LAMA-congenital muscular dystrophy (LAMA2-CMD) is a severe neuromuscular disorder caused by mutations in the laminin alpha-2 (LAMA2) gene. It leads to muscle degeneration and weakness. Chronic inflammation in skeletal muscles further exacerbates disease progression and poses significant challenges for therapeutic development.
In this study, we aimed to characterize the inflammatory environment in LAMA2-CMD muscles and evaluate inflammation-targeted treatment strategy. We profiled immune cell populations and cytokines in skeletal muscles and blood of dyW mice, a model for LAMA2-CMD. We found increased immune cell infiltration as early as 2 weeks of age, with a predominance of pro-inflammatory macrophages and activated regulatory T cells. Elevated levels of IL-6 and IFN-γ were also detected in the blood, suggesting that systemic inflammatory signals contribute to local muscle inflammation.
In parallel, unbiased transcriptomic analysis of the dyW quadriceps revealed significant upregulation of genes associated with leukocyte migration and myeloid activation, including Lgals3 (4-fold-increase), which encodes Galectin-3, a carbohydrate-binding protein involved in inflammation and cell migration. Importantly, immunofluorescence staining further demonstrated co-localization of Galectin-3 with macrophages in the highly fibrotic dyW muscles.
To investigate whether Galectin-3 inhibition could improve inflammation in LAMA2-CMD, we treated dyW and WT mice with intraperitoneal injections of TD-139 (5 mg/kg, 5x/week for two weeks), a Galectin-3 inhibitor initially developed for the treatment of idiopathic pulmonary fibrosis. In the treated dyW mice, we observed a reduction in leukocyte infiltration, macrophage-specific Galectin-3 expression, and macrophage numbers, along with a shift in the macrophage profile towards a more anti-inflammatory phenotype.
Taken together, these findings indicate that targeting Galectin-3 can significantly alter the inflammatory profile in LAMA2-CMD by reducing pro-inflammatory macrophages and promoting a shift to an anti-inflammatory state. This approach holds promise as a therapeutic strategy to mitigate chronic inflammation and improve disease outcomes, potentially in combination with gene therapy.