Leiden;
Dept Med Hematol Oncol;
Netherlands;
Univ Groningen;
Leiden Univ;
Dept Cell Biol;
Paul Ehrlich Inst;
Germany;
Med Ctr;
Dept Immunohematol & Blood Transfus IHB;
Inst Tumor Biol & Expt Therapy;
Goethe Univ Frankfurt;
Inst Transfus Med &;
German Red Cross Blood Donor Serv Baden Wuerttemb;
Univ Med Ctr Groningen;
D-60054 Frankfurt;
Langen;
NL-9713 AV Groningen;
D-60596 Frankfurt;
期刊名称：
Molecular therapy: the journal of the American Society of Gene Therapy
i s s n：
1525-0016
年卷期：
2015 年
23 卷
1 期
页 码：
63-70
页 码：
摘 要：
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.
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