Michael Blaese's laboratory continues to focus on the development of gene therapy. He led the group which performed the first authorized use of gene transfer to treat human disease when they infused autologous ADA gene-corrected T cells into two girls with ADA deficiency SCID. Retroviral vectors were used to insert a normal human ADA gene into polyclonal peripheral blood T cells which had been stimulated in tissue culture with an anti-T cell receptor monoclonal antibody and IL-2. The gene-corrected T cells were culture expanded and then returned intravenously within 2 weeks to maintain a polyclonal repertoire. These ADA deficient patients have been treated 10-12 times over the past three years with such gene-corrected T cell infusions and are now each showing signs of reconstituted immune reactivity including the production of isohemagglutinins and DTH in response to environmental antigenic stimulation. As the next phase in the development of this treatment, Dr. Blaese and his colleagues have used retroviral-mediated gene- transfer to insert a corrective ADA gene into CD34 selected lymphohematopoietic stem cells. GM-CSF was used to mobilize stem cells into the peripheral blood in a 12-year-old with ADA deficiency. Further, umbilical cord blood was used as a stem cell source in three newborn infants who have been diagnosed with ADA deficiency in utero. In these four cases, the gene-corrected cells were returned intravenously on Day 3. Dr. Blaese's laboratory has also developed a unique new approach to direct gene therapy of cancer using inoculation of murine fibroblasts producing retroviral vectors directly into tumors in situ. Using vectors containing the gene for herpes simplex thymidine kinase, he has shown cure of brain tumors in rats following systemic administration of the anti-herpes virus drug, ganciclovir. This antitumor effect was shown to be aided by a """"""""bystander effect"""""""" in which phosphorylate ganciclovir is transmitted from tk-gene containing tumor cells to neighboring unmodified tumor cells through """"""""gap junctions"""""""" extending delivery of toxin widely in the treated tumors.
