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Advanced late-onset retinitis pigmentosa with dominant-acting D477G RPE65 mutation is responsive to oral synthetic retinoid therapy
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 wheth...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BMJ Publishing Group
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7228561/ https://www.ncbi.nlm.nih.gov/pubmed/32426524 http://dx.doi.org/10.1136/bmjophth-2020-000462 |
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author | Kenna, Paul F Humphries, Marian M Kiang, Anna-Sophia Brabet, Philippe Guillou, Laurent Ozaki, Ema Campbell, Matthew Farrar, G Jane Koenekoop, Robert Humphries, Pete |
author_facet | Kenna, Paul F Humphries, Marian M Kiang, Anna-Sophia Brabet, Philippe Guillou, Laurent Ozaki, Ema Campbell, Matthew Farrar, G Jane Koenekoop, Robert Humphries, Pete |
author_sort | Kenna, Paul F |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7228561 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | BMJ Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-72285612020-05-18 Advanced late-onset retinitis pigmentosa with dominant-acting D477G RPE65 mutation is responsive to oral synthetic retinoid therapy Kenna, Paul F Humphries, Marian M Kiang, Anna-Sophia Brabet, Philippe Guillou, Laurent Ozaki, Ema Campbell, Matthew Farrar, G Jane Koenekoop, Robert Humphries, Pete BMJ Open Ophthalmol Original Research 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. BMJ Publishing Group 2020-05-05 /pmc/articles/PMC7228561/ /pubmed/32426524 http://dx.doi.org/10.1136/bmjophth-2020-000462 Text en © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. http://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/. |
spellingShingle | Original Research Kenna, Paul F Humphries, Marian M Kiang, Anna-Sophia Brabet, Philippe Guillou, Laurent Ozaki, Ema Campbell, Matthew Farrar, G Jane Koenekoop, Robert Humphries, Pete Advanced late-onset retinitis pigmentosa with dominant-acting D477G RPE65 mutation is responsive to oral synthetic retinoid therapy |
title | Advanced late-onset retinitis pigmentosa with dominant-acting D477G RPE65 mutation is responsive to oral synthetic retinoid therapy |
title_full | Advanced late-onset retinitis pigmentosa with dominant-acting D477G RPE65 mutation is responsive to oral synthetic retinoid therapy |
title_fullStr | Advanced late-onset retinitis pigmentosa with dominant-acting D477G RPE65 mutation is responsive to oral synthetic retinoid therapy |
title_full_unstemmed | Advanced late-onset retinitis pigmentosa with dominant-acting D477G RPE65 mutation is responsive to oral synthetic retinoid therapy |
title_short | Advanced late-onset retinitis pigmentosa with dominant-acting D477G RPE65 mutation is responsive to oral synthetic retinoid therapy |
title_sort | advanced late-onset retinitis pigmentosa with dominant-acting d477g rpe65 mutation is responsive to oral synthetic retinoid therapy |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7228561/ https://www.ncbi.nlm.nih.gov/pubmed/32426524 http://dx.doi.org/10.1136/bmjophth-2020-000462 |
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