Adenoviruses are promising vectors for therapeutic applications in humans. The striking discrepancy between profound phenotypes of Ad mutants, possessing modifications in individual capsid proteins, and our inability to selectively target tumor cells after intravascular virus delivery underscores poorly appreciated redundancy and overlap of molecular pathways, which become engaged when virus is delivered via intravascular route. This proposal is to conduct comprehensive mechanistic studies to define the contribution of each of the major structural elements of the Ad capsid in mediating virus interaction with liver cells in vivo. Using a large set of previously constructed capsid- modified Ad vectors, we will analyze the role of 1) the fiber structure;2) the penton-host integrin interactions;and 3) the hexon-blood factor interactions in mediating Ad trapping in the liver and hepatocyte transduction after intravascular Ad delivery. Based on the accumulated data we will 4) construct a lung carcinoma cell-targeted oncolytic Ad vector that escapes trapping by the liver and evaluate its anti-tumor efficacy in a mouse model. These studies will dramatically improve our understanding of the mechanisms governing Ad-host interactions in vivo and will ultimately lead to the development of clinically useful targeted Ad vectors for the therapy of localized and disseminated metastatic tumor diseases.

Public Health Relevance

Adenovirus vectors (Ad) are the most common viral vector type used in clinical studies worldwide. Despite extensive use in gene transfer applications as well as vaccinations against life threatening infectious agents, Ad's use as an anti-cancer therapeutic is greatly impeded due to poor understanding of the molecular mechanisms that govern virus infectivity and bio-distribution in vivo. Ad liver cell transduction causes clinically significant hepatotoxicity and complicates strategies for Ad targeting to disseminated metastatic tumor cells in vivo. This proposal is to fill the major void in our understanding of Ad interactions with host cells and factors in vivo. These studies will ultimately lead to the development of a first panel of clinically useful targeted Ad vectors for the therapy of localized and disseminated metastatic tumor diseases.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA141439-04
Application #
8267055
Study Section
Gene and Drug Delivery Systems Study Section (GDD)
Program Officer
Daschner, Phillip J
Project Start
2009-07-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
4
Fiscal Year
2012
Total Cost
$412,933
Indirect Cost
$148,232
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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Di Paolo, Nelson C; Shayakhmetov, Dmitry M (2013) Interleukin-1 receptor 2 keeps the lid on interleukin-1?. Immunity 38:203-5
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Shayakhmetov, Dmitry M; Di Paolo, Nelson C; Mossman, Karen L (2010) Recognition of virus infection and innate host responses to viral gene therapy vectors. Mol Ther 18:1422-9
Di Paolo, Nelson C; van Rooijen, Nico; Shayakhmetov, Dmitry M (2009) Redundant and synergistic mechanisms control the sequestration of blood-born adenovirus in the liver. Mol Ther 17:675-84
Di Paolo, Nelson C; Shayakhmetov, Dmitry M (2009) Adenovirus de-targeting from the liver. Curr Opin Mol Ther 11:523-31