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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL098295-04
Application #
8434877
Study Section
Gene and Drug Delivery Systems Study Section (GDD)
Program Officer
Link, Rebecca P
Project Start
2009-12-20
Project End
2014-11-30
Budget Start
2012-12-01
Budget End
2014-11-30
Support Year
4
Fiscal Year
2013
Total Cost
$309,296
Indirect Cost
$60,197
Name
University of Georgia
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
004315578
City
Athens
State
GA
Country
United States
Zip Code
30602
Ma, Yongjie; Gao, Mingming; Liu, Dexi (2016) N-acetylcysteine Protects Mice from High Fat Diet-induced Metabolic Disorders. Pharm Res 33:2033-42
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Yan, Linna; Song, Kexiu; Gao, Mingming et al. (2016) Modulation of Cell-Mediated Immunity to Suppress High Fat Diet-Induced Obesity and Insulin Resistance. Pharm Res 33:395-403
Ma, Yongjie; Gao, Mingming; Liu, Dexi (2016) Alternating Diet as a Preventive and Therapeutic Intervention for High Fat Diet-induced Metabolic Disorder. Sci Rep 6:26325
Ma, Yongjie; Gao, Mingming; Liu, Dexi (2016) Preventing High Fat Diet-induced Obesity and Improving Insulin Sensitivity through Neuregulin 4 Gene Transfer. Sci Rep 6:26242
Sun, H; Liu, D (2016) IL-15/sIL-15Rα gene transfer suppresses Lewis lung cancer growth in the lungs, liver and kidneys. Cancer Gene Ther 23:54-60
Alsaggar, Mohammad; Yao, Qian; Cai, Houjian et al. (2016) Differential growth and responsiveness to cancer therapy of tumor cells in different environments. Clin Exp Metastasis 33:115-24
Gao, Mingming; Zhang, Chunbo; Ma, Yongjie et al. (2015) Cold Exposure Improves the Anti-diabetic Effect of T0901317 in Streptozotocin-Induced Diabetic Mice. AAPS J 17:700-10
Sun, H; Liu, D (2015) Hydrodynamic delivery of interleukin 15 gene promotes resistance to high fat diet-induced obesity, fatty liver and improves glucose homeostasis. Gene Ther 22:341-7
Ma, Yongjie; Gao, Mingming; Sun, Hao et al. (2015) Interleukin-6 gene transfer reverses body weight gain and fatty liver in obese mice. Biochim Biophys Acta 1852:1001-11

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