Erythroid-specific human factor IX delivery from in vivo selected hematopoietic stem cells following nonmyeloablative conditioning in hemophilia B mice.
Erythroid-specific human factor IX delivery from in vivo selected hematopoietic stem cells following nonmyeloablative conditioning in hemophilia B mice.
复制标题
DOI：
10.1038/mt.2008.161
复制
发表时间：
2008-10
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
我们开发了一种慢病毒载体系统，用于人因子IX （hFIX）基因在造血干细胞（hsc）中的转移，该系统在非清髓条件和体内甲基鸟嘌呤甲基转移酶（MGMT）药物选择后提供红系细胞来源的全身蛋白递送。在适度的Busulfan条件下进行骨髓移植后，嵌合体中初始的hFIX表达是最低限度的。然而，在体内mgmt药物选择后，hFIX水平急剧上升，并最终达到血友病B治疗中被认为可以治愈的水平（>500 ng/ml）。hFIX水平的升高与外周血中载体拷贝（VC）数量的增加成正比。在连续移植的小鼠嵌合体中，hFIX的高水平表达维持了18个月。重要的是，红细胞高水平表达hFIX不会导致贫血或对红细胞计数产生不利影响。由于低VC数量要求和红细胞限制性转基因表达，可能降低插入突变的风险，以及长期高水平的蛋白表达，结合降低强度调节的前景，有力地支持了基于成体干细胞的基因治疗在非致命性血液或代谢疾病中的潜在适用性，如血友病。
We have developed a lentiviral vector system for human factor IX (hFIX) gene transfer in hematopoietic stem cells (HSCs) that provides erythroid cell-derived systemic protein delivery following nonmyeloablative conditioning and in vivo methylguanine methyltransferase (MGMT) drug selection. After bone marrow transplantation under moderate Busulfan conditioning, the initial hFIX expression in the chimeras was minimally detectable. However, the hFIX levels rose sharply following in vivo MGMT-drug selection and eventually reached a level that is considered curative in hemophilia B therapy (>500 ng/ml). The rise of hFIX levels was proportional to the increase in vector copy (VC) number in peripheral blood cells. High levels of hFIX expression were maintained in serially engrafted mice chimeras for 18 months. Importantly, high-level hFIX expression by erythroid cells did not result in anemia or adversely affect red blood cell counts. The prospect of combining reduced intensity conditioning, a presumably lowered risk of insertional mutagenesis due to low VC number requirement and erythroid-restricted transgene expression, as well as long-term protein expression at high level, strongly supports the potential applicability of adult stem cell-based gene therapy in nonlethal blood or metabolic disorders, as demonstrated here for hemophilia.
登录
查看更多内容
影响因子：
4.2
作者：
Chinnasamy, D;Fairbairn, LJ;Chinnasamy, N
通讯作者：
Chinnasamy, N
DOI：
10.1073/pnas.95.10.5734
发表时间：
1998-05-12
影响因子：
11.1
作者：
Evans, GL;Morgan, RA
通讯作者：
Morgan, RA
DOI：
10.1073/pnas.79.21.6461
发表时间：
1982-01-01
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES
影响因子：
--
作者：
KURACHI, K;DAVIE, EW
通讯作者：
DAVIE, EW
影响因子：
12.4
作者：
Bowman, JE;Reese, JS;Gerson, SL
通讯作者：
Gerson, SL
影响因子：
20.3
作者：
Kuramoto, K;Follman, D;Dunbar, CE
通讯作者：
Dunbar, CE