Laminin-111 protein therapy prevents muscle disease in the mdx mouse model for Duchenne muscular dystrophy

Abstract

Duchenne muscular dystrophy (DMD) is a devastating neuromuscular disease caused by mutations in the gene encoding dystrophin. Loss of dystrophin results in reduced sarcolemmal integrity and increased susceptibility to muscle damage. The α 7 β 1 -integrin is a laminin-binding protein up-regulated in the skeletal muscle of DMD patients and in the mdx mouse model. Transgenic overexpression of the α 7 -integrin alleviates muscle disease in dystrophic mice, making this gene a target for pharmacological intervention. Studies suggest laminin may regulate α 7 -integrin expression. To test this hypothesis, mouse and human myoblasts were treated with laminin and assayed for α 7 -integrin expression. We show that laminin-111 (α 1 , β 1 , γ 1 ), which is expressed during embryonic development but absent in normal or dystrophic skeletal muscle, increased α 7 -integrin expression in mouse and DMD patient myoblasts. Injection of laminin-111 protein into the mdx mouse model of DMD increased expression of α 7 -integrin, stabilized the sarcolemma, restored serum creatine kinase to wild-type levels, and protected muscle from exercised-induced damage. These findings demonstrate that laminin-111 is a highly potent therapeutic agent for the mdx mouse model of DMD and represents a paradigm for the systemic delivery of extracellular matrix proteins as therapies for genetic diseases.

Transgenic overexpression of the α7 integrin reduces muscle pathology and improves viability in the dyW mouse model of merosin-deficient congenital muscular dystrophy type 1A

“…Studies have indicated that the 71 integrin might act to modulate the organization and deposition of the muscle extracellular matrix (Colognato et al, 1999;Rooney et al, 2009a). To investigate the mechanism by which enhanced 7 integrin expression improved the myopathic phenotype in the absence of the laminin-211-laminin-221 ligand, we examined changes in levels of other ;itga7+ animals have 7-fold and 2.9-fold more galectin-3 protein compared with that in both wildtype and dy W-/-animals, respectively (***P<0.001).…”

“…Cryosections from 4-week-old TA and diaphragm muscle were stained using hematoxylin and eosin, as previously described (Rooney et al, 2009a), and were used to determine the percentage of myofibers that contained CLN using a Zeiss Axioskop 2 Plus fluorescence microscope. A minimum of 1000 fibers per animal (five animals per group) were counted and the percentage of myofibers with CLN calculated.…”

A mutation-independent approach via transcriptional upregulation of a disease modifier gene rescues muscular dystrophy in vivo

“…27 . The most advanced approach is via delivery of Laminin-111 protein, although the efficacy remains low and the need to produce a large amount of bioactive protein is challenging 27 .…”

“…27 . The most advanced approach is via delivery of Laminin-111 protein, although the efficacy remains low and the need to produce a large amount of bioactive protein is challenging 27 . In addition, the utilization of CRISPR/dCas9 system to upregulate Lama1 in mdx mice has been achieved locally via electroporation, which is not easily translatable into clinical settings 28 .…”

Laminin Enriched Scaffolds for Tissue Engineering Applications

“…14 LM-111 supplementation has demonstrated remarkable regenerative capacity in several models of muscular disease [15][16][17] and injury, 18 primarily by enhancing satellite cell activity. In mice with congenital muscular dystrophy due to missing LM α 2 chains, overall health and survival can be improved by administration of LM α1 chains, 19,20 In vitro, LM-111 promotes muscle stem cell proliferation and differentiation to a greater extent than other ECM components such as collagen type I and fibronectin.…”