| First Author | Rooney JE | Year | 2012 |
| Journal | Am J Pathol | Volume | 180 |
| Issue | 4 | Pages | 1593-602 |
| PubMed ID | 22322301 | Mgi Jnum | J:182001 |
| Mgi Id | MGI:5314563 | Doi | 10.1016/j.ajpath.2011.12.019 |
| Citation | Rooney JE, et al. (2012) Laminin-111 protein therapy reduces muscle pathology and improves viability of a mouse model of merosin-deficient congenital muscular dystrophy. Am J Pathol 180(4):1593-602 |
| abstractText | 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-alpha2 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-alpha2 is required for the formation of heterotrimeric laminin-211 (ie, alpha2, beta1, and gamma1) and laminin-221 (ie, alpha2, beta2, and gamma1), which are major constituents of skeletal muscle basal lamina. Laminin-111 (ie, alpha1, beta1, and gamma1) is the predominant laminin isoform in embryonic skeletal muscle and supports normal skeletal muscle development in laminin-alpha2-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-alpha2-deficient mice prevents muscle pathology, improves muscle strength, and dramatically increases life expectancy. Laminin-111 also prevented apoptosis in laminin-alpha2-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. |
