2026-05-27 | MOLECULAR MECHANISMS AND THERAPEUTIC STRATEGIES IN CMT1 NEUROPATHIES

Charcot–Marie–Tooth (CMT) disease comprises a heterogeneous group of inherited peripheral neuropathies for which effective therapies are still lacking. Limited understanding of the molecular and developmental mechanisms underlying the most common CMT subtypes represents a major obstacle to therapeutic progress. This thesis addresses this gap by investigating two complementary aspects of CMT pathogenesis and treatment: the developmental origins of CMT1A neuropathy and a targeted therapeutic strategy for CMT1B. In the first part of the work, we explored the early structural and molecular alterations occurring in a rat model of CMT1A. Through an integrated longitudinal approach combining high-resolution lipidomics and quantitative morphometric analyses, we characterized the maturation of peripheral myelin and myelinated fibers from early postnatal stages to adulthood. We demonstrate that CMT1A nerves exhibit a profound developmental delay, evident as early as postnatal day 20, affecting both myelin lipid composition and axonal growth. CMT1A myelin fails to become enriched in long-chain sphingolipids and retains features typical of unspecialized plasma membranes. These molecular abnormalities are paralleled by defective axonal enlargement, reduced fiber diameters, and persistent hypermyelination of small-caliber axons. Together, these findings indicate that CMT1A is primarily a disorder of impaired neurodevelopment and dysmyelination rather than progressive demyelination and identify a critical temporal window for potential therapeutic intervention. In the second part, we focused on a CMT1B form caused by the dominant-negative heterozygous D61N mutation in the MPZ gene. Exploiting a knock-in mouse model faithfully recapitulating the human disease, we tested an allele-specific RNA interference strategy aimed at selectively silencing the mutant MPZ allele while preserving the wild-type. Candidate siRNA sequences were identified in vitro and are now being tested in dorsal root ganglia myelinating cultures using lentiviral vectors. Ongoing studies aim to validate functional rescue ex vivo and in vivo. Overall, this work provides novel mechanistic insight into CMT pathogenesis and establishes a translational framework for mutation-specific therapy. By revealing the developmental nature of CMT1A and advancing allele-specific silencing for CMT1B, this thesis contributes to both fundamental knowledge and therapeutic direction in the field of inherited peripheral neuropathies.

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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.

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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.

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