Sickle Cell Anemia is one of the most common genetic diseases world-wide, estimated to affect one in 600 new births in African-Americans. Progress in the management of the disease have improved the quality of life in some patients, however a curative treatment is not yet available. With the advent in gene transfer technology, gene therapy is under clinical trial for several genetic and neoplastic diseases. However, more research is needed for gene therapy in sickle cell anemia because it is necessary to insert genes into pluripotent hematopoietic stem cells and to carry a gene that is expressed at a high level to inhibit the sickling process. It is the purpose of this program project to address these problems with a group of complementary projects. Based on recent findings that retroviral infection can be made to be tissue-specific by means of ligand receptor interaction, vectors will be constructed to infect hematopoietic stem cells through interaction with cKit and CD34. As the present retroviral vectors are produced at relatively low titer, novel retroviral vectors with either two to three logs higher titer will be tested. To improve the chance of transducing pluripotent stem cells, retroviral vectors which can integrate into non-dividing cells will be designed. As liposomes can deliver DNA to many cells, this vehicle will also be explored as a means of targeting hematopoietic tissue. To pave the way for future gene therapy protocols, experiments will be performed to determine the best source of hematopoietic stem cell in patients with sickle cell anemia. Since patient trials with various treatment modalities must be preceded by animal experimentation, a concerted effort will be made to produce a mouse model which carries the sickle hemoglobin as the major hemoglobin in the adult. To support these projects are a DNA/viral core, a stem cell core, and an animal core. The program has recruited three pilot projects investigating the transduction of fetal rhesus monkey hematopoietic cells, homologous recombination approach to replace the beta-S globin gene, and drug testing mouse models to increase fetal hemoglobin.
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