MassIVE MSV000098631

Partial Public PXD066528

Dual AAV gene therapy using laminin-linking proteins ameliorates muscle and nerve defects in LAMA2-related muscular dystrophy

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Description

Adeno-associated virus (AAV)-mediated gene replacement holds promise for treating genetic diseases but faces challenges due to AAVs limited packaging capacity and potential immune responses to transgene products - particularly in cross-reactive immunologic material (CRIM) - negative patients. LAMA2-related muscular dystrophy (LAMA2 MD), a severe congenital disorder caused by loss of laminin-a2, presents both hurdles: the LAMA2 gene exceeds AAV capacity, and severely affected patients lack endogenous protein, increasing immunogenicity risk. Here, we developed an AAV-based therapy using two engineered linker proteins derived from endogenously expressed components. These linkers restore laminin receptor binding and polymerization, enabling reassembly of a functional basement membrane. Dual AAV delivery of the linkers in a severe LAMA2 MD mouse model resulted in robust expression and significant improvements in muscle histology and function. Using myotropic capsids allowed for efficacy at reduced vector doses. However, muscle-only targeting unmasked LAMA2-related peripheral neuropathy. To address this, we expressed one linker under a muscle-specific promoter and the other under a ubiquitous promoter, delivered via AAV9 or AAV8. This approach achieved near-complete phenotypic restoration when administered neonatally and still provided significant benefit when given at progressed disease stages. Our strategy offers a mutation-independent, size-compatible, and potentially immune-tolerable treatment for LAMA2 MD with broad clinical potential. [doi:10.25345/C5M902G3R] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: LAMA2, Muscular Dystrophy ; DatasetType:Proteomics

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Principal Investigators:
(in alphabetical order) 		Alexander Schmidt, Biozentrum, Universtiy of Basel, 4056 Basel, Switzerland, N/A
Submitting User: tbockPCF
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