PDGF-receptor beta-targeted adenovirus redirects gene transfer from hepatocytes to activated stellate cells.
PDGF-receptor beta-targeted adenovirus redirects gene transfer from hepatocytes to activated stellate cells.
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PDGF 受体 β 靶向腺病毒将基因转移从肝细胞重定向到激活的星状细胞。
DOI：
10.1021/mp700118p
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发表时间：
2008
影响因子：
4.9
通讯作者：
H. Haisma
中科院分区：
文献类型：
--
作者：
M. Schoemaker;M. Rots;L. Beljaars;Arjen Y. Ypma;P. Jansen;K. Poelstra;H. Moshage;H. Haisma
慢性肝损伤可导致肝纤维化。在这个过程中，肝活化的星状细胞是关键的参与者。因此，活化的星状细胞是抗纤维化基因治疗的有吸引力的靶点。重组腺病毒是一种很有前途的载体，用于将治疗基因递送到肝细胞。然而，该载体对肝细胞和枯否细胞具有相当大的向性。因此，本研究的目的是将腺病毒重新靶向活化的星状细胞，同时降低其对肝细胞的亲和力。我们构建了一种融合蛋白，该融合蛋白对腺病毒和血小板衍生生长因子受体β（PDGF-R β）都具有亲和力。与其他细胞相比，PDFG-R β在活化的星状细胞上高度表达。将靶向部分PDGF肽CSRNLIDC克隆在针对腺病毒结的单链抗体片段（S11）之前。该融合蛋白增强腺病毒基因在3 T3成纤维细胞和原代分离的活化大鼠星状细胞中的转移10-60倍。具有乱序PDGF肽的融合蛋白（CIDNLSRC）没有实现这种效果。重要的是，PDGF-R β重靶向腺病毒显示出对原代大鼠肝细胞的向性降低了25倍。我们的新方法表明，治疗基因可以选择性地定向到星状细胞。这为肝纤维化的治疗开辟了新的可能性。
Chronic liver damage may lead to liver fibrosis. In this process, hepatic activated stellate cells are the key players. Thus, activated stellate cells are attractive targets for antifibrotic gene therapy. Recombinant adenovirus is a promising vehicle for delivering therapeutic genes to liver cells. However, this vector has considerable tropism for hepatocytes and Kupffer cells. The aim of this study is therefore to retarget the adenovirus to the activated stellate cells while reducing its affinity for hepatocytes. We constructed a fusion protein with affinity for both the adenovirus and the platelet derived growth factor-receptor beta (PDGF-Rbeta). In contrast to other cells, the PDFG-Rbeta is highly expressed on activated stellate cells. The targeting moiety, the PDGF peptide CSRNLIDC, was cloned in front of the single-chain antibody fragment (S11) directed against the adenoviral knob. This fusion protein enhanced adenoviral gene transfer in both 3T3 fibroblasts and primary isolated activated rat stellate cells by 10-60-fold. A fusion protein with a scrambled PDGF peptide (CIDNLSRC) did not accomplish this effect. Importantly, the PDGF-Rbeta-retargeted adenovirus showed a 25-fold reduced tropism for primary rat hepatocytes. Our novel approach demonstrates that therapeutic genes can be selectively directed to stellate cells. This opens new possibilities for the treatment of liver fibrosis.
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影响因子：
25.7
作者：
A. Lang;R. Schoonhoven;S. Tuvia;D. Brenner;R. Rippe
通讯作者：
A. Lang;R. Schoonhoven;S. Tuvia;D. Brenner;R. Rippe
影响因子：
6.5
作者：
Silke Vogel;R. Piantedosi;Jorge Frank;Avraham Lalazar;Don C. Rockey;Scott L. Friedman;W. Blaner-
通讯作者：
Silke Vogel;R. Piantedosi;Jorge Frank;Avraham Lalazar;Don C. Rockey;Scott L. Friedman;W. Blaner-
影响因子：
15.9
作者：
Hidaka, C;Milano, E;Crystal, RG
通讯作者：
Crystal, RG
将短肽配体添加到腺病毒纤维蛋白中。
DOI：
--
发表时间：
1995
期刊：
Gene therapy.
影响因子：
--
作者：
Michael,SI;Hong,JS;Curiel,DT;Engler,JA
通讯作者：
Engler,JA
DOI：
10.1073/pnas.95.5.2509
发表时间：
1998-03-03
影响因子：
11.1
作者：
He, TC;Zhou, SB;Vogelstein, B
通讯作者：
Vogelstein, B