This 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 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 8th year. Development of new vector designs, improved vector packaging, and optimized transduction protocols have all advanced allowing the institution of a 2nd generation gene therapy protocol for ADA. 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 have conclusively shown that even immunodeficient patients are capable of becoming immune to an expressed foreign transgene (neo) as well as to bovine serum proteins used to supplement tissue culture production of vector and cells. 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 todays 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 t o improve this treatment. Transfer of the TK gene to cancer using an E1 deleted adenovirus have been extensively studied in rodent models demonstrating an additional iimmunologic bystander effecti with this system. A second generation clinical suicide-gene protocol treating malignant melanoma with Ad-tk and increaseing ganciclovir dosing will begin 4th Q 1998.
