Efficacious, safe, and stable inhibition of corneal neovascularization by AAV-vectored anti-VEGF therapeutics.
Efficacious, safe, and stable inhibition of corneal neovascularization by AAV-vectored anti-VEGF therapeutics.
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通过AAV矢量抗VEGF疗法，有效，安全和稳定的角膜新血管化。
DOI：
10.1016/j.omtm.2021.06.007
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发表时间：
2021-09-10
期刊：
影响因子：
--
通讯作者：
Lin H
中科院分区：
文献类型：
--
作者：
Su W;Sun S;Tian B;Tai PWL;Luo Y;Ko J;Zhan W;Ke X;Zheng Q;Li X;Yan H;Gao G;Lin H
角膜新生血管（CoNV）导致视力损害，在美国每年影响超过140万人。它是由多种病理引起的，如炎症、缺氧和边缘屏障功能障碍。注射抗血管内皮生长因子（VEGF）药物KH902（概念）可以抑制CoNV，但需要重复给药，并产生相关的副作用，如角膜疤痕。为了探索更有效和持久的治疗方法，我们利用重组腺相关病毒（rAAV）2和rAAV8载体通过单次细胞内注射介导KH902的表达，并在碱烧伤和缝合诱导的CoNV小鼠模型中研究其抗血管生成作用和安全性。我们的研究结果显示，单次角膜内注射raav介导的KH902 mRNA表达在角膜中持续至少3个月。而且rAAV8-KH902的表达量远远超过rAAV2-KH902。在小鼠CoNV模型中，每个角膜8 × 108个基因组拷贝（GCs）的单剂量rAAV8-KH902治疗可在较长时间内显著抑制CoNV，无不良事件，而单次细胞内给药对CoNV的抑制仅持续10 - 14天。总的来说，我们的研究表明，单剂量的rAAV8-KH902通过细胞内给药治疗CoNV是安全、有效和持久的，代表了一种新的治疗CoNV的策略。目前，最有希望的抗vegf治疗角膜新生血管（CoNV）的方法受到半衰期短和重复给药的潜在副作用的限制。在此，我们将临床证实的抗vegf药物conberept （KH902）植入AAV载体，并证明rAAV-KH902有效且安全，一剂后可长期抑制CoNV。
Corneal neovascularization (CoNV) leads to visual impairment, affecting over 1.4 million people in the United States per year. It is caused by a variety of pathologies, such as inflammation, hypoxia, and limbal barrier dysfunction. Injection of the anti-vascular endothelial growth factor (VEGF) drug KH902 (conbercept) can inhibit CoNV but requires repeated dosing that produces associated side effects, such as cornea scar. To explore more efficacious and long-lasting treatment of CoNV, we employed recombinant adeno-associated virus (rAAV)2 and rAAV8 vectors to mediate KH902 expression via a single intrastromal injection and investigated its anti-angiogenic effects and safety in both alkali-burn- and suture-induced CoNV mouse models. Our results showed that rAAV-mediated KH902 mRNA expression in the cornea was sustained for at least 3 months after a single intrastromal injection. Moreover, the expression level of rAAV8-KH902 far exceeded that of rAAV2-KH902. A single-dose rAAV8-KH902 treatment at 8 × 108 genome copies (GCs) per cornea dramatically inhibited CoNV for an extended period of time in mouse CoNV models without adverse events, whereas the inhibition of CoNV by a single intrastromal administration of the conbercept drug lasted for only 10−14 days. Overall, our study demonstrated that the treatment of CoNV with a single dose of rAAV8-KH902 via intrastromal administration was safe, effective, and long lasting, representing a novel therapeutic strategy for CoNV. Currently, the most promising anti-VEGF therapies for corneal neovascularization (CoNV) are restricted by their short half-life and potential side effects of repeat dosing. Here, we engineered into AAV vectors the clinically proven anti-VEGF drug, conbercept (KH902), and demonstrated rAAV-KH902 was efficacious and safe with long-term inhibition of CoNV following one dose.
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影响因子：
2.8
作者：
Ferrari G;Dastjerdi MH;Okanobo A;Cheng SF;Amparo F;Nallasamy N;Dana R
通讯作者：
Dana R
影响因子：
4.6
作者：
Hirsch ML;Conatser LM;Smith SM;Salmon JH;Wu J;Buglak NE;Davis R;Gilger BC
通讯作者：
Gilger BC
影响因子：
4.1
作者：
Abhinand, Chandran S.;Raju, Rajesh;Sudhakaran, Perumana R.
通讯作者：
Sudhakaran, Perumana R.
DOI：
10.1097/iae.0000000000001763
发表时间：
2018-08-01
影响因子：
3.3
作者：
Jin, Enzhong;Yin, Hong;Zhao, Mingwei
通讯作者：
Zhao, Mingwei
影响因子：
5.4
作者：
Blanco, Raquel;Gerhardt, Holger
通讯作者：
Gerhardt, Holger