NAC Attack AOSLO Reading Center

NAC 攻击 AOSLO 阅读中心

• 批准号: 10334337
• 负责人: Joseph Carroll
• 金额: $ 18.02万
• 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/10334337
• 关键词: Abbreviations; Acetylcysteine; Affect; Agreement; Animal Model; Blindness; Cells; Cessation of life; Ciliary Neurotrophic Factor; Clinical; Clinical Management; Clinical Trials; Cone; Contralateral; Cysteine; Data; Development; Disease; Disease Progression; Dose; Enrollment; Evaluation; Eye; Future; Genes; Genetic; Goals; Healthcare; Human; Human Resources; Image; Imaging Techniques; Individual; Infrastructure; Intervention; Investigational Therapies; Lead; Light; Measures; Methods; Mosaicism; 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; Vision; Visual Acuity; Visual Fields; adaptive optics; adaptive optics scanning laser ophthalmoscopy; antioxidant therapy; clinical imaging; commercialization; cost; cost effective; density; effective therapy; efficacy testing; improved; improved functioning; inherited retinal degeneration; macula; non-invasive imaging; overtreatment; oxidative damage; phase III trial; photoreceptor degeneration; prevent; response; retinal rods; 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.

项目摘要/摘要 视网膜炎色素（RP）是一组遗传异质性疾病，影响了约100,000人 美国。 RP导致杆的渐进死亡，然后导致锥体，感光体导致无情的视力 损失和最终失明。没有治疗方法，有效的治疗非常有限。并发 治疗工作是一个超过65个基因的突变引起RP的事实。因此，靶向常见的疗法 光感受器死亡和促进光感受器存活的机制是基因的有吸引力的替代品 特定方法。尽管杆最早在RP中丢失，但随后的锥变性是 患者特别毁灭性。该锥变性可能部分是由于氧化应激，并且 减少氧化损伤（例如N-乙酰半胱氨酸（NAC））的处理已显示可改善锥体 动物模型的功能和生存。最近，一项针对RP患者（Fight-RP）的单中心研究 在所有研究的NAC剂量方面都显示出视力的提高，并提高了黄斑灵敏度 接受最高剂量的患者。这些有希望的结果促使了 多中心，随机，安慰剂控制的第三阶段试验（NAC攻击）测试NAC的疗效缓慢 RP的进展。 NAC攻击试验可以提供氧化应激作用的临床证据和铅的作用 改善RP中锥变性机制的理解。尽管NAC攻击审判的目的是 通过证明具有改善的感光体存活，标准结果来影响RP的临床管理 措施的敏感性有限，可以检测治疗对单个锥体的影响，即NAC的靶标。 自适应光学扫描光眼镜检查（AOSLO）允许对锥体镶嵌的侵入性成像与 单细胞分辨率。使用AOSLO的初步研究显示，经过RP处理的眼睛的锥体损失减少 与对侧假治疗的眼睛相比，与睫状神经营养因子（CNTF）相比；但是，经CNTF处理 眼睛没有视力改善（说明视觉功能临床量度的低灵敏度）。 这些数据在临床试验中表明了AOSLO的关键作用。这个Aoslo资源的目的 中心旨在支持NAC对RP患者的安全性和功效的评估。四十位患者 随机分组后的9、27和45个月，将在6个具有AOSLO系统的站点招募，将成像 每天两次接受口服NAC 1800毫克或安慰剂。 AOSLO图像将用于测量锥体的变化 与安慰剂相比 在基线到45个月之间治疗的眼睛。成功完成此处描述的拟议研究 将支持FDA批准NAC治疗RP患者。结果还将提供定量 数据以支持验证锥体结构的AOSLO图像作为客观，敏感的结果度量的数据 疾病进展可能会大大减少所需的患者的时间和数量 其他实验疗法是否对稀有IRD的患者安全有效。