Inhibition of choroidal neovascularization by intravenous injection of adenoviral vectors expressing secretable endostatin
Inhibition of choroidal neovascularization by intravenous injection of adenoviral vectors expressing secretable endostatin
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DOI：
10.1016/s0002-9440(10)61697-5
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发表时间：
2001-07-01
影响因子：
6
通讯作者：
Campochiaro, PA
中科院分区：
文献类型：
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作者：
Mori, K;Ando, A;Campochiaro, PA
内皮抑素是XVIII胶原蛋白的裂解产物，抑制肿瘤血管生成和生长。干扰素α 2a阻断肿瘤血管生成并导致血管瘤消退，但对脉络膜新生血管（CNV）无影响。因此，肿瘤血管生成抑制剂不一定抑制眼部新生血管。在这项研究中，我们通过静脉注射含有sigmEndo转基因的腺病毒载体，该转基因由小鼠免疫球蛋白kappa链先导序列与小鼠内皮抑素序列编码偶联组成，研究了高血清水平内皮抑素对小鼠CNV的影响。与注射空白载体的小鼠相比，注射由劳斯肉瘤病毒启动子驱动sigmendo表达的构建体的小鼠血清内皮抑素水平较高，激光诱导布鲁氏膜破裂部位的CNV病变明显更小。小鼠注射了由猿类巨细胞病毒启动子驱动的sign - mendo构建物，其血清内皮抑素水平提高了10倍，几乎完全预防了CNV。内皮抑素水平与CNV面积呈显著负相关。本研究为基因治疗提高内皮抑素水平可以预防CNV的发展提供了原理证明，并可能为老年性黄斑变性患者严重视力丧失的主要原因提供新的治疗方法。
Endostatin is a cleavage product of collagen XVIII that inhibits tumor angiogenesis and growth. Interferon alpha 2a blocks tumor angiogenesis and causes regression of hemangiomas, but has no effect on choroidal neovascularization (CNV). Therefore, inhibitors of tumor angiogenesis do not necessarily inhibit ocular neovascularization. In this study, we used an intravenous injection of adenoviral vectors containing a sigmEndo transgene consisting of murine immunoglobulin kappa -chain leader sequence coupled to sequence coding for murine endostatin to investigate the effect of high serum levels of endostatin on CNV in mice. Mice injected with a construct in which sig-mEndo expression was driven by the Rous sarcoma virus promoter had moderately high serum levels of endostatin and significantly smaller CNV lesions at sites of laser-induced rupture of Bruch's membrane than mice injected with null vector. Mice injected with a construct in which sig-mEndo was driven by the simian cytomegalovirus promoter had similar to 10-fold higher endostatin serum levels and had nearly complete prevention of CNV. There was a strong inverse correlation between endostatin serum level and area of CNV. This study provides proof of principle that gene therapy to increase levels of endostatin can prevent the development of CNV and may provide a new treatment for the leading cause of severe loss of vision in patients with age-related macular degeneration.