In Vivo Hematopoietic Stem Cell Gene Therapy of Beta-Thalassemia and Sickle Cell Disease

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Abstract: Hematopoietic stem cell (HSC) gene therapy could provide a curative treatment for a number of blood diseases. The conventional approach is based on ex vivo HSC gene transfer and has achieved encouraging results. However, the high cost and side effects limit the patient accessibility of ex vivo HSC gene therapy. We have developed an in vivo HSC transduction approach involving HSC mobilization and intravenous viral vector injection. The approach is highlighted by its relatively low cost and technical simplicity. It could be provided as an outpatient treatment. We have demonstrated its safety and efficacy in several murine disease models, including β-thalassemia, Sickle Cell Anemia, and hemophilia A, and more recently, in rhesus macaques. With more gene therapy products on the horizon, the application of in vivo HSC transduction could extrapolate genetic treatments to a larger patient population. Further improvements of in vivo HSC gene therapy on the road to clinical application include more effective mobilization protocols, complete elimination of innate responses upon intravenous vector injection, more advanced virus capsid modifications that circumvent pre-existing anti-vector immunity, improved in vivo selection regimens, as well as new methods for purification of gene transfer vectors. In this application, we will successively test hypotheses to improve in vivo HSC gene therapy approaches for thalassemia and Sickle Cell Disease in mouse models. We will then validate the best combination of improvements in hon-human primates. Safety, efficacy, portability, and low costs are the major driving forces in the design/optimization of each technological unit.