Accession Number : AD1032862


Title :   A Translational Pathway Toward a Clinical Trial Using the Second-Generation AAV Micro-Dystrophin Vector


Descriptive Note : Technical Report,01 Sep 2015,31 Aug 2016


Corporate Author : University of Missouri System Columbia United States


Personal Author(s) : Duan,Dongsheng ; Emter,Craig ; Lai,Yi ; Tung Yang,Hsiao ; Hakim,Chady ; Yue,Yongping


Full Text : https://apps.dtic.mil/dtic/tr/fulltext/u2/1032862.pdf


Report Date : 01 Sep 2016


Pagination or Media Count : 89


Abstract : 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 Pg.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 for12 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 AAVDMD gene therapy.


Descriptors :   muscular diseases , clinical trails , cardiomyopathies , viral structures , stem cells , cultured cells , polymeric films , gene therapy , muscle cells , peptides , proteins , skeletal muscle


Subject Categories : Medicine and Medical Research


Distribution Statement : APPROVED FOR PUBLIC RELEASE