The purpose of the proposed research is to develop a gene targeting vector as a potential treatment for patients with Beta-hemoglobinopathies, in particular, Sickle Cell Disease (SCD). Since any correction of the mutations responsible for these diseases must maintain the highly coordinated regulation of beta-globin expression, we are investigating the potential of targeted gene replacement via homologous recombination as a therapy, the ultimate goal being the permanent correction of genetic defects in the beta-globin gene, and thus a possible cure for SCD and other globin diseases. A targeting construct capable of undergoing homologous recombination with the defective beta-globin locus will be generated, and will contain a pair of novel high efficiency selectable markers that will allow us to rapidly and efficiently isolate correctly targeted cells by flow cytometry. Phase II studies would be directed towards standardization and optimization of delivery and production for future clinical use. Commercially appealing aspects of this approach are: the high incidence of hemoglobinopathies, the fact that current treatments for these diseases and their numerous complications are ineffective and extremely costly, and the proposed therapy would be economical, quick, safe, free of side-effects and offers the potential for a permanent cure.
A genetic vector capable of targeting, replacing, and thus correcting defective beta-globin genes would provide a highly attractive. cost- effective tool for treating patients with beta -hemoglobinopathies. The rapid and efficient selection of correctly targeted hematopoietic stem cells by flow cytometry would ultimately make it feasible to offer this type of treatment in any out-patient bone marrow transplant setting.
