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, Molecular Genetics & Microbiology, and Powell Gene Therapy Center. He received his PhD 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 35 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 18 US Patents on his research on human parvoviruses and their potential use as vectors for 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, University of Florida Research Foundation Professor, and Children’s Miracle Network Scholar. More recently, he was named the University of Florida Term 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. A. Srivastava. AAV: From almost a virus to an awesome vector. https://www.openaccessgovernment.org/aav-from-almost-a-virus-to-an-awesome-vector-for-human-gene-therapy/41720/, 2018.
  2. A. Srivastava. The AAV Club: Applying AAV vectors to gene therapy, Scientia, 114: 88-91, 2017 (http://www.scientia.global/wp-content/uploads/2017/08/Arun-Srivastava.pdf)
  3. D.M. 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. Journal of Translation Medicine, 15: 94, 2017.
  4. G.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, 129: 3184-3195, 2017.
  5. M 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, 130: 1041-1051, 2017.
  6. A. Srivastava. Advances and challenges in the use of recombinant adeno-associated virus vectors for human gene therapy. Cell & Gene Therapy Insights, 553-575, 2016.
  7. A. Srivastava, and B.J. Carter. AAV Infection: Protection from Cancer. Human Gene Therapy, 28: 323-327, 2016.
  8. A. Srivastava. Adeno-associated virus: The naturally occurring virus versus the recombinant vector. Human Gene Therapy, 27: 1-6, 2016.
  9. C. 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.
  10. K. 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.
  11. S. 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.
  12. C. 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. Journal of Virology, 89: 952-961, 2015.
  13. C. 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.
  14. L. 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.
  15. G.V. Aslanidi, A.E. Rivers, L. Ortiz, C. Ling, 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.
  16. A.T. Martino, E. Basner-Tschakarjan, D.M. Markusic, J. Finn, C. Hinderer, S. Zhou, D.A. Ostrov, A. Srivastava, H.C.J. Ertl, C. Terhorst, K.A. High, F. Mingozzi, and R.W. Herzog. Engineered AAV vector minimizes in vivo targeting of transduced hepatocytes by capsid-specific CD8+ T cells.  Blood, 121: 2224-33, 2013.
  17. B. Cheng, C. Ling, Y. Dai, L.G. Glushakova, Y. Lu, S.W.Y. Gee, K.E. McGoogan, G.V. Aslanidi, M. Park, P.W. Stacpoole, D. Siemann, C. Liu, A. Srivastava, and C. Ling. Development of optimized AAV3 serotype vectors: Mechanism of high-efficiency transduction of human liver cancer cells. Gene Therapy, 19: 375-384, 2012.
  18. J. Silver, M. Elder, T. Conlon, P. Cruz, A. Wright, A. Srivastava, and T.R. Flotte. Recombinant AAV-mediated gene transfer for the potential therapy of adenosine deaminase-deficient severe combined immune deficiency. Human Gene Therapy, 22: 935-949, 2011.
  19. H. Petrs-Silva, A. Dinculescu, Q. Li, W. Deng, J.-J. Pang, S.-H. Min, V. Chiodo, A.W. Neely, L. Govindasamy, A. Bennett, M. Agbandje-McKenna, L. Zhong, B. Li, G.R. Jayandharan, A. Srivastava, A.S. Lewin, and W.W. Hauswirth. Novel properties of tyrosine-mutant AAV2 vectors in the mouse retina.  Molecular Therapy, 19: 293-301, 2011.
  20. C. Ling, Y. Lu, J. Kalsi, G.R. Jayandharan, B. Li, W. Ma, B. Cheng, S. Gee, K. McGoogan, L. Zhong, L. Govindasamy, M. Agbandje-McKenna, and A. Srivastava. Hepatocyte growth factor receptor is a cellular coreceptor for adeno-associated virus 3.  Human Gene Therapy, 21: 1741-1747, 2010.
  21. M. Li, G.R. Jayandharan, B. Li, W. Ma, C. Ling, A. Srivastava, and L. Zhong.  High-efficiency transduction of fibroblasts and mesenchymal stem cells by tyrosine-mutant AAV2 vectors for their potential use in cellular therapy. Human Gene Therapy, 21: 1527-1543, 2010.
  22. D. Markusic, R.W. Herzog, G. Aslanidi, B. Hoffman, B. Li, M. Li, G.R. Jayandharan, C. Ling, I. Zolotukhin, W. Ma, S. Zolotukhin, A. Srivastava, and L. Zhong.  High-efficiency transduction and correction of murine hemophilia B using AAV2 vectors devoid of multiple surface-exposed tyrosines.  Molecular Therapy, 18: 2048-2056, 2010.
  23. H. Petrs-Silva, A. Dinculescu, Q. Li, S.H. Min, V. Chiodo, J. Pang, L. Zhong, S. Zolotukhin, A. Srivastava, A.S. Lewin, and W.W. Hauswirth. High-efficiency transduction of the mouse retina by tyrosine-mutant AAV serotype vectors.  Molecular Therapy, 17: 463-471, 2009.
  24. L. Zhong, X. Zhou, Y. Li, K. Qing, X. Xiao, R.J. Samulski, and A. Srivastava. Single-polarity recombinant adeno-associated virus 2 vector-mediated transgene expression in vitro and in vivo:  Mechanism of transduction. Molecular Therapy, 16: 290-295, 2008.
  25. N. Maina, Z. Han, W. Zhao, X. Li, Z. Hu, L. Zhong, D. Bischof, K.A. Weigel-Van Aken, W.B. Slayton, M.C. Yoder, and A. Srivastava.  Recombinant scAAV serotype vector-mediated transduction of hematopoietic stem cells and lineage-restricted long-term transgene expression in progenitor cells in a murine serial bone marrow transplantation model. Hum. Human Gene Therapy, 19: 376-383, 2008.
  26. L. 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.
  27. K.A. Weigel-Kelley, M.C. Yoder and A. Srivastava. α5β1 integrin as a cellular co-receptor for human parvovirus B19:  Requirement of β1 integrin activation for viral entry.  Blood, 102: 3927-3933, 2003.
  28. M.Q. Tan, K.Y. Qing, S.Z. Zhou, M.C. Yoder and A. Srivastava.  Adeno-associated virus 2-mediated transduction and erythroid lineage-restricted, long-term expression of the normal human β-globin gene in hematopoietic cells from homozygous β-thalassemic mice.  Molecular Therapy, 3: 940-946, 2001.
  29. 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.
  30. S.Z. Zhou, Q. Li, G. Stamatoyannopoulos and A. Srivastava.  Adeno-associated virus 2-mediated transduction and erythroid cell-specific expression of a human β-globin gene.  Gene Therapy, 3: 223-229, 1996.
  31. X.-S. Wang, M.C. Yoder, S.Z. Zhou, and A. Srivastava.  Parvovirus B19 promoter at map unit 6 confers autonomous replication competence and erythroid specificity to adeno-associated virus 2 in primary human hematopoietic progenitor cells.  Proc. Natl. Acad. Sci., USA, 92: 12416-12420, 1995.
  32. S. Ponnazhagan, M.L. Nallari, and A. Srivastava.  Suppression of human α-globin gene expression mediated by the recombinant adeno-associated virus 2-based anti-sense vectors.  Journal of Experimental Medicine 179: 733-738, 1994.
  33. C.H. Srivastava, R.J. Samulski, L. Lu, S.H. Larsen and A. Srivastava.   Construction of a recombinant human parvovirus B19:  Adeno-associated virus 2 DNA inverted terminal repeats are functional in an AAV-B19 hybrid virus.  Proc. Natl. Acad. Sci., USA,  86: 8078-8082, 1989.
  34. R.J. Samulski, A. Srivastava, K.I. Berns, and N. Muzyczka.  Rescue of adeno-associated virus from recombinant plasmids:  Gene correction within the terminal repeats of AAV.  Cell, 33: 135-143, 1983.
  35. A. Srivastava, E.W. Lusby, and K.I. Berns.  Nucleotide sequence and organization of the adeno-associated virus 2 genome.  Journal of Virology, 45: 555-564, 1983.