NAC Attack AOSLO Reading Center

NAC 攻击 AOSLO 阅读中心

• 批准号: 10593914
• 负责人: Joseph Carroll
• 金额: $ 20.31万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-17 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10593914
• 关键词: Abbreviations; Acetylcysteine; Affect; Agreement; Animal Model; Blindness; Cells; Certification; Cessation of life; Ciliary Neurotrophic Factor; Clinical; Clinical Management; Clinical Trials; Cone; Contralateral; Cysteine; Data; Development; Disease; Disease Progression; Dose; Evaluation; Eye; Future; Genes; Genetic; Goals; Healthcare; Human; Human Resources; Image; Imaging Techniques; Individual; Infrastructure; Intervention; Investigational Therapies; Light; Measures; Methods; Mutation; Night Blindness; Ophthalmoscopy; Optical Coherence Tomography; Oral; Outcome Measure; Oxidative Stress; Participant; Patients; Peripheral; Persons; Photoreceptors; Placebo Control; Placebos; Randomized; Reading; Resolution; Resources; Retina; Retinal Cone; Retinal Degeneration; Retinitis Pigmentosa; Rod; Role; Safety; Scanning; Site; Structure; System; Testing; Time; Training; United States; Validation; Vertebrate Photoreceptors; Vision; Visit; Visual Acuity; Visual Fields; adaptive optics; antioxidant therapy; clinical imaging; commercialization; cost; cost effective; density; effective therapy; efficacy testing; functional improvement; improved; inherited retinal degeneration; macula; mosaic; non-invasive imaging; oxidative damage; participant enrollment; phase III trial; photoreceptor degeneration; prevent; response; success; targeted treatment; therapy development; treatment duration; treatment effect; treatment trial

PROJECT SUMMARY/ABSTRACT Retinitis pigmentosa (RP) is a genetically heterogeneous group of diseases affecting about 100,000 people in the United States. RP causes progressive death of rod, then cone, photoreceptors resulting in relentless vision loss and ultimate blindness. There are no cures, and effective treatments are extremely limited. Complicating treatment efforts is the fact that mutations in over 65 genes cause RP. As such, therapies that target common mechanisms of photoreceptor death and promote photoreceptor survival are attractive alternatives to gene- specific methods. Although rods are lost earliest in RP, it is the subsequent cone degeneration that is particularly devastating for patients. This cone degeneration may be due in part to oxidative stress, and treatments that reduce oxidative damage such as N-acetylcysteine (NAC) have been shown to improve cone function and survival in animal models. Recently, a single-center study in patients with RP (FIGHT-RP) demonstrated improvement in visual acuity at all NAC doses studied, and improvement in macular sensitivity in patients who received the highest dose. These promising results have motivated the development of a multicenter, randomized, placebo-controlled Phase 3 trial (NAC Attack) to test the efficacy of NAC to slow progression of RP. The NAC Attack trial may provide clinical evidence of the role of oxidative stress and lead to improved understanding of cone degeneration mechanisms in RP. Although the NAC Attack trial aims to impact clinical management of RP by demonstrating improved photoreceptor survival, standard outcome measures have limited sensitivity to detect effects of treatments on individual cones, the target of NAC. Adaptive optics scanning light ophthalmoscopy (AOSLO) allows non-invasive imaging of the cone mosaic with single-cell resolution. Preliminary studies using AOSLO showed reduced cone loss in eyes with RP treated with ciliary neurotrophic factor (CNTF) compared to contralateral sham-treated eyes; however, CNTF-treated eyes showed no improvement in vision (illustrating the low sensitivity of clinical measures of visual function). These data demonstrate a critical role for AOSLO in clinical trials. The objective of this AOSLO Resource Center is to support the evaluation of the safety and efficacy of NAC in patients with RP. Forty patients enrolled at 6 sites with AOSLO systems will be imaged at baseline, 9, 27 and 45 months after randomization to receive oral NAC 1800 mg or a placebo twice a day. AOSLO images will be used to measure changes in cone density, cone spacing, cone mosaic regularity and cone reflectivity in NAC-treated compared to placebo- treated eyes between baseline and 45 months. Successful completion of the proposed studies described here would support FDA approval of NAC for treatment of patients with RP. The results will also provide quantitative data to support validation of AOSLO images of cone structure as objective, sensitive outcome measures of disease progression which could significantly reduce the time and numbers of patients required to demonstrate whether other experimental therapies are safe and effective for patients with rare IRDs.

项目概要/摘要 色素性视网膜炎 (RP) 是一组遗传异质性疾病，影响约 100,000 人 美国。 RP 导致视杆细胞逐渐死亡，然后是视锥细胞、光感受器逐渐死亡，导致视力持续下降 损失和最终失明。目前尚无治愈方法，有效的治疗方法也极其有限。并发 治疗努力的一个事实是，超过 65 个基因的突变会导致 RP。因此，针对常见的治疗 光感受器死亡机制和促进光感受器存活是基因治疗的有吸引力的替代方案 具体方法。虽然视杆细胞在 RP 中最早丧失，但随后的视锥细胞退化才是最重要的。 对患者来说尤其具有毁灭性。这种视锥细胞退化可能部分是由于氧化应激，并且 减少氧化损伤的治疗如 N-乙酰半胱氨酸 (NAC) 已被证明可以改善锥体 动物模型中的功能和生存。最近，一项针对 RP 患者的单中心研究（FIGHT-RP） 证明在所有研究的 NAC 剂量下视力均有所改善，并且黄斑敏感性有所改善 接受最高剂量的患者。这些有希望的结果推动了 多中心、随机、安慰剂对照 3 期试验（NAC Attack），测试 NAC 减缓的功效 RP 的进展。 NAC Attack 试验可能提供氧化应激和铅作用的临床证据 提高对 RP 视锥细胞退化机制的理解。尽管 NAC 攻击试验的目的是 通过证明光感受器存活率和标准结果的改善来影响 RP 的临床管理 措施对于检测治疗对单个视锥细胞（NAC 的目标）的影响的敏感性有限。 自适应光学扫描光检眼镜 (AOSLO) 可以对锥形镶嵌体进行非侵入性成像 单细胞分辨率。使用 AOSLO 的初步研究表明，经过 RP 治疗的眼睛中视锥细胞损失减少 与对侧假治疗眼相比，使用睫状神经营养因子（CNTF）；然而，CNTF处理 眼睛的视力没有改善（说明视觉功能的临床测量灵敏度较低）。 这些数据证明了 AOSLO 在临床试验中的关键作用。此 AOSLO 资源的目标 中心将支持评估 NAC 对 RP 患者的安全性和有效性。四十名患者 在 6 个地点使用 AOSLO 系统登记的患者将在随机分组后的基线、9、27 和 45 个月进行成像 每天两次口服 NAC 1800 mg 或安慰剂。 AOSLO 图像将用于测量锥体的变化 与安慰剂相比，NAC 治疗组的密度、视锥间距、视锥镶嵌规则性和视锥反射率 在基线和 45 个月之间接受过治疗的眼睛。成功完成此处描述的拟议研究 将支持 FDA 批准 NAC 用于治疗 RP 患者。结果还将提供定量 数据支持验证锥体结构的 AOSLO 图像作为客观、敏感的结果测量 疾病进展可以显着减少证明所需的时间和患者数量 其他实验疗法对于罕见 IRD 患者是否安全有效。