Ranibizumab for Advanced Ocular Disease of VHL Disease

Von Hippel-Lindau综合征（VHL）是一种常染色体显性遗传病，在肾脏、肾上腺、胰腺、脑、脊髓、眼睛、内耳、附睾和宽韧带中发生多种良性和恶性肿瘤和囊肿。视网膜血管瘤可能是VHL疾病的早期表现之一，并可能导致受影响个体的视力显著下降。这些肿瘤很少自发消退。视力丧失的主要原因是视网膜水肿，特别是继发于视网膜周围血管瘤或视盘上或周围血管瘤扩大的黄斑水肿。视网膜血管瘤的治疗取决于病变的位置和大小，但通常包括光凝或冷冻治疗。然而，对于视神经上或视神经周围的VHL眼部病变或视网膜周围的病变太大而无法对传统疗法产生反应，目前还没有被证明有效的治疗方法。在VHL疾病中发现的基因突变上调了血管内皮生长因子（VEGF）的产生。VHL眼部病变的免疫化学研究，以及在身体其他部位发现的其他病变，显示VEGF显著增加。这项开放标签研究将在5名参与者中试点使用抗vegf疗法雷尼珠单抗（rhuFab V2），以研究其治疗视网膜血管瘤相关VHL的潜在疗效。参与者将在6个月的时间内接受7次研究药物的玻璃体内注射，在治疗开始后的1年随访期间，可以选择最多7次相同剂量和时间表的额外注射。主要结果将是1年后最佳矫正视力改变15个字母或更多。次要结果将是一年内视网膜增厚和渗漏的减少，以及包括局部和全身毒性在内的不良事件。

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, ranibizumab (rhuFab V2) in 5 participants to investigate the potential efficacy as a treatment for retinal angiomas associated with VHL. Participants will receive 7 intravitreal injections of study drug over a 6-month period, with the option of up to seven additional injections at the same dose and schedule during follow-up for a period of 1 year after the initiation of treatment. The primary outcome will be a change in the best-corrected visual acuity of 15 letters or more at 1 year. The secondary outcomes will be a reduction in retinal thickening and leakage at one year, and adverse events including local and systemic toxicities.