Low-Dose Recombinant Adeno-Associated Virus-Mediated Inhibition of Vascular Endothelial Growth Factor Can Treat Neovascular Pathologies Without Inducing Retinal Vasculitis.
Low-Dose Recombinant Adeno-Associated Virus-Mediated Inhibition of Vascular Endothelial Growth Factor Can Treat Neovascular Pathologies Without Inducing Retinal Vasculitis.
复制标题
DOI：
10.1089/hum.2021.132
复制
发表时间：
2021-07
影响因子：
4.2
通讯作者：
Punzo C
中科院分区：
文献类型：
--
作者：
Cheng SY;Luo Y;Malachi A;Ko J;Su Q;Xie J;Tian B;Lin H;Ke X;Zheng Q;Tai PWL;Gao G;Punzo C
湿性年龄相关性黄斑变性的特点是新生血管病变，如果不及时治疗，可能会导致水肿，随后视力迅速丧失。血管内皮生长因子（VEGF）的抑制已被用于成功治疗眼部新生血管病变。尽管如此，一些患者需要频繁玻璃体内注射抗 VEGF 药物，这增加了患者的负担和手术并发症的风险。重组腺相关病毒（rAAV）介导的抗 VEGF 蛋白表达是降低患者风险和负担的一种有吸引力的替代方案。然而，对于眼部长期抑制 VEGF 的安全性仍存在争议。在这里，我们表明，通过玻璃体内递送测试表达抗 VEGF 药物康柏西普的四种 rAAV 血清型中的两种会导致剂量依赖性血管鞘病理学，其特征是免疫细胞浸润，让人想起人类血管炎。我们发现，这种病理学伴随着血管细胞粘附分子 1 (VCAM1) 和细胞间粘附分子 1 (ICAM1) 表达的增加，这两种分子都会促进免疫细胞从脉管系统外渗。虽然在缺乏 B 和 T 细胞的免疫缺陷 Rag-1 小鼠中，血管鞘病理的形成被阻止，但 VACM1 和 ICAM1 的表达仍然增加，表明抑制 VEGF 功能会导致细胞粘附分子的表达变化，从而促进免疫细胞的外渗。重要的是，导致血管鞘病变的载体之一的剂量降低 10 倍，仍然能够减少脉络膜新生血管形成引起的水肿，而不会引起任何血管鞘病变，并且 VCAM1 表达仅出现最小程度的增加。数据表明，可以安全地开发利用 rAAV 介导的抗 VEGF 药物表达来治疗新生血管眼部病变。然而，病毒载量需要根据血清型的趋向性和启动子的表达模式进行调整。
The wet form of age-related macular degeneration is characterized by neovascular pathologies that, if untreated, can result in edemas followed by rapid vision loss. Inhibition of vascular endothelial growth factor (VEGF) has been used to successfully treat neovascular pathologies of the eye. Nonetheless, some patients require frequent intravitreal injections of anti-VEGF drugs, increasing the burden and risk of complications from the procedure to affected individuals. Recombinant adeno-associated virus (rAAV)-mediated expression of anti-VEGF proteins is an attractive alternative to reduce risk and burden to patients. However, controversy remains as to the safety of prolonged VEGF inhibition in the eye. Here, we show that two out of four rAAV serotypes tested by intravitreal delivery to express the anti-VEGF drug conbercept lead to a dose-dependent vascular sheathing pathology that is characterized by immune cell infiltrates, reminiscent of vasculitis in humans. We show that this pathology is accompanied by increased expression in vascular cell adhesion molecule 1 (VCAM1) and intercellular adhesion molecule 1 (ICAM1), both of which promote extravasation of immune cells from the vasculature. While formation of the vascular sheathing pathology is prevented in immunodeficient Rag-1 mice that lack B and T cells, increased expression of VACM1 and ICAM1 still occurs, indicating that inhibition of VEGF function leads to expression changes in cell adhesion molecules that promote extravasation of immune cells. Importantly, a 10-fold lower dose of one of the vectors that cause a vascular sheathing pathology is still able to reduce edemas resulting from choroidal neovascularization without causing any vascular sheathing pathology and only a minimal increase in VCAM1 expression. The data suggest that treatments of neovascular eye pathologies with rAAV-mediated expression of anti VEGF drugs can be developed safely. However, viral load needs to be adjusted to the tropisms of the serotype and the expression pattern of the promoter.
登录
查看更多内容
影响因子：
6.2
作者：
Eastlake K;Banerjee PJ;Angbohang A;Charteris DG;Khaw PT;Limb GA
通讯作者：
Limb GA
影响因子：
1.4
作者：
Hartnett, M. Elizabeth
通讯作者：
Hartnett, M. Elizabeth
影响因子：
5.5
作者：
Cheng SY;Malachi A;Cipi J;Ma S;Brush RS;Agbaga MP;Punzo C
通讯作者：
Punzo C
影响因子：
5.1
作者：
Hickey DG;Edwards TL;Barnard AR;Singh MS;de Silva SR;McClements ME;Flannery JG;Hankins MW;MacLaren RE
通讯作者：
MacLaren RE
影响因子：
6.7
作者：
Favot, L;Keravis, T;Lugnier, C
通讯作者：
Lugnier, C