The purpose of this application is to develop better vectors and reagents that will improve the genetic therapy of brain tumors. The applicant's overall strategy is novel and circumvents present technological limitations in at least three fundamentally important ways. First, it permits the targeted delivery of specific genes to cancer cells, avoiding for the most part normal tissue. Second, his strategy reduces many important safety concerns associated with present gene therapy approaches. Finally, it improves on the efficiency of gene delivery and the low virus titers available. The applicant's strategy involves the specific delivery of the modified human ecotropic retrovirus receptor (MERR) to targeted cells. During the period in which MERR is expressed on those cells they will become infectable by ecotropic retroviruses carrying a desired therapeutic gene. An important component of his technology is the use of monoclonal antibodies and their antigen binding domains for targeting human tumors. The applicant will use targeting components, such as antibodies in conjunction with a retrovirus receptor to permit infection of non- permissive cells from one species by a virus from another species. For example, he will construct fusion proteins between the targeting component (e.g., VH and VL genes of a monoclonal antibody) and the receptor. This approach greatly enhances safety and provides the only means of targeting for gene therapy available today. The applicant has accumulated substantial preliminary data indicating that the approach will work. This application seeks to complete in vitro studies, move the technology into animal models and eventually to clinical protocols.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA068498-04
Application #
2748815
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Kelsey, Morris I
Project Start
1995-09-30
Project End
2000-07-31
Budget Start
1998-08-10
Budget End
1999-07-31
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost
Name
New York University
Department
Pathology
Type
Schools of Medicine
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10016
Jamieson, Kelly V; Hubbard, Stevan R; Meruelo, Daniel (2011) Structure-guided identification of a laminin binding site on the laminin receptor precursor. J Mol Biol 405:24-32
Tseng, J-C; Granot, T; DiGiacomo, V et al. (2010) Enhanced specific delivery and targeting of oncolytic Sindbis viral vectors by modulating vascular leakiness in tumor. Cancer Gene Ther 17:244-55
Tseng, J-C; Daniels, G; Meruelo, D (2009) Controlled propagation of replication-competent Sindbis viral vector using suicide gene strategy. Gene Ther 16:291-6
Jamieson, Kelly V; Wu, Jinhua; Hubbard, Stevan R et al. (2008) Crystal structure of the human laminin receptor precursor. J Biol Chem 283:3002-5
Tseng, J-C; Zheng, Y; Yee, H et al. (2007) Restricted tissue tropism and acquired resistance to Sindbis viral vector expression in the absence of innate and adaptive immunity. Gene Ther 14:1166-74
Tseng, Jen-Chieh; Zanzonico, Pat B; Levin, Brandi et al. (2006) Tumor-specific in vivo transfection with HSV-1 thymidine kinase gene using a Sindbis viral vector as a basis for prodrug ganciclovir activation and PET. J Nucl Med 47:1136-43
Hurtado, Alicia; Tseng, Jen-Chieh; Meruelo, Daniel (2006) Gene therapy that safely targets and kills tumor cells throughout the body. Rejuvenation Res 9:36-44
Hurtado, Alicia; Tseng, Jen-Chieh; Boivin, Christopher et al. (2005) Identification of amino acids of Sindbis virus E2 protein involved in targeting tumor metastases in vivo. Mol Ther 12:813-23
Tseng, Jen-Chieh; Levin, Brandi; Hurtado, Alicia et al. (2004) Systemic tumor targeting and killing by Sindbis viral vectors. Nat Biotechnol 22:70-7
Tseng, Jen-Chieh; Hurtado, Alicia; Yee, Herman et al. (2004) Using sindbis viral vectors for specific detection and suppression of advanced ovarian cancer in animal models. Cancer Res 64:6684-92

Showing the most recent 10 out of 23 publications