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Communication Dans Un Congrès Année : 2022

Gene therapy for striated muscle laminopathy

Résumé

LMNA-related Congenital Muscular Dystrophy (L-CMD) is the most severe form of striated muscle laminopathies caused by mutations in LMNA. Our purpose is to development gene therapy for L-CMD to correct LMNA mutations at mRNA level and improve the function of affected organs. Homozygous Lmna-delk32 mice model L-CMD, pathology caused by both the expression of toxic mutant lamin A/C and absence of WT lamin A/C expression, while heterozygous mice, a model of dilated cardiomyopathy, present with reduced WT lamin A/C expression and residual mutant lamin A/C expression in the heart. Based on these facts, we aim at developing a therapeutic approach that both reduces the expression of the mutant proteins and restores the normal lamin A/C levels. To achieve such strategy, we developed AAV2/9 vector containing either human mature lamin A under control of a CMV promoter, or in combination with shRNA against either only mutant mouse Lmna mRNA or both alleles. These AAVs were injected intravenously at 1x10E11 viral genomes for WT, homozygous and heterozygous Lmna-delk32 mice at 2 days of age. All these treatments showed benefits in terms of max survival of homozygous mice. While, only transient benefit was shown for heterozygous mice. In addition, we could not find clear effects on cardiac function for heterozygous mice. Interestingly, 6 mice had liver nodule of total 50 treated mice, and three of them were diagnosed with hepatocellular carcinoma. From molecular analysis at end stage, expression of human lamin A mRNA was increased in both heart and liver. While, expression of endogenous mouse Lmna mRNA was decreased only in liver. Furthermore, we detected more quantity of viral genome in liver than heart. From this in vivo study, we will optimize and improve the therapeutic cassette to increase the efficacy of tissue targeting of these tools in the affected organs.
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Dates et versions

hal-03989233 , version 1 (14-02-2023)

Identifiants

  • HAL Id : hal-03989233 , version 1

Citer

Mariko Okubo, Astrid Brull, Isabelle Nelson, Maud Beuvin, Laura Julien, et al.. Gene therapy for striated muscle laminopathy. 12th French-Japanese Workshop on Neuromuscular Diseases, Gisèle Bonne; Ichizo Nishino, Sep 2022, Giverny, France. ⟨hal-03989233⟩
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