Abstract

It is the purpose of the present proposal to develop a gene transfer vector capable of specific and selective transduction of disseminated neoplastic cells. The development of a vector with this capacity would allow the targeting of malignant cells in situ after systemic delivery. Capitalizing on the unique capacity of recombinant adenoviral vectors to accomplish high efficiency in vivo gene delivery, it is the hypothesis of the investigators that further modifications of this vector may be achieved to alter parent virus tropism such that selective transduction of malignant cells may be accomplished.
The specific aim of this proposal is thus to modify the tropism of recombinant adenoviral vectors employing genetic and immunologic methods to modify the adenoviral fiber protein. The capacity of the tropism-modified adenoviral vectors to accomplish targeted tumor cell-specific transduction in vivo in the context of animal models of disseminated neoplastic disease will be determined. The derivation of this 'targetable injectable' vector system would represent a potentially powerful technical advance allowing the implementation of a variety of strategies to accomplish gene therapy for cancer.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA074242-05
Application #
6350231
Study Section
Medical Biochemistry Study Section (MEDB)
Project Start
1997-04-01
Project End
2002-01-31
Budget Start
2001-04-04
Budget End
2002-01-31
Support Year
5
Fiscal Year
2001
Total Cost
$210,414
Indirect Cost

  Institution

Name
University of Alabama Birmingham
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294

  Publications

Hangalapura, Basav N; Oosterhoff, Dinja; Gupta, Tarun et al. (2011) Delivery route, MyD88 signaling and cross-priming events determine the anti-tumor efficacy of an adenovirus based melanoma vaccine. Vaccine 29:2313-21
Yamamoto, Masato; Curiel, David T (2004) Nonreplicating DNA viral vectors for suicide gene therapy: the adenoviral vectors. Methods Mol Med 90:61-70
Uil, Taco G; Seki, Toshiro; Dmitriev, Igor et al. (2003) Generation of an adenoviral vector containing an addition of a heterologous ligand to the serotype 3 fiber knob. Cancer Gene Ther 10:121-4
Brandao, Joana G; Scheper, Rik J; Lougheed, Sinead M et al. (2003) CD40-targeted adenoviral gene transfer to dendritic cells through the use of a novel bispecific single-chain Fv antibody enhances cytotoxic T cell activation. Vaccine 21:2268-72
Arafat, Waleed O; Buchsbaum, Donald J; Gomez-Navarro, Jesus et al. (2003) An adenovirus encoding proapoptotic Bax synergistically radiosensitizes malignant glioma. Int J Radiat Oncol Biol Phys 55:1037-50
Kim, M; Zinn, K R; Barnett, B G et al. (2002) The therapeutic efficacy of adenoviral vectors for cancer gene therapy is limited by a low level of primary adenovirus receptors on tumour cells. Eur J Cancer 38:1917-26
Sullivan, Deborah E; Mondelli, Mario U; Curiel, David T et al. (2002) Construction and characterization of an intracellular single-chain human antibody to hepatitis C virus non-structural 3 protein. J Hepatol 37:660-8
Seki, T; Dmitriev, I; Suzuki, K et al. (2002) Fiber shaft extension in combination with HI loop ligands augments infectivity for CAR-negative tumor targets but does not enhance hepatotropism in vivo. Gene Ther 9:1101-8
Dmitriev, Igor P; Kashentseva, Elena A; Curiel, David T (2002) Engineering of adenovirus vectors containing heterologous peptide sequences in the C terminus of capsid protein IX. J Virol 76:6893-9
Reynolds, Paul N; Curiel, David T (2002) New generation adenoviral vectors improve gene transfer by coxsackie and adenoviral receptor-independent cell entry. Kidney Int 61:S24-31

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