Article Text
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/m2) 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.
- clinical trial
- degeneration
- genetics
- retina
- treatment medical
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Footnotes
Contributors Contributors PFK: mouse ocular injections, electroretinographic analysis, Clinical Trial Investigator in Dublin, manuscript preparation. MMH: AAV and cDNA vector construction, RNA and PCR analysis, manuscript preparation. A-SK: cell viability assays and manuscript preparation. PB/LG: enzymatic assays and western blot analysis. EO: retinal sectioning. MC: OCT analysis. GJF: experimental design, manuscript preparation. RKK: clinical trial at Montreal, manuscript preparation. PH: experimental design, manuscript preparation.
Funding Supported at Trinity College Dublin by FB-Ireland/Health Research Board (MRCG) and Science Foundation Ireland; at Neurosciences Institute, Montpellier by ANR; RKK financed by FB-Canada, NIH, CIHR. Programme sponsored by Novelion (formerly QLT).
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, conduct, reporting or dissemination plans of this research.
Patient consent for publication Not required.
Ethics approval This two-centre study was carried out at the Montreal Children’s Hospital, McGill University Health Center in Montreal and at the Royal Victoria Eye and Ear Hospital, Dublin, approved by the MUHC and MCH, REB in Montreal and the Ethics and Medical Research Committee of St. Vincent's University Hospital, Dublin.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.