Laminin α1 reduces muscular dystrophy in dy2J mice

Muscular dystrophies, including laminin alpha 2 chain-deficient muscular dystrophy (LAMA2-CMD), are associated with immense personal, social and economic burdens. Thus, effective treatments are urgently needed. LAMA2-CMD is either a severe, early-onset condition with complete laminin alpha 2 chain-deficiency or a milder, late-onset form with partial laminin alpha 2 chain-deficiency. Mouse models dy(3K)/dy(3K) and dy(2J)/dy(2J), respectively, recapitulate these two forms of LAMA2-CMD very well. We have previously demonstrated that laminin alpha 1 chain significantly reduces muscular dystrophy in laminin alpha 2 chain-deficient dy(3K)/dy(3K) mice. Among all the different pre-clinical approaches that have been evaluated in mice, laminin alpha 1 chain-mediated therapy has been shown to be one of the most effective lines of attack. However, it has remained unclear if laminin alpha 1 chain-mediated treatment is also applicable for partial laminin alpha 2 chain-deficiency. Hence, we have generated dy(2J)/dy(2J) mice (that express a substantial amount of an N-terminal truncated laminin alpha 2 chain) overexpressing laminin alpha 1 chain in the neuromuscular system. The laminin alpha 1 chain transgene ameliorated the dystrophic phenotype, restored muscle strength and reduced peripheral neuropathy. Thus, these findings provide additional support for the development of laminin alpha 1 chain-based therapy for LAMA2-CMD. (C) 2018 Elsevier B.V. All rights reserved.