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Abstract

-related muscular dystrophy () is caused by mutations in , the gene encoding laminin-α2, the long arm of the heterotrimeric (α2, β1, γ1) protein laminin-211 (Lm-211). In most patients, biallelic mutations in result in the complete absence of Lm-211, the main laminin found in muscle basement membrane. As the cDNA encoding laminin-α2 is large (> 9), and the protein does not tolerate even subtle mutations because of its interaction with β1- and γ1-laminin chains, gene replacement or gene editing strategies are difficult to envisage. By studying the molecular mechanisms involved in the disease, we detect compensatory expression of laminin-α4, giving rise to (α4, β1, γ1) in ’ biopsies and laminin-α2-deficient mice. Based on in vitro studies, was shown to be deficient in binding to muscle fibers and in forming a fully assembled basement membrane. In an attempt to restore muscle fiber binding and basement membrane assembly, we have designed two small, AAV-compatible linker proteins1. One linker, called mini-agrin (mag), works to mediate binding of to the muscle fiber via α-dystroglycan. The second linker, called αLNNd, involving the N-terminal part of laminin-α1 and the laminin-binding site of nidogen-1, allows polymerization of Lm-411. When expressed transgenically in mice, a mouse model for MD, the two linkers ameliorate the muscle dystrophy, increase overall body weight and drastically extend lifespan. We will also report on our current efforts to evaluate the therapeutic potential of the linker proteins when expressed postnatally at different time points using AAV-mediated delivery to mice. These experiments aim to provide essential information for a possible translation of the linker strategy into MD patients.

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/content/papers/10.5339/qproc.2020.NMD.11
2020-09-15
2020-09-21
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http://instance.metastore.ingenta.com/content/papers/10.5339/qproc.2020.NMD.11
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