Locus-Level Changes in Macular Sensitivity in Patients with Retinitis Pigmentosa Treated with Oral N-acetylcysteine

Abstract

Purpose: To identify characteristics of loci associated with locus-level sensitivity loss or improvement during treatment with N-acetylcysteine (NAC) in retinitis pigmentosa (RP).

Design: Retrospective analysis of prospectively collected data in the FIGHT RP clinical trial.

Methods: Patients (n = 30) were treated with 600, 1,200, or 1,800 mg of NAC twice daily for 3 months and then 3 times/day for 3 months. Microperimetry locus-level changes between baseline and month 6 were correlated with baseline characteristics of loci using regression models. The main outcome measurement was locus-level sensitivity change ≥6 dB.

Results: Baseline mean sensitivity (3,468 loci; 51 evaluable eyes) was 7.7 dB and for foveal, parafoveal, and perifoveal loci were 20.2, 11.8, and 5.8 dB. During treatment, 287 loci (8.28%) increased ≥6 dB, and 119 of 1,613 loci with baseline sensitivity ≥6 dB decreased ≥6 dB (7.38%). A higher dose of NAC was associated with lower likelihood of sensitivity loss ≥6 dB (P = .033). Loci with low baseline sensitivity were more likely to decrease ≥6 dB (P = .034) but also more likely to increase ≥6 dB (P < .001). Foveal versus perifoveal loci (P < .001) and superior versus inferior loci (P = .005) were more likely to increase ≥6 dB.

Conclusions: Higher doses of NAC reduced risk of macular loci sensitivity loss in RP. Greater sensitivity depression reversibility in the fovea during treatment suggests that high foveal cone density protects cones from irreversible loss of function in RP making them more likely to show improved function during NAC treatment.

Conflict of interest statement

Declaration of Interests: None of the JHU authors have any conflict of interest related to this study. However, Johns Hopkins University has a licensing agreement concerning N-acetylcysteine amide with a company, Nacuity Pharmaceuticals, Inc (Nacuity), under which the University is entitled to royalty distributions and has equity in Nacuity. While this manuscript does not deal with N-acetylcysteine amide, it was judged by the Conflict of Interest Committee of Johns Hopkins University, that there is enough overlap between the drugs that reported results with N-acetylcysteine might have an effect on the value of N-acetylcysteine amide, and therefore we are declaring an institutional conflict of interest.

PAC has potential conflicts of interest unrelated to the subject of the manuscript: grants and personal fees from AERPIO Pharmaceuticals, personal fees and equity from Allegro, personal fees from Applied Genetic Technologies Corporation, personal fees from Asclepix Therapeutics, personal fees from Baucsh and Lomb, personal fees from Curevac, personal fees from Exonate Ltd, grants and personal fees from Genentech/Roche Inc, grants and personal fees from Sanofi Genzyme, grants, personal fees, and equity from Graybug Vision, personal fees from Merck & Co, Inc, personal fees from NOVARTIS Pharmaceuticals Corporation, grants and personal fees from Oxford Biomedica, grants and personal fees from Regeneron Pharmaceuticals, Inc, grants and personal fees from Regenxbio, Inc, personal fees from Wave Life Sciences.

None of the other authors have any conflicts of interest.

Copyright © 2020 Elsevier Inc. All rights reserved.

Figures

Figure 1.. The microperimetry test pattern used in the Fight-RP study.

The pattern included 68 test loci covering the central 20° of the retina. Eccentricy of the test loci was categorized into 3 regions: Foveal region included 4 loci distributed on the ring of 2° eccentricity (Loci 29, 30, 39, and 40); Parafoveal region included 12 loci distributed on the ring of 4° eccentricity (Loci 19–22, 28, 31, 38, 41, 47–50); and Perifoveal region included 52 loci distributed on the rings of 6°−10° eccentricity (Loci 1–18, 23–27, 32–37, 42–46, 51–68).

Figure 2.. Percent of loci losing sensitivity by ≥6dB during the 6 months of treatment by baseline loci sensitivity level

Bars show the percentage of loci with sensitivity loss ≥ 6 decibels (dB) during treatment as a function of baseline sensitivity. On the x-axis, parentheses beneath each group of 3 bars is the range of locus baseline sensitivity for that group: [6,8] = 6 to 8 dB, (8,12] = >8 to 12 dB, (12,16] = >12 to 16 dB, (16,20] = >16 to 20 dB, (20,24] = >20 to 24 dB, (24,28] = >24 to 28 dB, (28,32] = >28 to 32 dB, and (32,36] = >32 to 36 dB. The dose of NAC for each cohort was 600 mg bid for 3 months followed by 600 mg tid for 3 months for cohort 1, 1200 mg bid for 3 months followed by 1200 mg tid for 3 months for cohort 2, and 1800 mg bid for 3 months followed by 1800 mg tid for 3 months for cohort 3.

Figure 3.. Percent of loci gaining sensitivity by ≥6dB during the 6 months of treatment by baseline loci sensitivity level

Bars show the percentage of loci with sensitivity gain ≥ 6 decibels (dB) during treatment as a function of baseline sensitivity. On the x-axis, parentheses beneath each group of 3 bars is the range of locus baseline sensitivity for that group: [0] = 0 dB, (0,4] = >0 to 4 dB, (4,8] = >4 to 8 dB, (8,12] = >8 to 12 dB, (12,16] = >12 to 16 dB, (16,20] = >16 to 20 dB, (20,24] = >20 to 24 dB, (24,28] = >24 to 28 dB, and (28,32] = >28 to 32 dB. The dose of NAC for each cohort was 600 mg bid for 3 months followed by 600 mg tid for 3 months for cohort 1, 1200 mg bid for 3 months followed by 1200 mg tid for 3 months for cohort 2, and 1800 mg bid for 3 months followed by 1800 mg tid for 3 months for cohort 3.