期刊
MOLECULAR THERAPY
卷 16, 期 6, 页码 1154-1160出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/mt.2008.67
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资金
- NHLBI NIH HHS [R01 HL081499] Funding Source: Medline
- NIDDK NIH HHS [DK074310] Funding Source: Medline
Fanconi anemia ( FA) is a rare recessive syndrome, characterized by congenital anomalies, bone marrow failure, and predisposition to cancer. Two earlier clinical trials utilizing gamma-retroviral vectors for the transduction of autologous FA hematopoietic stem cells ( HSCs) required extensive in vitro manipulation and failed to achieve detectable long-term engraftment of transduced HSCs. As a strategy for minimizing ex vivo manipulation, we investigated the use of a rapid lentiviral transduction protocol in a murine Fanca(-/-) model. Importantly, while this and most murine models of FA fail to completely mimic the human hematopoietic phenotype, we observed a high incidence of HSC transplant engraftment failure and low donor chimerism after conventional transduction ( CT) of Fanca(-/-) donor cells. In contrast, rapid transduction ( RT) of Fanca(-/-) HSCs preserved engraftment to the level achieved in wild-type cells, resulting in long-term multilineage engraftment of gene-modified cells. We also demonstrate the correction of the characteristic hypersensitivity of FA cells against the cross-linking agent mitomycin C ( MMC), and provide evidence for the advantage of using pharmacoselection as a means of further increasing gene-modified cells after RT. Collectively, these data support the use of rapid lentiviral transduction for gene therapy in FA.
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