Dr. Michael Blaese's laboratory continues to work on several long term projects involving both clinical and basic research with studies of the development of gene therapy for treatment of inherited and acquired diseases continues to be the primary focus. Work involves the use of viral and non-viral gene delivery systems for use both ex vivo and in vivo. Major areas of emphasis include study and treatment of primary immunodeficiency diseases including ADA-SCID, X-SCID, Wiskott-Aldrich syndrome and JAK3 deficiency. Clinical trials of gene therapy for ADA-SCID are now in their 6th year and continue to show strong positive results as the first clinical application of this technology. Preclinical development of new vector designs, improved vector packaging, and optimized transduction protocols have all advanced. Preclinical development towards gene therapy of other primary immunodeficiencies has also progressed and now is in animal model testing. Development of a clinical model to permit testing gene therapy strategies for HIV infection has also progressed very well. The availability of sets of identical twins discordant for HIV infection has provided a very powerful tool to assess the potential value of different therapeutic gene modifications of T lymphocytes in providing protection from HIV infection or viral replication. These studies are being used as a screening technique to allow us to choose the best vector designs for full therapeutic trials involving non-twin AIDS patients. The power of gene transfer could potentially provide previously unavailable tools for the treatment of cancer. Issues such as targeted delivery or expression of genes in malignant tissues, choice of the therapeutic gene and optimal vector design have all been major areas of investigation. The herpes simplex thymidine kinase suicide gene system has been explored as the leading approach. With this system, the bystander effect is critical for amplifying the effect of the limited gene transfer achievable with today's technology. We have shown that cell to cell transmission of phosphorylated ganciclovir via gap junctions is the major mechanism underlying the bystander effect so that approaches to augment these structures of cellular metabolic communication also have potential to improve this treatment. New vectors to transfer the TK gene to cancer including E1 deleted adenovirus have been extensively studied in rodent models and preclinical safety testing is underway in preparation for clinical introduction of this second generation suicide-gene treatment strategy.
