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

Am J Pathol. 2012 Apr;180(4):1593-602. doi: 10.1016/j.ajpath.2011.12.019. Epub 2012 Feb 6.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Cell Line
  • Disease Models, Animal
  • Drug Evaluation, Preclinical / methods
  • Female
  • Fibrosis
  • Humans
  • Injections, Intramuscular
  • Injections, Intraperitoneal
  • Kaplan-Meier Estimate
  • Laminin / administration & dosage
  • Laminin / deficiency
  • Laminin / metabolism
  • Laminin / therapeutic use*
  • Mice
  • Motor Activity / drug effects
  • Muscle Strength / drug effects
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / pathology
  • Muscle, Skeletal / physiopathology
  • Muscular Dystrophies / drug therapy*
  • Muscular Dystrophies / metabolism
  • Muscular Dystrophies / pathology
  • Muscular Dystrophies / physiopathology
  • Myoblasts / drug effects
  • Myoblasts / pathology
  • Myositis / prevention & control
  • Protein Isoforms / administration & dosage
  • Protein Isoforms / therapeutic use
  • Weight Loss / drug effects


  • Laminin
  • Protein Isoforms
  • laminin 1
  • laminin alpha 2
  • laminin A

Supplementary concepts

  • Muscular dystrophy congenital, merosin negative