Preclinical development and qualification of ZFN-mediated CCR5 disruption in human hematopoietic stem/progenitor cells.
Preclinical development and qualification of ZFN-mediated CCR5 disruption in human hematopoietic stem/progenitor cells.
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DOI：
10.1038/mtm.2016.67
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发表时间：
2016
期刊：
影响因子：
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文献类型：
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Gene therapy for HIV-1 infection is a promising alternative to lifelong combination antiviral drug treatment. Chemokine receptor 5 (CCR5) is the coreceptor required for R5-tropic HIV-1 infection of human cells. Deletion of CCR5 renders cells resistant to R5-tropic HIV-1 infection, and the potential for cure has been shown through allogeneic stem cell transplantation with naturally occurring homozygous deletion of CCR5 in donor hematopoietic stem/progenitor cells (HSPC). The requirement for HLA-matched HSPC bearing homozygous CCR5 deletions prohibits widespread application of this approach. Thus, a strategy to disrupt CCR5 genomic sequences in HSPC using zinc finger nucleases was developed. Following discussions with regulatory agencies, we conducted IND-enabling preclinical in vitro and in vivo testing to demonstrate the feasibility and (preclinical) safety of zinc finger nucleases-based CCR5 disruption in HSPC. We report here the clinical-scale manufacturing process necessary to deliver CCR5-specific zinc finger nucleases mRNA to HSPC using electroporation and the preclinical safety data. Our results demonstrate effective biallelic CCR5 disruption in up to 72.9% of modified colony forming units from adult mobilized HSPC with maintenance of hematopoietic potential in vitro and in vivo. Tumorigenicity studies demonstrated initial product safety; further safety and feasibility studies are ongoing in subjects infected with HIV-1 (NCT02500849@clinicaltrials.gov).
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影响因子：
56.9
作者：
Feng, Y;Broder, CC;Berger, EA
通讯作者：
Berger, EA
影响因子：
64.8
作者：
Deng, HK;Liu, R;Landau, NR
通讯作者：
Landau, NR
影响因子：
9.8
作者：
Miller, David T.;Adam, Margaret P.;Ledbetter, David H.
通讯作者：
Ledbetter, David H.
DOI：
10.4049/jimmunol.1001002
发表时间：
2011-01-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Lin KL;Sweeney S;Kang BD;Ramsburg E;Gunn MD
通讯作者：
Gunn MD
影响因子：
46.9
作者：
Gabriel, Richard;Lombardo, Angelo;von Kalle, Christof
通讯作者：
von Kalle, Christof