Phenotypic correction of Fanconi anemia cells in the murine bone marrow after carrier cell mediated delivery of lentiviral vector.
Phenotypic correction of Fanconi anemia cells in the murine bone marrow after carrier cell mediated delivery of lentiviral vector.
复制标题
DOI：
10.1186/s13287-016-0431-z
复制
发表时间：
2016-11-19
影响因子：
7.5
通讯作者：
Kurre P
中科院分区：
文献类型：
--
作者：
Chakkaramakkil Verghese S;Goloviznina NA;Kurre P
范可尼贫血（FA）是一种常染色体隐性遗传的造血功能障碍性疾病，是造血干细胞（HSC）定向基因治疗的候选者。然而，FA患者中发现的典型的HSC数量减少、骨髓动员无效以及离体操作过程中的再氧合损伤阻碍了使用传统体外方法的临床成功。我们以前证明，慢病毒载体（LV）颗粒可逆地附着在细胞表面，在那里它们获得保护，免受血清补体中和。我们推断，将LV细胞递送至骨髓龛可避免FA HSC动员和体外修饰期间的有害损失。在这里，我们证明了携带FANCC转基因的VSV-G假型慢病毒载体可以从载体传递到旁观者细胞。在FA的细胞培养和移植模型中，我们进一步证明LV载体细胞沿着SDF-1α梯度迁移，并转移稳定整合的载体颗粒，并在小鼠和人FA缺陷靶旁观者细胞中表型校正特征性DNA烷化剂敏感性。总之，我们证明，细胞归巢机制可以利用小鼠FA造血细胞的功能表型校正。本文的在线版本（doi：10.1186/s13287-016-0431-z）包含补充材料，可供授权用户使用。
Fanconi anemia (FA) is an autosomal-recessive disorder associated with hematopoietic failure and it is a candidate for hematopoietic stem cell (HSC)-directed gene therapy. However, the characteristically reduced HSC numbers found in FA patients, their ineffective mobilization from the marrow, and re-oxygenation damage during ex vivo manipulation have precluded clinical success using conventional in vitro approaches. We previously demonstrated that lentiviral vector (LV) particles reversibly attach to the cell surface where they gain protection from serum complement neutralization. We reasoned that cellular delivery of LV to the bone marrow niche could avoid detrimental losses during FA HSC mobilization and in vitro modification. Here, we demonstrate that a VSV-G pseudotyped lentivector, carrying the FANCC transgene, can be transmitted from carrier to bystander cells. In cell culture and transplantation models of FA, we further demonstrate that LV carrier cells migrate along SDF-1α gradients and transfer vector particles that stably integrate and phenotypically correct the characteristic DNA alkylator sensitivity in murine and human FA-deficient target bystander cells. Altogether, we demonstrate that cellular homing mechanisms can be harnessed for the functional phenotype correction in murine FA hematopoietic cells. The online version of this article (doi:10.1186/s13287-016-0431-z) contains supplementary material, which is available to authorized users.
登录
查看更多内容
影响因子：
3.6
作者：
Javier Molina-Estevez, F.;Nowrouzi, Ali;Schmidt, Manfred
通讯作者：
Schmidt, Manfred
影响因子：
12.4
作者：
Noll, M;Bateman, RL;Grompe, M
通讯作者：
Grompe, M
影响因子：
82.9
作者：
Cole, C;Qiao, J;Vile, RG
通讯作者：
Vile, RG
影响因子：
4.3
作者：
Kaschutnig, Paul;Bogeska, Ruzhica;Milsom, Michael D.
通讯作者：
Milsom, Michael D.
DOI：
10.1073/pnas.0510613103
发表时间：
2006-02-14
影响因子：
11.1
作者：
Cohen-Haguenauer, O;Péault, B;Marty, M
通讯作者：
Marty, M