Oral N-acetylcysteine improves cone function in retinitis pigmentosa patients in phase I trial
Peter A. Campochiaro, … , Mandeep S. Singh, Xiangrong Kong
Peter A. Campochiaro, … , Mandeep S. Singh, Xiangrong Kong
Published December 5, 2019
Citation Information: J Clin Invest. 2020;130(3):1527-1541. https://doi.org/10.1172/JCI132990.
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Clinical Medicine Neuroscience Ophthalmology

Oral N-acetylcysteine improves cone function in retinitis pigmentosa patients in phase I trial

Abstract

BACKGROUND In 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.METHODS Subjects (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.RESULTS There 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.CONCLUSION Oral 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 REGISTRATION NCT03063021.FUNDING Mr. and Mrs. Robert Wallace, Mr. and Mrs. Jonathan Wallace, Rami and Eitan Armon, Marc Sumerlin, Cassandra Hanley, and Nacuity Pharmaceuticals, Inc.

Authors

Peter A. Campochiaro, Mustafa Iftikhar, Gulnar Hafiz, Anam Akhlaq, Grace Tsai, Dagmar Wehling, Lili Lu, G. Michael Wall, Mandeep S. Singh, Xiangrong Kong

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Figure 7

Heatmaps and fundus images from microperimetry testing during treatment and posttreatment observation in 2 patients from cohort 3.

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Heatmaps and fundus images from microperimetry testing during treatment ...
The heatmaps generated by the Macular Integrity Assessment Instrument software (A–D and I–L) and fundus images showing the sensitivity value at each retinal location (E–H and M–P) obtained pretreatment, during treatment at weeks 12 and 24, and after treatment at week 36 are shown for 1 eye of patients 3-06 and 3-08 in cohort 3. Two pretreatment tests were obtained and the one with the highest mean sensitivity is shown. In heatmaps, the arrows point to regions where the retinal sensitivity improved after the onset of treatment. A change from an arrow to an arrowhead indicates improvement had occurred, and any subsequent decline is noted by a change from arrowhead to arrow. The loci circled in yellow on the pretreatment fundus images (E and M) show loci at which sensitivity increased equal to or more than 6 dB after the onset of treatment. On subsequent fundus images, green circles indicate that sensitivity at that location was increased equal to or more than 6 dB from pretreatment and a change back to yellow indicates a decline below the 6 dB threshold. In the right eye of patient 3-06, there was a large improvement in macular sensitivity during treatment that regressed after treatment. In the right eye of patient 3-08, there was a large improvement in macular sensitivity that was partially sustained 3 months after stopping treatment.