Arun Srivastava, Ph.D.

Arun Srivastava, Ph.D.Division

Cellular and Molecular Therapy

Academic Title

George H. Kitzman Professor of Genetics and Division Chief

Contact Information

352-273-8259 (phone)
352-273-8342 (fax)
aruns@peds.ufl.edu

Office

Cancer & Genetics Research Complex, Room 492-A

Lab

Cancer & Genetics Research Complex, Rooms 485-G/490-B

Research Overview

For the past over three decades and a half, Dr. Srivastava’s research has been focused on the following two parvoviruses, the non-pathogenic adeno-associated virus (AAV), and a common human pathogen, the parvovirus B19, and the development of recombinant parvovirus vectors for human gene therapy. His laboratory has made seminal contributions to the field of parvoviruses, which include: identification of cellular co-receptors for AAV as well as parvovirus B19; elucidation of various steps involved in parvovirus trafficking in the cell and nuclear transport; identification of cellular proteins involved in the regulation of AAV DNA replication and encapsidation; development of recombinant AAV and parvovirus B19 vectors; transgenic and knockout mouse models to study parvovirus-induced pathogenicity, and the use of parvovirus vectors for gene transfer and gene therapy. Parvovirus-based vectors have gained attention as a useful alternative for human gene therapy. The stable integration of the AAV genome, and the erythroid cell tropism of B19 have been exploited to construct the following two types of AAV-B19 hybrid vectors. Type I vectors allow stable integration of the viral DNA in infected cells but the viral gene expression occurs predominantly in the erythroid progenitor cells. Type II vectors allow efficient erythroid progenitor cell-specific gene delivery as well as expression of transduced genes. However, it has become increasingly clear that the full potential of the first generation of AAV vectors is unlikely to be realized. For example, AAV vectors composed of the naturally occurring capsids trigger a host immune response, especially at high doses, since specific surface-exposed amino acid residues on the naked icosahedral capsids are readily targeted by the host cell machinery. Furthermore, the AAV genome is a single-stranded DNA, which is transcriptionally-inactive, and thus negatively impacts the transduction efficiency of the first generation of AAV vectors. During the past decade, strategies have been developed in Dr. Srivastava’s laboratory that circumvent both of these problems associated with the first generation of AAV vectors. For example, specific surface-exposed amino acid residues on the AAV capsids have been modified to develop the next generation (‘NextGen’) AAV vectors that are significantly more efficient, and are less immunogenic. The single-stranded AAV genome has also been modified to develop generation X (‘GenX’) AAV vectors with which enhanced transgene expression can be achieved. The combination of the NextGen and the GenX vectors has resulted in the development of optimized (‘Opt’) AAV vectors that are more efficient at further reduced doses. The current emphasis is on developing recombinant parvovirus vectors for gene therapy/gene editing of genetic diseases such as beta-thalassemia and sickle cell disease, and gene therapy of malignant disorders such as hepatoblastoma and hepatocellular carcinoma.

About

Dr. Srivastava is George H. Kitzman Professor of Genetics and Chief of Division of Cellular & Molecular Therapy in the Departments of Pediatrics, and Molecular Genetics & Microbiology, and Powell Gene Therapy Center. He received his Ph.D. degree from the Indian Institute of Science in Bangalore, India. After completing his postdoctoral training at the Memorial Sloan-Kettering Cancer Center in New York, he worked as a Research Associate at the University of Florida. For nearly two decades, he was on the faculty at Indiana University School of Medicine in Indianapolis, where he rose to the rank of Professor. He was recruited back to the University of Florida in 2004. He has mentored 10 Clinical Fellows and 41 Postdoctoral Fellows. Two students have graduated with MS degrees, and 13 students have received their PhD degrees from his laboratory. His research activities are currently supported by grants from the National Institutes of Health. He has also been awarded 5 US Patents on his research on human parvoviruses and their potential use as vectors in human gene therapy. He has served on several NIH Study Sections, and he also serves on the Editorial Boards of Gene Therapy and Molecular Biology, Journal of Virology, Human Gene Therapy, Recent Patents on DNA and Gene Sequences, Journal of Integrative Medicine, and as an Executive Editor of the Journal of Genetic Syndromes and Gene Therapy. He was appointed as Honorary Professor and Advisor, Shenzhen Institute of Xiangya Biomedicine, Central South University, Shenzhen, PR China, and University of Florida Research Foundation Professor, and Children’s Miracle Network Scholar. More recently, he was named the University of Florida Team Professor.

Key Publications

Dr. Srivastava has published 189 research articles, mostly on human parvoviruses, in peer-reviewed journals, reviews, and book chapters. Selected publications are listed below. Additional publications can be found in PubMed.

  1. Markusic, T.C. Nichols E.P. Merricks, B. Palaschak, I. Zolotukhin; D. Marsic; S. Zolotukhin, A. Srivastava, and R.W. Herzog. Evaluation of engineered AAV capsids for hepatic factor IX gene transfer in murine and canine models. J. Trans. Medicine, in press, 2017.
  1. L. Rogers, J. Shirley, I. Zolotukhin, S. Kumar, A. Sherman, G. Q. Perrin, B.E Hoffman, A. Srivastava, E. Basner-Tschakarjan, M. Wallet, C. Terhorst, M. Biswas, and R.W. Herzog. Plasmacytoid and conventional dendritic cells cooperate to cross-prime AAV capsid-specific CD8+ T cells. Blood, in press, 2017.
  1. Li, Y. Tang, L. Wu, F. Mo, X. Wang, H. Li, R. Qi, H. Zhang, A. Srivastava, and C. Ling. Hepatocyte-specific HNF4α/miR-122 pathway contributes to the iron-overload mediated hepatic inflammation. Blood, in press, 2017.
  1. Chen, K. Maeng, A. Nawab, R.A. Francois, J.K. Bray, M.K. Reinhard, S.L. Boye, W.W. Hauswirth, F.J. Kaye, G.V. Aslanidi, A. Srivastava, and M. Zajac-Kaye. Efficient gene delivery and Expression in pancreas and pancreatic tumors by capsid-optimized AAV8 Vectors. Human Gene Therapy Methods. Feb;28(1):49-59. doi: 10.1089/hgtb.2016.089.
  1. Srivastava. Advances and challenges in the use of recombinant adeno-associated virus vectors for human gene therapy. Cell & Gene Therapy Insights, 553-575, 2016.
  1. Srivastava, and B.J. Carter. AAV Infection: Protection from Cancer. Human Gene Therapy, Apr;28(4):323-327, 2016.
  1. Srivastava. Adeno-associated virus: The naturally occurring virus versus the recombinant vector. Human Gene Therapy, 27: 1-6, 2016.
  1. 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.
  1. Srivastava. In vivo tissue-tropism of adeno-associated viral vectors. Curr. Opin. Virology, 21C: 75-80, 2016.
  1. Ling, B. Li, W. Ma, and A. Srivastava. Development optimized AAV serotype vectors for high-efficiency transduction at further reduced doses. Hum. Gene Therapy Methods, 27: 143-149, 2016.
  1. Ling, Z. Yin, J. Li, D. Zhang, G. Aslanidi, and A. Srivastava. Strategies to generate high-titer, high-potency recombinant AAV3 serotype vectors. Mol. Ther. Methods & Clin. Dev., 3:16029, 2016.
  1. Vercauteren, B.E. Hoffman, I. Zolotukhin, J.W.  Xiao, E. Basner-Tshakarjan, K.A. High, H.C.J. Ertl, C.M. Rice, A. Srivastava, Y.P. de Jong, and R.W. Herzog. Superior in vivo transduction of human hepatocytes using engineered AAV3 capsid. Molecular Therapy, 24: 1042-1049, 2016.
  1. Li, W. Ma, G.V. Aslanidi, C. Ling, K.V. Vliet, L.-y. Huang, M. Agbandje-McKenna, A. Srivastava, and G.A. Aslanidi. Site-directed mutagenesis of surface-exposed lysine residues leads to high-efficiency transduction by recombinant AAV2, but not AAV8 vectors. Hum. Gene Therapy Methods, 26: 211-220, 2015. 
  1. Li, C. Ling, L. Zhong, M. Li, Q. Su R. He, Q. Tang, D.L. Greiner, L.D. Shultz, M.A. Brehm, T.R. Flotte, C. Mueller, A. Srivastava, and G. Gao. Efficient and targeted transduction of nonhuman primate liver with systemically delivered optimized AAV3B vectors.  Molecular Therapy, 23: 1867-1876, 2015.
  1. Ling, Y. Wang, Y. Lu, L. Wang, G.R. Jayandharan, G.V. Aslanidi, B. Li, B. Cheng, W. Ma, T. Lentz, C. Ling, X. Xiao, R.J. Samulski, N. Muzyczka, and A. Srivastava. The adeno-associated virus genome packaging puzzle. J. Mol. Genet. Medicine, 9: 3, 1000178, 2015.
  1. Ling, Y. Wang, Y.L. Feng, Y.N. Zhang, J. Li, X.R. Hu, L.N. Wang, M.F. Zhong, X.F. Zhai, I. Zolotukhin, A. Srivastava, and C.Q. Ling. Prevalence of neutralizing antibodies against liver-tropic adeno-associated virus serotype vectors in 100 healthy Chinese and its potential relation to body constitutions. J. Int. Medicine, 13: 341-346, 2015.
  1. Wang, Z. Yin, Y. Wang, Y. Lu, D. Zhang, G.V. Aslanidi, A. Srivastava, C. Ling, and C. Ling. Productive life cycle of the adeno-associated virus serotype 2 in the complete absence of a conventional polyadenylation signal. J. Gen. Virology, 96, 2780–2787, 2015.
  1. Ling, Y. Wang, Y. Lu, L. Wang, G.R. Jayandharan, G.V. Aslanidi, B. Li, B. Cheng, W. Ma, T. Lentz, C. Ling, X. Xiao, R.J. Samulski, N. Muzyczka, and A. Srivastava. Enhanced transgene expression from recombinant single-stranded AAV vectors in human cell lines in vitro and in murine hepatocytes in vivo. J. Virology, 89: 952-961, 2015. 
  1. Zhang, L, Wang, Y. Lu, G.V. Aslanidi, A. Srivastava, C. Ling, and C. Ling. Cytotoxic genes from traditional Chinese medicine inhibit tumor growth both in vitro and in vivo. J. Int. Medicine, 12: 483-494, 2014.
  1. Ling, Y. Wang, Y. Zhang, A. Ejjigani, Z. Yin, Y. Lu, L. Wang, M. Wang, J. Li, Z. Hu, G.V. Aslanidi, L. Zhong, G. Gao, A. Srivastava, and C. Ling. Selective in vivo targeting of human liver tumors by optimized recombinant AAV3 vectors in a murine xenograft model.  Human Gene Therapy, 25: 1023-1034, 2014.
  1. -J. Chen, Y. Lu, K.E. Erger, T.J. Conlon, E. Ahmed, L. Hong, M.L. Brantly, A. Srivastava, W.W. Hauswirth, N. Terada, C. Yao, T. Hamazaki, and S. Song. Reprogramming adipose tissue derived mesenchymal stem cells (AT-MSCs) into pluripotent stem cells by a mutant AAV vector. Hum. Gene Therapy Methods, 25: 72-82, 2014.
  1. Wang, L. Wang, Z. Yin Y. Zhang, G.V. Aslanidi, A. Srivastava, C. Ling and C. Ling. Pristimerin enhances recombinant adeno-associated virus serotype 2 vector-mediated hepatocyte transgene expression both in vitro and in vivo. J. Integrative Medicine, 12: 20-34, 2014. 
  1. Song L, M.A. Kauss, M. Chandra, E. Kopin, G.R. Jayandharan, E. Miller, 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 vivoCytotherapy, 15: 986-998, 2013.
  1. 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.
  1. Song L, M.A. Kauss, M. Chandra, E. Kopin, G.R. Jayandharan, E. Miller, 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 vivoCytotherapy, 15: 986-998, 2013.
  1. V. Aslanidi, A.E. Rivers, L. Ortiz, C. L. Song, L. Govindasamy, M. Tan, M. Agbandje-McKenna, and A. Srivastava. Optimization of recombinant AAV2 vectors for gene therapy: The final threshold? PLoS One, 8(3): e59142, 2013.
  1. R. Jayandharan, G.V. Aslanidi, A.T. Martino, S.C. Jahn, G.Q. Perrin, R.W. Herzog, and A. Srivastava. Activation of the NF-κB pathway by AAV vectors and its implications in immune response and gene therapy.  Proc. Natl. Acad. Sci., USA, 108: 3743-3748, 2011.
  1. Zhong, B. Li, C.S. Mah, L. Govindasamy, M. Agbandje-McKenna, M.A. Cooper, R.W. Herzog, I. Zolotukhin, K.H. Warrington, Jr., K.A. Weigel-Van Aken, J.A. Hobbs, S. Zolotukhin, N. Muzyczka, and A. Srivastava. Next generation of adeno-associated virus 2 vectors: Point mutations in tyrosines lead to high-efficiency transduction at reduced doses. Proc. Natl. Acad. Sci., USA, 105: 7827-7832, 2008.
  1. A. Weigel-Kelley, M.C. Yoder and A. Srivastava. a5b1 integrin as a cellular co-receptor for human parvovirus B19: Requirement of b1 integrin activation for viral entry. Blood, 102: 3927-3933, 2003.
  2. K.Y. Qing, C. Mah, J. Hansen, S.Z. Zhou, V.J. Dwarki and A. Srivastava. Human fibroblast growth factor receptor 1 is a co-receptor for infection by adeno-associated virus 2. Nature Medicine, 5: 71-77, 1999.