Campochiaro Peter A, Lauer Andreas K, Sohn Elliott H, Mir Tahreem A, Naylor Stuart, Anderton Matthew C, Kelleher Michelle, Harrop Richard, Ellis Scott, Mitrophanous Kyriacos A
1 The Wilmer Eye Institute, Johns Hopkins University School of Medicine , Baltimore, Maryland.
2 Casey Eye Institute, Oregon Health and Science University , Portland Oregon.
Hum Gene Ther. 2017 Jan;28(1):99-111. doi: 10.1089/hum.2016.117. Epub 2016 Sep 26.
Neovascular age-related macular degeneration (NVAMD) is a prevalent cause of vision loss. Intraocular injections of VEGF-neutralizing proteins provide benefit, but many patients require frequent injections for a prolonged period. Benefits are often lost over time due to lapses in treatment. New treatments that sustain anti-angiogenic activity are needed. This study tested the safety and expression profile of a lentiviral Equine Infectious Anemia Virus (EIAV) vector expressing endostatin and angiostatin (RetinoStat). Patients with advanced NVAMD were enrolled at three centers in the United States, and the study eye received a subretinal injection of 2.4 × 10 (n = 3), 2.4 × 10 (n = 3), or 8.0 × 10 transduction units (TU; n = 15). Each of the doses was well-tolerated with no dose-limiting toxicities. There was little or no ocular inflammation. There was one procedure-related serious adverse event (AE), a macular hole, which was managed without difficulty and resolved. There was a vector dose-related increase in aqueous humor levels of endostatin and angiostatin with high reproducibility among subjects within cohorts. Mean levels of endostatin and angiostatin peaked between 12 and 24 weeks after injection of 2.4 × 10 TU or 8.0 × 10 TU at 57-81 ng/mL for endostatin and 15-27 ng/mL for angiostatin, and remained stable through the last measurement at week 48. Long-term follow-up demonstrated expression was maintained at last measurement (2.5 years in eight subjects and >4 years in two subjects). Despite an apparent reduction in fluorescein angiographic leakage that broadly correlated with the expression levels in the majority of patients, only one subject showed convincing evidence of anti-permeability activity in these late-stage patients. There was no significant change in mean lesion size in subjects injected with 8.0 × 10 TU. These data demonstrate that EIAV vectors provide a safe platform with robust and sustained transgene expression for ocular gene therapy.
新生血管性年龄相关性黄斑变性（NVAMD）是导致视力丧失的常见原因。眼内注射VEGF中和蛋白可带来益处，但许多患者需要长期频繁注射。由于治疗中断，益处往往会随着时间的推移而丧失。因此需要能够维持抗血管生成活性的新疗法。本研究测试了表达内皮抑素和血管生成抑素的慢病毒马传染性贫血病毒（EIAV）载体（RetinoStat）的安全性和表达谱。美国三个中心招募了晚期NVAMD患者，研究眼接受了视网膜下注射2.4×10（n = 3）、2.4×10（n = 3）或8.0×10转导单位（TU；n = 15）。每个剂量均耐受性良好，无剂量限制性毒性。几乎没有眼部炎症。有1例与手术相关的严重不良事件（AE），即黄斑裂孔，处理起来没有困难且已解决。在各队列的受试者中，房水中内皮抑素和血管生成抑素水平与载体剂量相关增加，且具有高度可重复性。在注射2.4×10 TU或8.0×10 TU后，内皮抑素和血管生成抑素的平均水平在12至24周达到峰值，内皮抑素为57 - 81 ng/mL，血管生成抑素为15 - 27 ng/mL，并在第48周的最后一次测量时保持稳定。长期随访表明，在最后一次测量时表达得以维持（8名受试者为2.5年，2名受试者超过4年）。尽管大多数患者中荧光素血管造影渗漏明显减少，且与表达水平大致相关，但在这些晚期患者中只有1名受试者显示出令人信服的抗渗漏活性证据。注射8.0×10 TU的受试者平均病变大小无显著变化。这些数据表明，EIAV载体为眼部基因治疗提供了一个安全的平台，具有强大且持续的转基因表达。
