Anti-VEGF Pegylated Aptamer for Advanced Ocular Disease

Von Hippel-Lindau综合征（VHL）是一种常染色体显性遗传性疾病， 多发性良性和恶性肿瘤和囊肿的特定组织病理发展， 肾脏、肾上腺、胰腺、脑、脊髓、眼、内耳、附睾和全身 韧带视网膜血管瘤可能是VHL病的最早表现之一， 导致受影响个体的视敏度显著降低。这些肿瘤很少 会自动退化视力下降的主要原因是视网膜水肿，特别是黄斑水肿。 继发于周围视网膜血管瘤或在其上或周围发现的血管瘤扩大的水肿 视盘视网膜血管瘤的治疗取决于病变的位置和大小， 通常包括光凝固或冷冻疗法。然而，没有被证明有效的 治疗视神经上或周围的VHL眼部损伤或 周边视网膜太大，无法对传统疗法作出反应。发现的基因突变 在VHL疾病中上调血管内皮生长因子（VEGF）的产生。 VHL眼部病变的免疫化学研究，以及其他发现在其他地方， 体部VEGF明显增高。这项开放标签研究将试验使用抗VEGF 在5例患者中进行EYE 001治疗，以研究作为视网膜病变治疗的潜在疗效 与VHL相关的血管瘤。患者将接受6次玻璃体内注射研究药物， 30-周期间，然后在开始注射后1年返回进行随访。主 结果将是在1年时最佳矫正视力改善15个字母或更多， 一年时视网膜增厚和渗漏减少，ERG振幅和隐式 时间和不良事件，包括局部和全身毒性。研究已经完成，手稿已提交出版。

Von Hippel-Lindau Syndrome (VHL) is an autosomal dominant heritable disorder in which multiple benign and malignant neoplasms and cysts of specific histopathologies develop in the kidney, adrenal gland, pancreas, brain, spinal cord, eye, inner ear, epididymis, and broad ligament. Retinal angioma may be one of the earliest manifestations of VHL disease and may lead to a significant decrease in visual acuity of the affected individual. These tumors rarely regress spontaneously. The main cause of vision loss is retinal edema, specifically macular edema secondary to enlargement of peripheral retinal angiomas or angiomas found on or around the optic disk. Treatment of retinal angiomas depends on the location and size of the lesions but typically consists of photocoagulation or cryotherapy. However, there is no proven effective therapy for the treatment of VHL ocular lesions on or surrounding the optic nerve or lesions in the peripheral retina too large to respond to the traditional therapies. The genetic mutation found in VHL disease up-regulates the production of vascular endothelial growth factor (VEGF). Immunochemical studies of the VHL ocular lesions, as well as others found elsewhere in the body show marked increase in VEGF. This open-label study will pilot the use of an anti-VEGF therapy (EYE001) in 5 patients to investigate the potential efficacy as a treatment for retinal angiomas associated with VHL. Patients will receive 6 intravitreal injections of study drug over a 30-week period, then return for a follow-up visit 1 year after initiating injections. The primary outcomes will be improvement in best corrected visual acuity of 15 letters or more at 1 year, reduction in retinal thickening and leakage at one year, changes in ERG amplitude and implicit time, and adverse events including local and systemic toxicities. The study is completed and the manuscript has been submitted for publication.