Laminin-111 Protein Therapy for the Treatment of Merosin Deficient Congenital Muscular Dystrophy Type 1A

Abstract

Merosin-deficient congenital muscular dystrophy type 1A (MDC1A) is a serious neuromuscular disease caused by a mutant LAMA2 gene. Loss of function of the LAMA2 gene leads to a deficiency of laminin-211/221, which are crucial to the basal lamina and the integrity of skeletal muscle. Currently, there is no cure or effective treatment for MDC1A. These patients have a shortened life expectancy and severely decreased quality of life. Previous research has shown Engelbreth-Holm Swarm (EHS) laminin- 111 protein replacement therapy decreases disease phenotype in both mouse and human models of muscular dystrophy. However previous research did not examine the role EHS laminin-111 treatment plays in the restorative/regenerative capacity of laminin-?2 deficient muscle after muscle injury. Recently we have shown that one treatment of laminin-111 protein therapy prior to cardiotoxin injury can increase extracellular matrix proteins and improve the deficient myogenic repair pathway in laminin-?2 deficient mice. The improvements in the repair and regenerative capacity seen with one treatment four days after cardiotoxin damage were not seen ten days after injury suggesting loss of the therapeutic benefit of laminin-111 protein in muscle over time. In order to investigate if additional laminin-111 was required to maintain the regenerative capacity of muscle, the dyW-/- animal model of MDC1A was pretreated intramuscularly with EHS derived mouse laminin-111 prior to injury with cardiotoxin and mice then received weekly booster treatments to observe the impact on muscle repair and regeneration. Our results show that weekly treatment promoted an improvement in the timing and extent of muscle repair in laminin-?2 deficient muscle 10 and 28 days after injury, as had been seen previously prior to injury and four days after injury. This result provides further evidence that laminin- 111 could prove to be a valuable treatment for this extremely serious form of muscular dystrophy and confirms the need for weekly treatments to maintain the beneficial effects.