[HTML][HTML] Laminin-111 protein therapy reduces muscle pathology and improves viability of a mouse model of merosin-deficient congenital muscular dystrophy

JE Rooney, JR Knapp, BL Hodges… - The American journal of …, 2012 - Elsevier
JE Rooney, JR Knapp, BL Hodges, RD Wuebbles, DJ Burkin
The American journal of pathology, 2012Elsevier
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-α2 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-α2 is required for
the formation of heterotrimeric laminin-211 (ie, α2, β1, and γ1) and laminin-221 (ie, α2, β2 …
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-α2 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-α2 is required for the formation of heterotrimeric laminin-211 (ie, α2, β1, and γ1) and laminin-221 (ie, α2, β2, and γ1), which are major constituents of skeletal muscle basal lamina. Laminin-111 (ie, α1, β1, and γ1) is the predominant laminin isoform in embryonic skeletal muscle and supports normal skeletal muscle development in laminin-α2–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 dyW−/− mouse model. We demonstrate that laminin-111 protein systemically delivered to the muscles of laminin-α2–deficient mice prevents muscle pathology, improves muscle strength, and dramatically increases life expectancy. Laminin-111 also prevented apoptosis in laminin-α2–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 dyW−/− mouse model and establish the potential for its use in the treatment of MDC1A.
Elsevier