Department of Pediatrics, Ophthalmology, Pharmacology, Hôpital Ste-Justine, Université de Montréal, Montreal, Quebec, Canada.
Invest Ophthalmol Vis Sci. 2012 Mar 9;53(3):1195-203. doi: 10.1167/iovs.11-9064.
Aganirsen, an antisense oligonucleotide inhibiting insulin receptor substrate (IRS)-1 expression, has been shown to promote the regression of pathologic corneal neovascularization in patients. In this study, the authors aimed to demonstrate the antiangiogenic activity of aganirsen in animal models of retinal neovascularization.
Eyedrops of aganirsen were applied daily in nonhuman primates after laser-induced choroidal neovascularization (CNV; model of wet age-related macular degeneration [AMD]) and in newborn rats after oxygen-induced retinopathy (OIR; model of ischemic retinopathy). Retinal aganirsen concentrations were assessed in rabbits and monkeys after topical delivery (21.5, 43, or 86 μg). Clinical significance was further evaluated by determination of IRS-1 expression in monkey and human retinal biopsy specimens.
Topical corneal application of aganirsen attenuated neovascular lesion development dose dependently in African green monkeys. The incidence of high-grade CNV lesions (grade IV) decreased from 20.5% in vehicle-treated animals to 1.7% (P < 0.05) at the 86-μg dose. Topical aganirsen inhibited retinal neovascularization after OIR in rats (P < 0.05); furthermore, a single intravitreal injection of aganirsen reduced OIR as effectively as ranibizumab, and their effects were additive. Significantly, topical applications of aganirsen did not interfere with physiological retinal vessel development in newborn rats. Retinal delivery after topical administration was confirmed, and retinal expression of IRS-1 was demonstrated to be elevated in patients with subretinal neovascularization and AMD.
Topical application of aganirsen offers a safe and effective therapy for both choroidal and retinal neovascularization without preventing its normal vascularization. Together, these findings support the clinical testing of aganirsen for human retinal neovascular diseases.
一种抑制胰岛素受体底物（IRS-1）表达的反义寡核苷酸 aganirsen 已被证明可促进病理性角膜新生血管消退。在这项研究中，作者旨在证明 aganirsen 在动物模型中对视网膜新生血管形成的抗血管生成活性。
在激光诱导脉络膜新生血管（CNV；湿性年龄相关性黄斑变性[AMD]模型）后，非人类灵长类动物每天应用 aganirsen 滴眼剂，在氧诱导视网膜病变（OIR；缺血性视网膜病变模型）后，新生大鼠应用 aganirsen 滴眼剂。在兔和猴中通过局部给药（21.5、43 或 86μg）评估视网膜 aganirsen 浓度。通过确定猴和人视网膜活检标本中的 IRS-1 表达进一步评估临床意义。
局部应用角膜 aganirsen 可剂量依赖性地减轻非洲绿猴的新生血管病变发展。高等级 CNV 病变（等级 IV）的发生率从载体处理动物的 20.5%降低至 86μg 剂量的 1.7%（P<0.05）。局部 aganirsen 抑制 OIR 后大鼠的视网膜新生血管形成（P<0.05）；此外，单次玻璃体内注射 aganirsen 可有效减少 OIR，且其作用具有相加性。重要的是，局部应用 aganirsen 不会干扰新生大鼠的生理视网膜血管发育。确认了局部给药后的视网膜递药，并且在有脉络膜新生血管和 AMD 的患者中观察到 IRS-1 的视网膜表达升高。
局部应用 aganirsen 为脉络膜和视网膜新生血管形成提供了一种安全有效的治疗方法，而不会阻止其正常血管化。这些发现共同支持了 aganirsen 用于人类视网膜新生血管疾病的临床测试。
