The success of gene therapy relies critically on the development of new technologies that can be used to produce site-specific gene delivery without causing systemic toxicity and immunogenic response, as well as the ability to regulate transgene expression in vivo. Despite extensive efforts in the past, these primary obstacles in gene therapy still exist. This proposal aims to develop novel ultrasound systems that have the potential to overcome these obstacles by providing new techniques for 1) targeted gene delivery to internal organs and 2) spatial and temporal regulation of transgene expression in vivo. In preliminary studies, we have already demonstrated the feasibility of ultrasound-mediated gene transfer in vitro using cultured HeLa cells and lithotripter shock wave (LSW)-mediated site-specific gene delivery in vivo in porcine kidney. We have also shown that ultrasound can be used as a simple and convenient physical means to activate transgene expression under the control of heat shock protein (hsp) 70B promoter. The work outlined in this proposal will be a significant expansion of these preliminary studies and will encompass a multidisciplinary and comprehensive investigation combining innovative engineering approaches with modem techniques in cell and molecular biology, and animal experimentations.
Our specific aims are: 1. Development of novel ultrasound systems for targeted gene delivery and activation. 2. Physical characterization of the acoustic fields and associated cavitation bubble dynamics produced by the novel ultrasound systems both in water and in tissue phantoms. 3. Optimization of ultrasound-mediated gene delivery in vitro. 4. Ultrasound-targeted gene delivery in porcine kidney, and 5. Ultrasound-regulated gene delivery and activation in skeletal muscle -a novel approach for erythropoietin (Epo) gene therapy in a rat model with chronic renal failure. Because ultrasound can penetrate deep into tissue and be focused on specific organs of the body, the prospect for ultrasound-targeted gene delivery and activation in vivo is very appealing. Such a versatile physical method for gene delivery and activation could be of great value for molecular therapies of a wide range of diseases, including cancer, cardiovascular disease, and various renal disorders (polycystic kidney, renal cancer, acute glomerulonephritis, and chronic interstitial disease).

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
5R01EB002682-02
Application #
6799577
Study Section
Special Emphasis Panel (ZRG1-SSS-2 (55))
Program Officer
Moy, Peter
Project Start
2003-09-08
Project End
2008-07-31
Budget Start
2004-08-01
Budget End
2005-07-31
Support Year
2
Fiscal Year
2004
Total Cost
$346,500
Indirect Cost
Name
Duke University
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
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Xing, Yifei; Lu, Xiaochun; Pua, Eric C et al. (2008) The effect of high intensity focused ultrasound treatment on metastases in a murine melanoma model. Biochem Biophys Res Commun 375:645-50
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Liu, Yunbo; Kon, Takashi; Li, Chuanyuan et al. (2006) High intensity focused ultrasound-induced gene activation in solid tumors. J Acoust Soc Am 120:492-501
Zhou, Yufeng; Zhai, Liang; Simmons, Rebecca et al. (2006) Measurement of high intensity focused ultrasound fields by a fiber optic probe hydrophone. J Acoust Soc Am 120:676-85
Sankin, G N; Simmons, W N; Zhu, S L et al. (2005) Shock wave interaction with laser-generated single bubbles. Phys Rev Lett 95:034501

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