Advanced late-onset retinitis pigmentosa with dominant-acting D477G RPE65 mutation is responsive to oral synthetic retinoid therapy. Issue 1 (5th May 2020)

• Record Type: Journal Article
• Authors: Kenna, Paul F; Humphries, Marian M; Kiang, Anna-Sophia; Brabet, Philippe; Guillou, Laurent; Ozaki, Ema; Campbell, Matthew; Farrar, G Jane; Koenekoop, Robert; Humphries, Pete
• Is Part Of: BMJ open ophthalmology. Volume 5:Issue 1(2020)
• Publication Date: 2020-05-05
• Subjects: clinical trial -- degeneration -- genetics -- retina -- treatment medical; Ophthalmology -- Periodicals; 617.7005
• DOI: 10.1136/bmjophth-2020-000462
• Languages: English
• ISSNs: 2397-3269

Abstract

Abstract : Objectives: No therapeutic interventions are currently available for autosomal dominant retinitis pigmentosa (adRP). An RPE65 Asp477Gly transition associates with late-onset adRP, reduced RPE65 enzymatic activity being one feature associated with this dominant variant. Our objective: to assess whether in a proof-of-concept study, oral synthetic 9 cis -retinyl acetate therapy improves vision in such advanced disease. Methods and analysis: A phase 1b proof-of-concept clinical trial was conducted involving five patients with advanced disease, aged 41–68 years. Goldmann visual fields (GVF) and visual acuities (VA) were assessed for 6–12 months after 7-day treatment, patients receiving consecutive oral doses (40 mg/m 2 ) of 9- cis- retinyl acetate, a synthetic retinoid replacement. Results: Pathological effects of D477G variant were preliminarily assessed by electroretinography in mice expressing AAV-delivered D477G RPE65, by MTS [3-(4, 5-dimethylthiazol-2-yl)−5-(3-carboxyme- thoxyphenyl)−2-(4-sulfophenyl)−2H-tetrazolium] assays on RPE viability and enzyme activity in cultured cells. In addition to a mild dominant effect reflected in reduced electroretinographics in mice, and reduced cellular function in vitro, D477G exhibited reduced enzymatic RPE65 activity in vitro . In patients, significant improvements were observed in GVF from baseline ranging from 70% to 200% in three of five subjects aged 67–68 years, with largest improvements at 7–10 months. Of two GVF non-responders, one had significant visual acuity improvement (5–15 letters) from baseline after 6 months. Conclusion: Families with D477G variant have been identified in Ireland, the UK, France, the USA and Canada. Effects of single 7-day oral retinoid supplementation lasted at least 6 months, possibly giving visual benefit throughout remaining life in patients with advanced disease, where gene therapy is unlikely to prove beneficial.