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.

Public Health Relevance

Hemophilia B is an x-linked inherited bleeding disorder occurring in about one in ~25,000 male birth. It is the second most common type of hemophilia. The study aims at developing a computer-controlled gene delivery system for treatment of hemophilia B using gene therapy approach.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Gene and Drug Delivery Systems Study Section (GDD)
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Link, Rebecca P
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University of Georgia
Schools of Pharmacy
United States
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Gao, Mingming; Ma, Yongjie; Cui, Ran et al. (2014) Hydrodynamic delivery of FGF21 gene alleviates obesity and fatty liver in mice fed a high-fat diet. J Control Release 185:1-11
Cui, R; Gao, M; Qu, S et al. (2014) Overexpression of superoxide dismutase 3 gene blocks high-fat diet-induced obesity, fatty liver and insulin resistance. Gene Ther 21:840-8
Gao, Mingming; Liu, Dexi (2014) Gene therapy for obesity: progress and prospects. Discov Med 17:319-28
Gao, Mingming; Ma, Yongjie; Liu, Dexi (2013) Rutin suppresses palmitic acids-triggered inflammation in macrophages and blocks high fat diet-induced obesity and fatty liver in mice. Pharm Res 30:2940-50
Gao, Mingming; Liu, Dexi (2013) The liver X receptor agonist T0901317 protects mice from high fat diet-induced obesity and insulin resistance. AAPS J 15:258-66
Gao, Mingming; Zhang, Chunbo; Ma, Yongjie et al. (2013) Hydrodynamic delivery of mIL10 gene protects mice from high-fat diet-induced obesity and glucose intolerance. Mol Ther 21:1852-61
Gao, Mingming; Bu, Le; Ma, Yongjie et al. (2013) Concurrent activation of liver X receptor and peroxisome proliferator-activated receptor alpha exacerbates hepatic steatosis in high fat diet-induced obese mice. PLoS One 8:e65641
Ma, Y; Liu, D (2013) Hydrodynamic delivery of adiponectin and adiponectin receptor 2 gene blocks high-fat diet-induced obesity and insulin resistance. Gene Ther 20:846-52
Bu, Le; Gao, Mingming; Qu, Shen et al. (2013) Intraperitoneal injection of clodronate liposomes eliminates visceral adipose macrophages and blocks high-fat diet-induced weight gain and development of insulin resistance. AAPS J 15:1001-11
Ma, Yongjie; Huang, Yixian; Yan, Linna et al. (2013) Synthetic FXR agonist GW4064 prevents diet-induced hepatic steatosis and insulin resistance. Pharm Res 30:1447-57

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