NAC Attack AOSLO Reading Center

项目总结/摘要 视网膜色素变性（RP）是一种遗传异质性疾病，影响约100，000人， 美国的RP导致杆细胞逐渐死亡，然后是锥细胞，光感受器导致无情的视觉 失去和最终失明。没有治愈方法，有效的治疗方法非常有限。复杂化 事实上，超过65个基因的突变导致RP。因此，针对常见的 光感受器死亡和促进光感受器存活的机制是有吸引力的替代基因， 具体方法。虽然在RP中杆最早丢失，但随后的视锥变性是RP的主要原因。 对病人来说尤其是毁灭性的。这种视锥细胞退化可能部分是由于氧化应激， 减少氧化损伤的治疗，如N-乙酰半胱氨酸（NAC），已被证明可以提高锥 在动物模型中的功能和存活。最近，一项在RP患者中进行的单中心研究（FIGHT-RP） 在所有研究的NAC剂量下， 接受最高剂量的患者。这些令人鼓舞的结果推动了 一项多中心、随机、安慰剂对照的3期试验（NAC发作），旨在测试NAC减缓 RP的进展。NAC攻击试验可能为氧化应激和铅的作用提供临床证据 以提高对RP中视锥细胞变性机制的理解。虽然NAC攻击试验旨在 通过证明改善感光细胞存活、标准结局来影响RP临床管理 测量对于检测治疗对单个视锥细胞（NAC的靶）的影响具有有限的灵敏度。 自适应光学扫描光检眼镜检查（AOSLO）允许锥镶嵌的非侵入性成像， 单细胞分辨率。使用AOSLO的初步研究显示RP治疗的眼睛中的视锥细胞丢失减少 睫状神经营养因子（CNTF）与对侧假治疗的眼睛相比， 眼睛显示视力没有改善（说明视觉功能的临床测量的低灵敏度）。 这些数据证明了AOSLO在临床试验中的关键作用。本AOSLO资源的目标 中心旨在支持评价NAC在RP患者中的安全性和有效性。四十名患者 将在基线、随机化后9个月、27个月和45个月对6家研究中心使用AOSLO系统入组的受试者进行成像， 口服NAC 1800 mg或安慰剂，每日两次。AOSLO图像将用于测量锥细胞的变化 与安慰剂相比，NAC治疗组的密度、视锥间距、视锥镶嵌规律性和视锥反射率 基线至45个月之间的治疗眼。成功完成此处所述的拟议研究 将支持FDA批准NAC用于治疗RP患者。研究结果还将提供定量的 数据，以支持验证AOSLO图像的锥体结构作为客观，敏感的结果措施， 疾病进展，这可能会显着减少所需的时间和患者数量，以证明 其他实验性疗法对罕见IRD患者是否安全有效。

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.