Laminin-111 Protein Therapy Reduces Muscle Pathology and Improves Viability of a Mouse Model of Merosin-Deficient Congenital Muscular Dystrophy

Abstract

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.

Chimeric protein repair of laminin polymerization ameliorates muscular dystrophy phenotype

“…However, application of this therapeutic approach will be difficult to translate to patients, given the large size (9.3 kb) of the DNA construct. Whether recombinant protein injection would be efficacious remains to be established (44). Adeno-associated virus (AAV) is one of the most promising of the gene delivery systems, as high expression levels can be achieved.…”

Tendon development and musculoskeletal assembly: emerging roles for the extracellular matrix

“…For example, laminins (Lama2, Lama4) bind Itga7/b1 in the muscle basement membrane (Fig. 5) (Yurchenco et al, 2004;Durbeej, 2010;Carmignac and Durbeej, 2012), and defects in LAMA2 have been associated with merosin-deficient muscular dystrophy in humans (Tomé et al, 1994;Rooney et al, 2012). Furthermore, mutations that disrupt genes encoding crosslinking collagens (e.g.…”

“…5) (Docheva et al, 2014;Mayer et al, 1997;Pan et al, 2013;Rooney et al, 2006Rooney et al, , 2012. In muscle, these continuous structural links between ECM proteins, the sarcolemma and the cytoskeleton, maintain fiber integrity and modulate adhesion and gene expression.…”

Axial and limb muscle development: dialogue with the neighbourhood

“…Furthermore, although significant advances are being made showing the essential role of extrinsic factors in maintaining a homeostatic equilibrium between skeletal muscle cells and their surroundings (e.g. [8,138,139]), more still needs to be learned about what signals maintain this equilibrium which is so profoundly disturbed in muscular dystrophies and muscle wasting. A better understanding of the balance of signals regulating normal muscle development and repair is likely to significantly improve our toolkit against these devastating muscular diseases.…”