期刊
BLOOD ADVANCES
卷 1, 期 23, 页码 2088-2104出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/bloodadvances.2017007773
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资金
- Agence Francais dystrophie musculaire
- Agence nationale de recherche sur les sida
- Agence de recherche sur le cancer
- European Community [FP7-HEALTH-2007-B/222878 PERSIST]
- ERA-Net for Research Programmes on Rare Diseases E-RARE grant GETHERTHALPLUS
- Lentigen Inc Miltenyi
Hematopoietic stem cell (HSC)-based gene therapy trials are now moving toward the use of lentiviral vectors (LVs) with success. However, one challenge in the field remains: efficient transduction of HSCs without compromising their stem cell potential. Here we showed that measles virus glycoprotein-displaying LVs (hemagglutinin and fusion protein LVs [H/F-LVs]) were capable of transducing 100% of early-acting cytokine-stimulated human CD34(+) (hCD34(+)) progenitor cells upon a single application. Strikingly, these H/F-LVs also allowed transduction of up to 70% of nonstimulated quiescent hCD34(+) cells, whereas conventional vesicular stomatitis virus G (VSV-G)-LVs reached 5% at the most with H/F-LV entry occurring exclusively through the CD46 complement receptor. Importantly, reconstitution of NOD/SCID gamma c(-/-) (NSG) mice with H/F-LV transduced prestimulated or resting hCD34(+) cells confirmed these high transduction levels in all myeloid and lymphoid lineages. Remarkably, for resting CD34(+) cells, secondary recipients exhibited increasing transduction levels of up to 100%, emphasizing that H/F-LVs efficiently gene-marked HSCs in the resting state. Because H/F-LVs promoted ex vivo gene modification of minimally manipulated CD34(+) progenitors that maintained stemness, we assessed their applicability in Fanconi anemia, a bone marrow (BM) failure with chromosomal fragility. Notably, only H/F-LVs efficiently gene-corrected minimally stimulated hCD34(+) cells in unfractionated BM from these patients. These H/F-LVs improved HSC gene delivery in the absence of cytokine stimulation while maintaining their stem cell potential. Thus, H/F-LVs will facilitate future clinical applications requiring HSC gene modification, including BM failure syndromes, for which treatment has been very challenging up to now.
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