Publication

CD133-targeted Gene Transfer Into Long-term Repopulating Hematopoietic Stem Cells

Brendel, C., Goebel, B., Daniela, A., Brugman, M., Kneissl, S., Schwaeble, J., Kaufmann, K. B., Mueller-Kuller, U., Kunkel, H., Chen-Wichmann, L., Abel, T., Serve, H., Bystrykh, L., Buchholz, C. J. & Grez, M., Jan-2015, In : Molecular Therapy. 23, 1, p. 63-70 8 p.

Research output: Contribution to journalArticleAcademicpeer-review

  • Christian Brendel
  • Benjamin Goebel
  • Abriss Daniela
  • Martijn Brugman
  • Sabrina Kneissl
  • Joachim Schwaeble
  • Kerstin B. Kaufmann
  • Uta Mueller-Kuller
  • Hana Kunkel
  • Linping Chen-Wichmann
  • Tobias Abel
  • Hubert Serve
  • Leonid Bystrykh
  • Christian J. Buchholz
  • Manuel Grez

Gene therapy for hematological disorders relies on the genetic modification of CD34(+) cells, a heterogeneous cell population containing about 0.01% long-term repopulating cells. Here, we show that the lentiviral vector CD133-LV, which uses a surface marker on human primitive hematopoietic stem cells (HSCs) as entry receptor, transfers genes preferentially into cells with high engraftment capability. Transduction of unstimulated CD34(+) cells with CD133-LV resulted in gene marking of cells with competitive proliferative advantage in vitro and in immunodeficient mice. The CD133-LV-transduced population contained significantly more cells with repopulating capacity than cells transduced with vesicular stomatitis virus (VSV)-LV, a lentiviral vector pseudotyped with the vesicular stomatitis virus G protein. Upon transfer of a barcode library, CD133-LV-transduced cells sustained gene marking in vivo for a prolonged period of time with a 6.7-fold higher recovery of barcodes compared to transduced control cells. Moreover, CD133-LV-transduced cells were capable of repopulating secondary recipients. Lastly, we show that this targeting strategy can be used for transfer of a therapeutic gene into CD34(+) cells obtained from patients suffering of X-linked chronic granulomatous disease. In conclusion, direct gene transfer into CD133(+) cells allows for sustained long-term engraftment of gene corrected cells.

Original languageEnglish
Pages (from-to)63-70
Number of pages8
JournalMolecular Therapy
Volume23
Issue number1
Publication statusPublished - Jan-2015

    Keywords

  • MOBILIZED PERIPHERAL-BLOOD, PSEUDOTYPE LENTIVIRAL VECTORS, IMMUNE-DEFICIENT MICE, PROGENITOR CELLS, MEASLES-VIRUS, MOLECULAR EVIDENCE, ENVELOPE PROTEINS, CD34(+) CELLS, LDL RECEPTOR, IN-VITRO

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