Our lab has been interested in understanding the pathogenesis of limb girdle muscular dystrophies (LGMD) for the past twenty years, particularly in understanding the disease LGMDR1/2A due to CAPN3 mutations. LGMDR1 is the most prevalent form of the LGMDs but is one of the most complicated to understand, since the pathogenesis does not follow any of the common MD pathways. We showed that Calpain 3 is a loading sensor that mediates muscle remodeling through activation of calcium calmodulin kinase (CaMKII beta) signaling. In the absence of Capn3, muscles are essentially experiencing an anti-gravity state and doesn’t respond to loading cues that are necessary to activate gene expression for remodeling. We identified the first therapeutic compound to treat LGMDR1, that is now being optimized through medicinal chemistry efforts. Furthermore, we have initiated a gene therapy program along with Drs, Jeff Chamberlain and Steve Hauschka to develop AAV-based gene therapy vectors to treat the underlying cause of LGMD R1. The basic science that we uncovered in the course of this work has unexpectedly revealed the importance of muscle remodeling as fundamental for muscle health. We aim to initiate phase I clinical trials for our compound and gene therapy vectors in the next 5-7 years.
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