NAC Attack AOSLO Reading Center

项目摘要/摘要 视网膜色素变性(RP)是一组遗传上不同的疾病，在中国约有10万人患病 美国。RP导致视杆细胞、视锥细胞和感光细胞进行性死亡，导致视力下降 失落和最终失明。没有治愈方法，有效的治疗方法也极其有限。使问题复杂化 治疗的努力是这样一个事实，即超过65个基因的突变会导致RP。因此，针对常见疾病的疗法 光感受器死亡和促进光感受器存活的机制是替代基因的有吸引力的选择。 具体方法。尽管杆状细胞在RP中最早丢失，但随后的锥体退变才是 对病人来说尤其具有破坏性。这种视锥细胞退化可能部分是由于氧化应激，以及 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细胞 动物模型中的功能和存活率。最近，一项关于RP(Fight-RP)患者的单中心研究 在所研究的所有NAC剂量下，视力都有改善，黄斑敏感度也有改善 接受最高剂量的患者。这些有希望的结果推动了一种 多中心、随机、安慰剂对照的第三阶段试验(NAC发作)，以测试NAC对减缓疾病的疗效 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。尽管南汽攻击审判的目的是 通过显示光感受器存活率的改善和标准结果来影响RP的临床治疗 在检测处理对NAC目标--单个锥体的影响方面，措施的敏感性有限。 自适应光学扫描光眼底镜(AOSLO)允许无创成像锥体马赛克与 单元格分辨率。AOSLO的初步研究显示，接受RP治疗的眼睛减少了视锥丢失 睫状神经营养因子(CNTF)与对侧假手术眼的比较；然而，CNTF治疗 视力没有改善(说明临床视觉功能测量的敏感性很低)。 这些数据显示了AOSLO在临床试验中的关键作用。此AOSLO资源的目标 该中心的目的是支持评价NAC在RP患者中的安全性和有效性。40名患者 在6个使用AOSLO系统的地点登记将在基线、随机后9个月、27个月和45个月进行成像，以 每天两次口服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，NAC治疗组的密度、锥体间距、锥体镶嵌规律性和锥体反射率 治疗眼在基线至45个月之间。圆满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。结果还将提供定量的 支持将锥体结构的AOSLO图像作为客观、敏感的结果衡量标准的数据 疾病进展，可以显著减少患者需要演示的时间和数量 其他实验性疗法对罕见的红斑狼疮患者是否安全有效。

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.