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Communication Dans Un Congrès Année : 2023

Gene therapy for striated muscle laminopathy (in vivo study)

Résumé

LMNA encodes for the nuclear envelope proteins: lamin A/C. LMNA mutation induces numerous disorders called laminopathies, mainly affecting striated muscles. All striated muscle laminopathies are characterized by the development of a life-threatening dilated cardiomyopathy. We developed a mouse model mimicking a human LMNA variant. Heterozygous LmnaK32del mice develop dilated cardiomyopathy due to a combination of lamin haploinsufficiency and expression of toxic mutant. Based on these facts, we develop therapeutic approach aiming both at reducing the expression of the mutant proteins and restoring the normal lamin level. We produced different AAV2/9 vectors containing human mature lamin A under control of a CMV promoter, either alone, or in combination with shRNA specifically targeting K32del Lmna mRNA or WT and mutated allele under a H1 promoter. These AAVs were injected intravenously in WT and heterozygous LmnaK32del new-born mice. All treatments showed similar results: transient benefit in term of survival but no effect on cardiac function. Absence of benefit at long term is neither due to a loss of AAV genome particle nor to a loss of its expression with time as we observed maintenance of AAV particle number and sustained human lamin A mRNA and protein expression in heart of injected mice. Rather, it is due to the absence of mouse Lmna mRNA knock-down and side effect in the liver, strongly targeted by AAV2/9. Future development of our gene therapy will include new shRNA design, new promoters and AAV capsids to increase mouse Lmna mRNA knock-down and tissue specificity.
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Dates et versions

hal-04189734 , version 1 (08-09-2023)

Identifiants

  • HAL Id : hal-04189734 , version 1

Citer

Mariko Okubo, Astrid Brull, Maud Beuvin, Nathalie Mougenot, Valérie Paradis, et al.. Gene therapy for striated muscle laminopathy (in vivo study). 4th International Meeting on Laminopathies, May 2023, Madrid, Spain. ⟨hal-04189734⟩
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