NAC Attack AOSLO Reading Center

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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.