A Translational Pathway Toward a Clinical Trial Using the Second-Generation AAV Micro Dystrophin Vector
Technical Report,01 Sep 2016,31 Aug 2017
University of Missouri System Columbia United States
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Duchenne muscular dystrophy DMD is a life threatening disease affecting all muscles in the body. An important therapeutic goal of DMD gene therapy is to deliver a therapeutic gene to all muscles in the body. The overarching goal of this project is to achieve systemic AAV micro-dystrophin gene therapy in young adult affected dogs. In the last funding period, we proposed to incorporate the CpG-free feature to our vector to further diminish the untoward immune response. In this funding period, we demonstrated that elimination of CpG from AAV ITR does not affect therapeutic efficacy but it reduces packaging efficiency. We also showed that CpG-free microgenes are functional. However, removal of hinge3 resulted in better protection against eccentric contraction. We further showed that the CK8 promoter is highly effective in driving muscle-specific expression. Based on these results, we develop a novel XP49 vector. In this vector, a CpG-free codon-optimized, hinge3-deleted human microgene is expressed from the CK8 promoter. We will move forward with this vector for dog studies and future human trials. In the last funding period, we showed that systemic delivery of a canine microdystrophin AAV vector is safe in young adult affected dogs. We now further extended this result and demonstrated robust expression for 12 months. Importantly, we observed amelioration of muscle pathology and improvement of muscle force. In addition, we have developed a novel noninvasive assay to evaluate whole body mobility in dogs. Finally, we published three review papers on the current status of AAV DMD gene therapy.