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 Chatterjee & 1 others Arun Srivastava

Research output: Contribution to journalArticle

29 Citations (Scopus)

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 - 2013

Fingerprint

Capsid
Hematopoietic Stem Cells
Heterografts
Tyrosine
Macaca fascicularis
Serogroup
In Vitro Techniques
Dependovirus
Phase II Clinical Trials
Clinical Trials, Phase I
Phenylalanine
Transgenes
Point Mutation
Genetic Therapy
Safety
Amino Acids
Mutation

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)

Cite this

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

In: Cytotherapy, Vol. 15, No. 8, 2013, p. 986-998.

Research output: Contribution to journalArticle

Song, L, Kauss, MA, Kopin, E, Chandra, M, Ul-Hasan, T, Miller, E, Jayandharan, GR, Rivers, AE, Aslanidi, GV, Ling, C, Li, B, Ma, W, Li, X, Andino, LM, Zhong, L, Tarantal, AF, Yoder, MC, Wong, KK, Tan, M, Chatterjee, S & 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, vol. 15, no. 8, pp. 986-998. https://doi.org/10.1016/j.jcyt.2013.04.003
Song, Liujiang ; Kauss, M. Ariel ; Kopin, Etana ; Chandra, Manasa ; Ul-Hasan, Taihra ; Miller, Erin ; Jayandharan, Giridhara R. ; Rivers, Angela E. ; Aslanidi, George V. ; Ling, Chen ; Li, Baozheng ; Ma, Wenqin ; Li, Xiaomiao ; Andino, Lourdes M. ; Zhong, Li ; Tarantal, Alice F ; Yoder, Mervin C. ; Wong, Kamehameha K. ; Tan, Mengqun ; Chatterjee, Saswati ; Srivastava, Arun. / 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. In: Cytotherapy. 2013 ; Vol. 15, No. 8. pp. 986-998.
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T1 - 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

AU - Song, Liujiang

AU - Kauss, M. Ariel

AU - Kopin, Etana

AU - Chandra, Manasa

AU - Ul-Hasan, Taihra

AU - Miller, Erin

AU - Jayandharan, Giridhara R.

AU - Rivers, Angela E.

AU - Aslanidi, George V.

AU - Ling, Chen

AU - Li, Baozheng

AU - Ma, Wenqin

AU - Li, Xiaomiao

AU - Andino, Lourdes M.

AU - Zhong, Li

AU - Tarantal, Alice F

AU - Yoder, Mervin C.

AU - Wong, Kamehameha K.

AU - Tan, Mengqun

AU - Chatterjee, Saswati

AU - Srivastava, Arun

PY - 2013

Y1 - 2013

N2 - 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.

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KW - Gene transfer

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