mechanisms involve impaired myelin maintenance, disrupted axonal transport, mitochondrial dysfunction, and aberrant Schwann cell biology. Despite these insights, therapeutic options remain limited, and there is a pressing need to translate genetic findings into effective interventions. This review aims to provide a comprehensive synthesis of current knowledge compiling all known mutations resulting in hereditary polyneuropathies. In addition, it underscores the molecular pathomechanisms of hereditary polyneuropathies and evaluates emerging therapeutic strategies, including adeno-associated virus mediated RNA interference, CRISPR-based gene editing, antisense oligonucleotide therapy, and small-molecule modulators of axonal degeneration. Furthermore, the integration of precision diagnostics, such as next-generation sequencing and functional genomic approaches, is discussed in the context of personalized disease management. Collectively, this review underscores the need for patient-centered approaches in advancing care for individuals with hereditary polyneuropathies.
2025-02-27 | Charcot-Marie-Tooth disease: a review of clinical developments and its management - What's new in 2025?
Charcot-Marie-Tooth disease (CMT) understanding and diagnostic rates are improving. Symptomatic management is still the only option, but many therapeutic approaches are under investigation, some in the clinical trial phase. Through a comprehensive search in PubMed, the ClinicalTrials.gov website, and the latest abstracts on the topic, the authors review the diagnostic advances and promising treatments, focusing on pharmacological and gene therapy/silencing approaches, and on clinical trial challenges. They also review current CMT management, including rehabilitation, orthotics, and associated symptoms and comorbidities. The CMT field is evolving rapidly, with significant advances in genetic diagnosis and disease recognition. International networks and patient organization partnerships are vital for progress, enabling collaboration and large-scale studies. Metabolic neuropathies are relatively easier to target, and interim analysis results from the CMT-SORD trial suggest govorestat may become the first approved CMT drug. Gene therapy shows promise but currently faces safety and targeting challenges; PMP22 silencers for CMT1A are close to being tested in patients. New drugs, such as HDAC6 inhibitors, are also approaching the clinical trial phase, despite existing hurdles. Supportive care, including rehabilitation and orthotics, continues to improve quality of life. There is optimism that within the next decade, approved therapies will reduce disease burden.
2025-01-25 | Therapeutic potential of siRNA PMP22-SQ nanoparticles for Charcot-Marie-Tooth 1A neuropathy in rodents and non-human primates.
Small interfering RNA (siRNA) has shown promising results for the treatment of Charcot-Marie-Tooth disease 1A (CMT1A) caused by overexpression of peripheral myelin protein (PMP22), leading to myelin dysfunction and axonal damage. Recently, we developed siRNA PMP22-squalene (SQ) nanoparticles (NPs) for intravenous use. Three consecutive injections of siRNA PMP22-SQ NPs at a cumulative dose of 1.5 mg/kg restored motor function in C61 transgenic mouse models. Pharmacokinetic studies showed a long half-life of antisense siRNA PMP22 in the sciatic nerve, and spinal cord, indicating targeted release potential. We further assessed the efficiency and safety of siRNA PMP22-SQ NPs in two healthy male non-human primates (Macaca fascicularis) after administering four escalating doses (0.1, 0.5, 2.5 and 4.5 mg/kg at one week interval). Interestingly, the siRNA PMP22-SQ NPs reduced PMP22 mRNA expression by approximately 70 % and probably induced an early-stage hereditary neuropathy with pressure palsies (HNPP)-like condition in two normal NHP. No preliminary toxicity was observed in organs or blood parameters of the two NHPs. Interestingly, the nerve conduction velocity decreased after the third injection of siRNA PMP22-SQ NPS. These results demonstrate the therapeutic potential of siRNA PMP22-SQ NPs, supporting advancement to further pre-clinical testing.
2024-09-28 | Current Treatment Methods for Charcot-Marie-Tooth Diseases.
Charcot-Marie-Tooth (CMT) disease, the most common inherited neuromuscular disorder, exhibits a wide phenotypic range, genetic heterogeneity, and a variable disease course. The diverse molecular genetic mechanisms of CMT were discovered over the past three decades with the development of molecular biology and gene sequencing technologies. These methods have brought new options for CMT reclassification and led to an exciting era of treatment target discovery for this incurable disease. Currently, there are no approved disease management methods that can fully cure patients with CMT, and rehabilitation, orthotics, and surgery are the only available treatments to ameliorate symptoms. Considerable research attention has been given to disease-modifying therapies, including gene silencing, gene addition, and gene editing, but most treatments that reach clinical trials are drug treatments, while currently, only gene therapies for CMT2S have reached the clinical trial stage. In this review, we highlight the pathogenic mechanisms and therapeutic investigations of different subtypes of CMT, and promising therapeutic approaches are also discussed.
other
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.
2025-11-14 | 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.
2025-10-06 | Comparison of the presentation and electrophysiological characteristics of autoimmune nodopathies in patients with antibody-negative CIDP and CMT1.
Autoimmune nodopathy (AN), as patients positive for IgG4 autoantibodies against NF155, NF186, CNTN1, or CASPR1, is a distinct form of chronic inflammatory demyelinating polyneuropathy (CIDP) that shares similar clinical and electrophysiological characteristics with Charcot-Marie-Tooth disease type 1 (CMT1). This study aimed to determine the clinical presentation and electrophysiological features of AN and compare them with antibody-negative CIDP and CMT1. We collected clinical data from 29 patients who met the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) electrophysiological diagnostic criteria for definite CIDP. Autoimmune antibodies (anti-NF155, NF186, CNTN1, and CASPR1) were tested using cell-based assays. Additionally, 17 CMT1 patients, diagnosed with hereditary motor sensory neuropathy type 1, were included. We compared the clinical and electrophysiological characteristics of AN, antibody-negative CIDP, and CMT1 patients. Among the 29 CIDP patients, 10 tested positive for autoantibodies (8 for NF155, 1 for CASPR1, and 1 for CNTN1). AN patients had a younger age of onset compared to antibody-negative CIDP and were similar in age to CMT1 patients. Hand tremor was more common in AN patients (60%) compared to antibody-negative CIDP (21%) and CMT1 (5.8%). Conversely, 76.4% of CMT1 patients exhibited cavus foot, significantly higher than the 20% in AN patients. Cerebrospinal fluid (CSF) analysis revealed higher cell count and protein levels in AN patients compared to antibody-negative CIDP and CMT1. AN patients showed poor response to corticosteroids and intravenous immunoglobulin (IVIG), but rituximab was more effective. Electrophysiological findings revealed significantly prolonged distal motor latencies (DML) in the tibial posterior and peroneal nerves, as well as prolonged F-wave latencies in the ulnar and posterior tibial nerves in AN patients than antibody-negative CIDP. In contrast, compared with AN, CMT1 patients showed prolonged DML and significantly reduced motor conduction velocities (MCV) in the median and ulnar nerves. AN patients exhibited sparing of the sural nerve, whereas this phenomenon was not observed in CMT1 patients. In young male patients with hand tremors, demyelinating electrophysiological features (especially prolonged DML and F-wave latencies), elevated CSF protein levels, and poor response to corticosteroids, autoimmune nodopathy, AN antibody testing is recommended. Compared to AN, CMT1 patients tend to have a slower disease course, less frequent tremors, and normal CSF protein levels. A median nerve DML greater than 10 ms and MCV less than 25 m/s supports a diagnosis of CMT1.
small molecules
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.
2026-06-29 | GDAP1 orchestrates redox signaling at membrane contact sites to preserve axonal integrity in Charcot-Marie-Tooth disease.
Pathogenic variants in GDAP1 cause Charcot-Marie-Tooth disease (CMT), an inherited peripheral neuropathy characterized by progressive axonal degeneration. Although GDAP1 is an atypical glutathione S-transferase localized to the outer mitochondrial membrane, it has been proposed to function as a redox sensor that likely maintains inter-organelle communication in neurons. However, the mechanisms by which GDAP1 performs these functions remain unclear. To address this question, we here used a robust multi-tier approach that combines high-resolution and live-cell imaging with pH-sensitive probes, membrane contact sites (MCSs) analysis, lipid studies, transcriptomics, and nerve ultrastructural studies in both patient-derived fibroblasts and Gdap1-/- mice. We find that deletion of the GDAP1 gene induces localized pH and redox imbalances at mitochondria-lysosomes contact sites, which propagate to defective mitochondria-peroxisome interactions, impaired peroxisome biogenesis and morphology, leading to altered lipid homeostasis. These defects are accompanied by axonal organelle mislocalization, disruption of nodes of Ranvier, and structural abnormalities in peripheral nerves. Investigations on the potential reversibility of these processes, reveal that restoration of redox balance rescues MCS organization, identifying a therapeutically tractable MCS-peroxisome axis downstream of GDAP1. Together, our findings position GDAP1 as a redox-sensing organizer of mitochondrial membrane contact sites whose dysfunction triggers a cascade of organelle and axonal defects underlying CMT pathogenesis. Thus, this new knowledge should be taken into consideration in the future design of therapeutic interventions that can ameliorate the symptoms of this dismal disease.
2026-05-19 | Neuromuscular junction dysfunction in a subset of Charcot-Marie Tooth and related peripheral neuropathies mouse models.
Charcot-Marie Tooth (CMT) disease is a clinically and genetically heterogeneous inherited peripheral neuropathy for which there is no treatment. CMT patients often present with weakness, fatigue, and muscle atrophy in the distal limbs. Improving function at the neuromuscular junction (NMJ) may improve function in some CMT patients. Using mouse models, we investigated eight CMT subtypes for NMJ phenotypes by morphology and functional deficits assessed by electromyography (EMG). We did not find NMJ abnormalities in mice with mutations in Gjb1Y/Δ2 (CMT1X), or Yars1E196K/E196K (diCMTC). Mice with mutations in Ighmbp2Y918S/Y918S (CMT2S) and Pla2g6M1J/M1J (Infantile Neuroaxonal Dystrophy) have neuromuscular phenotypes that could imply NMJ dysfunction, but we did not find defects in synaptic transmission or anatomy. A transgenic model of PMP22 overexpression (CMT1A) had EMG deficits with high frequency stimulation that are consistent with NMJ involvement. Three models showed indications of altered NMJ morphology and/or function. Gars+/ΔETAQ mice, modeling CMT2D, displayed robust synaptic deficits morphologically and by EMG. Nadk2S330P/S330P mice, modeling an ultrarare neuromuscular disease, had an EMG phenotype coinciding with symptom onset. Nefl+/N98S mice, modeling CMT2E, had normal EMG; but pre-synaptic axon terminals were dysmorphic, with large varicosities, which were more pronounced in proximal muscles. Across multiple models, we found that the extensor digitorum longus was resistant to disease phenotypes based on NMJ innervation status and/or muscle weight and atrophy. Our results indicate that some subtypes of CMT have NMJ deficits, and that assessing neuromuscular disease patients for NMJ dysfunction may reveal a population that could benefit from therapies that enhance transmission.
2026-05-17 | An updated patent review of histone deacetylase 6 inhibitors in neurodegenerative diseases (2020-2025).
Histone deacetylase 6 (HDAC6) inhibitors have been widely explored as potential therapeutic approaches for oncological, autoimmune, cardiovascular, and neurodegenerative disorders. Recent clinical advancements in non-hydroxamate-based HDAC6 inhibitors highlight favorable drug-like properties and improved safety margins, enhancing suitability for long-term treatment. This review updates the clinical status of HDAC6 inhibitors, the evolution of HDAC6 inhibitor pharmacophores, and patent disclosures from 2020 to 2025 identified by SciFinder search and manual confirmation. It also describes pharmacological assessment of new selective HDAC6 inhibitors in in vitro and in vivo models of neurodegenerative diseases. Expanding interest in the development of 2-(difluoromethyl)-1,3,4-oxadiazole (1,3,4-DFMO) derivatives has yielded a diverse set of HDAC6 inhibitors with superior HDAC6 potency and selectivity and enhanced oral pharmacokinetic profiles. These characteristics have facilitated the identification of optimized drug candidates for treating both peripheral and central nervous neurodegenerative diseases. Among the emerging therapeutic applications, Charcot-Marie-Tooth (CMT) disease has become the leading focus in preclinical and early clinical development using HDAC6 inhibitors.
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.
2026-08-17 | 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.
2026-02-12 | Stress-Driven Selective Neuronal Vulnerability in Charcot-Marie-Tooth Disease: From Prodromal Pathology to Therapeutic Implications.
Charcot-Marie-Tooth (CMT) disease represents the most prevalent inherited peripheral neuropathy with a broad range of clinical manifestations, inheritance patterns, and causative genes. The primary pathological hallmark is progressive degeneration, predominantly affecting sensory and motor neurons, leading to prominent sensory deficits and progressive motor impairments. While neuropathy-causing mutations in the ubiquitously expressed small heat shock protein HSPB1 account for a subset of axonal CMT cases, the mechanisms underlying the selective vulnerability of peripheral neurons remain poorly understood. In this review, we synthesize emerging evidence to reframe HSPB1-related CMT as a prototypical gene-environment interaction disorder. The unique anatomical exposure and high metabolic demands of the peripheral nervous system (PNS) render it particularly vulnerable to HSPB1 mutation-mediated homeostatic collapse, which manifests through three interconnected pathological axes: proteostatic disturbance, cytoskeletal dysregulation, and mitochondrial dysfunction. Crucially, these deficits converge to impair the stress adaptability of peripheral neurons, creating a maladaptive feedback loop wherein environmental stressors exacerbate intrinsic vulnerabilities. We further propose a phase-specific therapeutic framework that prioritizes early intervention during the clinically silent yet biologically active prodromal stage, when targeted modulation of the HSPB1 chaperone interactome and remodeling neural homeostasis may forestall neurodegeneration. This therapeutic paradigm shift from symptomatic management to preclinical neuroprotection underscores the imperative for precision medicine approaches in future CMT intervention.
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.
2025-04-17 | The Spectrum of Small Heat Shock Protein B8 (HSPB8)-Associated Neuromuscular Disorders.
The heat shock protein B8 (HSPB8) is one of the small heat shock proteins (sHSP or HSPB) and is a ubiquitous protein in various organisms, including humans. It is highly expressed in skeletal muscle, heart, and neurons. It plays a crucial role in identifying misfolding proteins and participating in chaperone-assisted selective autophagy (CASA) for the removal of misfolded and damaged, potentially cytotoxic proteins. Mutations in HSPB8 can cause distal hereditary motor neuropathy (dHMN), Charcot-Marie-Tooth (CMT) disease type 2L, or myopathy. The disease can manifest from childhood to mid-adulthood. Most missense mutations in the N-terminal and α-crystallin domains of HSPB8 lead to dHMN or CMT2L. Frameshift mutations in the C-terminal domain (CTD), resulting in elongation of the HSPB8 C-terminal, cause myopathy with myofibrillar pathology and rimmed vacuoles. Myopathy and motor neuropathy can coexist. HSPB8 frameshift mutations in the CTD result in HSPB8 mutant aggregation, which weakens the CASA ability to direct misfolded proteins to autophagic degradation. Cellular and animal models indicate that HSPB8 mutations drive pathogenesis through a toxic gain-of-function mechanism. Currently, no cure is available for HSPB8-associated neuromuscular disorders, but numerous therapeutic strategies are under investigation spanning from small molecules to RNA interference to exogenous HSPB8 delivery.
gene therapies
2026-09-27 | Promoter-Targeted CRISPR Correction of PMP22 Gene Dosage Restores Schwann Cell Homeostasis in Charcot-Marie-Tooth Disease Type 1A.
Charcot-Marie-Tooth disease type 1A (CMT1A), the most common inherited peripheral neuropathy, arises from a 1.4 Mb duplication of the Peripheral Myelin Protein 22 (PMP22) gene, causing gene-dosage-dependent toxic overexpression that drives Schwann cell dysfunction and demyelination. We developed a gene-dosage-targeted therapeutic strategy using an sgRNA-mediated bidirectional promoter microdeletion (sgRNA-BPM) approach to selectively suppress pathogenic PMP22 overexpression while preserving physiological expression levels. Clinical evaluation of an index patient (pedigree analysis, muscle MRI, electrophysiological assessment) confirmed an inherited demyelinating neuropathy with distal muscle atrophy. Patient-derived pluripotent stem cells (iPSCs) were used to establish a single-cell-derived clone in which all three PMP22 P1 promoter TATA boxes were disrupted (- 2, - 2, and - 17 bp deletions). This promoter-targeted editing attenuated PMP22 expression during directed differentiation into Schwann cell lineage. Edited cells exhibited partial restoration of Schwann cell maturation-associated, promyelinating-like transcriptional features, accompanied by upregulation of SOX9 and AP2α, attenuation of aberrant PMP22 overexpression, and improvement of Schwann cell morphology. Quantitative imaging revealed ~ 50% reduction (p < 0.01) in PMP22/S100β co-expression index, indicating substantial molecular and structural correction. Despite P1 promoter disruption, basal PMP22 expression was preserved, consistent with transcription driven by the downstream TATA-less P2 promoter. This promoter-level repression of PMP22 was reproducible in mature human primary Schwann cells, where quantitative PCR confirmed reduced PMP22 expression (p < 0.05), supporting translational feasibility of this gene-dosage modulation strategy beyond iPSC-derived systems. Collectively, patient-anchored, promoter-targeted genome editing can potentially correct pathogenic PMP22 dosage while preserving basal expression, establishing a translational iPSC-based framework for treating dosage-sensitive demyelinating neuropathies such as CMT1A.
2026-09-23 | DNM2-Charcot-Marie-Tooth neuropathy stems from disrupted Schwann cell function and shows limited therapeutic reversibility.
Dominant loss-of-function mutations in DNM2 cause Charcot-Marie-Tooth neuropathy characterized by sensory and motor deficits associated with myelin and/or axonal abnormalities and muscle atrophy. Increasing DNM2 activity from embryogenesis has been reported to ameliorate neuromuscular phenotypes in the Dnm2K562E/+ Charcot-Marie-Tooth mouse; however, this model displays predominantly muscle pathology and limited nerve involvement, precluding rigorous evaluation of neuropathic mechanisms and potential therapies. Here, we performed comprehensive behavioural, electrophysiological, histological and molecular analyses to characterize the Dnm2K562E/ SC- mouse, which combines systemic heterozygosity for the common K562E mutation together with Schwann cell-specific deletion of wild-type Dnm2. This model faithfully reproduces key clinical and pathological features of DNM2-Charcot-Marie-Tooth, including motor deficits, reduced general force and coordination, and severe sensory and motor conduction deficits associated with axonal loss, demyelination and inflammation. Mechanistically, we delineate a coherent pathological sequence that explains the profound functional deficits. In particular, a downregulation of the transcription factor EGR2, a master regulator of myelin gene expression, and of the myelin protein MPZ correlates with demyelination. To evaluate the therapeutic potential of DNM2 supplementation, post-symptomatic intrathecal delivery of AAV9-DNM2 driven by the Schwann cell-specific MPZ promoter was performed at 4 weeks. Although DNM2 expression increased in peripheral nerves (∼1.9-fold), no significant improvements were observed across behavioural, electrophysiological, structural or molecular parameters. Together, these findings establish the Dnm2K562E/ SC- mouse as a robust preclinical model, recapitulating key features of DNM2-Charcot-Marie-Tooth, and provide crucial insight into the biological and temporal constraints that must guide future therapeutic strategies for DNM2-Charcot-Marie-Tooth.
2026-09-07 | Tyrosyl-tRNA sequestration triggers tyrosyl-tRNA synthetase-associated peripheral neuropathy.
Mono-allelic mutations in seven cytosolic aminoacyl-tRNA synthetase genes cause Charcot-Marie-Tooth (CMT) peripheral neuropathy. Here, we report that tyrosyl-tRNA (tRNATyr) sequestration by CMT-mutant tyrosyl-tRNA synthetase (TyrRS) is the molecular root cause of CMT-YARS1. tRNATyr sequestration depletes the cellular free tRNATyr pool, leading to insufficient tyrosyl-tRNATyr production and ribosome stalling at tyrosine codons. In three Drosophila CMT-YARS1 models, transgenic overexpression of tRNATyr rescued peripheral neuropathy phenotypes and defective mRNA translation. We provide biochemical evidence for tRNATyr sequestration by the three CMT-TyrRS variants expressed in the Drosophila models and ribosome profiling revealed selective ribosome pausing at the two tyrosine codons. In the Yars1E196K mouse model, adeno-associated virus serotype 9 (AAV9)-mediated overexpression of tRNATyr-but not wild-type TyrRS protein-fully rescued motor performance deficits, reduced nerve conduction velocity and reduced motor axon calibre. Furthermore, AAV9-tRNATyr gene therapy prevented activation of the integrated stress response in spinal motor neurons, indicating resolution of ribosome stalling. Thus, elevating tRNATyr levels constitutes a novel therapeutic approach for CMT-YARS1.
2026-09-06 | A phase III clinical trial of PXT3003 in Chinese patients with Charcot-Marie-Tooth disease type 1A.
Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common inherited peripheral neuropathy and currently lacks disease-modifying therapy. PXT3003, a low-dose oral combination targeting PMP22 overexpression, has shown efficacy in two trials, while one recent confirmatory trial failed to meet its primary efficacy endpoints. In this trial, eligible participants aged 16 to 65 years with genetically confirmed mild-to-moderate CMT1A were randomly assigned to receive oral PXT3003 or placebo twice daily for 15 months. The primary endpoint was the change in the overall neuropathy limitations scale (ONLS) total score from baseline to month 15. At month 15, mean ONLS change from baseline was -0.268 (SD: 0.82) in the PXT3003 group versus 0.013 (SD: 0.65) in the placebo group, with a between-group difference of -0.249 (95% confidence interval [CI]: -0.467 to -0.030; p = 0.0257). Significant improvements were observed in the ONLS leg subscore and ankle-dorsiflexion strength. These findings support PXT3003 as a promising therapeutic option for alleviating limb symptoms in patients with CMT1A.
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.
oligonucleotides
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.
2026-01-28 | Hereditary Polyneuropathies in the Era of Precision Medicine: Genetic Complexity and Emerging Strategies.
Hereditary polyneuropathies represent a genetically and clinically heterogeneous group of disorders affecting the peripheral nervous system, characterized by progressive motor, sensory, and autonomic impairment. Advances in molecular genetics have identified key causative genes, including PMP22, MPZ, MFN2, TTR, EGR2, and CX32 (GJB1), which are implicated in Charcot-Marie-Tooth disease, Dejerine-Sottas syndrome, and related neuropathies. These conditions display substantial allelic and locus heterogeneity. Pathogenetically, mechanisms involve impaired myelin maintenance, disrupted axonal transport, mitochondrial dysfunction, and aberrant Schwann cell biology. Despite these insights, therapeutic options remain limited, and there is a pressing need to translate genetic findings into effective interventions. This review aims to provide a comprehensive synthesis of current knowledge compiling all known mutations resulting in hereditary polyneuropathies. In addition, it underscores the molecular pathomechanisms of hereditary polyneuropathies and evaluates emerging therapeutic strategies, including adeno-associated virus mediated RNA interference, CRISPR-based gene editing, antisense oligonucleotide therapy, and small-molecule modulators of axonal degeneration. Furthermore, the integration of precision diagnostics, such as next-generation sequencing and functional genomic approaches, is discussed in the context of personalized disease management. Collectively, this review underscores the need for patient-centered approaches in advancing care for individuals with hereditary polyneuropathies.
2025-02-27 | Charcot-Marie-Tooth disease: a review of clinical developments and its management - What's new in 2025?
Charcot-Marie-Tooth disease (CMT) understanding and diagnostic rates are improving. Symptomatic management is still the only option, but many therapeutic approaches are under investigation, some in the clinical trial phase. Through a comprehensive search in PubMed, the ClinicalTrials.gov website, and the latest abstracts on the topic, the authors review the diagnostic advances and promising treatments, focusing on pharmacological and gene therapy/silencing approaches, and on clinical trial challenges. They also review current CMT management, including rehabilitation, orthotics, and associated symptoms and comorbidities. The CMT field is evolving rapidly, with significant advances in genetic diagnosis and disease recognition. International networks and patient organization partnerships are vital for progress, enabling collaboration and large-scale studies. Metabolic neuropathies are relatively easier to target, and interim analysis results from the CMT-SORD trial suggest govorestat may become the first approved CMT drug. Gene therapy shows promise but currently faces safety and targeting challenges; PMP22 silencers for CMT1A are close to being tested in patients. New drugs, such as HDAC6 inhibitors, are also approaching the clinical trial phase, despite existing hurdles. Supportive care, including rehabilitation and orthotics, continues to improve quality of life. There is optimism that within the next decade, approved therapies will reduce disease burden.
2025-01-25 | Therapeutic potential of siRNA PMP22-SQ nanoparticles for Charcot-Marie-Tooth 1A neuropathy in rodents and non-human primates.
Small interfering RNA (siRNA) has shown promising results for the treatment of Charcot-Marie-Tooth disease 1A (CMT1A) caused by overexpression of peripheral myelin protein (PMP22), leading to myelin dysfunction and axonal damage. Recently, we developed siRNA PMP22-squalene (SQ) nanoparticles (NPs) for intravenous use. Three consecutive injections of siRNA PMP22-SQ NPs at a cumulative dose of 1.5 mg/kg restored motor function in C61 transgenic mouse models. Pharmacokinetic studies showed a long half-life of antisense siRNA PMP22 in the sciatic nerve, and spinal cord, indicating targeted release potential. We further assessed the efficiency and safety of siRNA PMP22-SQ NPs in two healthy male non-human primates (Macaca fascicularis) after administering four escalating doses (0.1, 0.5, 2.5 and 4.5 mg/kg at one week interval). Interestingly, the siRNA PMP22-SQ NPs reduced PMP22 mRNA expression by approximately 70 % and probably induced an early-stage hereditary neuropathy with pressure palsies (HNPP)-like condition in two normal NHP. No preliminary toxicity was observed in organs or blood parameters of the two NHPs. Interestingly, the nerve conduction velocity decreased after the third injection of siRNA PMP22-SQ NPS. These results demonstrate the therapeutic potential of siRNA PMP22-SQ NPs, supporting advancement to further pre-clinical testing.
2024-09-28 | Current Treatment Methods for Charcot-Marie-Tooth Diseases.
Charcot-Marie-Tooth (CMT) disease, the most common inherited neuromuscular disorder, exhibits a wide phenotypic range, genetic heterogeneity, and a variable disease course. The diverse molecular genetic mechanisms of CMT were discovered over the past three decades with the development of molecular biology and gene sequencing technologies. These methods have brought new options for CMT reclassification and led to an exciting era of treatment target discovery for this incurable disease. Currently, there are no approved disease management methods that can fully cure patients with CMT, and rehabilitation, orthotics, and surgery are the only available treatments to ameliorate symptoms. Considerable research attention has been given to disease-modifying therapies, including gene silencing, gene addition, and gene editing, but most treatments that reach clinical trials are drug treatments, while currently, only gene therapies for CMT2S have reached the clinical trial stage. In this review, we highlight the pathogenic mechanisms and therapeutic investigations of different subtypes of CMT, and promising therapeutic approaches are also discussed.
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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.
2025-11-14 | 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.
2025-10-06 | Comparison of the presentation and electrophysiological characteristics of autoimmune nodopathies in patients with antibody-negative CIDP and CMT1.
Autoimmune nodopathy (AN), as patients positive for IgG4 autoantibodies against NF155, NF186, CNTN1, or CASPR1, is a distinct form of chronic inflammatory demyelinating polyneuropathy (CIDP) that shares similar clinical and electrophysiological characteristics with Charcot-Marie-Tooth disease type 1 (CMT1). This study aimed to determine the clinical presentation and electrophysiological features of AN and compare them with antibody-negative CIDP and CMT1. We collected clinical data from 29 patients who met the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) electrophysiological diagnostic criteria for definite CIDP. Autoimmune antibodies (anti-NF155, NF186, CNTN1, and CASPR1) were tested using cell-based assays. Additionally, 17 CMT1 patients, diagnosed with hereditary motor sensory neuropathy type 1, were included. We compared the clinical and electrophysiological characteristics of AN, antibody-negative CIDP, and CMT1 patients. Among the 29 CIDP patients, 10 tested positive for autoantibodies (8 for NF155, 1 for CASPR1, and 1 for CNTN1). AN patients had a younger age of onset compared to antibody-negative CIDP and were similar in age to CMT1 patients. Hand tremor was more common in AN patients (60%) compared to antibody-negative CIDP (21%) and CMT1 (5.8%). Conversely, 76.4% of CMT1 patients exhibited cavus foot, significantly higher than the 20% in AN patients. Cerebrospinal fluid (CSF) analysis revealed higher cell count and protein levels in AN patients compared to antibody-negative CIDP and CMT1. AN patients showed poor response to corticosteroids and intravenous immunoglobulin (IVIG), but rituximab was more effective. Electrophysiological findings revealed significantly prolonged distal motor latencies (DML) in the tibial posterior and peroneal nerves, as well as prolonged F-wave latencies in the ulnar and posterior tibial nerves in AN patients than antibody-negative CIDP. In contrast, compared with AN, CMT1 patients showed prolonged DML and significantly reduced motor conduction velocities (MCV) in the median and ulnar nerves. AN patients exhibited sparing of the sural nerve, whereas this phenomenon was not observed in CMT1 patients. In young male patients with hand tremors, demyelinating electrophysiological features (especially prolonged DML and F-wave latencies), elevated CSF protein levels, and poor response to corticosteroids, autoimmune nodopathy, AN antibody testing is recommended. Compared to AN, CMT1 patients tend to have a slower disease course, less frequent tremors, and normal CSF protein levels. A median nerve DML greater than 10 ms and MCV less than 25 m/s supports a diagnosis of CMT1.
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Drug Discovery Landscape
1 orphan drug designation for Charcot-Marie-Tooth disease type 1.
1 orphan drug designation for Charcot-Marie-Tooth disease type 1.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
allogeneic mesenchymal stem cells derived neuronal regeneration promoting cells | cell therapies | FDA | Cellatoz Therapeutics, Inc. |
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