Arun Srivastava, PhD
George H. Kitzman Professor of Genetics
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.
- Tan, K. Qing, S. Zhou, M.C. Yoder, and A. Srivastava. Adeno-associated virus 2-mediated transduction and erythroid lineage-restricted long-term expression of the human b-globin gene in hematopoietic cells from homozygous b-thalassemic mice. Molecular Therapy, 3: 940-946, 2001.
- Maina, L. Zhong, X.Li, W. Zhao, Z. Han, D. Bischof, G, Aslanidi, S, Zolotukhin, K. Weigel-Van Aken, A. Rivers, W.B. Slayton, M.C. Yoder, and Srivastava, A. Optimization of recombinant adeno-associated virus serotype vectors for human b-globin gene transfer and transgene expression. Human Gene Therapy, 19: 365-375, 2008.
- Song, M.A. Kauss, E. Kopin, M. Chandra, T. Ul-Hasan, E. Miller, G.R. Jayandharan, A.E. Rivers, G.V. Aslanidi, C. Ling, B. Li, W. Ma, X. Li, L.M. Andino, L. Zhong, A.F. Tarantal, M.C.Yoder, K.K. Wong, Jr., M. Tan, S. Chatterjee, and A. Srivastava. Optimizing the transduction efficiency of capsid-modified AAV6 vectors in primary human hematopoietic stem cells in vitro and in a xenograft mouse model in vivo. Cytotherapy, 15: 986-998, 2013.
- Song, X. Li, G.R. Jayandharan, Y. Wang, G.V. Aslanidi, C. Ling, L. Zhong, G. Gao, M.C. Yoder, C. Ling, M. Tan, and A. Srivastava. High-efficiency transduction of primary human hematopoietic stem cells and erythroid lineage-restricted expression by optimized AAV6 serotype vectors in vitro and in a murine xenograft model in vivo. PLoS One, 8(3): e58757, 2013.
- Ling, K. Bhukhai, Z. Yin, M.Q. Tan, M.C. Yoder, P. Leboulch, E. Payen, and A. Srivastava. High-efficiency transduction of primary human CD34+ hematopoietic stem/progenitor cells by AAV6 serotype vectors: Strategies for overcoming donor-variation and implications in genome editing. Scientific Reports, 6, 35495, 2016.
- Yang, K. Qing, G.D. Keeler, L. Yin, M. Mietzsch, C. Ling, B.E. Hoffman, M. Agbandje-McKenna, M. Tan, W. Wang, and A. Srivastava. Enhanced transduction of human hematopoietic stem cells by AAV6 vectors: Implications in gene therapy and genome editing. Molecular Therapy-Nucleic Acids. under review, 2020.