Galectin-1 Protein Therapy for Congenital Muscular Dystrophy

Strykagen Corporation, Reno NV

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Abstract

Abstract Laminin-?2 related congenital muscular dystrophy (LAMA2-CMD), also known as Merosin Deficient Congenital Muscular Dystrophy (MDC1A), is a fatal muscle wasting disease that affects patients from birth. LAMA2-CMD results from mutations in the LAMA2 gene resulting in loss of laminin-?2 protein. Laminin-?2 is required for the formation of the heterotrimers laminin-211 (?2, ?1, ?1) and laminin-221 (?2, ?1, ??), which are major constituents of the skeletal and cardiac muscle basal lamina. LAMA2-CMD patients exhibit severe muscle weakness from birth, are confined to a wheelchair, require ventilator assistance to breathe and have reduced life expectancy. There is currently no effective treatment or cure for LAMA2-CMD and all affected children will die from this genetic disease. Galectin-1 is a 14kDa protein localized in the myomatrix that interacts with laminin and ?7?1 integrin and has been shown to stabilize dystrophic muscle. The Burkin lab has recently shown that treatment with recombinant human Galectin-1 protein leads to elevated levels of ?7?1 integrin in the skeletal muscle of the dyW mouse model of LAMA2-CMD. Galectin-1 treatment increased the capacity for muscle repair and functioned to limit muscle inflammation and fibrosis. Galectin-1 could interact with other laminin isoforms that are up-regulated in LAMA2-CMD to stabilize their interaction with muscle. What is unclear from these studies is the mechanism of action, the optimal dosing and pharmacokinetic and pharmacodynamic (PK/PD) and toxicology profile of exogenously delivered Galectin-1 to prevent disease progression in laminin-?2 deficient muscle. In the proposal Strykagen will optimize Galectin-1 dosing, define the PK/PD profile, toxicology and determine the effectiveness of optimized Galectin-1 protein treatment on disease progression in a mouse model of LAMA2-CMD. Together these studies will contribute to an IND application to develop recombinant human Galectin-1 protein as a novel treatment for patients with LAMA2- CMD.