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

ABSTRACT: Adeno-associated virus (AAV)-mediated gene replacement holds promise for treating genetic diseases but faces challenges due to AAV’s limited packaging capacity and potential immune responses to transgene products, especially in patients lacking endogenous protein. LAMA2-related muscular dystrophy (LAMA2 MD), a severe congenital disorder caused by loss of laminin-α2, presents both hurdles: the LAMA2 gene exceeds AAV capacity, and severely affected patients do not produce the native protein. Here, we developed an AAV-based therapy using two engineered linker proteins derived from endogenously expressed components. These linker proteins 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. Employing myotropic capsids enabled therapeutic efficacy at lower vector doses. However, muscle-specific targeting unmasked a 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 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE312724 | GEO | 2026/02/03

REPOSITORIES: GEO

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Project description:LAMA2-deficient congenital muscular dystrophy (LAMA2-CMD) is a severe neuromuscular disorder caused by LAMA2 mutations, leading to muscle degeneration, chronic inflammation, and fibrosis. Histopathological assessment of muscle biopsies from LAMA2-CMD patients and mouse models show clear evidence of inflammation, which oftentimes are regarded as one of the typical dystrophic hallmarks. However, the composition of immune cells in the laminin-deficient muscles remain understood. Consequently, targeted pharmacological intervention to reduce inflammation has never been tested. In this study, we characterized the immune landscape in dyW mouse model of LAMA2-CMD using RNA sequencing and flow cytometry. Transcriptomic analysis of dyW quadriceps identified 2,143 differentially expressed genes, with most of the upregulated genes belong to immune-related pathways. Lgals3 (Galectin-3) was significantly upregulated (log₂FC = 4.27, FDR p-value= 9.21x10-88) and identified as a key upstream regulator of the immune-related pathways. In parallel, flow cytometry analysis revealed elevated leukocyte (CD45⁺) infiltration, with macrophages as the predominant cell population. Pro-inflammatory (M1) macrophages were increased, whereas anti-inflammatory (M2) macrophages remained low, indicating persistent inflammation and impaired resolution. Interestingly, Galectin-3+ macrophages were significantly enriched, which strongly suggest that Galectin-3 drives inflammation in LAMA2-CMD. Treatment of dyW mice with TD-139, a Galectin-3 inhibitor, reduced leukocyte infiltration, decreased Galectin-3+ macrophages, and shifted macrophage polarization toward an M2 anti-inflammatory profile. In addition, RNA sequencing of TD-139-treated dyW muscles showed upregulation of muscle repair pathways and downregulation of fibrosis-related genes. These findings establish Galectin-3-expressing macrophages as an important player in LAMA2-CMD pathophysiology. Importantly, it warrants further investigation on the therapeutic potential of TD-139-mediated inhibition of Galectin-3, including long-term preclinical study, in LAMA2-CMD and potentially other dystrophic conditions driven by chronic immune activation.

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

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