Research Tim Vangansewinkel

Abstract

Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common inherited peripheral neuropathy, caused by duplication of the PMP22 gene in Schwann cells (SCs), leading to demyelination, slow nerve conduction, and progressive muscle weakness. Recent evidence indicates that disrupted lipid metabolism and plasma membrane composition contribute to defective myelination in CMT1A. In particular, the fatty acid translocase CD36, a key regulator of lipid and cholesterol uptake, is downregulated in patient-derived SCs, suggesting a central role in disease pathogenesis. This project aims to determine whether enhancing CD36 activity can restore lipid homeostasis and promote functional remyelination in CMT1A. Using patient-derived induced pluripotent stem cells, we will generate neuromuscular organoids (NMOs) containing SCs, neurons, and muscle cells, and apply advanced in toto light-sheet fluorescence microscopy (LSFM) for high-resolution, whole-organoid imaging. We will optimize lipid-compatible tissue clearing and antibody labeling protocols, integrate pharmacological CD36 modulation with or without lipid supplementation, and establish high-throughput imaging and quantitative pipelines to assess myelination and SC dynamics. By combining mechanistic intervention with state-of-the-art 3D imaging, this project will provide unprecedented insights into myelination defects in human-relevant CMT1A models, validate CD36 as a therapeutic target, and create a scalable platform for quantitative organoid analysis. The outcomes will advance translational CMT1A research, accelerate preclinical screening, and strengthen interdisciplinary collaboration between disease modeling and imaging technology, bridging biomedical research with high-throughput phenotyping applications.

Researcher(s)

• Promoter: Vangansewinkel Tim

Research team(s)

• Peripheral Neuropathies Group

Project type(s)

• Research Project

Abstract

The overarching objective of the CureCMT MSCA network is to facilitate the training and graduation of future expert leaders, comprising both scientists and clinicians, in the domain of Charcot-Marie- Tooth (CMT) neuropathies. The planned resubmission of this proposal is underpinned by the imperative to address the pressing challenges posed by the development of effective treatments for these rare inherited disorders, a subject of high relevance, urgency, and innovation. In addition to the diverse CMT disease mechanisms that dictate individualised treatment strategies, effective gene therapy approaches to target nerves remain to be established. The restricted availability of genetic testing, coupled with the variability in its outcomes, contributes to diagnostic delays. The rarity of most CMT subtypes further complicates the understanding of the natural history of the disease. The absence of sensitive outcome measures renders the design of clinical trials for rare CMT neuropathies within a viable time frame challenging, while the rarity of most subtypes discourages industry investment. The objective of CureCMT is to establish effective gene delivery methods to the peripheral nerves and to provide proof of concept in neuropathy models. Subtype-specific patient registries, which are currently lacking, will be developed, and natural history studies including sensitive outcome measures and novel disease biomarkers will be established for rare CMTs, with a view to accelerating clinical trial readiness. The evaluation will encompass the financial implications of CMT neuropathies for patients and society, with the objective of informing future regulatory and policy decisions and facilitating the availability of accessible therapies for patients. The CureCMT initiative will address the challenges and address the gaps in doctoral training and intreating CMT neuropathies by bringing together the multidisciplinary expertise of the leading experts and educators in the field of CMT, including gene therapy, clinical, social, and economic outcomes. In collaboration with industry partners, as well as relevant scientific, clinical, and patient networks and associations established in Europe and beyond, this project will significantly advance education and research towards therapies for CMT neuropathies.

Researcher(s)

• Promoter: Baets Jonathan
• Co-promoter: Ermanoska Biljana
• Co-promoter: Timmerman Vincent
• Co-promoter: Vangansewinkel Tim

Research team(s)

• Translational Neurosciences (TNW)

Project type(s)

• Research Project

Abstract

Charcot-Marie-Tooth disease (CMT1A) is the most common hereditary neuropathy, caused by a PMP22 gene duplication, leading to myelin defects and slow nerve conduction. Despite advances in targeting PMP22, no effective treatment exists for CMT1A patients. Increasing evidence indicates that the immune system, and especially macrophages, plays a secondary role in the pathology, but this is far from understood. Macrophages are considered to be one of the most plastic cells of the immune system, and they have the capacity to profoundly adapt to their tissue of residence and to change in response to injury or disease. By using state-of-the-art transcriptomics and lipidomic approaches, advanced microscopy, metabolism assays, preclinical models, and unique human CMT1A patient nerve biopsies, I here aim to phenotype the metabolic and functional properties of macrophages in CMT1A, and explore how they influence Schwann cell differentiation and myelination. The findings of this study will provide deeper insight into the role of macrophages in CMT1A disease pathology and uncover novel immuno- and lipid metabolism-based strategies to enhance recovery and promote remyelination in CMT1A.

Researcher(s)

• Promoter: Timmerman Vincent
• Co-promoter: Vangansewinkel Tim
• Fellow: Van Brussel Melanie

Research team(s)

• Peripheral Neuropathies Group

Project type(s)

• Research Project