Alan Davis, Ph.D.
Department of Pediatrics
Section of Hematology-Oncology
Baylor College of Medicine
Ph.D., University of California, Los Angeles, CA
Dr. Davis' 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 mesothelloma and glioma. This vector is used in combinationwith 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 tumorspecific 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 recombiant 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.
- Gugala Z, Olmsted-Davis EA, Gannon FH, Lindsey RW, Davis AR. Osteoinduction by ex vivo adenovirus-mediated BMP2 delivery is independent of cell type. Gene Ther. 2003 Aug;10(16):1289-96.
- Maduro MR, Davis E, Davis A, Lamb DJ. Osteotesticular protein tyrosine phosphatase expression in rodent testis. J Urol. 2002 May;167(5):2282-3.
- Olmsted-Davis EA, Gugala Z, Gannon FH, Yotnda P, McAlhany RE, Lindsey RW, Davis AR. Use of a chimeric adenovirus vector enhances BMP2 production and bone formation. Hum Gene Ther. 2002 Jul 20;13(11):1337-47.
- Olmsted EA, Blum JS, Rill D, Yotnda P, Gugala Z, Lindsey RW, Davis AR. Adenovirus-mediated BMP2 expression in human bone marrow stromal cells. J Cell Biochem. 2001 Apr 2-27;82(1):11-21.
- Yotnda P, Onishi H, Heslop HE, Shayakhmetov D, Lieber A, Brenner M, Davis A. Efficient infection of primitive hematopoietic stem cells by modified adenovirus. Gene Ther. 2001 Jun;8(12):930-7.
- Oka K, Davis AR, Chan L. Recent advances in liver-directed gene therapy: implications for the treatment of dyslipidemia. Curr Opin Lipidol. 2000 Apr;11(2):179-86.
- Claudio PP, Fratta L, Farina F, Howard CM, Stassi G, Numata S, Pacilio C, Davis A, Lavitrano M, Volpe M, Wilson JM, Trimarco B, Giordano A, Condorelli G. Adenoviral RB2/p130 gene transfer inhibits smooth muscle cell proliferation and prevents restenosis after angioplasty. Circ Res. 1999 Nov 26;85(11):1032-9.
- Howard DS, Rizzierri DA, Grimes B, Upchurch D, Phillips GL, Stewart AK, Yannelli JR, Jordan CT. Genetic manipulation of primitive leukemic and normal hematopoietic cells using a novel method of adenovirus-mediated gene transfer. Leukemia. 1999 Oct;13(10):1608-16.
- Davis AR, Meyers K, Wilson JM. High throughput method for creating and screening recombinant adenoviruses. Gene Ther. 1998 Aug;5(8):1148-52.
- Parry S, Holder J, Halterman MW, Weitzman MD, Davis AR, Federoff H, Strauss JF 3rd. Transduction of human trophoblastic cells by replication-deficient recombinant viral vectors. Promoting cellular differentiation affects virus entry. Am J Pathol. 1998 Jun;152(6):1521-9.
- Qin XQ, Tao N, Dergay A, Moy P, Fawell S, Davis A, Wilson JM, Barsoum J. Interferon-beta gene therapy inhibits tumor formation and causes regression of established tumors in immune-deficient mice. Proc Natl Acad Sci U S A. 1998 Nov 24;95(24):14411-6.
- Lubeck MD, Natuk R, Myagkikh M, Kalyan N, Aldrich K, Sinangil F, Alipanah S, Murthy SC, Chanda PK, Nigida SM Jr, Markham PD, Zolla-Pazner S, Steimer K, Wade M, Reitz MS Jr, Arthur LO, Mizutani S, Davis A, Hung PP, Gallo RC, Eichberg J, Robert-Guroff M. Long-term protection of chimpanzees against high-dose HIV-1 challenge induced by immunization. Nat Med. 1997 Jun;3(6):651-8.
- Eck SL, Alavi JB, Alavi A, Davis A, Hackney D, Judy K, Mollman J, Phillips PC, Wheeldon EB, Wilson JM. Treatment of advanced CNS malignancies with the recombinant adenovirus H5.010RSVTK: a phase I trial. Hum Gene Ther. 1996 Aug 1;7(12):1465-82.
- Mauro LJ, Olmsted EA, Davis AR, Dixon JE. Parathyroid hormone regulates the expression of the receptor protein tyrosine phosphatase, OST-PTP, in rat osteoblast-like cells. Endocrinology. 1996 Mar;137(3):925-33.
- Treat J, Kaiser LR, Sterman DH, Litzky L, Davis A, Wilson JM, Albelda SM. Treatment of advanced mesothelioma with the recombinant adenovirus H5.010RSVTK: a phase 1 trial (BB-IND 6274). Hum Gene Ther. 1996 Oct 20;7(16):2047-57.
- Mauro LJ, Olmsted EA, Skrobacz BM, Mourey RJ, Davis AR, Dixon JE. Identification of a hormonally regulated protein tyrosine phosphatase associated with bone and testicular differentiation. J Biol Chem. 1994 Dec 2;269(48):30659-67.
- Natuk RJ, Chanda PK, Lubeck MD, Davis AR, Wilhelm J, Hjorth R, Wade MS, Bhat BM, Mizutani S, Lee S, et al. Adenovirus-human immunodeficiency virus (HIV) envelope recombinant vaccines elicit high-titered HIV-neutralizing antibodies in the dog model. Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7777-81.
- Lubeck MD, Davis AR, Chengalvala M, Natuk RJ, Morin JE, Molnar-Kimber K, Mason BB, Bhat BM, Mizutani S, Hung PP, et al. Immunogenicity and efficacy testing in chimpanzees of an oral hepatitis B vaccine based on live recombinant adenovirus. Proc Natl Acad Sci U S A. 1989 Sep;86(17):6763-7.
- Davis AR, Kostek B, Mason BB, Hsiao CL, Morin J, Dheer SK, Hung PP. Expression of hepatitis B surface antigen with a recombinant adenovirus. Proc Natl Acad Sci U S A. 1985 Nov;82(22):7560-4.
- Davis AR, Bos TJ, Nayak DP. Active influenza virus neuraminidase is expressed in monkey cells from cDNA cloned in simian virus 40 vectors. Proc Natl Acad Sci U S A. 1983 Jul;80(13):3976-80.
- Roth MG, Compans RW, Giusti L, Davis AR, Nayak DP, Gething MJ, Sambrook J. Influenza virus hemagglutinin expression is polarized in cells infected with recombinant SV40 viruses carrying cloned hemagglutinin DNA. Cell. 1983 Jun;33(2):435-43.
- Nayak DP, Sivasubramanian N, Davis AR, Cortini R, Sung J. Complete sequence analyses show that two defective interfering influenza viral RNAs contain a single internal deletion of a polymerase gene. Proc Natl Acad Sci U S A. 1982 Apr;79(7):2216-20.
- Davis AR, Nayak DP, Ueda M, Hiti AL, Dowbenko D, Kleid DG. Expression of antigenic determinants of the hemagglutinin gene of a human influenza virus in Escherichia coli. Proc Natl Acad Sci U S A. 1981 Sep;78(9):5376-80.
- Davis AR, Hiti AL, Nayak DP. Influenza defective interfering viral RNA is formed by internal deletion of genomic RNA. Proc Natl Acad Sci U S A. 1980 Jan;77(1):215-9.
- Davis AR, Nayak DP. Sequence relationships among defective interfering influenza viral RNAs. Proc Natl Acad Sci U S A. 1979 Jul;76(7):3092-6.
- Davis AR, Nayak DP. Expression of endogenous retroviral genes in leukemic guinea pig cells. J Virol. 1977 Aug;23(2):263-71.