Early intra-amniotic gene transfer using lentiviral vector improves skin blistering phenotype in a murine model of Herlitz junctional epidermolysis bullosa.
Early intra-amniotic gene transfer using lentiviral vector improves skin blistering phenotype in a murine model of Herlitz junctional epidermolysis bullosa.
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DOI：
10.1038/gt.2011.135
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发表时间：
2012-05
期刊：
影响因子：
5.1
通讯作者：
Flake AW
中科院分区：
文献类型：
--
作者：
Endo M;Zoltick PW;Radu A;Jiang Q;Matsui C;Marinkovich PM;McGrath J;Tamai K;Uitto J;Flake AW
LAMB3 基因突变会导致致命的交界性大疱性表皮松解症 (JEB)。我们假设，在严重的 JEB 小鼠模型中进行早期羊膜内基因转移将改善或纠正皮肤表型。来自杂合子 LAMB3IAP 育种对的已确定日期的胎儿在胚胎第 8 天 (E8) 接受超声引导下羊膜内注射编码小鼠 LAMB3 基因的慢病毒载体。通过免疫组织化学监测基因表达。转基因层粘连蛋白-β3 链与其内源性伴侣链组装，导致皮肤和粘膜基底膜区产生可检测量的层粘连蛋白-332。从超微结构上看，还注意到约 60% 的半桥粒结构得到了恢复。尽管我们可以纠正 11.9% 的纯合 LAMB3IAP 小鼠的皮肤表型，但没有一只存活超过 48 小时。然而，来自经过治疗的 E18 纯合子 LAMB3IAP 胎儿的皮肤移植物在 6 个月内保持正常外观，并且层粘连蛋白 332 的正常组装持续存在。这些结果首次证明通过体内产前基因转移对严重 JEB 模型中皮肤病理学的长期表型校正。尽管由于该小鼠模型的局限性，存活率仍然有限，但这项研究支持通过产前基因转移治疗 JEB 的潜力。
Mutations of the LAMB3 gene cause a lethal form of junctional epidermolysis bullosa (JEB). We hypothesized that early intra-amniotic gene transfer in a severe murine model of JEB would improve or correct the skin phenotype. Time-dated fetuses from heterozygous LAMB3IAP breeding pairs underwent ultrasound guided intra-amniotic injection of lentiviral vector encoding the murine LAMB3 gene at embryonic day 8 (E8). Gene expression was monitored by immunohistochemistry. The transgenic laminin-β3 chain was shown to assemble with its endogenous partner chains, resulting in detectable amounts of laminin-332 in the basement membrane zone of skin and mucosa. Ultrastructually, the restoration of ~60% of hemidesmosomal structures was also noted. Although we could correct the skin phenotype in 11.9% of homozygous LAMB3IAP mice, none survived beyond 48 h. However, skin transplants from treated E18 homozygous LAMB3IAP fetuses maintained normal appearance for 6 months with persistence of normal assembly of laminin-332. These results demonstrate for the first time long-term phenotypic correction of the skin pathology in a severe model of JEB by in vivo prenatal gene transfer. Although survival remained limited due to the limitations of this mouse model, this study supports the potential for treatment of JEB by prenatal gene transfer.
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影响因子：
2.4
作者：
Laimer, Martin;Lanschuetzer, Christoph M.;Bauer, Johann W.
通讯作者：
Bauer, Johann W.
DOI：
10.1073/pnas.232688199
发表时间：
2003-01-07
影响因子：
11.1
作者：
Qin, XF;An, DS;Baltimore, D
通讯作者：
Baltimore, D
影响因子：
2.5
作者：
Kuster, JE;Guarnieri, MH;Swiatek, PJ
通讯作者：
Swiatek, PJ
影响因子：
12.4
作者：
Endoh, M;Koibuchi, N;Kaneda, Y
通讯作者：
Kaneda, Y
影响因子：
--
作者：
Laimer, M.;Lanschuetzer, C. M.;Hintner, H.
通讯作者：
Hintner, H.