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Theses

APPROCHES DE THÉRAPIES GÉNIQUES POUR DES MALADIES NEUROMUSCULAIRES

Abstract : Gene therapy of myopathies such as Duchenne muscular dystrophy requires a systemic approach in order to treat the whole musculature. The AAV vector is currently the most efficient delivery system for muscle transduction. We show that the biodistribution of AAV administered intravenously can be modified using different adjuvant strategies in healthy mice. In particular, the pre-injection of polymers enables an improvement of muscle transduction by AAV, and can also decrease the neutralizing immune response induced by the intravenous injection of this vector. We also explored in this work the impact of exogenous and endogenous modulating factors – such as the administration procedure or some blood factors – on the AAV transduction capacity. In a second approach, we evaluated gene transfer in dystrophic muscles in order to secrete in the blood circulation a transgenic protein associating the soluble TNF-α receptor I and the Fc fragment of an immunoglobulin (TNFR-Is/mIgG1). The comparison of the kinetic of secretion after muscle gene transfer in healthy and dystrophic mice indicates that the inflammatory context of dystrophic muscle increases the immune response against the transgene. We also show that while the expression and secretion of a low immunogenic murine variant of TNFR-Is/mIgG1 improves the mdx muscle function, it does not confer a selective advantage to muscle fibers which still undergo cycles of necrosis and regeneration.
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https://tel.archives-ouvertes.fr/tel-00507450
Contributor : Gilles Moulay <>
Submitted on : Friday, July 30, 2010 - 2:08:31 PM
Last modification on : Wednesday, October 14, 2020 - 3:58:07 AM
Long-term archiving on: : Thursday, November 4, 2010 - 10:17:13 AM

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  • HAL Id : tel-00507450, version 1

Citation

Gilles Moulay. APPROCHES DE THÉRAPIES GÉNIQUES POUR DES MALADIES NEUROMUSCULAIRES. Sciences du Vivant [q-bio]. Université d'Evry-Val d'Essonne, 2010. Français. ⟨tel-00507450⟩

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