CMT1A results from the duplication of Peripheral Myelin Protein 22 (PMP22) gene. This gene encodes for a small protein of 22 kDa, PMP22. The excess of this protein leads to demyelination. There is no cure for CMTs but one approach for a treatment is gene therapy. A transgenic rat model exists for CMT1A, which possesses 3 copies of the mouse PMP22 gene. Our goal is to provide a proof of principle for gene therapy in peripheral nerves using this CMT1A rat model: reduce the overexpression of mouse PMP22 protein in rats Schwann cells using short hairpin RNAs (shRNAs) cloned in an adeno-associated viral vector (AAV serotype 9). The efficiency of this gene therapy is being checked by behavioral studies, electrophysiology, biochemical, molecular and histological analysis. Our findings suggest that AAV is a promising therapeutic strategy that could possibly be later on used in clinical trials.
We recently discovered a very early step in the Schwann cell demyelination mechanism that involve the release of calcium from the mitochondrial matrix to the cytoplasm through an important transmembrane protein on mitochondria, VDAC channel. The inhibition of this calcium release appears to prevent demyelination in several models of demyelinating peripheral neuropathies. So we are designing a peptide-based drug in order to provide a pharmacological solution for demyelinating diseases.
Our groups also focus on other CMT forms such as the CMT4G, a severe form of the disease characterized by peripheral demyelination which can result in complete muscle paralysis below the knee. Sequence variants within the gene encoding hexokinase I (HKI), an important enzyme involved in the initial steps of glycolysis, have been hypothesized to cause CMT4G through as yet not understood mechanisms. The aim of this project is to ascertain the consequence of these sequence variants within HKI including changes to the N-terminal, a highly conserved region of the protein and how this might affect VDAC. Changes to this crucial interaction could be involved in the mechanisms of demyelination in CMT4G and open up avenues for possible therapy.
Our approaches rely on:
- Live imaging
- Animal models
- CARS imaging
- Viral transductions
- Cell-based assay for drug design
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- Patrick Aubourg, INSERM U745/U986, Fontenay aux Roses, France
- Roman Chrast, Karolinska Institute, Sweden
- Fatiha Nothias, UPMC, Paris, France
- Florence Perrin, MMDN, Montpellier
- Hwan Tae Park, Dong-A University, Busan, South Korea
- Hervé Rigneault, Institut Fresnel, Marseille, France
- Guy Lenaers PREMMi, Angers, France