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Alan Davis, PhD

Dr. Alan Davis’s 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 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 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 regidons (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.

Dr. Davis is a member of the Center for Cell and Gene Therapy (CAGT).