Laminin-111 Protein Therapy Reduces Muscle Pathology and Improves Viability of a Mouse Model of Merosin-Deficient Congenital Muscular Dystrophy

Merosin-deficient congenital muscular dystrophy type 1A (MDC1A) is a lethal muscle-wasting disease that is caused by mutations in the LAMA2 gene, resulting in the loss of laminin-alpha 2 protein. MDC1A patients exhibit severe muscle weakness from birth, are confined to a wheelchair, require ventilator assistance, and have reduced life expectancy. There are currently no effective treatments or cures for MDC1A. Laminin-alpha 2 is required for the formation of heterotrimeric laminin-211 (ie, alpha 2, beta 1, and gamma 1) and laminin-221 (ie, alpha 2, beta 2, and gamma 1), which are major constituents of skeletal muscle basal lamina. Laminin-111 (ie, alpha 1, beta 1, and gamma 1) is the predominant laminin isoform in embryonic skeletal muscle and supports normal skeletal muscle development in laminin-alpha 2-deficient muscle but is absent from adult skeletal muscle. In this study, we determined whether treatment with Engelbreth-Holm-Swarm-derived mouse laminin-111 protein could rescue MDC1A in the dy(w-/-) mouse model We demonstrate that laminin-111 protein systemically delivered to the muscles of laminin-alpha 2-deficient mice prevents muscle pathology, improves muscle strength, and dramatically increases life expectancy. Laminin-111 also prevented apoptosis in laminin-alpha 2-deficient mouse muscle and primary human MDC1A myogenic cells, which indicates a conserved mechanism of action and cross-reactivity between species. Our results demonstrate that laminin-111 can serve as an effective protein substitution therapy for the treatment of muscular dystrophy in the dy(w-/-) mouse model and establish the potential for its use in the treatment of MDC1A. (Am J Pathol 2012, 180: 1593-1602; DOE 10.1016/j.ajpath.2011.12.019)