Computer-Assisted Hydrodynamic Gene Delivery for Hemophilia Gene Therapy

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DESCRIPTION (provided by applicant): Development of new and improved methods for a safe, site specific and efficient gene delivery has become a major focus in gene therapy research. To accelerate the process, we have developed a computer-controlled injection device for hydrodynamic gene delivery to different organs in vivo, particularly to liver. Employing an image-guided catheter insertion technique, we have demonstrated in pigs that the computer-assisted hydrodynamic gene delivery to pig liver is effective and safe. In the study outlined in this proposal, we will evaluate the effectiveness and safety of our newly developed gene delivery system for treatment of hemophilia B using hemophilia B dogs as an animal model. The overall objective of the proposed study is to establish a minimally invasive, reliable and safe procedure for human gene therapy. In specific aim 1, we will employ the procedure of image-guided, liver specific hydrodynamic gene delivery to optimize the hydrodynamic parameters for gene delivery to dog liver. In specific aim 2, we will characterize the long-term impact of the hydrodynamic gene delivery with respect to persistence of transgene expression, effect on tissue toxicity, potential immune response against transgene product, and tissue distribution of the transgene. Specific aim 3 was designed to assess the effectiveness of repeated hydrodynamic gene delivery to the same animals. In specific aim 4, we will perform pre-clinical evaluation of the optimized procedure for treatment of hemophilia in hemophilia B dogs and characterize the long-term effects of the treatment. This translational research is designed to validate a newly developed computer-controlled device for gene delivery and to establish a clinically applicable procedure. Data collected from the study will be critical for preparation of clinical trials. If successfully accomplished, the proposed study will provide a new technology for gene delivery and will significantly advance the field of gene therapy.