Translational Studies of GALGT2 Gene Therapy for Duchenne Muscular Dystrophy.

摘要

Galgt2 overexpression in skeletal myofibers has been demonstrated to protect both wild type and dystrophic muscles from injury and to inhibit the development of muscular dystrophy in three mouse models of human disease, including the mdx mouse model of Duchenne Muscular Dystrophy (DMD)1-5. We have developed two gene therapy vectors for use in human DMD clinical trials that allow expression of the human GALGT2 gene driven by a skeletal muscle-specific promoter (AAV(rh.74)-MCK-GALGT2) or cardiac and skeletal muscle-specific promoter (AAV(rh.74)-MHCK7-GALGT2). Using these AAV8-like gene therapy vectors, which can cross the vascular barrier, we can effectively deliver GALGT2 transgene to skeletal muscles via the bloodstream, providing functional correction in mdx mice1. In order for such studies to have reference to clinical meaning in human trials, additional dose response studies will be done in this proposal using the mdx mouse and the more severe DMD-like Cmah-/-mdx mouse, a mouse with a humanized sialoglycome6. The objective of the proposed work is to provide pre-clinical data in support of a planned IND application to use GALGT2 gene therapy to treat Duchenne muscular dystrophy.