Gene therapy-related research in my laboratory is directed toward the optimization of gene transfer methodology for genetic modification of human hematopoietic stem cells and the development of novel gene-based therapeutic strategies to treat cancer.
Although retroviral vectors based on Moloney murine leukemia virus (MoMLV) are currently the vehicles of choice for somatic cell gene therapy applications, a problem frequently associated with these vectors is that of sustained in vivo gene expression. In an attempt to circumvent this problem, my laboratory developed a highly transmissible retroviral vector (designated MSCV for murine stem cell virus) containing modifications shown to cooperatively enable transcription of MoMLV in embryonic stem cells. Recombinant MSCV vectors have subsequently proven to be superior in their capacity to deliver functional copies of exogenous genes to the murine hematopoietic system and are now in use in almost 150 laboratories worldwide, including those of a number of pharmaceutical and biotechnology companies. In addition, initial reports of successful transduction of human hematopoietic progenitors with functional MSCV-based viruses have prompted several investigators in the United States and Canada to take MSCV vectors into clinical trials.
Another major area of gene therapy-related research currently underway in the laboratory involves a malignancy of immune cells, multiple myeloma, which is characterized by the accumulation of terminally differentiated B lymphocytes (neoplastic plasma cells called myeloma cells) in the bone marrow. Because there is no cure for multiple myeloma, we have established a murine model of the disease and are employing MSCV retroviral vectors expressing interleukin-12 (a cytokine with potent anticancer effects on solid tumours) and the costimulatory molecule B7-1 to assess the potential of this "modified paracrine cytokine" approach as adjuvant treatment for multiple myeloma patients undergoing bone marrow transplantation following high dose chemo-radiotherapy. The results of this "cancer vaccine" strategy are anticipated to lay the foundation for the rational design of a clinical protocol for multiple myeloma (as well as other hematologic malignancies) in collaboration with Dr. Keith Stewart, the medical director of The Toronto Hospital Oncology Gene Therapy Program.
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