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Onset Retinitis Pigmentosa with Dominant- Acting D477G RPE65

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Onset Retinitis Pigmentosa with Dominant- Acting D477G RPE65 Original research BMJ Open Ophth: first published as 10.1136/bmjophth-2020-000462 on 5 May 2020. Downloaded from Advanced late- onset retinitis pigmentosa with dominant- acting D477G RPE65 mutation is responsive to oral synthetic retinoid therapy Paul F Kenna ,1,2 Marian M Humphries,1 Anna- Sophia Kiang,1 Philippe Brabet ,3 Laurent Guillou,3 Ema Ozaki,1 Matthew Campbell,1 G Jane Farrar,1 Robert Koenekoop,4 Pete Humphries 1 To cite: Kenna PF, ABSTRACT Humphries MM, Kiang A- S, Objectives No therapeutic interventions are currently Significance of the study et al. Advanced late- onset available for autosomal dominant retinitis pigmentosa retinitis pigmentosa with (adRP). An RPE65 Asp477Gly transition associates with What is already known about this subject? dominant- acting D477G RPE65 late- onset adRP, reduced RPE65 enzymatic activity being ► Oral synthetic retinoid therapy has been shown to be mutation is responsive to oral effective in improving vision in autosomal recessive synthetic retinoid therapy. one feature associated with this dominant variant. Our objective: to assess whether in a proof- of- concept study, cases of Leber congenital amaurosis (LCA) and reti- BMJ Open Ophthalmology nitis pigmentosa (RP). 2020;5:e000462. doi:10.1136/ oral synthetic 9 cis- retinyl acetate therapy improves vision bmjophth-2020-000462 in such advanced disease. What are the new findings? Methods and analysis A phase 1b proof- of- concept ► Oral retinoid therapy can be extended to families Additional material is ► clinical trial was conducted involving five patients with so far identified in five countries, in which a unique published online only. To view, advanced disease, aged 41–68 years. Goldmann visual please visit the journal online dominant- acting RPE65 mutation is present causing (http:// dx. doi. org/ 10. 1136/ fields (GVF) and visual acuities (VA) were assessed for late- onset RP with choroidal involvement. bmjophth- 2020- 000462). 6–12 months after 7- day treatment, patients receiving consecutive oral doses (40 mg/m2) of 9-cis- retinyl acetate, How might these results change the focus of a synthetic retinoid replacement. research or clinical practice? Received 9 March 2020 Results Pathological effects of D477G variant ► Oral synthetic retinoid therapy can be effective in Revised 30 March 2020 were preliminarily assessed by electroretinography subjects with this late- onset dominant form of dis- Accepted 2 April 2020 in mice expressing AAV-delivered D477G RPE65, by ease, where extensive retinal degeneration is evi- http://bmjophth.bmj.com/ MTS [3-(4,5- dimethylthiazol-2- yl)−5-(3- carboxyme- dent and where gene therapy would be unlikely to thoxyphenyl)−2-(4- sulfophenyl)−2H- tetrazolium] be beneficial. 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 (RP) and Leber congenital amaurosis (LCA).1 cellular function in vitro, D477G exhibited reduced In principle, administration of 11-cis - retinal enzymatic RPE65 activity in vitro. In patients, significant would assist in preventing retinal degenera- improvements were observed in GVF from baseline ranging tion in those IRDs where mutations within on September 26, 2021 by guest. Protected copyright. from 70% to 200% in three of five subjects aged 67–68 years, with largest improvements at 7–10 months. Of two genes of the retinoid cycle are present. While GVF non-responders, one had significant visual acuity 11-cis -retinal is unstable and not suitable for improvement (5–15 letters) from baseline after 6 months. pharmacological use, 9-cis -retinal can be used Conclusion Families with D477G variant have been as a replacement, forming iso-r hodopsin which identified in Ireland, the UK, France, the USA and Canada. retains function in photon capture and which Effects of single 7- day oral retinoid supplementation lasted has been shown, following intravitreal inoc- © Author(s) (or their at least 6 months, possibly giving visual benefit throughout ulation, to improve vision in dogs with null employer(s)) 2020. Re-use remaining life in patients with advanced disease, where mutations within the RPE65 gene.2 permitted under CC BY-NC. No gene therapy is unlikely to prove beneficial. QLT091001 (9-cis - retinyl acetate) is a late- commercial re- use. See rights and permissions. Published by stage synthetic retinoid replacement therapy BMJ. being developed for inherited retinal diseases For numbered affiliations see INTRODUCTION in humans (Retinagenix). It is a prodrug, end of article. Mutations in genes encoding enzymatic converted by hydrolysis in vivo to 9-cis - retinol, components of the retinoid cycle, reducing the which is then converted to 9- cis- retinal, thus Correspondence to availability of 11-cis - retinal, have been encoun- restoring the key biochemical component Dr Pete Humphries; Pete. tered in recessive forms of inherited retinal of the retinoid cycle. QLT091001 treatment Humphries@ tcd. ie degenerations (IRDs), retinitis pigmentosa has previously been shown to result in vision Kenna PF, et al. BMJ Open Ophth 2020;5:e000462. doi:10.1136/bmjophth-2020-000462 1 Open access BMJ Open Ophth: first published as 10.1136/bmjophth-2020-000462 on 5 May 2020. Downloaded from improvement (VA) and/or visual field (VF) in subjects pAAV expression vector (Cell Biolabs). AAV2/9 was with LCA or RP due to recessive mutations in either RPE65 generated using a triple transfection system in a stable or LRAT genes.3 4 The mutation, D477G in exon 13 of the transfected HEK293 cell line to enable generation of RPE65 gene is the only mutation within this gene so far high titre virus (Vector BioLabs); 3 µL of AAV2/9 virus identified manifesting autosomal dominant transmission.5 (3.56×1011 vector genomes/mL) was subretinally injected Families displaying this dominant mutation have now into WT C57BL/6J mice. been identified in Ireland, the UK, France, the USA and Newfoundland (Professor J. Green, personal communica- Animals tion).5–7 Procedures and animals used in this study were carried Knock- in mice expressing D477G allele have defi- out in accordance with regulations set out by The Health cits in retinal structure and function, with disruption Products Regulatory Authority, who are responsible for of the visual cycle, indicative of decreased RPE65 enzy- implementation of EU directive 2010/63/EU. C57BL/6J matic activity. Shin et al reported slower regeneration mice were used in this study. Animals were housed in a of 11-cis - retinaldehyde with lower electroretinographic specific pathogen- free environment in the University of (ERG) a- wave recovery following photobleaching, indi- Dublin, Trinity College. cating delayed dark adaptation.8 Choi et al conclude from Murine electroretinographic analysis X- ray crystallographic structural analysis that a possible mechanism for photoreceptor degeneration may involve Mice were dark- adapted overnight and all manipulations 9 carried out under dim red light as described previously D477G RPE65 cellular toxicity. They also observed 11 retinyl ester accumulation and slower regeneration of by Palfi et al. 11-cis - retinal after photobleaching in knock- in mice aged Transient plasmid transfection 9 months, and slow thinning of the retinal outer nuclear Human WT and D477G RPE65 cDNAs were individu- layer accompanied by decline in scotopic and photopic ally subcloned into mammalian expression vector pRK7 ERG, indicating loss of cone and rod photoreceptor downstream of a CMV promoter. Constructs were puri- function. Our in vitro data confirm a reduced enzymatic fied using QIAGEN Midi Prep kit (Qiagen, France) and activity of the variant of approximately 25%. However, transiently transfected into ARPE-19 cells (MTS assay) or aberrant splicing of D477G transcripts has recently been HEK293- L cells expressing lecithin retinol acyltransferase suggested as an alternative mechanism contributing to (isomerase activity assay) using Lipofectamine 2000 and reduced enzymatic activity and ultimately photoreceptor LTX Reagent, respectively (Invitrogen). degeneration.10 Hence, in vitro data may not accurately reflect the reduction in enzymatic activity occurring MTS assay in vivo. Nevertheless, it can be strongly inferred that a ARPE-19 cells (ATCC #CRL2302) were cultured under 3 component of the disease process in this very slowly standard conditions, plated in 96- well plates at 5×10 cells http://bmjophth.bmj.com/ progressing dominant retinopathy is limited availability per well and grown to 50% confluency. Transfection with of chromophore 11-cis - retinal and that oral synthetic reti- 40 ng plasmid per well was carried out in reduced serum noid therapy may be extendable in improving remaining medium. Transfected cells were incubated for 24 hours vision in patients with this genetic subtype of disease, and viability assessed by MTS assay using CellTiter 96 where, as yet, no means of prevention are available for AQueous One Solution as outlined by the manufacturer any form of dominant RP. ( www. promega. com). This experiment was repeated We report here further observations on the molecular eight times. For each experiment absorbance readings pathology of the disease relevant to a pilot proof- of- obtained were standardised to a percentage viability scale on September 26, 2021 by guest. Protected copyright. concept study in which effects of a single 1 week course by deeming those from cells transfected with WT RPE65 of oral retinoid therapy were assessed, and where VFs
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