RARE DISEASE
Charcot-Marie-Tooth disease/Hereditary motor and sensory neuropathy
Charcot-Marie-Tooth disease/Hereditary motor and sensory neuropathy
Charcot-Marie-Tooth disease/Hereditary motor and sensory neuropathy
Synonyms: CMT/HMSN, Charcot-Marie-Tooth hereditary neuropathy
Synonyms: CMT/HMSN, Charcot-Marie-Tooth hereditary neuropathy
Synonyms: CMT/HMSN, Charcot-Marie-Tooth hereditary neuropathy
Drug discovery
18
drugs
With orphan designations
Overview
Charcot-Marie-Tooth disease (CMT), the most common inherited neuromuscular disorder, encompasses genetic peripheral neuropathies characterized by progressive muscle atrophy, sensory loss, and foot deformities. It results from mutations in over 100 genes affecting myelin or axons, with symptoms typically emerging in adolescence or early adulthood and variable severity [1][7][12]. Management focuses on symptom alleviation and functional support.
Therapies
Rehabilitation: Physical/occupational therapy to maintain mobility and reduce disability [5][16].
Orthotics/surgery: Ankle-foot braces, corrective procedures for deformities [3][18].
Emerging therapies: Gene editing (e.g., SH3TC2 replacement), RNAi, and antisense oligonucleotides in preclinical trials [3][8].
Categories: rare genetic diseases, rare neurological diseases
Research Papers
1,047 drug discovery papers about Charcot-Marie-Tooth disease/Hereditary motor and sensory neuropathy, with 5 first-in-class and 15 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,047 drug discovery papers about Charcot-Marie-Tooth disease/Hereditary motor and sensory neuropathy, with 5 first-in-class and 15 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-29 | Variable phenotypic manifestations of two splice-site variants in DNAJB2: insights from two families and a systematic review.
DNAJB2 encodes an HSP40 co‑chaperone involved in protein quality control and maintenance of neuronal proteostasis. Pathogenic variants in this gene, typically inherited in an autosomal recessive manner, cause hereditary motor neuropathy (HMN), Charcot-Marie-Tooth disease (CMT), and other neuromuscular disorders. In this study, we report two unrelated families harboring two distinct splice-site variants within the same intron of DNAJB2: one affecting the acceptor site and the other the donor site, identified in patients presenting with HMN and CMT, respectively. We also performed a systematic review of previously reported variants to further investigate phenotypic variabilities and likely genotype-phenotype correlations. Whole‑exome sequencing (WES) was performed for probands with clinical diagnosis of hereditary neuropathy. Identified variants were confirmed by Sanger sequencing, and co‑segregation analysis was conducted within the families. A systematic review was performed following PRISMA 2020 guidelines using PubMed, Scopus, and Google Scholar databases (January 2000-May 2026). WES identified a known variant, c.446‑1 G > C, in one proband and a novel one, c.445+1del, in another. Clinically, the first patient showed an HMN phenotype, whereas the second presented with an axonal CMT (CMT2). In total, 25 distinct DNAJB2 variants were identified across 46 families in the literature, with most occurring in the homozygous state. Our study expands the mutational spectrums of this gene, and the systematic evaluation of DNAJB2-related cases demonstrates the marked clinical heterogeneity but not a significant genotype-phenotype correlation.
2026-09-22 | PXT3003: Lessons for therapeutic development in Charcot-Marie-Tooth disease type 1A and related neuropathies
Most drug development stories end predictably: promising compounds either succeed or fail. Occasionally, however, a therapy repeatedly returns from apparent extinction. PXT3003 for Charcot-Marie-Tooth disease type 1A (CMT1A) represents one such example. More than a decade after early promise, the program has survived formulation instability, interrupted clinical development, regulatory uncertainty, and controversy surrounding efficacy before re-emerging with renewed evidence of clinical benefit. Yet, as with many therapeutic development programs, interpretation of the available evidence is influenced by the extent to which findings are publicly accessible. In a recent issue of iScience , a phase 3 clinical trial evaluated PXT3003, a combination of baclofen, naltrexone, and D-sorbitol, versus placebo over 15 months in participants aged 16–65 years with mild-to-moderate CMT1A across 25 sites in China. PXT3003 is not simply the story of one drug; it highlights the scientific, methodological, operational, and reporting challenges of developing disease-modifying therapies for slowly progressive inherited neuropathies.
2026-09-11 | P2X7 Receptor in Rare Diseases: Shared Molecular Mechanisms and Therapeutic Implications.
Rare diseases (RDs) are individually uncommon but collectively affect a large global population, and the vast majority still lack effective disease-modifying therapies. With advances in genomics and data-sharing platforms, research has increasingly shifted from a single-disease perspective to the search for convergent molecular pathways that might be shared across clinically distinct entities. In this context, the purinergic P2X7 receptor (P2X7R) has emerged as a putative "shared molecular platform" due to its central role in inflammation amplification, cell death and immune regulation. P2X7R is an ATP-gated ion channel with unique structural and functional features: under high extracellular ATP, it not only forms a non-selective cation channel but can also dilate into a "large pore" permeable to macromolecules, thereby triggering Ca2+overload, NLRP3 inflammasome assembly, reactive oxygen species (ROS) production and apoptotic/necrotic-like cell death. This review briefly outlines the epidemiology of RDs and the structural-functional characteristics of P2X7R, then systematically summarizes current evidence linking P2X7R to multiple rare diseases, including Charcot-Marie-Tooth disease, Guillain-Barré syndrome, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, and selected inflammatory and metabolic RDs (CAPS, familial Mediterranean fever, Systemic sclerosis, Dravet syndrome and Gaucher disease). By comparing P2X7R expression and functional alterations, downstream signaling pathways and pharmacological data from animal models across these conditions, we propose that a P2X7R-dependent network centered on a "Ca2+-NLRP3-inflammation/cell death axis" may constitute a common pathogenic backbone for diverse RDs. At the same time, disease-specific spatiotemporal expression patterns of P2X7R in central vs peripheral nervous systems and in immune vs target organ cells confer marked context dependence and "double-edged sword" properties. Finally, we discuss opportunities and challenges for P2X7R-targeted strategies, including the impact of disease stage and sex differences on therapeutic efficacy, and key bottlenecks in translating preclinical findings into clinical benefit. A deeper understanding of both shared and disease-specific roles of P2X7R may provide a conceptual framework and therapeutic entry point for precision stratification and multi-target interventions in rare diseases.
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.
2026-08-28 | Exploring the clinical and mutational spectrum of MORC2-associated disorders.
Pathogenic missense variants in the MORC2 gene are associated with two distinct disorders: Charcot-Marie-Tooth disease type 2Z (CMT2Z) and the recently described DIGFAN (developmental delay, impaired growth, dysmorphic facies and axonal neuropathy) phenotype, which encompasses a broad range of clinical manifestations that vary significantly between individuals. Clinical and imaging data from 16 patients were collected. Western blot analysis was performed on 10 identified variants in affected patients as well as on two novel variants without clinical data. Those missense variants were introduced into the wild-type vector transfected into HEK293T cells, and western blot analysis was performed to assess protein expression level. A total of 11 different missense variants in the MORC2 gene were identified in our cohort, including four novel variants. We demonstrate that early-onset MORC2-associated disorders segregate into two principal neurological phenotypes: a predominantly neuromuscular form and a central nervous system-predominant form. The p.Ser87Leu variant, which defines the neuromuscular cluster, was uniquely characterised by a significant reduction in MORC2 protein levels, distinguishing it mechanistically from other variants. Overall, western blot analysis revealed no statistically significant difference in protein expression levels between variants related to CMT2Z and DIGFAN cases. A comparison of our patients with previously reported cases revealed an intriguing trend suggesting a probable dependence of the leading clinical features on specific variants in the MORC2 gene. Further accumulation of patient data is required to determine whether this observation correlates with other specific variants.
gene therapies
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.
2026-06-16 | Restoring the interplay between the endoplasmic reticulum and mitochondria by gene therapy improves Charcot-Marie-Tooth type 2A disease.
Charcot-Marie-Tooth disease type 2A (CMT2A) is the most common axonal CMT and is associated with an early onset and severe motor neuropathy. CMT2A is mainly caused by dominant mutations in the MFN2 gene, encoding mitofusin-2, a GTPase located in the outer membrane of the mitochondria and endoplasmic reticulum (ER). Mutations in MFN2 affect mitochondrial dynamics. We previously demonstrated that mutated MFN2 further disrupts contacts between the ER and the mitochondria, leading to axonal degeneration. There are no treatments for CMT2A, and those currently under development primarily focus on restoring mitochondrial function. Here, we provide proof of concept that neuronal overexpression of wild-type MFN2 (MFN2WT) provides therapeutic benefit in transgenic CMT2A mice as well as in CMT2A-motor neurons derived from induced pluripotent stem cells. Intrathecal delivery of an AAV9 vector expressing MFN2WT effectively targets motor and sensory neurons, restoring ER-mitochondria contacts and mitochondrial morphology, thereby preserving both neuromuscular junction integrity and motor function. Strikingly, therapeutic efficacy is also achieved by administering the vector after the onset of symptoms. Importantly, AAV administration was well tolerated, with no evidence of hepatotoxicity or dorsal root ganglion inflammation. We further show that CMT2A pathology can be corrected in vitro and in vivo using an ER-targeting MFN1 isoform that selectively enhances ER-mitochondria contacts. These results establish that restoring contacts between the ER and mitochondria using gene therapy is a promising therapeutic avenue for CMT2A.
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.
2026-05-13 | A dose-escalation and safety gene therapy study in a model of CMT4C neuropathy.
Charcot-Marie-Tooth disease type 4C is a demyelinating neuropathy caused by loss of function mutations in the SH3TC2 gene, that is highly expressed in myelinating Schwann cells. We generated and tested a clinical stage vector with a minimal human MPZ promoter driving expression of SH3TC2. Groups of 1-month old Sh3tc2-/- mice were treated with 3 different doses of AAV9-hMPZmini.SH3TC2.SV40pA or the formulation buffer by lumbar intrathecal injection. Outcomes were compared 8 weeks post injection by behavioral, electrophysiological, proteomics, morphological analysis and evaluation of tissue integrity and inflammatory responses. Vector biodistribution to the peripheral nerves and high rates of cell-specific therapeutic gene expression in Schwann cells resulted in significant therapeutic benefits in the CMT4C model. Treated mice showed improved motor performance in grip strength and motor nerve conduction velocities. Morphological analysis revealed significant improvement in g-ratios, myelin thickness and ratios of demyelinated fibers in lumbar roots and femoral nerves of treated mice. Proteomic profiles showed correction of muscle denervation associated pathobiochemical processes in treated mice. Not observed tissue toxicity or immune reactions in neural tissues or peripheral organs. This study provides proof of principle for dose-dependent effectiveness and safety of intrathecal AAV9-mediated gene replacement paving the way for clinical translation.
2026-04-08 | Safety, efficacy, and distal nerve Schwann cell biodistribution in mice and NHPs to support translation of AAV9 RNAi therapy for CMT1A.
Charcot-Marie-Tooth (CMT) type 1A, the most common inherited demyelinating peripheral neuropathy, is caused by PMP22 gene duplication, leading to overproduction of PMP22 protein in Schwann cells. To treat CMT1A, we developed a PMP22 gene silencing therapy using adeno-associated viral vectors (AAV9) to deliver a therapeutic miRNA expression cassette (U6.miR871) via lumbar intrathecal administration. A single injection produced long-term miR871 expression, triggered selective RNA interference against the PMP22 mRNA, and subsequently lowered protein levels and improved disease manifestations in a humanized CMT1A model. To support clinical translation, we confirmed on-target specificity of miR871 for PMP22 in vitro, identified a safe and effective dosing range in mice, demonstrated absence of significant toxicity in rodents and non-human primates (NHPs), and performed a detailed AAV biodistribution study in a large animal model. We found vector biodistribution and miR871 expression in distal peripheral nerves, PMP22 target engagement in mice and NHPs, and silencing to levels expected to support normal myelination in humans. We identified the minimally efficacious to maximum tolerated dose range of AAV9.U6.miR871 in mice and confirmed safety range in NHPs for extrapolation to anticipated clinical trials. Our study supports the scale-up potential of gene therapy to treat CMT1A and other demyelinating peripheral neuropathies.
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.
2026-07-13 | Neuropathy-Associated HSPB1 Mutant Impairs Neuronal Mechanoadaptation and Axonal Regeneration.
The small heat shock protein HSPB1 is a ubiquitously expressed mechanoresponsive chaperone essential for cytoskeletal remodeling under mechanical load. Mutations in HSPB1, including S135F, cause Charcot-Marie-Tooth (CMT) peripheral neuropathy, yet the mechanisms underlying the selective vulnerability of peripheral nerves remain enigmatic. Here we demonstrate that substrate stiffness is a critical determinant of HSPB1S135F-mediated neurodegeneration. Using stiffness-tunable polydimethylsiloxane (PDMS) substrates (1 kPa, 10 kPa, 2 MPa) and uniaxial cyclic stretch, we show that primary dorsal root ganglia (DRG) neurons and SH-SY5Y cells expressing HSPB1S135F exhibit profound deficits in mechanoadaptation. On compliant substrates (10 kPa), HSPB1S135F causes stretch-induced axon fragmentation and neuronal death, whereas HSPB1WT confers robust neuroprotection. HSPB1S135F also disrupts stiffness-directed neuritogenesis in differentiated SH-SY5Y cells: HSPB1WT-expressing cells show optimal axonal outgrowth and βIII-tubulin expression on 10 kPa substrates mimicking muscle tissue stiffness, while HSPB1S135F mutants display disorganized focal adhesions and complete differentiation failure. Mechanistically, we uncover that HSPB1S135F dysregulates stage-specific transglutaminase (TGase) expression-insufficient TGase during early neuritogenesis impairs filopodia stabilization, whereas aberrant TGase persistence at late stages constrains axon extension. Our findings establish HSPB1 as a biomechanical sensor that integrates ECM stiffness signals to coordinate peripheral nerve regeneration, and identify defective mechanoadaptation as a previously unrecognized pathomechanism in CMT. These results open new avenues for stiffness-targeted therapeutic strategies in peripheral neuropathy.
2026-02-25 | Mitofusin MFN2 acts as a molecular sensor preventing protein aggregation and mitophagy, with a protective effect against apoptosis in Charcot-Marie-Tooth type 2A disease.
Mitochondria are central hubs for cellular fitness, empowered by plastic remodeling of their shape, proteome composition, and/or metabolic state. MFN2 (mitofusin 2) mediates mitochondrial fusion and ensures adaptations in response to metabolic changes and stresses. Besides this canonical role, MFN2 serves as a communication hub with other organelles. It tethers mitochondria to the endoplasmic reticulum (ER), lipid droplets, and peroxisomes, regulating calcium buffering, apoptosis, lipid biosynthesis, and lipolysis. Dysfunctional MFN2 causes the hereditary neuropathy Charcot-Marie-Tooth type 2A (CMT2A) and is linked to several metabolic diseases. In a recent publication, we described another fusion-independent role of MFN2 in proteostasis and mitophagy. MFN2 binds the chaperone HSPA8/HSC70 (heat shock protein family A [Hsp70] member 8) and the proteasome, a key function in maintaining mitochondrial and cellular protein quality control, which appears to be lost in the context of CMT2A-associated MFN2 variants.
2025-07-07 | Increased BNIP3-mediated mitophagy attenuates GDAP1 loss of function - implications for Charcot-Marie-Tooth disease 4A.
Charcot-Marie-Tooth disease type 4 A ((CMT4A), an autosomal recessive neuropathy, is caused by mutations in ganglioside-induced differentiation-associated protein 1 (GDAP1). GDAP1 resides in the outer mitochondrial membrane facing the cytosol and is involved in mitochondrial dynamics and function. Its perturbation affects mitochondrial shape, contact sites, redox homeostasis and cellular metabolism. In response to GDAP1 knockdown in a human neuronal cell line, we found increased mitochondrial turnover, biogenesis and mitophagy. This was associated with more lysosomal proteins in mitochondrial fractions including BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3) and its homolog BNIP3-like (BNIP3L) - proteins involved in the recruitment of autophagy machinery via direct interaction. Flies with neural Gdap1 knockdown also exhibited upregulated levels of the sole BNIP3 ortholog. Neural expression of human BNIP3 reduced the detrimental effects of Gdap1 knockdown on eclosion and climbing ability in adult flies, while simultaneous knockdown of both genes was detrimental. These findings suggest that increased BNIP3-driven mitophagy may act as a protective mechanism, partially counteracting the cellular dysfunction caused by GDAP1 loss of function, and highlight the potential of targeting mitophagy pathways as a therapeutic strategy for CMT4A.
oligonucleotides
2026-07-02 | A class of deep intronic IGHMBP2 variants activate a shared cryptic splice donor, enabling correction of select variants with a single antisense oligonucleotide.
Biallelic disease-causing variants in IGHMBP2 cause spinal muscular atrophy with respiratory distress type I (SMARD1) and Charcot-Marie-Tooth type 2S (CMT2S). We present 12 unrelated patients with clinically suspected IGHMBP2-related-disease, each carrying a variant deep in intron 8 of IGHMBP2 (c.1235+1076G>A (n=6), c.1235+450G>A (n=5), and c.1235+894C>A (n=1)), along with a known deleterious variant in trans. To assess aberrant pathogenic splicing induced by these deep intronic variants in a relevant model, patient-derived induced pluripotent stem cells were differentiated into motor neurons (iMNs). Long-read RNA sequencing revealed introduction of different pseudoexons by each variant: c.1235+450G>A (626bp), c.1235+1076G>A (112bp and 77bp) and c.1235+894C>A (182bp). Although each variant utilizes a unique splice acceptor site, they all activate the same cryptic donor site, enabling a therapeutic approach to redirect aberrant splicing for all the variants using a single shared antisense oligonucleotide (ASO). Treatment of iMNs with this single ASO restored full-length IGHMBP2 protein in c.1235+894G>A and c.1235+1076G>A by decreasing the use of the novel acceptor site. In contrast, ASO treatment did not correct the splicing in c.1235+450G>A, suggesting that additional splice correction will be needed for this specific variant. A CRISPR interference screen of IGHMBP2 loss-of-function in iMNs identified ribonucleoprotein complex biogenesis (RNP), and rRNA and tRNA processing as top pathways implicated in motor neuron vulnerability. Proteomics and transcriptomics analysis of successfully treated patient iMNs revealed correction of RNP biogenesis and rRNA processing defects. This study highlights the importance of characterizing deep intronic variants in disease-relevant cells to assist the diagnostic process and inform therapeutics development.
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.
2025-11-14 | [Charcot-Marie-Tooth Disease: Historical Evolution and Present Understanding].
Charcot-Marie-Tooth disease is a hereditary motor and sensory neuropathy characterized by progressive distal muscle weakness, atrophy, and sensory impairment. In this article, we review the original reports published in 1886 by Charcot, Marie, and Tooth, analyzing the clinical features they used to distinguish Charcot-Marie-Tooth disease from other forms of muscle atrophy. We then trace the historical development of the disease concept and examine evolving classification systems based on clinical, electrophysiological, and genetic findings. The identification of more than 140 causative genes has complicated traditional classifications based on nerve conduction studies and inheritance patterns. Thus, we also provide an overview of the current diagnostic strategies that combine clinical evaluation with genetic testing. Although no curative treatment is currently available, advances in molecular biology have introduced new avenues for pharmacological and gene-based interventions. Accordingly, we present emerging therapeutic approaches, including siRNA and CRISPR-Cas9 targeting PMP22 for CMT1A, as well as other nucleic acid-based drugs under development.
2025-05-01 | A Brief Review of Inherited Neuropathies: A Perspective from Saudi Arabia.
Inherited neuropathies are a heterogeneous group of disorders that affect the peripheral nervous system, leading to motor, sensory, and autonomic dysfunction. These disorders are classified into various subgroups, including hereditary sensory and motor neuropathies, distal hereditary motor neuropathies, hereditary sensory and autonomic neuropathies, and more complex forms. Advances in genetic testing, particularly next-generation sequencing (NGS), have significantly improved the identification of these disorders. Emerging therapies, such as gene therapy, small molecule therapies, and antisense oligonucleotides, offer promising treatment options. However, current treatments remain limited, and their clinical benefits in humans are not yet fully established. This review provides a comprehensive overview of recent developments and evolving therapeutic options for hereditary neuropathies, focusing on gene therapy, small molecule therapies, and antisense oligonucleotides. It also highlights the current state of inherited neuropathies in Saudi Arabia, emphasizing the need for national guidelines, patient registries, and collaborative research efforts. By integrating advanced genomic technologies and fostering international collaboration, we can improve the diagnosis, management, and treatment outcomes for patients with inherited neuropathies.
2025-03-10 | Potential ASO-based personalized treatment for Charcot-Marie-Tooth disease type 2S.
Immunoglobulin mu-binding protein 2 (IGHMBP2) pathogenic variants lead to a spectrum of disorders characterized by alpha-motor neuron degeneration. We describe a compound heterozygous patient diagnosed with Charcot-Marie-Tooth disease type 2S with variants in IGHMBP2: a pathogenic missense variant acting in trans with a confirmed intronic cryptic splice site variant. This variant was shown to result in the creation of a new splice acceptor site, loss of reading frame and nonsense-mediated decay. We designed a 19-mer antisense oligonucleotide targeting this cryptic intronic variant to restore IGHMBP2 levels. ASO treatment of patient fibroblasts significantly increased the ratio of restored wild-type transcript to cryptic exon-containing transcript and resulted in over a 50% increase in IGHMBP2 protein levels. Neuromuscular junction analyses revealed high fatigue and chaotic tetanus formulation in untreated patient cells. We demonstrate rescue of NMJ function following ASO treatment, captured by a reduction in fatigue and chaotic tetanus responses. Furthermore, toxicity testing revealed that intrathecal administration of the ASO to wild-type Sprague-Dawley rats over 3 months was well tolerated. Our preclinical data support this ASO as a potential CMT2S treatment by rescuing IGHMBP2. N-of-1 ASO-based therapeutics may prove instrumental in the design of treatments for this diverse genetic disorder.
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.
2026-05-19 | 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.
2026-04-25 | [Generation of induced pluripotent stem cells from peripheral blood mononuclear cells of a patient with autosomal recessive Charcot-Marie-Tooth disease type 2S caused by IGHMBP2 mutations].
Charcot-Marie-Tooth disease (CMT) is a group of common monogenic peripheral neuropathies listed in the first National Rare Disease Catalog of China and is characterized by marked clinical and genetic heterogeneity. Immunoglobulin μ-binding protein 2 (IGHMBP2) is a ubiquitously expressed nucleic acid helicase, and mutations in the IGHMBP2 gene can cause autosomal recessive CMT type 2S (AR-CMT2S). However, the underlying pathogenic mechanisms remain unclear. This study aims to generate induced pluripotent stem cells (iPSCs) derived from peripheral blood mononuclear cells (PBMCs) of a patient with AR-CMT2S caused by IGHMBP2 mutations (c.884A>G and c.791G>A), thereby providing a novel cellular model for mechanistic studies and stem cell-based therapeutic research. Clinical data of a patient with AR-CMT2S who was diagnosed in September 2022 at the Department of Neurology, Third Xiangya Hospital of Central South University, were collected and analyzed. Pathogenic variants in IGHMBP2 were confirmed by next-generation sequencing. After obtaining written informed consent, 20 mL of peripheral blood was collected, and PBMCs were isolated. PBMCs were reprogrammed into iPSCs using Sendai virus-mediated transduction. The generated iPSCs were characterized for pluripotency marker expression, self-renewal capacity, in vitro differentiation potential, karyotype integrity, and short tandem repeat (STR) profiling. The iPSCs derived from the AR-CMT2S patient were successfully generated. The established iPSC line retained the same IGHMBP2 mutations as those identified in the patient and expressed key pluripotency markers. The cells exhibited robust self-renewal and the ability to differentiate in vitro. Karyotype analysis demonstrated a normal diploid karyotype (46, XX). An iPSC line derived from a patient with AR-CMT2S caused by IGHMBP2 mutations is successfully established. This patient-specific iPSC line provides a valuable cellular model for investigating the pathogenesis of AR-CMT2S and offers a novel tool for the development of effective therapeutic strategies.
2026-01-06 | Combined Posterior Tibial Tendon Transfer and Forefoot Reconstruction for Foot Drop and Forefoot Pain Secondary to Charcot-Marie-Tooth Disease: A Case Report and Literature Review.
Foot drop is a debilitating condition characterized by impaired ankle dorsiflexion and is commonly associated with neuromuscular disorders such as Charcot-Marie-Tooth (CMT) disease. CMT1A, the most prevalent subtype, leads to progressive weakness of the anterior compartment musculature and a cavovarus deformity. Posterior tibial tendon (PTT) transfer remains a well-established surgical technique for restoring active dorsiflexion in cases of irreversible foot drop. We present the case of a 59-year-old female with CMT1A, diabetes mellitus, and peripheral neuropathy who developed progressive left-sided foot drop. Conservative treatment, including a custom ankle-foot orthosis (AFO), was initially attempted. Following failed conservative management, the patient underwent a PTT transfer through the interosseous membrane with interference screw fixation into the intermediate cuneiform. This was combined with a tendoachilles lengthening, hammertoe correction, and Weil osteotomies of the second and third metatarsals. Clinically, she achieved 4° of dorsiflexion above neutral, transitioned to regular footwear, discontinued AFO use, and returned to full functional activity. This case report reinforces the role of PTT transfer as an effective, single-stage reconstructive option for neuromuscular foot drop when combined with appropriate adjunctive procedures and structured rehabilitation.
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.
small molecules
2026-09-29 | Variable phenotypic manifestations of two splice-site variants in DNAJB2: insights from two families and a systematic review.
DNAJB2 encodes an HSP40 co‑chaperone involved in protein quality control and maintenance of neuronal proteostasis. Pathogenic variants in this gene, typically inherited in an autosomal recessive manner, cause hereditary motor neuropathy (HMN), Charcot-Marie-Tooth disease (CMT), and other neuromuscular disorders. In this study, we report two unrelated families harboring two distinct splice-site variants within the same intron of DNAJB2: one affecting the acceptor site and the other the donor site, identified in patients presenting with HMN and CMT, respectively. We also performed a systematic review of previously reported variants to further investigate phenotypic variabilities and likely genotype-phenotype correlations. Whole‑exome sequencing (WES) was performed for probands with clinical diagnosis of hereditary neuropathy. Identified variants were confirmed by Sanger sequencing, and co‑segregation analysis was conducted within the families. A systematic review was performed following PRISMA 2020 guidelines using PubMed, Scopus, and Google Scholar databases (January 2000-May 2026). WES identified a known variant, c.446‑1 G > C, in one proband and a novel one, c.445+1del, in another. Clinically, the first patient showed an HMN phenotype, whereas the second presented with an axonal CMT (CMT2). In total, 25 distinct DNAJB2 variants were identified across 46 families in the literature, with most occurring in the homozygous state. Our study expands the mutational spectrums of this gene, and the systematic evaluation of DNAJB2-related cases demonstrates the marked clinical heterogeneity but not a significant genotype-phenotype correlation.
2026-09-22 | PXT3003: Lessons for therapeutic development in Charcot-Marie-Tooth disease type 1A and related neuropathies
Most drug development stories end predictably: promising compounds either succeed or fail. Occasionally, however, a therapy repeatedly returns from apparent extinction. PXT3003 for Charcot-Marie-Tooth disease type 1A (CMT1A) represents one such example. More than a decade after early promise, the program has survived formulation instability, interrupted clinical development, regulatory uncertainty, and controversy surrounding efficacy before re-emerging with renewed evidence of clinical benefit. Yet, as with many therapeutic development programs, interpretation of the available evidence is influenced by the extent to which findings are publicly accessible. In a recent issue of iScience , a phase 3 clinical trial evaluated PXT3003, a combination of baclofen, naltrexone, and D-sorbitol, versus placebo over 15 months in participants aged 16–65 years with mild-to-moderate CMT1A across 25 sites in China. PXT3003 is not simply the story of one drug; it highlights the scientific, methodological, operational, and reporting challenges of developing disease-modifying therapies for slowly progressive inherited neuropathies.
2026-09-11 | P2X7 Receptor in Rare Diseases: Shared Molecular Mechanisms and Therapeutic Implications.
Rare diseases (RDs) are individually uncommon but collectively affect a large global population, and the vast majority still lack effective disease-modifying therapies. With advances in genomics and data-sharing platforms, research has increasingly shifted from a single-disease perspective to the search for convergent molecular pathways that might be shared across clinically distinct entities. In this context, the purinergic P2X7 receptor (P2X7R) has emerged as a putative "shared molecular platform" due to its central role in inflammation amplification, cell death and immune regulation. P2X7R is an ATP-gated ion channel with unique structural and functional features: under high extracellular ATP, it not only forms a non-selective cation channel but can also dilate into a "large pore" permeable to macromolecules, thereby triggering Ca2+overload, NLRP3 inflammasome assembly, reactive oxygen species (ROS) production and apoptotic/necrotic-like cell death. This review briefly outlines the epidemiology of RDs and the structural-functional characteristics of P2X7R, then systematically summarizes current evidence linking P2X7R to multiple rare diseases, including Charcot-Marie-Tooth disease, Guillain-Barré syndrome, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, and selected inflammatory and metabolic RDs (CAPS, familial Mediterranean fever, Systemic sclerosis, Dravet syndrome and Gaucher disease). By comparing P2X7R expression and functional alterations, downstream signaling pathways and pharmacological data from animal models across these conditions, we propose that a P2X7R-dependent network centered on a "Ca2+-NLRP3-inflammation/cell death axis" may constitute a common pathogenic backbone for diverse RDs. At the same time, disease-specific spatiotemporal expression patterns of P2X7R in central vs peripheral nervous systems and in immune vs target organ cells confer marked context dependence and "double-edged sword" properties. Finally, we discuss opportunities and challenges for P2X7R-targeted strategies, including the impact of disease stage and sex differences on therapeutic efficacy, and key bottlenecks in translating preclinical findings into clinical benefit. A deeper understanding of both shared and disease-specific roles of P2X7R may provide a conceptual framework and therapeutic entry point for precision stratification and multi-target interventions in rare diseases.
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.
2026-08-28 | Exploring the clinical and mutational spectrum of MORC2-associated disorders.
Pathogenic missense variants in the MORC2 gene are associated with two distinct disorders: Charcot-Marie-Tooth disease type 2Z (CMT2Z) and the recently described DIGFAN (developmental delay, impaired growth, dysmorphic facies and axonal neuropathy) phenotype, which encompasses a broad range of clinical manifestations that vary significantly between individuals. Clinical and imaging data from 16 patients were collected. Western blot analysis was performed on 10 identified variants in affected patients as well as on two novel variants without clinical data. Those missense variants were introduced into the wild-type vector transfected into HEK293T cells, and western blot analysis was performed to assess protein expression level. A total of 11 different missense variants in the MORC2 gene were identified in our cohort, including four novel variants. We demonstrate that early-onset MORC2-associated disorders segregate into two principal neurological phenotypes: a predominantly neuromuscular form and a central nervous system-predominant form. The p.Ser87Leu variant, which defines the neuromuscular cluster, was uniquely characterised by a significant reduction in MORC2 protein levels, distinguishing it mechanistically from other variants. Overall, western blot analysis revealed no statistically significant difference in protein expression levels between variants related to CMT2Z and DIGFAN cases. A comparison of our patients with previously reported cases revealed an intriguing trend suggesting a probable dependence of the leading clinical features on specific variants in the MORC2 gene. Further accumulation of patient data is required to determine whether this observation correlates with other specific variants.
gene therapies
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.
2026-06-16 | Restoring the interplay between the endoplasmic reticulum and mitochondria by gene therapy improves Charcot-Marie-Tooth type 2A disease.
Charcot-Marie-Tooth disease type 2A (CMT2A) is the most common axonal CMT and is associated with an early onset and severe motor neuropathy. CMT2A is mainly caused by dominant mutations in the MFN2 gene, encoding mitofusin-2, a GTPase located in the outer membrane of the mitochondria and endoplasmic reticulum (ER). Mutations in MFN2 affect mitochondrial dynamics. We previously demonstrated that mutated MFN2 further disrupts contacts between the ER and the mitochondria, leading to axonal degeneration. There are no treatments for CMT2A, and those currently under development primarily focus on restoring mitochondrial function. Here, we provide proof of concept that neuronal overexpression of wild-type MFN2 (MFN2WT) provides therapeutic benefit in transgenic CMT2A mice as well as in CMT2A-motor neurons derived from induced pluripotent stem cells. Intrathecal delivery of an AAV9 vector expressing MFN2WT effectively targets motor and sensory neurons, restoring ER-mitochondria contacts and mitochondrial morphology, thereby preserving both neuromuscular junction integrity and motor function. Strikingly, therapeutic efficacy is also achieved by administering the vector after the onset of symptoms. Importantly, AAV administration was well tolerated, with no evidence of hepatotoxicity or dorsal root ganglion inflammation. We further show that CMT2A pathology can be corrected in vitro and in vivo using an ER-targeting MFN1 isoform that selectively enhances ER-mitochondria contacts. These results establish that restoring contacts between the ER and mitochondria using gene therapy is a promising therapeutic avenue for CMT2A.
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.
2026-05-13 | A dose-escalation and safety gene therapy study in a model of CMT4C neuropathy.
Charcot-Marie-Tooth disease type 4C is a demyelinating neuropathy caused by loss of function mutations in the SH3TC2 gene, that is highly expressed in myelinating Schwann cells. We generated and tested a clinical stage vector with a minimal human MPZ promoter driving expression of SH3TC2. Groups of 1-month old Sh3tc2-/- mice were treated with 3 different doses of AAV9-hMPZmini.SH3TC2.SV40pA or the formulation buffer by lumbar intrathecal injection. Outcomes were compared 8 weeks post injection by behavioral, electrophysiological, proteomics, morphological analysis and evaluation of tissue integrity and inflammatory responses. Vector biodistribution to the peripheral nerves and high rates of cell-specific therapeutic gene expression in Schwann cells resulted in significant therapeutic benefits in the CMT4C model. Treated mice showed improved motor performance in grip strength and motor nerve conduction velocities. Morphological analysis revealed significant improvement in g-ratios, myelin thickness and ratios of demyelinated fibers in lumbar roots and femoral nerves of treated mice. Proteomic profiles showed correction of muscle denervation associated pathobiochemical processes in treated mice. Not observed tissue toxicity or immune reactions in neural tissues or peripheral organs. This study provides proof of principle for dose-dependent effectiveness and safety of intrathecal AAV9-mediated gene replacement paving the way for clinical translation.
2026-04-08 | Safety, efficacy, and distal nerve Schwann cell biodistribution in mice and NHPs to support translation of AAV9 RNAi therapy for CMT1A.
Charcot-Marie-Tooth (CMT) type 1A, the most common inherited demyelinating peripheral neuropathy, is caused by PMP22 gene duplication, leading to overproduction of PMP22 protein in Schwann cells. To treat CMT1A, we developed a PMP22 gene silencing therapy using adeno-associated viral vectors (AAV9) to deliver a therapeutic miRNA expression cassette (U6.miR871) via lumbar intrathecal administration. A single injection produced long-term miR871 expression, triggered selective RNA interference against the PMP22 mRNA, and subsequently lowered protein levels and improved disease manifestations in a humanized CMT1A model. To support clinical translation, we confirmed on-target specificity of miR871 for PMP22 in vitro, identified a safe and effective dosing range in mice, demonstrated absence of significant toxicity in rodents and non-human primates (NHPs), and performed a detailed AAV biodistribution study in a large animal model. We found vector biodistribution and miR871 expression in distal peripheral nerves, PMP22 target engagement in mice and NHPs, and silencing to levels expected to support normal myelination in humans. We identified the minimally efficacious to maximum tolerated dose range of AAV9.U6.miR871 in mice and confirmed safety range in NHPs for extrapolation to anticipated clinical trials. Our study supports the scale-up potential of gene therapy to treat CMT1A and other demyelinating peripheral neuropathies.
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.
2026-07-13 | Neuropathy-Associated HSPB1 Mutant Impairs Neuronal Mechanoadaptation and Axonal Regeneration.
The small heat shock protein HSPB1 is a ubiquitously expressed mechanoresponsive chaperone essential for cytoskeletal remodeling under mechanical load. Mutations in HSPB1, including S135F, cause Charcot-Marie-Tooth (CMT) peripheral neuropathy, yet the mechanisms underlying the selective vulnerability of peripheral nerves remain enigmatic. Here we demonstrate that substrate stiffness is a critical determinant of HSPB1S135F-mediated neurodegeneration. Using stiffness-tunable polydimethylsiloxane (PDMS) substrates (1 kPa, 10 kPa, 2 MPa) and uniaxial cyclic stretch, we show that primary dorsal root ganglia (DRG) neurons and SH-SY5Y cells expressing HSPB1S135F exhibit profound deficits in mechanoadaptation. On compliant substrates (10 kPa), HSPB1S135F causes stretch-induced axon fragmentation and neuronal death, whereas HSPB1WT confers robust neuroprotection. HSPB1S135F also disrupts stiffness-directed neuritogenesis in differentiated SH-SY5Y cells: HSPB1WT-expressing cells show optimal axonal outgrowth and βIII-tubulin expression on 10 kPa substrates mimicking muscle tissue stiffness, while HSPB1S135F mutants display disorganized focal adhesions and complete differentiation failure. Mechanistically, we uncover that HSPB1S135F dysregulates stage-specific transglutaminase (TGase) expression-insufficient TGase during early neuritogenesis impairs filopodia stabilization, whereas aberrant TGase persistence at late stages constrains axon extension. Our findings establish HSPB1 as a biomechanical sensor that integrates ECM stiffness signals to coordinate peripheral nerve regeneration, and identify defective mechanoadaptation as a previously unrecognized pathomechanism in CMT. These results open new avenues for stiffness-targeted therapeutic strategies in peripheral neuropathy.
2026-02-25 | Mitofusin MFN2 acts as a molecular sensor preventing protein aggregation and mitophagy, with a protective effect against apoptosis in Charcot-Marie-Tooth type 2A disease.
Mitochondria are central hubs for cellular fitness, empowered by plastic remodeling of their shape, proteome composition, and/or metabolic state. MFN2 (mitofusin 2) mediates mitochondrial fusion and ensures adaptations in response to metabolic changes and stresses. Besides this canonical role, MFN2 serves as a communication hub with other organelles. It tethers mitochondria to the endoplasmic reticulum (ER), lipid droplets, and peroxisomes, regulating calcium buffering, apoptosis, lipid biosynthesis, and lipolysis. Dysfunctional MFN2 causes the hereditary neuropathy Charcot-Marie-Tooth type 2A (CMT2A) and is linked to several metabolic diseases. In a recent publication, we described another fusion-independent role of MFN2 in proteostasis and mitophagy. MFN2 binds the chaperone HSPA8/HSC70 (heat shock protein family A [Hsp70] member 8) and the proteasome, a key function in maintaining mitochondrial and cellular protein quality control, which appears to be lost in the context of CMT2A-associated MFN2 variants.
2025-07-07 | Increased BNIP3-mediated mitophagy attenuates GDAP1 loss of function - implications for Charcot-Marie-Tooth disease 4A.
Charcot-Marie-Tooth disease type 4 A ((CMT4A), an autosomal recessive neuropathy, is caused by mutations in ganglioside-induced differentiation-associated protein 1 (GDAP1). GDAP1 resides in the outer mitochondrial membrane facing the cytosol and is involved in mitochondrial dynamics and function. Its perturbation affects mitochondrial shape, contact sites, redox homeostasis and cellular metabolism. In response to GDAP1 knockdown in a human neuronal cell line, we found increased mitochondrial turnover, biogenesis and mitophagy. This was associated with more lysosomal proteins in mitochondrial fractions including BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3) and its homolog BNIP3-like (BNIP3L) - proteins involved in the recruitment of autophagy machinery via direct interaction. Flies with neural Gdap1 knockdown also exhibited upregulated levels of the sole BNIP3 ortholog. Neural expression of human BNIP3 reduced the detrimental effects of Gdap1 knockdown on eclosion and climbing ability in adult flies, while simultaneous knockdown of both genes was detrimental. These findings suggest that increased BNIP3-driven mitophagy may act as a protective mechanism, partially counteracting the cellular dysfunction caused by GDAP1 loss of function, and highlight the potential of targeting mitophagy pathways as a therapeutic strategy for CMT4A.
oligonucleotides
2026-07-02 | A class of deep intronic IGHMBP2 variants activate a shared cryptic splice donor, enabling correction of select variants with a single antisense oligonucleotide.
Biallelic disease-causing variants in IGHMBP2 cause spinal muscular atrophy with respiratory distress type I (SMARD1) and Charcot-Marie-Tooth type 2S (CMT2S). We present 12 unrelated patients with clinically suspected IGHMBP2-related-disease, each carrying a variant deep in intron 8 of IGHMBP2 (c.1235+1076G>A (n=6), c.1235+450G>A (n=5), and c.1235+894C>A (n=1)), along with a known deleterious variant in trans. To assess aberrant pathogenic splicing induced by these deep intronic variants in a relevant model, patient-derived induced pluripotent stem cells were differentiated into motor neurons (iMNs). Long-read RNA sequencing revealed introduction of different pseudoexons by each variant: c.1235+450G>A (626bp), c.1235+1076G>A (112bp and 77bp) and c.1235+894C>A (182bp). Although each variant utilizes a unique splice acceptor site, they all activate the same cryptic donor site, enabling a therapeutic approach to redirect aberrant splicing for all the variants using a single shared antisense oligonucleotide (ASO). Treatment of iMNs with this single ASO restored full-length IGHMBP2 protein in c.1235+894G>A and c.1235+1076G>A by decreasing the use of the novel acceptor site. In contrast, ASO treatment did not correct the splicing in c.1235+450G>A, suggesting that additional splice correction will be needed for this specific variant. A CRISPR interference screen of IGHMBP2 loss-of-function in iMNs identified ribonucleoprotein complex biogenesis (RNP), and rRNA and tRNA processing as top pathways implicated in motor neuron vulnerability. Proteomics and transcriptomics analysis of successfully treated patient iMNs revealed correction of RNP biogenesis and rRNA processing defects. This study highlights the importance of characterizing deep intronic variants in disease-relevant cells to assist the diagnostic process and inform therapeutics development.
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.
2025-11-14 | [Charcot-Marie-Tooth Disease: Historical Evolution and Present Understanding].
Charcot-Marie-Tooth disease is a hereditary motor and sensory neuropathy characterized by progressive distal muscle weakness, atrophy, and sensory impairment. In this article, we review the original reports published in 1886 by Charcot, Marie, and Tooth, analyzing the clinical features they used to distinguish Charcot-Marie-Tooth disease from other forms of muscle atrophy. We then trace the historical development of the disease concept and examine evolving classification systems based on clinical, electrophysiological, and genetic findings. The identification of more than 140 causative genes has complicated traditional classifications based on nerve conduction studies and inheritance patterns. Thus, we also provide an overview of the current diagnostic strategies that combine clinical evaluation with genetic testing. Although no curative treatment is currently available, advances in molecular biology have introduced new avenues for pharmacological and gene-based interventions. Accordingly, we present emerging therapeutic approaches, including siRNA and CRISPR-Cas9 targeting PMP22 for CMT1A, as well as other nucleic acid-based drugs under development.
2025-05-01 | A Brief Review of Inherited Neuropathies: A Perspective from Saudi Arabia.
Inherited neuropathies are a heterogeneous group of disorders that affect the peripheral nervous system, leading to motor, sensory, and autonomic dysfunction. These disorders are classified into various subgroups, including hereditary sensory and motor neuropathies, distal hereditary motor neuropathies, hereditary sensory and autonomic neuropathies, and more complex forms. Advances in genetic testing, particularly next-generation sequencing (NGS), have significantly improved the identification of these disorders. Emerging therapies, such as gene therapy, small molecule therapies, and antisense oligonucleotides, offer promising treatment options. However, current treatments remain limited, and their clinical benefits in humans are not yet fully established. This review provides a comprehensive overview of recent developments and evolving therapeutic options for hereditary neuropathies, focusing on gene therapy, small molecule therapies, and antisense oligonucleotides. It also highlights the current state of inherited neuropathies in Saudi Arabia, emphasizing the need for national guidelines, patient registries, and collaborative research efforts. By integrating advanced genomic technologies and fostering international collaboration, we can improve the diagnosis, management, and treatment outcomes for patients with inherited neuropathies.
2025-03-10 | Potential ASO-based personalized treatment for Charcot-Marie-Tooth disease type 2S.
Immunoglobulin mu-binding protein 2 (IGHMBP2) pathogenic variants lead to a spectrum of disorders characterized by alpha-motor neuron degeneration. We describe a compound heterozygous patient diagnosed with Charcot-Marie-Tooth disease type 2S with variants in IGHMBP2: a pathogenic missense variant acting in trans with a confirmed intronic cryptic splice site variant. This variant was shown to result in the creation of a new splice acceptor site, loss of reading frame and nonsense-mediated decay. We designed a 19-mer antisense oligonucleotide targeting this cryptic intronic variant to restore IGHMBP2 levels. ASO treatment of patient fibroblasts significantly increased the ratio of restored wild-type transcript to cryptic exon-containing transcript and resulted in over a 50% increase in IGHMBP2 protein levels. Neuromuscular junction analyses revealed high fatigue and chaotic tetanus formulation in untreated patient cells. We demonstrate rescue of NMJ function following ASO treatment, captured by a reduction in fatigue and chaotic tetanus responses. Furthermore, toxicity testing revealed that intrathecal administration of the ASO to wild-type Sprague-Dawley rats over 3 months was well tolerated. Our preclinical data support this ASO as a potential CMT2S treatment by rescuing IGHMBP2. N-of-1 ASO-based therapeutics may prove instrumental in the design of treatments for this diverse genetic disorder.
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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.
2026-05-19 | 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.
2026-04-25 | [Generation of induced pluripotent stem cells from peripheral blood mononuclear cells of a patient with autosomal recessive Charcot-Marie-Tooth disease type 2S caused by IGHMBP2 mutations].
Charcot-Marie-Tooth disease (CMT) is a group of common monogenic peripheral neuropathies listed in the first National Rare Disease Catalog of China and is characterized by marked clinical and genetic heterogeneity. Immunoglobulin μ-binding protein 2 (IGHMBP2) is a ubiquitously expressed nucleic acid helicase, and mutations in the IGHMBP2 gene can cause autosomal recessive CMT type 2S (AR-CMT2S). However, the underlying pathogenic mechanisms remain unclear. This study aims to generate induced pluripotent stem cells (iPSCs) derived from peripheral blood mononuclear cells (PBMCs) of a patient with AR-CMT2S caused by IGHMBP2 mutations (c.884A>G and c.791G>A), thereby providing a novel cellular model for mechanistic studies and stem cell-based therapeutic research. Clinical data of a patient with AR-CMT2S who was diagnosed in September 2022 at the Department of Neurology, Third Xiangya Hospital of Central South University, were collected and analyzed. Pathogenic variants in IGHMBP2 were confirmed by next-generation sequencing. After obtaining written informed consent, 20 mL of peripheral blood was collected, and PBMCs were isolated. PBMCs were reprogrammed into iPSCs using Sendai virus-mediated transduction. The generated iPSCs were characterized for pluripotency marker expression, self-renewal capacity, in vitro differentiation potential, karyotype integrity, and short tandem repeat (STR) profiling. The iPSCs derived from the AR-CMT2S patient were successfully generated. The established iPSC line retained the same IGHMBP2 mutations as those identified in the patient and expressed key pluripotency markers. The cells exhibited robust self-renewal and the ability to differentiate in vitro. Karyotype analysis demonstrated a normal diploid karyotype (46, XX). An iPSC line derived from a patient with AR-CMT2S caused by IGHMBP2 mutations is successfully established. This patient-specific iPSC line provides a valuable cellular model for investigating the pathogenesis of AR-CMT2S and offers a novel tool for the development of effective therapeutic strategies.
2026-01-06 | Combined Posterior Tibial Tendon Transfer and Forefoot Reconstruction for Foot Drop and Forefoot Pain Secondary to Charcot-Marie-Tooth Disease: A Case Report and Literature Review.
Foot drop is a debilitating condition characterized by impaired ankle dorsiflexion and is commonly associated with neuromuscular disorders such as Charcot-Marie-Tooth (CMT) disease. CMT1A, the most prevalent subtype, leads to progressive weakness of the anterior compartment musculature and a cavovarus deformity. Posterior tibial tendon (PTT) transfer remains a well-established surgical technique for restoring active dorsiflexion in cases of irreversible foot drop. We present the case of a 59-year-old female with CMT1A, diabetes mellitus, and peripheral neuropathy who developed progressive left-sided foot drop. Conservative treatment, including a custom ankle-foot orthosis (AFO), was initially attempted. Following failed conservative management, the patient underwent a PTT transfer through the interosseous membrane with interference screw fixation into the intermediate cuneiform. This was combined with a tendoachilles lengthening, hammertoe correction, and Weil osteotomies of the second and third metatarsals. Clinically, she achieved 4° of dorsiflexion above neutral, transitioned to regular footwear, discontinued AFO use, and returned to full functional activity. This case report reinforces the role of PTT transfer as an effective, single-stage reconstructive option for neuromuscular foot drop when combined with appropriate adjunctive procedures and structured rehabilitation.
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.
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Drug Discovery Landscape
18 orphan drug designations for Charcot-Marie-Tooth disease/Hereditary motor and sensory neuropathy.
18 orphan drug designations for Charcot-Marie-Tooth disease/Hereditary motor and sensory neuropathy.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Allogeneic human Wharton's jelly-derived mesenchymal stem cells | cell therapies | EMA | IQVIA RDS Ireland Limited | |
curcuminoid of turmeric (Curcuma longa) | small molecules | FDA | — | Curlim S.A.S |
small molecule mitofusin activator | small molecules | FDA | — | Mitochondria in Motion Discovery, Inc |
eukaryotic initiation factor 2B (eIF2B) activating small molecule | small molecules | FDA | — | ReviR Therapeutics |
highly selective non-hydroxamate, non-hydrazine producing, small molecule histone deacetylase 6 inhibitor | small molecules | FDA | — | Augustine Therapeutics NV |
Curcumin | small molecules | EMA | — | Curlim |
human Wharton¿s jelly derived mesenchymal stem cells | cell therapies | FDA | ENCell Co., Ltd. | |
bromophenoxyazole propanoic acid | small molecules | FDA | NMD Pharma A/S | |
Small molecule allosteric mitofusin activator | small molecules | FDA | — | Mitochondria in Motion, Inc. |
Alpha 1 anti-trypsin (AAT), human alpha 1 anti-trypsin, alpha 1 proteinase inhibitor | proteins | FDA | — | Ageronix SA |
Govorestat | small molecules | EMA | Veristat Spain S.L. | |
Biotin | small molecules | FDA | MedDay Pharmaceuticals | |
highly selective histone deacetylase 6 inhibitor | small molecules | FDA | — | Chong Kun Dang Pharmaceutical Co., Ltd. |
efmitermant alfa | proteins | FDA | Acceleron Pharma Inc. | |
2-[N-(2-hydroxyethyl)]-N-(4-methoxybenzenesulfonyl)]amino-N-(4-chlorocinnamyl)-N-methylbenzylamine | small molecules | EMA | — | Repositioning SAS |
2-(2-chlorobenzylidene)hydrazinecarboximidamide acetate | small molecules | EMA | — | Enemsa Pharma |
2-(2-chlorobenzylidene)hydrazinecarboximidamide acetate | small molecules | FDA | — | Enemsa Pharma |
Dynamine | proteins | FDA | — | Mayo Foundation |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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