Dr. Blaese is Chief of the Clinical Gene Therapy Branch. Work in his laboratory focuses on the use of the gene discoveries of NHGRI and the Genome Project to develop new treatments for a wide range of human diseases. In 1990, he began the first human gene therapy trial with his colleague French Anderson when they used retroviral vectors to transfer a normal ADA cDNA into the peripheral blood T cells of two girls with Severe Combined Immunodeficiency (SCID) caused by an inherited defect in the adenosine deaminase gene. These pioneering patients have experienced reconstitution of their immune systems and are leading essentially normal lives since this treatment was begun. Following up on this initial successful use of genes to treat blood T cells, in 1993 he and his colleague Donald Kohn used the ADA containing retrovirus to treat 3 newborn ADA deficient SCID babies using CD34+ stem cells isolated from their own umbilical cord blood taken at the time of birth. These infants have shown multilineage persistence of the introduced transgene for over 5 years and a selective advantage for gene-corrected T cells as the exogenous PEG-ADA treatment was reduced. Additional patients with ADA deficiency are now being enrolled in studies using new vector designs and improved gene transfer techniques for both T cell and stem cell populations. Dr. Blaese also continues his career-long interest in the study and care of patients with other forms of primary immuno deficiency including specifically the Wiskott-Aldrich syndrome.

In other work, his laboratory has been studying the use of gene transfer for treatment of other genetic diseases as well as for cancer and AIDS. His lab devised the strategy of treating cancer by inserting a "suicide gene," such as herpes thymidine kinase (HS-tk) to sensitize cancer cells to the otherwise benign chemotherapeutic agent ganciclovir. Initially cells producing retroviral vectors were injected directly into the tumor to target gene transfer and an initial clinical trial of this technique in patients with brain tumors has shown hopeful anti-tumor responses in some patients. His lab continues to explore the use of HS-tk and other "suicide genes" for cancer treatment as well as studies to understand the fundamental mechanisms involved in tumor cell destruction including the killing of bystander tumor cells. Major efforts are also underway to develop new viral and non-viral methods of gene transfer to address limitations of the currently available gene delivery techniques. The use of conditionally replication competent viral vectors such as adenovirus and vaccinia are being explored in this context.

The ADA clinical trial has shown that T cells can be successfully used as targets for gene therapy. Thus the tools are available now to begin testing new therapeutic strategies for other T-cell disorders such as AIDS. In collaboration with Richard Morgan of NHGRI and NIAID investigators Robert Walker and Clifford Lane, we have a long-term project to develop gene therapy for AIDS, testing various T-cell gene modifications in vitro and also in a clinical model of cellular and gene therapy using pairs of identical twins discordant for HIV infection. These studies are capable of demonstrating whether various genetic alterations directed at interfering with the life cycle of HIV are capable of prolonging the life of the gene-modified T cells in the bodies of HIV infected patients, hopefully providing rapid insights into new directions for therapeutic intervention in this disease.