Development of a gene therapy treatment for a rare lysosomal disorder

Responsable du Stage : Mario Amendola, Christine Jenny




Résumé du Projet de Stage 

Généthon is an international leader in the development of innovative therapies and especially gene therapy strategies to treat rare diseases. Among more than 6,000 genetic diseases, we are working on a rare lysosomal storage disorder, due to a deficient lipase (LAL: Lysosomal Acid Lipase). This disorder is due to a mutation in the LAL gene and is characterised by fats accumulation and failure in many organs. In the most severe cases, the life expectancy is limited to one year. The only available treatment consists of weekly and systemic injections of a synthetic recombinant LAL, but it is not curative and there are also immune adverse events occurring over time. Our objective is to develop innovative treatments based on gene therapy and edition strategies using CRISPR systems in order to treat LAL deficiencies. Preliminary in vitro studies have demonstrated that the phenotype of patient cells can be corrected either using AAV vectors containing a functional version of the LAL gene or edition of the deficient gene. These protocols now need to be further developed, optimised and validated through in vivo studies, involving an animal model of the disease.

References et publications récentes de l’équipe

Li, F., Zhang, H., 2019. Lysosomal Acid Lipase in Lipid Metabolism and Beyond. ATVB 39, 850–856.

Sun Y, Xu YH, Du H, Quinn B, Liou B, Stanton L, Inskeep V, Ran H, Jakubowitz P, Grilliot N, Grabowski GA. Reversal of advanced disease in lysosomal acid lipase deficient mice: a model for lysosomal acid lipase deficiency disease. Mol Genet Metab. 2014 Jul;112(3):229-41. doi: 10.1016/j.ymgme.2014.04.006. Epub 2014 May 4. PMID: 24837159.

Lam P, Ashbrook A, Zygmunt DA, Yan C, Du H, Martin PT. Therapeutic efficacy of rscAAVrh74.miniCMV.LIPA gene therapy in a mouse model of lysosomal acid lipase deficiency. Mol Ther Methods Clin Dev. 2022 Aug 4;26:413-426. doi: 10.1016/j.omtm.2022.08.001. PMID: 36092360; PMCID: PMC9403906.

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Intitulé de l’Unité : INTEGRARE UMR951

Nom du Responsable de l’Unité : Anne Galy

Nom du Responsable de l’Équipe : Mario Amendola

Adresse :  1 bis rue de l’Internationale, Evry