Galectin-1: A potential protein therapy for Limb Girdle Muscular Dystrophy type 2B
The skeletal muscles of patients with LGMD2B have defects in repair leading to heightened chronic immune response. We will define Gal-1 as a favorable suppressor of LGMD2B disease pathogenesis and further define the mechanism through which these changes are accomplished. Since Gal-1 can be found in monomeric or dimeric forms (each known to have unique functions), it is crucial to define the biochemical functions of Gal-1 responsible for varying therapeutic benefits in LGMD2B. Our recently published preliminary data using cell and skeletal muscle fibers of dysferlin-deficient models suggest recombinant histidine-tagged human Gal-1 (rHsGal-1) increases myogenesis and improves membrane repair. Additionally, we show data suggesting that the carbohydrate recognition domain of Gal-1 mechanistically interacts with glycosylated cell membrane proteins to provide membrane stability.
A significant disease characteristic in LGMD2B is chronic muscle inflammation due to either activation of the NF-B pathway and/or through an impaired transition from pro-inflammatory, cyto-destructive (M1) macrophages to macrophages with regenerative anti-inflammatory capacity (M2) is. We will measure the extent of M1 to M2 macrophage polarization with Gal-1 treatment. The objective of this proposal uses models of LGMD2B to test the hypothesis that Gal-1 treatment decreases disease pathology by increasing membrane repair capacity and decreasing chronic inflammatory response. Our ultimate goal is to develop a novel therapeutic intervention that improves overall patient outcomes.