Advanced late-onset retinitis pigmentosa with dominant-acting D477G RPE65 mutation is responsive to oral synthetic retinoid therapy
| Autor: | Philippe Brabet, Peter Humphries, Marian M. Humphries, Paul F. Kenna, Robert K. Koenekoop, Ema Ozaki, G. Jane Farrar, Matthew Campbell, Anna Sophia Kiang, Laurent Guillou |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Oncology medicine.medical_specialty retina Visual acuity Genetic enhancement degeneration Late onset 030105 genetics & heredity 03 medical and health sciences lcsh:Ophthalmology Internal medicine Retinitis pigmentosa Medicine genetics Pathological Original Research medicine.diagnostic_test business.industry clinical trial medicine.disease eye diseases Clinical trial Ophthalmology 030104 developmental biology RPE65 lcsh:RE1-994 medicine.symptom business treatment medical Electroretinography |
| Zdroj: | BMJ Open Ophthalmology BMJ Open Ophthalmology, Vol 5, Iss 1 (2020) |
| ISSN: | 2397-3269 |
| Popis: | ObjectivesNo 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 analysisA 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.ResultsPathological 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.ConclusionFamilies 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. |
| Databáze: | OpenAIRE |
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