Inherited retinal diseases (IRDs) have been in the front line of gene therapy development for the last decade, providing a useful platform to test novel therapeutic approaches. More than 40 clinical trials have been completed or are ongoing, tackling autosomal recessive and X-linked conditions, mostly through adeno-associated viral vector delivery of a normal copy of the disease-causing gene. However, only recently has autosomal dominant (ad) disease been targeted, with the commencement of a trial for rhodopsin (RHO)-associated retinitis pigmentosa (RP), implementing antisense oligonucleotide (AON) therapy, with promising preliminary results (NCT04123626).
Autosomal dominant RP represents 15%–25% of all RP, with RHO accounting for 20%–30% of these cases. Autosomal dominant macular and cone-rod dystrophies (MD/CORD) correspond to approximately 7.5% of all IRDs, and approximately 35% of all MD/CORD cases, with the main causative gene being BEST1. Autosomal dominant IRDs are not only less frequent than recessive, but also tend to be less severe and have later onset; for example, an individual with RHO-adRP would typically become severely visually impaired at an age 2–3 times older than in X-linked RPGR-RP.
Gain-of-function and dominant negative aetiologies are frequently seen in the prevalent adRP genes RHO, RP1 and PRPF31 among others, which would not be effectively addressed by gene supplementation alone and need creative, novel approaches. Zinc fingers, RNA interference, AON, translational read-through therapy, and gene editing by clustered regularly interspaced short palindromic repeats/Cas are some of the strategies that are currently under investigation and will be discussed here.
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Data availability statement
All data relevant to the study are included in the article or uploaded as online supplemental information.
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Correction notice The second author's first name has been corrected since this article was first published.
Contributors All authors contributed to the design of this review article, literature review, manuscript preparation and review. The authors were responsible for all content and editorial decision.
Funding This work was supported by grants from The Wellcome Trust (099173/Z/12/Z), the National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, Moorfields Eye Charity, Retina UK and the Foundation Fighting Blindness (no specific grant/award number for the latter).
Disclaimer The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.
Competing interests The authors alone are responsible for the content and writing of this article. MM consults for MeiraGTx Ltd and TG is MeiraGTx Ltd staff.
Provenance and peer review Not commissioned; externally peer reviewed.