AAV-mediated transfer of FKRP shows therapeutic efficacy in a murine model but requires control of gene expression
| Autor: | William J. Martin, Steven J. Foltz, Karine Charton, Nathalie Bourg, Aaron M. Beedle, Evelyne Gicquel, Isabelle Richard, Natacha Maizonnier, Fedor Svinartchouk |
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| Přispěvatelé: | Approches génétiques intégrées et nouvelles thérapies pour les maladies rares (INTEGRARE), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Généthon-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), University of Georgia [USA], École pratique des hautes études (EPHE)-Université d'Évry-Val-d'Essonne (UEVE)-GENETHON 3-Institut National de la Santé et de la Recherche Médicale (INSERM), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Généthon |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Glycosylation [SDV.BIO]Life Sciences [q-bio]/Biotechnology Gene Expression medicine.disease_cause Muscular Dystrophies Mice chemistry.chemical_compound 0302 clinical medicine Gene expression Muscular dystrophy Dystroglycans Laminin binding Genetics (clinical) ComputingMilieux_MISCELLANEOUS Mice Knockout Mutation Fukutin-related protein Articles General Medicine LGMD Cell biology FKRP Protein Binding Biology Abnormal glycosylation 03 medical and health sciences Muscle Dystrophy Transferases Genetics medicine Animals Pentosyltransferases Muscle Skeletal Molecular Biology Pentosephosphates Proteins Genetic Therapy medicine.disease Fukutin Disease Models Animal 030104 developmental biology Gene Expression Regulation Muscular Dystrophies Limb-Girdle chemistry biology.protein Protein Processing Post-Translational 030217 neurology & neurosurgery [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology |
| Zdroj: | Human Molecular Genetics Human Molecular Genetics, Oxford University Press (OUP), 2017, 26 (10), pp.1952-1965. ⟨10.1093/hmg/ddx066⟩ Human Molecular Genetics, 2017, 26 (10), pp.1952-1965. ⟨10.1093/hmg/ddx066⟩ |
| ISSN: | 0964-6906 1460-2083 |
| DOI: | 10.1093/hmg/ddx066⟩ |
| Popis: | Limb Girdle Muscular Dystrophies type 2I (LGMD2I), a recessive autosomal muscular dystrophy, is caused by mutations in the Fukutin Related Protein (FKRP) gene. It has been proposed that FKRP, a ribitol-5-phosphate transferase, is a participant in α-dystroglycan (αDG) glycosylation, which is important to ensure the cell/matrix anchor of muscle fibers. A LGMD2I knock-in mouse model was generated to express the most frequent mutation (L276I) encountered in patients. The expression of FKRP was not altered neither at transcriptional nor at translational levels, but its function was impacted since abnormal glycosylation of αDG was observed. Skeletal muscles were functionally impaired from 2 months of age and a moderate dystrophic pattern was evident starting from 6 months of age. Gene transfer with a rAAV2/9 vector expressing Fkrp restored biochemical defects, corrected the histological abnormalities and improved the resistance to eccentric stress in the mouse model. However, injection of high doses of the vector induced a decrease of αDG glycosylation and laminin binding, even in WT animals. Finally, intravenous injection of the rAAV-Fkrp vector into a dystroglycanopathy mouse model due to Fukutin (Fktn) knock-out indicated a dose-dependent toxicity. These data suggest requirement for a control of FKRP expression in muscles. |
| Databáze: | OpenAIRE |
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