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Communication Dans Un Congrès Année : 2023

Challenges in gene therapy for striated muscle laminopathy

Résumé

Lamins A/C, encoded by LMNA, are components of the nuclear lamina underlying the inner nuclear envelope. LMNA mutations lead to a great phenotype variability, mainly affecting striated muscles, called laminopathies. At the most severe spectrum of striated muscle laminopathies, LMNA-related congenital muscular dystrophy (L-CMD) is characterized by severe muscle atrophy and weakness, joint contracture and dilated cardiomyopathy. Dilated cardiomyopathy can also be the sole symptom. There is currently no curative treatment available. Taking advantage of our KI-LmnaK32del mouse model that develop a L-CMD-like phenotype at the homozygous state and isolated dilated cardiomyopathy at the heterozygous state, we assessed a therapeutic approach aiming both at reducing mutant lamin A/C expression and restoring normal lamin A/C levels. We first evaluated the potential of allele-specific lamin A/C knock down by siRNA, as well as human lamin A or C overexpression, to correct defects of KI-LmnaK32del primary myotubes in vitro. We then evaluated the therapeutic efficacy of systemic delivery of different AAV2/9 vectors, either containing human mature lamin A cDNA alone, or in combination with one of 2 different shRNAs against Lmna mRNA in homozygous and heterozygous mice. Our results show a moderate benefit in term of survival and a sustained human lamin A overexpression. However, we also observed a lack of mouse Lmna mRNA knock-down due to decreased expression of several proteins involved in miRNA/shRNA maturation pathway, and side effects in the liver preventing a better efficacy of the gene therapy. We investigate further these defects and pursue optimization of this therapeutic strategy.

Dates et versions

hal-04170075 , version 1 (25-07-2023)

Identifiants

Citer

Anne T Bertrand, Mariko Okubo, Astrid Brull, Maud Beuvin, Nathalie Mougenot, et al.. Challenges in gene therapy for striated muscle laminopathy. 4th International Meeting on Laminopathies, May 2023, Madrid, Spain. ⟨10.3233/JND-239001⟩. ⟨hal-04170075⟩
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