Designing a suitable delivery vehicle is very important to obtain the desired results in a gene therapy protocol. Human adenoviruses have attracted considerable interest lately for their potential use as delivery vehicles for gene therapy especially for treating genetic disorders, and cancer. Now it has been fully realized that currently available vectors do express some of the viral genes, and therefore, the cells carrying the desired vector are removed from the circulation resulting in transgene expression for a short duration. This suggests that there is a need to cripple the virus further to obtain transgene expression for an extended period of time. Non-human adenoviruses, such as bovine adenovirus type 3 (BAd3) and porcine adenovirus type 3 (PAd3) that do not replicate in human cells but can infect human cells in culture, could provide an attractive alternative to human adenovirus vectors for gene therapy. The long-term objectives are to develop replication-deficient BAd3 and PAd3 vectors for human gene therapy with a purpose of obtaining expression of the desired gene for a long period of time without significant side effects. Initially these vectors containing a reporter gene will be tested in human cell lines and experimental animals to evaluate the level and duration of transgene expression, the levels of vector's early and late gene expression, the state and duration of the presence of vector DNA, the inflammatory response at the site of inoculation in animals, and the host immune response against the vector. These experiments will form the basis for the future studies initially in human tissues and subsequently in a small human trial using either BAd3 or PAd3 vector for correcting a respiratory, hepatic or cardiovascular disorder or in cancer therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29GM055168-03
Application #
2900892
Study Section
Medical Biochemistry Study Section (MEDB)
Project Start
1997-04-01
Project End
2002-03-31
Budget Start
1999-04-01
Budget End
2000-03-31
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Purdue University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
072051394
City
West Lafayette
State
IN
Country
United States
Zip Code
47907
Sharma, Anurag; Bangari, Dinesh S; Tandon, Manish et al. (2010) Evaluation of innate immunity and vector toxicity following inoculation of bovine, porcine or human adenoviral vectors in a mouse model. Virus Res 153:134-42
Sharma, Anurag; Bangari, Dinesh S; Tandon, Manish et al. (2009) Comparative analysis of vector biodistribution, persistence and gene expression following intravenous delivery of bovine, porcine and human adenoviral vectors in a mouse model. Virology 386:44-54
Bangari, Dinesh S; Mittal, Suresh K (2004) Porcine adenoviral vectors evade preexisting humoral immunity to adenoviruses and efficiently infect both human and murine cells in culture. Virus Res 105:127-36
van Olphen, Alberto L; Mittal, Suresh K (2002) A 72-bp internal deletion in the left inverted terminal repeat of the bovine adenovirus type 3 genome does not affect virus replication. Intervirology 45:188-92
Sailaja, G; HogenEsch, H; North, A et al. (2002) Encapsulation of recombinant adenovirus into alginate microspheres circumvents vector-specific immune response. Gene Ther 9:1722-9
Aggarwal, N; Mittal, S K (2000) Sequence analysis of porcine adenovirus type 3 E1 region, pIX and pIVa2 genes, and two novel open reading frames. Intervirology 43:12-Jun
Mittal, S K; Aggarwal, N; Sailaja, G et al. (2000) Immunization with DNA, adenovirus or both in biodegradable alginate microspheres: effect of route of inoculation on immune response. Vaccine 19:253-63
van Olphen, A L; Mittal, S K (1999) Generation of infectious genome of bovine adenovirus type 3 by homologous recombination in bacteria. J Virol Methods 77:125-9
Aggarwal, N; HogenEsch, H; Guo, P et al. (1999) Biodegradable alginate microspheres as a delivery system for naked DNA. Can J Vet Res 63:148-52