Potential Gene Therapy of Sickle Cell Disease and β-Thalassemia

Faculty Mentor

Arun Srivastava, PhD
George H. Kitzman Professor of Genetics
(352) 273-8259

Research Project Description

Human hemoglobinopathies, such as sickle cell disease (SCD) and b-thalassemia, are by far the most common (1 in 600) monogenic diseases worldwide, and are among the likely candidates for their potential treatment provided that pluripotent hematopoietic stem cells (HSCs) can be stably transduced, and long-term, regulated expression of a functional b-globin gene in the erythroid progenitor cells can be achieved. Although lentiviral vectors have been shown to be effective in animal models, their safety remains to be established since clonal expansion in a human clinical trial with a patient with b-thalassemia was reported recently. Thus, we believe that further development of alternative vector systems, such as the adeno-associated virus (AAV), needs to be pursued for their potential ability to achieve high efficiency transduction of HSCs, given the proven safety and efficacy of AAV vectors in clinical trials in gene therapy of Leber’s congenital amaurosis and hemophilia B. We have developed optimized AAV vectors that are capable of high-efficiency transduction in general, and HSCs in particular. Medical students will be involved in using these optimized AAV anti-sickling b-globin vectors in hematopoietic stem cell transplantation and phenotypic correction of SCD in mouse models. Funding for the project is provided by the National Institutes of Health and the George H. Kitzman Endowment.