Gene therapy for striated muscle laminopathy
| العنوان: | Gene therapy for striated muscle laminopathy |
|---|---|
| المؤلفون: | Mariko Okubo, Astrid Brull, Isabelle Nelson, Maud Beuvin, Laura Julien, Valérie Paradis, Bertrand, Anne T., Gisèle Bonne |
| المساهمون: | National Center of Neurology and Psychiatry National Institute of Mental Health (NCNP), Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre de recherche biomédicale Bichat-Beaujon (CRB3), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Gisèle Bonne, Ichizo Nishino |
| المصدر: | 12th French-Japanese Workshop on Neuromuscular Diseases 12th French-Japanese Workshop on Neuromuscular Diseases, Gisèle Bonne; Ichizo Nishino, Sep 2022, Giverny, France HAL |
| بيانات النشر: | HAL CCSD, 2022. |
| سنة النشر: | 2022 |
| مصطلحات موضوعية: | [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Lamin A/C LMNA gene, laminopathies, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, gene therapy |
| الوصف: | International audience; 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. |
| اللغة: | English |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=dedup_wf_001::8589fc0248e88c8795dbc20569d7ec71 https://hal.science/hal-03989233 |
| رقم الأكسشن: | edsair.dedup.wf.001..8589fc0248e88c8795dbc20569d7ec71 |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |