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-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 dy(W-/-) 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 dy(W-/-) mouse model and establish the potential for its use in the treatment of MDC1A.
Department of Pharmacology, Center for Molecular Medicine, University of Nevada School of Medicine, Reno, Nevada 89557, USA.
Jachinta E
JE
Rooney
Jolie R
JR
Knapp
Bradley L
BL
Hodges
Ryan D
RD
Wuebbles
Dean J
DJ
Burkin
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D005355:Fibrosis; D006801:Humans; D007273:Injections, Intramuscular; D007274:Injections, Intraperitoneal; D053208:Kaplan-Meier Estimate; D007797:Laminin / Q000008:administration & dosage / Q000172:deficiency / Q000378:metabolism / Q000627:therapeutic use*; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D053580:Muscle Strength / Q000187:drug effects; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009136:Muscular Dystrophies / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D032446:Myoblasts / Q000187:drug effects / Q000473:pathology; D009220:Myositis / Q000517:prevention & control; D020033:Protein Isoforms / Q000008:administration & dosage / Q000627:therapeutic use; D015431:Weight Loss / Q000187:drug effects
D007797:Laminin; D020033:Protein Isoforms; C121346:laminin 1; C102645:laminin alpha 2; C084098:laminin A