Alan Davis, Ph.D.
Department of Pediatrics - Hematology-Oncology
- B.A., University of California, Los Angeles
- Ph.D., University of California, Los Angeles
My research interests are in gene targeting/integration using DNA viruses vectors, particularly adenovirus and adeno-associated virus. The use of adenovirus would be for oncology while adeno-associated virus, for cardiovascular disease.
Use of adenoviruses in gene targeting in cancer. A number of clinical studies are ongoing at our institute and others where adenovirus is used as a vector for delivery of suicide genes such as herpes virus thymidine kinase. In the clinical studies at our institution an adenovirus containing the herpes simplex thymidine kinase placed in the El region, with concomitant deletion in this region is being used in phase I/II studies in mesothelioma and glioma. This vector is used in combination with ganciclovir treatment. One problem with this approach is that extremely large doses of vector are required since these vectors cannot replicate. An alternative approach is to use replicating vectors that can spread through the tumor. However, insurmountable toxicity problems may be encountered in this approach since there is no targeting of the vector. One way to overcome this problem is to replace the El promoter with promoters which are highly active in the tumor tissue that is being targeted. In this way the vector can only replicate in the targeted tissue. The suicide gene can be placed in another region. This approach has been recently suggested for prostate cancer using the prostate-specific antigen promoter. In this approach it will be important to search for promoters that are active in the tumor tissue. Although certain promoters active in many tumors (e.g CEA) may be evaluated, active tumor specific promoters may be uncovered through the hybridization of tumor-specific cDNA to microarrays. In this way mRNAs that are highly and preferentially expressed in the tumor tissue can be uncovered. Finally, if tumor-specific antigens are present their cDNA(s) may be cloned by traditional methods. These genes can be mapped and their upstream regions (promoters) characterized and utilized. Other approaches would use adenovirus vectors, particularly EI/E4 deletions that express cytokines know to kill tumor cells. One of these is beta interferon. Systemic administration of this cytokine is limited because of toxicity. However, local delivery through the use of an EVE4 deleted adenovirus vector with a tissue specific promoter would allow tumor killing.
Use of adeno-associated virus (AAV) vectors in treatment of cardiovascular disease AAV is an integrating vector with increasing potential in gene therapy. Infection by AAV is usually dependent on co-infection with adenovirus. Recently, our group and others have uncovered certain tissues that can be infected by recombinant AAV alone. One of those is muscle. We have also shown, using AAVlacZ, that cardiac muscle can be infected by recombinant AAV and that transgene expression is long term and induces little immune response. Therefore the use of this vector presents an opportunity for treatment of cardiovascular disease. One of these is hypertrophic cardiomyopathy. AAV vectors could be designed to transduce cardiac muscle with troponin T and troponin I that have been shown to be mutated in hypertrophic cardiomyopathy.
- Davis, A. R. and Nayak, D.P. (1977). Expression of endogenous retroviral genes in leukemic guinea pig cells. J . Virol. 23, 263-271.
- Davis, A. R.and Nayak., D.P. (1979). Sequence relationships among influenza defective interfering viral RNA. Proc. Natl. Acad. Sci. USA 76, 3092-3096.
- Davis, A. R., Hiti, A.L., and Nayak, D.P. (1980). Influenza defective interfering viral RNA is formed by internal deletion of genomic RNA. Proc. Natl. Acad. Sci. USA 77, 215-219.
- Davis, A. R., Nayak, D.P., Ueda, M., Hiti, A.L., Dowbenko, and Kleid, D.G. (1981). Expression of antigenic determinants of the hemagglutinin gene of a human influenza virus in Escherichia coli. Proc. Natl. Acad. Sci. USA 78, 5376-5380.
- Nayak, D. P., Sivasubramanian, N., Davis, A.R., Cortini, R., and Sung, J. (1982). Complete sequence analyses show that two defective interfering influenza viral RNAs contain a single internal deletion of a polymerase gene. Proc. Natl. Acad. Sci. USA 79, 2216-2220.
- Roth, M. G., Compans, R.W., Giusti, L., Davis, A.R., Nayak, D.P., Gething, M.J., and Sambrook, J. (1983). Influenza virus hemagglutinin expression is polarized in cells infected with a recombinant SV40 virus carrying a cloned hemagglutinin DNA. Cell 33, 435-443.
- Davis, A. R., Bos, T.B., and Nayak, D.P. (1983). Active influenza virus neuraminidase is expressed in monkey cells from cloned cDNA using simian virus 40 vectors. Proc. Natl. Acad. Sci. USA 80, 3976-3980.
- Davis, A. R., Kostek, B., Mason, B.B., Hsiao, C.L., Morin, J., Dheer, S.K., and Hung, P.P. (1985). Expression of hepatitis-B surface antigen with a recombinant adenovirus. Proc. Natl. Acad. Sci. USA 82, 7560-7564.
- Lubeck, M. D., Davis, A.R., Morin, J.E., Molnar-Kimber, K., Chengalvala, M., Natuk, R., Mason, B.B., Mizutani, S., Hung, P.P., and Purcell, R. H. (1989). Immunogenicity and efficacy testing in chimpanzees of an oral hepatitis B vaccine based upon live recombinant adenovirus. Proc. Natl. Acad. Sci. USA 86, 6763-6767.
- Natuk, R. J., Chanda, P.K., Lubeck, M.D., Davis, A.R., Wilhelm, J., Hjorth, R., Wade, M.S., Bhat, B.M., Mizutani,S., Lee, S., Eichberg, J.W., Gallo, R. C., Robert-Guroff, M., and Hung, P.P. (1992). Adenovirus-human immunodeficiency virus (HIV) envelope recombinant vaccines elicit high-titered HIV-neutralizing antibodies in the dog model. Proc. Natl. Acad. Sci. USA 89, 7777-7781.
- Mauro, L. J., Olmsted, E.A., Skrobacz, B.M., Mourey, R.J., Davis, A.R., and Dixon, J.E. (1994). Identification of a hormonally-regulated protein tyrosine phosphatase associated with bone and testicular differentiation. J. Biol. Chem. 269, 30659-30667.
- Mauro, L. J., Olmsted, E.A., Davis, A.R., and Dixon, J.E. (1996). Parathyroid hormone regulates the expression of the receptor protein tyrosine phosphatase, OST-PTP, in rat osteoblast-like cells. Endocrinology 137, 925-933.
- Eck, S. L., Alavi, A., Davis, A.R., Hackney, D., Judy, K., Mollman, J., Phillips, P.C., Wheeldon, E., and Wilson, J.M. (1996). Treatment of advanced CNS malignancies with the recombinant adenovirus H5.010RSVTK: A Phase I Trial. Human Gene Therapy 7, 1465-1482.
- Treat, J., Kaiser, L.R., Litzky, L., Davis, A.R.,Wilson, J.M., and Albelda, S.M. (1996). Treatment of advanced mesothelioma with the recombinant adenovirus H5.010RSVTK: A Phase I Trial (BB-IND 6274). Human Gene Therapy 7, 2047-2057.
- Davis, A.R. and Wilson, J.M. (1996). Adenovirus Vectors. In Current Protocols in Human Genetics, N. C. Dracopoli, Haines, J.L., Korf, B.R., Muir, D.T., Morton, C.C., Seidman, C.E., Seidman, J.G., and Smith, D.R., ed. (New York: John Wiley and Sons), pp. 12.4-12.4-16.
- Lubeck, M. D., Natuk, R.N., Myagkikh, M., Kalyan, N., Aldrich, K., Sinangil, F., Alipanah, S., Murthy, S.C.S., Chanda, P., Nigada, S., arkham, P.D., Zolla-Pazner, S., Steimer, K., Wade, M., Reitz, M.S., Arthur, L.O., Davis, A.R., Hung, P., Gallo, R.C., Eichberg, J., and (1997). Long-term protection of chimpanzees against high-dose HIV-1 challenge induced by immunization. Nature Medicine 3, 651-658.
- Parry, S. H., Weitzman, M.D., Davis, A.R., Federoff, H., and Strauss, J.F. (1998). Transduction of human trophoblastic cells by replication-deficient recombinant viral vectors: promoting cellular differentiation affects virus entry. Am. J. Pathol. 152, 1521-1529.
- Davis, A.R. and Baker., C. (1998). Production of clinical lots of gene therapy vectors using good manufacturing practices: experience in a university setting. In Clinical Trials of Genetic Therapy with Antisense RNA and DNA Vectors, E. Wickstrom, ed. (New York: Marcel Dekker), pp. 101-111.
- Davis, A. R., Meyers, K., and Wilson, J.M. (1998). High throughput method for creating and screening recombinant adenovirus . Gene Therapy 5, 1148-1152.
- Qin, X.-C., Tao, N., Dergay, A., Moy, P., Fawell, S., Davis, A., Wilson, J.M., and Barsoum, J. (1998). Interferon-beta gene therapy inhibits tumor formation and causes regression of established tumors in immune-deficient mice. Proc. Natl. Acad. Sci. U.S.A. 95, 14411-14416.
- Claudio P.P., Fratta L., Farina F., Howard C.M., Stassi G., Numata S., Pacilio C., Davis A., Lavitrano M., Volpe M., Wilson J.M., Rimarco B., Giordano A., and Condorelli G. Adenoviral RB2/p130 gene transfer inhibits smooth muscle cell proliferation and prevents restenosis after angioplasty. Circ. Res. 85: 1032-1039 (1999).
- Oka, K., Davis, A.R., and Chan, L. Recent advances in liver-directed gene therapy: Implications for the treatment of dyslipidemia. Curr. Opin. Lipidol. 11: 179-186 (2000)
- Olmsted, E.A., Blum, J.S., Rill, D., Yotdna, P., Gugula, Z., Lindsey, R.W., and Davis, A.R. Adenovirus-mediated BMP2 expression in human bone marrow stromal cells. J. Cell. Biochem. 82:11-2 (2001)
- Yotnda, P., Onishi, H., Heslop, H.E., Shayakhmetov, D.M., Lieber, A., Brenner, M.K., and Davis, A.R. Highly efficient transduction of primitive hematopoietic stem cells by modified adenovirus. Gene Therapy 8:930-937 (2001).
- Olmsted-Davis E.A., Gugala Z., Gannon F.H., Yotnda P., McAlhany R.E., Lindsey R.W., and Davis A.R. Use of Chimeric Adenovirus Vector Enhances BMP2 Production and Bone Formation. Human Gene Therapy (In press).
- Maria Rosa Maduro, Elizabeth Davis, Alan Davis, Dolores J. Lamb (2002) Osteotesticular Protein Tyrosine Phosphatase (OST-PTP) Expression in Testis. J Urol 167(5):2282-2283.
- Zbigniew Gugala, Elizabeth A. Olmsted-Davis, Francis H. Gannon, Ronald W. Lindsey, Alan R. Davis (2002) Osteoinduction by Ex Vivo Adenovirus-Mediated BMP2 Delivery Is Independent of Cell Type (Submitted: Bone).