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
706 drug discovery papers related to Charcot-Marie-Tooth disease type 1, with 7 first-in-class and 0 next-in-class early-stage therapies forecasted to outperform the average preclinical success rate. Recent publications:
706 drug discovery papers related to Charcot-Marie-Tooth disease type 1, with 7 first-in-class and 0 next-in-class early-stage therapies forecasted to outperform the average preclinical success rate. Recent publications:
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.
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.
Access all drug discovery articles and probability of success in trials forecasts:
Access all drug discovery articles and probability of success in trials forecasts:
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 | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
allogeneic mesenchymal stem cells derived neuronal regeneration promoting cells | cell therapies | FDA | 2022-02-17 | — | Cellatoz Therapeutics, Inc. |
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