Optimizing the transduction efficiency of capsid-modified AAV6 serotype vectors in primary human hematopoietic stem cells in vitro and in a xenograft mouse model in vivo

Liujiang Song, M. Ariel Kauss, Etana Kopin, Manasa Chandra, Taihra Ul-Hasan, Erin Miller, Giridhara R. Jayandharan, Angela E. Rivers, George V. Aslanidi, Chen Ling, Baozheng Li, Wenqin Ma, Xiaomiao Li, Lourdes M. Andino, Li Zhong, Alice F. Tarantal, Mervin C. Yoder, Kamehameha K. Wong, Mengqun Tan, Saswati ChatterjeeArun Srivastava

Research output: Contribution to journalArticle

38 Scopus citations

Abstract

Background aims: Although recombinant adeno-associated virus serotype 2 (AAV2) vectors have gained attention because of their safety and efficacy in numerous phase I/II clinical trials, their transduction efficiency in hematopoietic stem cells (HSCs) has been reported to be low. Only a few additional AAV serotype vectors have been evaluated, and comparative analyses of their transduction efficiency in HSCs from different species have not been performed. Methods: We evaluated the transduction efficiency of all available AAV serotype vectors (AAV1 through AAV10) in primary mouse, cynomolgus monkey and human HSCs. The transduction efficiency of the optimized AAV vectors was also evaluated in human HSCs in a murine xenograft model in vivo. Results: We observed that although there are only six amino acid differences between AAV1 and AAV6, AAV1, but not AAV6, transduced mouse HSCs well, whereas AAV6, but not AAV1, transduced human HSCs well. None of the 10 serotypes transduced cynomolgus monkey HSCs in vitro. We also evaluated the transduction efficiency of AAV6 vectors containing mutations in surface-exposed tyrosine residues. We observed that tyrosine (Y) to phenylalanine (F) point mutations in residues 445, 705 and 731 led to a significant increase in transgene expression in human HSCs in vitro and in a mouse xenograft model in vivo. Conclusions: These studies suggest that the tyrosine-mutant AAV6 serotype vectors are the most promising vectors for transducing human HSCs and that it is possible to increase further the transduction efficiency of these vectors for their potential use in HSC-based gene therapy in humans.

Original languageEnglish (US)
Pages (from-to)986-998
Number of pages13
JournalCytotherapy
Volume15
Issue number8
DOIs
StatePublished - Jan 1 2013

Keywords

  • AAV vectors
  • Gene expression
  • Gene transfer
  • Hematopoietic stem cells

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Oncology
  • Genetics(clinical)
  • Transplantation
  • Cancer Research
  • Cell Biology
  • Medicine(all)

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    Song, L., Kauss, M. A., Kopin, E., Chandra, M., Ul-Hasan, T., Miller, E., Jayandharan, G. R., Rivers, A. E., Aslanidi, G. V., Ling, C., Li, B., Ma, W., Li, X., Andino, L. M., Zhong, L., Tarantal, A. F., Yoder, M. C., Wong, K. K., Tan, M., ... Srivastava, A. (2013). Optimizing the transduction efficiency of capsid-modified AAV6 serotype vectors in primary human hematopoietic stem cells in vitro and in a xenograft mouse model in vivo. Cytotherapy, 15(8), 986-998. https://doi.org/10.1016/j.jcyt.2013.04.003