Systemic inhibition of bone morphogenetic protein 1.3 as a possible treatment for laminin-related congenital muscular dystrophy.

Abstract

Congenital muscular dystrophy (CMD) is a group of rare neuromuscular disorders typically characterized by the onset of symptoms at birth or within the first two years of life. CMDs are relatively rare, but extremely severe pathological conditions currently without a safe and effective therapeutic solution. Merosin-deficient congenital muscular dystrophy type 1A (MDC1A) is among the most frequent CMDs and it is caused by mutations in the LAMA2 gene that encodes for the α2 chain of laminin-211 (merosin). Laminin-211 is a crucial constituent of the basement membrane that provides muscle fibre stability and signal transduction. Bone morphogenetic protein 1.3 (BMP1.3) is evolutionarily conserved and structurally related to mammalian Tolloid-like metalloproteinase (mTld) that is involved in the processing of procollagens, non-collagenous extracellular matrix proteins, and growth factor-related proteins. Recently, it has been shown that BMP1.3 is present in circulation and its levels are elevated in patients with chronic kidney failure, hepatic fibrosis, and acute myocardial infarction. It has been demonstrated that administering the BMP1.3 antibody ameliorated kidney, liver, and heart function in animal disease models. Furthermore, we observed highly enhanced BMP1.3 gene expression in the skeletal muscles of mice with congenital muscular dystrophy. Therefore, we hypothesize that BMP1.3 inhibition represents a novel therapeutic strategy for reversing the progression of CMD. The development of an anti-BMP1.3 therapy might lead to groundbreaking changes in CMD treatment and provide relief to numerous patients suffering from this disabling disease.