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Master Thesis

Les vecteurs adéno-associés pour le transfert de gène dans les maladies métaboliques : exemple de la glycogénose de type III

Abstract : Adeno-associated virus (AAV) are promising gene therapy vectors. They allow liver- or/and muscle-targeted gene transfer. Liver-targeting AAV gene therapy is among the simplest strategy, because the liver is highly vascularized hence easily reachable. Moreover, hepatic expression of a transgene induce its immune tolerance. Nevertheless, there are still some great challenges to overcome for AAV gene therapy: (i) anti-capsid immune response, (ii) the size-limited AAV’s encapsidating capacity, (iii) multi-tissues targeting, (iv) the loss of expression in a growing /proliferative liver. Glycogen storage disease type III (GSDIII) is a rare metabolic and genetic disease. Its pathophysiology turns it into an excellent disease model to study AAV gene transfer limitations. Indeed, liver and muscles are affected in GSDIII. More specifically, the liver impairment in GSDIII leads to fibrosis, to hepatocytes proliferation, and to hepatocellular carcinomas development. Meanwhile, muscular progressive weakness appears and worsen with aging. In addition, the size of the gene coding for the enzyme lacking in GSDIII reaches almost the AAV encapsidation capacity, which oblige to develop strategies to increase the encapsidation capacity. We developed a murine model of GSDIII that recapitulates the human phenotype observed in patients. In this study, we developed strategies based on AAV to overcome the therapeutic challenges associated with GSDIII. To do so, we developed dual AAV vectors approaches, the overlapping and the dual hybrid system, that allowed rescue of the muscular phenotype, but only a partial correction of the metabolic features.
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Master Thesis
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Contributor : Frédérique Gambade <>
Submitted on : Wednesday, October 30, 2019 - 9:44:23 AM
Last modification on : Saturday, November 16, 2019 - 1:42:42 AM


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  • HAL Id : dumas-02338674, version 1



Louisa Jauze. Les vecteurs adéno-associés pour le transfert de gène dans les maladies métaboliques : exemple de la glycogénose de type III. Sciences du Vivant [q-bio]. 2019. ⟨dumas-02338674⟩



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