The goal of this proposal is to develop methods by which genetically modified hematopoietic cells can be selectively expanded and in so doing treat patients with sickle cell anemia. The investigators have demonstrated that chemical inducers of dimerization (CIDs) can selectively direct proliferation of transduced cells that express a fusion protein containing a CID binding domain linked to the intracellular portion of the thrombopoietin receptor, mpl. Their recent studies have shown that CID-mediated activation of the mpl fusion protein can direct expansion of genetically modified primary hematopoietic cells in vitro and in vivo. Using a retroviral vector that incorporates both a therapeutic globin cassette as well as a gene encoding the mpl fusion protein, they aim to specifically expand genetically corrected blood cells in vivo, and in the process make gene therapy safer and more effective. It is their intention to develop methods that will lead to a clinical trial in which patients with hemoglobinopathies will have their peripheral blood stem cells collected, transduced with a therapeutic vector, reinfused, followed by selective expansion of the corrected blood cells. These studies will be accomplished with the aid of the unique resources of the recently instituted Gene and Cell Therapy Laboratory at the UW Medical Center (UWMC).
Their aims are as follows: 1) Develop methods for mobilization and collection of hematopoietic stem cells from patients with sickle cell disease. 2) Test whether CIDs can be used to selectively expand bone marrow progenitor cells transduced with a vector that encodes a humanized fusion protein and a (beta-like globin. 3) Test in vivo selection of genetically modified hematopoietic cells in a xenogeneic transplant model. 4) Develop necessary procedures for cell collection and transduction prior to initiating a clinical gene therapy trial in the hemoglobinopathies. At the conclusion of the above listed specific aims they will have developed a unique clinical reagent that will be ready for gene therapy trials. These goals are attainable given the unique facilities that are now available at the UW GCRC.
| Taylor, Jason A; Vojtech, Lucia; Bahner, Ingrid et al. (2008) Foamy virus vectors expressing anti-HIV transgenes efficiently block HIV-1 replication. Mol Ther 16:46-51 |
| Richard, Robert E; Siritanaratkul, Noppadol; Jonlin, Erica et al. (2005) Collection of blood stem cells from patients with sickle cell anemia. Blood Cells Mol Dis 35:384-8 |
| Richard, Robert E; De Claro, R Angelo; Yan, James et al. (2004) Differences in F36VMpl-based in vivo selection among large animal models. Mol Ther 10:730-40 |
