Our work has focused on bringing retroviral gene transfer techniques developed in the Clinical Hematology Branch into clinical applications targeting human hematopoietic stem cells. We have shown that clinical- grade retroviral supernatants can efficiently infect bone marrow and peripheral blood hematopoietic progenitor cells and long-term culture initiating cells as assayed in vitro. Based on this preclinical experience, we have received permission to incorporate three clinical gene marking studies into autologous stem cell transplantation protocols for multiple myeloma, CML, and breast cancer. Seven patients have received genetically-manipulated cells back thus far. 3/4 analyzed thus far post-transplant show evidence of marked hematopoietic cells. Further analysis of these and subsequent patients will allow us to answer important questions regarding the feasibility and efficiency of gene transfer to hematopoietic stem cells, characteristics of autologous engraftment from bone marrow versus peripheral blood sources, and mechanisms of relapse post-transplantation. Based on the data we are generating in breast cancer patients and murine and primate animal data, we are proposing a therapeutic protocol for breast cancer patients involving transfer of the multidrug-resistance gene to autologous marrow to confer chemoprotection. We have also collaborated on the extension of the human ADA gene therapy protocol to peripheral blood stem cells and cord blood cells in hopes of curing children with SCIDS with one gene- corrected cell infusion instead of multiple T-cell infusions. One child recently received gene-corrected peripheral blood CD34+ cells, and two newborns received transduced CD34+ cord blood cells. A third major focus is treatment of Gaucher disease with stem cell gene therapy. In the murine model and in human cells in vitro we can demonstrate transfer and expression of the glucocerebrosidase gene in target macrophages. We have also been exploring transplant of bone marrow and peripheral blood cells into nonablated recipients, a critical component for gene therapy of any genetic disease. Based on this data, we have permission to begin a clinical trial for Gaucher disease this fall.
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