A novel small molecule ameliorates ocular neovascularisation and synergises with anti-VEGF therapy.
A novel small molecule ameliorates ocular neovascularisation and synergises with anti-VEGF therapy.
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DOI：
10.1038/srep25509
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发表时间：
2016-05-05
影响因子：
4.6
通讯作者：
Corson TW
中科院分区：
文献类型：
--
作者：
Sulaiman RS;Merrigan S;Quigley J;Qi X;Lee B;Boulton ME;Kennedy B;Seo SY;Corson TW
眼部新生血管形成是致盲眼病的基础，例如早产儿视网膜病、增殖性糖尿病视网膜病和湿性年龄相关性黄斑变性。这些疾病会导致不可逆转的视力丧失，并带来重大的健康和经济负担。针对血管内皮生长因子（VEGF）的生物制剂是主要的治疗方法。然而，高达 30% 的患者对这些药物没有反应，并且与眼部和全身副作用有关。因此，需要小分子眼部血管生成抑制剂来补充现有疗法。我们在眼部新生血管模型中检查了 SH-11037（一种抗血管生成同异黄酮类克马甾酮的合成衍生物）的安全性和治疗潜力。 SH-11037 在离体脉络膜发芽测定中剂量依赖性地抑制血管生成，并抑制斑马鱼幼虫的眼部发育血管生成。此外，与抗 VEGF 抗体相比，玻璃体内注射 SH-11037 (1μM) 显着减少了激光诱导 CNV 小鼠模型中的脉络膜新生血管 (CNV) 病变体积。此外，SH-11037 在体外和体内与抗 VEGF 治疗具有协同作用。高达 100μM 的 SH-11037 与眼部毒性症状无关，并且不会干扰视网膜功能或预先存在的视网膜脉管系统。因此，SH-11037 是一种安全有效的治疗小鼠眼部新生血管的方法，值得进一步的机制和药代动力学评估。
Ocular neovascularisation underlies blinding eye diseases such as retinopathy of prematurity, proliferative diabetic retinopathy, and wet age-related macular degeneration. These diseases cause irreversible vision loss, and provide a significant health and economic burden. Biologics targeting vascular endothelial growth factor (VEGF) are the major approach for treatment. However, up to 30% of patients are non-responsive to these drugs and they are associated with ocular and systemic side effects. Therefore, there is a need for small molecule ocular angiogenesis inhibitors to complement existing therapies. We examined the safety and therapeutic potential of SH-11037, a synthetic derivative of the antiangiogenic homoisoflavonoid cremastranone, in models of ocular neovascularisation. SH-11037 dose-dependently suppressed angiogenesis in the choroidal sprouting assay ex vivo and inhibited ocular developmental angiogenesis in zebrafish larvae. Additionally, intravitreal SH-11037 (1 μM) significantly reduced choroidal neovascularisation (CNV) lesion volume in the laser-induced CNV mouse model, comparable to an anti-VEGF antibody. Moreover, SH-11037 synergised with anti-VEGF treatments in vitro and in vivo. Up to 100 μM SH-11037 was not associated with signs of ocular toxicity and did not interfere with retinal function or pre-existing retinal vasculature. SH-11037 is thus a safe and effective treatment for murine ocular neovascularisation, worthy of further mechanistic and pharmacokinetic evaluation.