Laminin-α2-related congenital muscular dystrophy (LAMA2-CMD) is a devastating neuromuscular disease caused by mutations in the LAMA2 gene. These mutations result in the complete absence or truncated expression of the laminin-α2 chain. The α2-chain is a major component of the laminin-211 and laminin-221 isoforms, the predominant laminin isoforms in healthy adult skeletal muscle. Mutations in this chain result in progressive skeletal muscle degeneration as early as neonatally. Laminin-211/221 is a ligand for muscle cell receptors integrin-α7β1 and α-dystroglycan. LAMA2 mutations are correlated with integrin-α7β1 disruption in skeletal muscle. In this review, we will summarize laminin-211/221 interactions with integrin-α7β1 in LAMA2-CMD muscle. Additionally, we will summarize recent developments using upregulation of laminin-111 in the sarcolemma of laminin-α2-deficient muscle. We will discuss potential mechanisms of action by which laminin-111 is able to prevent myopathy. These published studies demonstrate that laminin-111 is a disease modifier of LAMA2-CMD through different methods of delivery. Together, these studies show the potential for laminin-111 therapy as a novel paradigm for the treatment of LAMA2-CMD.

Background: Laminin-α2-related congenital muscular dystrophy (LAMA2-CMD) is a devastating genetic disease caused by mutations in the LAMA2 gene. These mutations result in progressive muscle wasting and inflammation leading to delayed milestones, and reduced lifespan in affected patients. There is currently no cure or treatment for LAMA2-CMD. Preclinical studies have demonstrated that mouse laminin-111 can serve as an effective protein replacement therapy in a mouse model of LAMA2-CMD. Methods: In this study, we generated a novel immunocompromised dy W mouse model of LAMA2-CMD to study the role the immune system plays in muscle disease progression. We used this immune-deficient dy W mouse model to test the therapeutic benefits of recombinant human laminin-111 and laminin-211 protein therapy on laminin-α2-deficient muscle disease progression. Results: We show that immunodeficient laminin-α2 null mice demonstrate subtle differences in muscle regeneration compared to immunocompetent animals during early disease stages but overall exhibit a comparable muscle disease progression. We found human laminin-111 and laminin-211 could serve as effective protein replacement strategies with mice showing improvements in muscle pathology and function. We observed that human laminin-111 and laminin-211 exhibit differences on satellite and myoblast cell populations and differentially affect muscle repair. Conclusions: This study describes the generation of a novel immunodeficient mouse model that allows investigation of the role the immune system plays in LAMA2-CMD. This model can be used to assess the therapeutic potential of heterologous therapies that would elicit an immune response. Using this model, we show that recombinant human laminin-111 can serve as effective protein replacement therapy for the treatment of LAMA2-CMD.

Background Laminin-α2 related Congenital Muscular dystrophy (LAMA2-CMD) is a devastating genetic disease caused by mutations in the LAMA2 gene. These mutations result in progressive muscle wasting and inflammation leading to delayed milestones, and reduced lifespan in affected patients. There is currently no cure or treatment for LAMA2-CMD. Preclinical studies have demonstrated that mouse Laminin-111 can serve as an effective protein replacement therapy in a mouse model of LAMA2-CMD. Methods In this study, we generated a novel immunocompromised dy W mouse model of LAMA2-CMD to study the role the immune system plays in muscle disease progression. We used this immune deficient dy W mouse model to test the therapeutic benefits of recombinant human laminin-111 and laminin-211 protein therapy on Laminin-α2 deficient muscle disease progression. Results We show that immune deficient Laminin-α2 null mice demonstrate subtle differences in muscle regeneration compared to immune competent animals during early disease stages, but overall exhibit a comparable muscle disease progression. We found human laminin-111 and laminin-211 could serve as effective protein replacement strategies with mice showing improvements in muscle pathology and function. We observed that human laminin-111 and laminin-211 exhibit differences on satellite and myoblast cell populations and differentially affect muscle repair. Conclusions This study describes the generation of a novel immune deficient mouse model that allows investigation of the role the immune system plays in LAMA2-CMD. This model can be used to assess the therapeutic potential of heterologous therapies that would illicit an immune response. Using this model, we show that recombinant human Laminin-111 can serve as effective protein replacement therapy for the treatment of LAMA2-CMD.