Ngom Mor, Imren Suzan, Maetzig Tobias, Adair Jennifer E, Knapp David J H F, Chagraoui Jalila, Fares Iman, Bordeleau Marie-Eve, Sauvageau Guy, Leboulch Philippe, Eaves Connie, Humphries Richard Keith
Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver BC V5Z 1L3, Canada.
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Mol Ther Methods Clin Dev. 2018 Jul 5;10:156-164. doi: 10.1016/j.omtm.2018.06.009. eCollection 2018 Sep 21.
Enhanced gene transfer efficiencies and higher yields of transplantable transduced human hematopoietic stem cells are continuing goals for improving clinical protocols that use stemcell-based gene therapies. Here, we examined the effect of the HSC agonist UM171 on these endpoints in both and systems. Using a 22-hr transduction protocol, we found that UM171 significantly enhances both the lentivirus-mediated transduction and yield of CD34 and CD34CD45RA hematopoietic cells from human cord blood to give a 6-fold overall higher recovery of transduced hematopoietic stem cells, including cells with long-term lympho-myeloid repopulating activity in immunodeficient mice. The ability of UM171 to enhance gene transfer to primitive cord blood hematopoietic cells extended to multiple lentiviral pseudotypes, gamma retroviruses, and non-integrating lentiviruses and to adult bone marrow cells. UM171, thus, provides an interesting reagent for improving the production of gene-modified cells and for reducing requirements of virus for a broad range of applications.
提高基因转移效率以及获得更高产量的可移植转导人造血干细胞，一直是改进使用基于干细胞的基因疗法的临床方案的目标。在此，我们研究了造血干细胞激动剂UM171对体外和体内系统中这些指标的影响。采用22小时转导方案，我们发现UM171显著提高了慢病毒介导的转导效率以及人脐带血中CD34+和CD34+CD45RA-造血细胞的产量，使转导的造血干细胞总体回收率提高了6倍，包括在免疫缺陷小鼠中具有长期淋巴细胞-髓系重建活性的细胞。UM171增强向原始脐带血造血细胞基因转移的能力扩展到多种慢病毒假型、γ逆转录病毒和非整合慢病毒以及成人骨髓细胞。因此，UM171为改进基因修饰细胞的生产以及减少广泛应用中对病毒的需求提供了一种有意义的试剂。
