The development of successful gene therapy for sickle cell disease will rely heavily upon animal experimentation in order to establish the clinical feasibility of this approach. These animal models are critical for assessing new approaches for transduction of human hematopoietic stem cells, for evaluating gene therapy approaches for modulating hemoglobin switching, and for designing clinical strategies for the selective amplification of genetically-modified hematopoietic stem cells. Repopulating of non-obese diabetic immunodeficient mice with human hematopoietic cells has proven to be an important assay for human stem cell function. This model system will be used to evaluate various retroviral vectors and transduction pro protocols . This system will also be used to directly evaluate potentially therapeutic vectors by targeting repopulating hematopoietic cells derived directly from normal patients and those with sickle cell anemia. A second system that will be provided by this core is transgenic mice that contain the human beta-globin cluster on a yeast artificial chromosome. These mice provide an in vivo model to study the transcriptional switching of fetal to adult globin synthesis. Various transcription factors and modulators thereof will be studied in this models to determine if fetal globin synthesis can be reactivated in the adult developmental stage. The third model provided by this core is a Rhesus macaque transplant model provided by our collaborators at the National Heart Lung and Blood Institute. This non-human primate model will be utilized to study novel approaches for efficient stem cell gene transfer to evaluate the efficacy of using drug selection to amplify a minority of genetically-altered stem cells (Project 4), and to test various sickle cell therapeutic vectors in a stringent and clinically relevant model. This core provides centralized access to these animal models, and provides standardized assays for evaluating gene transfer endpoints in these systems. Furthermore, the common gene therapy objectives that converge in this core will continue to serve as an important source of collaborative interactions between the investigations in the program project.
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