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BACKGROUNDIn retinitis pigmentosa (RP), rod photoreceptors degenerate from 1 of many mutations, after which cones are compromised by oxidative stress. N-acetylcysteine (NAC) reduces oxidative damage and increases cone function/survival in RP models. We tested the safety, tolerability, and visual function effects of oral NAC in RP patients.METHODSSubjects (n = 10 per cohort) received 600 mg (cohort 1), 1200 mg (cohort 2), or 1800 mg (cohort 3) NAC bid for 12 weeks and then tid for 12 weeks. Best-corrected visual acuity (BCVA), macular sensitivity, ellipsoid zone (EZ) width, and aqueous NAC were measured. Linear mixed-effects models were used to estimate the rates of changes during the treatment period.RESULTSThere were 9 drug-related gastrointestinal adverse events that resolved spontaneously or with dose reduction (maximum tolerated dose 1800 mg bid). During the 24-week treatment period, mean BCVA significantly improved at 0.4 (95% CI: 0.2-0.6, P < 0.001), 0.5 (95% CI: 0.3-0.7, P < 0.001), and 0.2 (95% CI: 0.02-0.4, P = 0.03) letters/month in cohorts 1, 2, and 3, respectively. There was no significant improvement in mean sensitivity over time in cohorts 1 and 2, but there was in cohort 3 (0.15 dB/month, 95% CI: 0.04-0.26). There was no significant change in mean EZ width in any cohort.CONCLUSIONOral NAC is safe and well tolerated in patients with moderately advanced RP and may improve suboptimally functioning macular cones. A randomized, placebo-controlled trial is needed to determine if oral NAC can provide long-term stabilization and/or improvement in visual function in patients with RP.TRIAL REGISTRATIONNCT03063021.FUNDINGMr. and Mrs. Robert Wallace, Mr. and Mrs. Jonathan Wallace, Rami and Eitan Armon, Marc Sumerlin, Cassandra Hanley, and Nacuity Pharmaceuticals, Inc.