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Linker-based gene therapy of LAMA2-related muscular dystrophy using AAV-MYO

Research Project
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01.08.2022
 - 31.07.2025

Extracellular matrix (ECM) acts as scaffold to provide essential structural support to the surrounding cells. Laminins are essential components of the ECM connecting it tightly with the underlying cell layer, just like the binds between scaffolding and a building. Mutations in this protein family cause a range of severe disorders that affect different organs. The rope-like laminin-211 protein, composed of three intertwined laminin chains, is the main isoform in skeletal muscle. Mutations in the LAMA2 gene, encoding one of the chains in laminin-211, leads to its loss and causes a rare, severe and early-onset muscular dystrophy, called MDC1A or LAMA2 MD. Affected children show muscle wasting and weakness and eventually die from respiratory insufficiency. There is no treatment for LAMA2 MD. We have shown that two specifically designed linker proteins strongly improve the pathology and lifespan in LAMA2 MD mice, which lack laminin-211 like LAMA2 MD patients and display very similar symptoms. In ongoing research, we are developing a gene therapy approach to deliver the two linkers to LAMA2 MD mice by using an adeno-associated viral vector (AAV9). Our initial results show that this gene therapy approach is indeed possible. We now aim to optimize linker delivery using newly developed AAV9 variants (myotropic AAVs) that are even more efficient at infecting skeletal muscles. We are hopeful these experiments will pave the way to a gene therapy treatment for LAMA2 MD patients.

Funding

Linker-based gene therapy of LAMA2-related muscular dystrophy using AAV-MYO

Weitere ausländische Förderagenturen (GrantsTool), 08.2022-07.2025 (36)
PI : Rüegg, Markus A..

Members (1)

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Markus A. Rüegg

Principal Investigator