Gene therapy is amenable for correcting inborn errors of metabolism, as well as for the treatment of cancer and HIV. Lentiviral vectors are among the most efficient tools for gene delivery into mammalian cells. Our long-term goal is to develop a targetable gene delivery system that can transduce a specific cell type, a specific tissue or a specific organ after intravenous adminstration. Our preliminary studies have uncovered a truly targetable lentiviral vector system for gene delivery. The experimental focus of this proposal is to evaluate the therapeutic potential of this method for in vivo targeting. The first specific aim is to study the molecular mechanism of targeted infection by engineered recombinant viruses. Understanding this process should lead to identification and design of new molecules for targeting. The second specific aim is to perfect the strategy to prepare lentiviruses, which will greatly enhance the efficacy of virus preparation. The third specific aim is to explore novel molecules for targeting lentiviral vectors, which will expand our ability to manipulate lentiviruses for targeting. The fourth specific aim is to explore the utility of targeted gene delivery using antibody- and SCF-bearing lentiviruses. These studies build upon our novel finding that viruses displaying membrane-bound antibodies or stem cell factor (SCF) can specifically infect cells expressing cognate antigens or SCF receptors. Various experiments are proposed to assess the therapeutic implications of this novel targeting strategy to treat HIV and cancer in animal models. Taken together, these novel studies will enlarge the therapeutic potential of targeted gene delivery to treat a diverse range of diseases, as well as advance our undstanding of viral infection. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI068978-01
Application #
7083925
Study Section
Gene and Drug Delivery Systems Study Section (GDD)
Program Officer
Park, Eun-Chung
Project Start
2006-02-01
Project End
2011-01-31
Budget Start
2006-02-01
Budget End
2007-01-31
Support Year
1
Fiscal Year
2006
Total Cost
$584,139
Indirect Cost
Name
University of Southern California
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Bryson, Paul D; Han, Xiaolu; Truong, Norman et al. (2017) Breast cancer vaccines delivered by dendritic cell-targeted lentivectors induce potent antitumor immune responses and protect mice from mammary tumor growth. Vaccine 35:5842-5849
Siegler, Elizabeth L; Kim, Yu Jeong; Chen, Xianhui et al. (2017) Combination Cancer Therapy Using Chimeric Antigen Receptor-Engineered Natural Killer Cells as Drug Carriers. Mol Ther 25:2607-2619
Han, Xiaolu; Bryson, Paul D; Zhao, Yifan et al. (2017) Masked Chimeric Antigen Receptor for Tumor-Specific Activation. Mol Ther 25:274-284
Han, Xiaolu; Cinay, Gunce E; Zhao, Yifan et al. (2017) Adnectin-Based Design of Chimeric Antigen Receptor for T Cell Engineering. Mol Ther 25:2466-2476
Siegler, Elizabeth; Li, Si; Kim, Yu Jeong et al. (2017) Designed Ankyrin Repeat Proteins as Her2 Targeting Domains in Chimeric Antigen Receptor-Engineered T Cells. Hum Gene Ther 28:726-736
Zhang, Xiaoyang; Liu, Yarong; Kim, Yu Jeong et al. (2017) Co-delivery of carboplatin and paclitaxel via cross-linked multilamellar liposomes for ovarian cancer treatment. RSC Adv 7:19685-19693
Fang, Jinxu; Xiao, Liang; Joo, Kye-Il et al. (2016) A potent immunotoxin targeting fibroblast activation protein for treatment of breast cancer in mice. Int J Cancer 138:1013-23
Fiacco, Stephen V; Kelderhouse, Lindsay E; Hardy, Amanda et al. (2016) Directed Evolution of Scanning Unnatural-Protease-Resistant (SUPR) Peptides for in Vivo Applications. Chembiochem 17:1643-51
Fang, Jinxu; Hu, Biliang; Li, Si et al. (2016) A multi-antigen vaccine in combination with an immunotoxin targeting tumor-associated fibroblast for treating murine melanoma. Mol Ther Oncolytics 3:16007
Kim, Yu Jeong; Liu, Yarong; Li, Si et al. (2015) Co-Eradication of Breast Cancer Cells and Cancer Stem Cells by Cross-Linked Multilamellar Liposomes Enhances Tumor Treatment. Mol Pharm 12:2811-22

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