AAV-mediated transfer of FKRP shows therapeutic efficacy in a murine model but requires control of gene expression.

Abstract

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.

• Authors: Evelyne Gicquel, Natacha Maizonnier, Steven J Foltz, William J Martin, Nathalie Bourg, Fedor Svinartchouk, Karine Charton, Aaron M Beedle, Isabelle Richard
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 26 Issue 10 Pg. 1952-1965 (05 15 2017) ISSN: 1460-2083 [Electronic] England
• PMID: 28334834 (Publication Type: Journal Article)
• Copyright: © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• Pentosephosphates
• Proteins
• Dystroglycans
• ribitol-5-phosphate
• Transferases
• Fkrp protein, mouse
• Pentosyltransferases

Topics

• Animals
• Disease Models, Animal
• Dystroglycans (metabolism)
• Gene Expression
• Gene Expression Regulation (genetics)
• Genetic Therapy (methods)
• Glycosylation
• Mice
• Mice, Knockout
• Muscle, Skeletal (metabolism)
• Muscular Dystrophies (genetics)
• Muscular Dystrophies, Limb-Girdle (genetics, therapy)
• Mutation
• Pentosephosphates (metabolism)
• Pentosyltransferases
• Protein Binding
• Protein Processing, Post-Translational
• Proteins (genetics, metabolism, therapeutic use)
• Transferases