RNA-based therapies in inherited retinal diseases

Aniz Girach¹, Isabelle Audo^{2

3

4}, David G Birch⁵, Rachel M Huckfeldt⁶, Byron L Lam⁷, Bart P Leroy^{8

9}, Michel Michaelides¹⁰, Stephen R Russell¹¹, Juliana M F Sallum^{12

13}, Katarina Stingl^{14

15}, Stephen H Tsang^{16

17}, Paul Yang¹⁸

Affiliations

¹ ProQR Therapeutics, Zernikedreef 9, 2333 CK Leiden, the Netherlands.
² Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, Centre de référence maladies rares REFERET and INSERM-DHOS CIC 1423, CHNO des Quinze-Vingts, Paris, France.
³ Institute of Ophthalmology, University College London, London, UK.
⁴ Sorbonne Université, INSERM, CNRS, Institut de la Vision, Paris, France.
⁵ Retina Foundation of the Southwest, Dallas, TX, USA.
⁶ Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA, USA.
⁷ Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA.
⁸ Department of Ophthalmology & Center for Medical Genetics, Ghent University Hospital & Ghent University, Ghent, Belgium.
⁹ Division of Ophthalmology & Center for Cellular & Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
¹⁰ UCL Institute of Ophthalmology, University College London and Moorfields Eye Hospital, London, UK.
¹¹ The University of Iowa Institute for Vision Research, University of Iowa, Iowa City, IA, USA.
¹² Department of Ophthalmology, Universidade Federal de São Paulo, São Paulo, Brazil.
¹³ Instituto de Genética Ocular, São Paulo, Brazil.
¹⁴ Center for Ophthalmology, University Eye Hospital, University of Tübingen, Tübingen, Germany.
¹⁵ Center for Rare Eye Diseases, University of Tübingen, Tübingen, Germany.
¹⁶ Jonas Children's Vision Care and Bernard and Shirlee Brown Glaucoma Laboratory, Columbia Stem Cell Initiative, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.
¹⁷ Edward S. Harkness Eye Institute, New York-Presbyterian Hospital, New York, NY, USA.
¹⁸ Casey Eye Institute, Oregon Health & Science University, Portland, OR, USA.

PMID: 36388727
PMCID: PMC9643766
DOI: 10.1177/25158414221134602

Review

RNA-based therapies in inherited retinal diseases

Aniz Girach et al. Ther Adv Ophthalmol. 2022.

. 2022 Nov 4:14:25158414221134602.

doi: 10.1177/25158414221134602. eCollection 2022 Jan-Dec.

Authors

Affiliations

¹ ProQR Therapeutics, Zernikedreef 9, 2333 CK Leiden, the Netherlands.
² Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, Centre de référence maladies rares REFERET and INSERM-DHOS CIC 1423, CHNO des Quinze-Vingts, Paris, France.
³ Institute of Ophthalmology, University College London, London, UK.
⁴ Sorbonne Université, INSERM, CNRS, Institut de la Vision, Paris, France.
⁵ Retina Foundation of the Southwest, Dallas, TX, USA.
⁶ Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA, USA.
⁷ Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA.
⁸ Department of Ophthalmology & Center for Medical Genetics, Ghent University Hospital & Ghent University, Ghent, Belgium.
⁹ Division of Ophthalmology & Center for Cellular & Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
¹⁰ UCL Institute of Ophthalmology, University College London and Moorfields Eye Hospital, London, UK.
¹¹ The University of Iowa Institute for Vision Research, University of Iowa, Iowa City, IA, USA.
¹² Department of Ophthalmology, Universidade Federal de São Paulo, São Paulo, Brazil.
¹³ Instituto de Genética Ocular, São Paulo, Brazil.
¹⁴ Center for Ophthalmology, University Eye Hospital, University of Tübingen, Tübingen, Germany.
¹⁵ Center for Rare Eye Diseases, University of Tübingen, Tübingen, Germany.
¹⁶ Jonas Children's Vision Care and Bernard and Shirlee Brown Glaucoma Laboratory, Columbia Stem Cell Initiative, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.
¹⁷ Edward S. Harkness Eye Institute, New York-Presbyterian Hospital, New York, NY, USA.
¹⁸ Casey Eye Institute, Oregon Health & Science University, Portland, OR, USA.

PMID: 36388727
PMCID: PMC9643766
DOI: 10.1177/25158414221134602

Abstract

Inherited retinal diseases (IRDs) are a genetically and phenotypically heterogeneous group of genetic eye disorders. There are more than 300 disease entities, and together this group of disorders affects millions of people globally and is a frequent cause of blindness or low-vision certification. However, each type is rare or ultra-rare. Characteristically, the impaired vision in IRDs is due to retinal photoreceptor dysfunction and loss resulting from mutation in a gene that codes for a retinal protein. Historically, IRDs have been considered incurable and individuals living with these blinding conditions could be offered only supportive care. However, the treatment landscape for IRDs is beginning to evolve. Progress is being made, driven by improvements in understanding of genotype-phenotype relationships, through advances in molecular genetic testing and retinal imaging. Alongside this expanding knowledge of IRDs, the current era of precision medicine is fueling a growth in targeted therapies. This has resulted in the first treatment for an IRD being approved. Several other therapies are currently in development in the IRD space, including RNA-based therapies, gene-based therapies (such as augmentation therapy and gene editing), cell therapy, visual prosthetics, and optogenetics. RNA-based therapies are a novel approach within precision medicine that have demonstrated success, particularly in rare diseases. Three antisense oligonucleotides (AONs) are currently in development for the treatment of specific IRD subtypes. These RNA-based therapies bring several key advantages in the setting of IRDs, and the potential to bring meaningful vision benefit to individuals living with inherited blinding disorders. This review will examine the increasing breadth and relevance of RNA-based therapies in clinical medicine, explore the key features that make AONs suitable for treating genetic eye diseases, and provide an overview of the three-leading investigational AONs in clinical trials.

Keywords: QR-1123; RNA therapies; antisense oligonucleotides; genetic eye diseases; inherited retinal diseases; sepofarsen; ultevursen.

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Conflict of interest statement

The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: K.S., I.A., B.P.L., and M.M. are the members of ERN-EYE (www.ern-eye.eu). A.G. is an employee of ProQR Therapeutics. I.A. is a consultant/advisor for Novartis, Sparing Vision, Janssen, Roche, and ProQR Therapeutics; she is supported by the Foundation Fighting Blindness, Retina France, and UNADEV. D.G.B. reports support from the National Eye Institute EY09076 and Foundation Fighting Blindness; he has served as a consultant for ProQR Therapeutics, AGTC, Nacuity, Editas, and Biogen and has received clinical trial support from AGTC, ProQR Therapeutics, NightstaRx, and 4D Therapeutics. R.M.H. is a consultant for AGTC, Annexon, ProQR, Regeneron, and Vida Ventures and an advisor for Intergalactic Therapeutics; she receives grant funding from FFB and clinical trial support from AGTC, Biogen, MeiraGTx/Janssen, ProQR, and Spark. B.L.L. reports grant funding from ProQR Therapeutics, Biogen, AGTC, Allergan, and Spark Therapeutics; he has served as a consultant for ProQR Therapeutics, Biogen, and Allergan. B.P.L. is a Senior Clinical Investigator of the Research Foundation – Flanders, Belgium (Grant No. 1.8.038.11 N); he reports trial support from Second Sight Medical Products, consultancy fees from Bayer, REGENXBIO, and Vedere Bio, and trial support and consultancy fees and travel support from GenSight Therapeutics, IVERIC Bio, Novartis Pharma, Spark Therapeutics, and ProQR Therapeutics; he reports no personal financial gain, with all consultancy fees paid into Ghent University Hospital research accounts to support research. M.M. is supported by a grant from the National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology. S.R.R. reports grant funding from Spark Therapeutics and ProQR Therapeutics, is a consultant for Novartis and co-founded an artificial intelligence-based retinal imaging company, Digital Diagnostics Incorporated (formerly IDx, LLC). J.M.F.S. has nothing to disclose. K.S. is or has served as a consultant for ProQR Therapeutics, ViGeneron, Novartis, Santen and Nayan, with consultancy fees paid to the Center for Ophthalmology, University of Tuebingen to support research. S.H.T. receives salary from the National Institute of Health (Health U01 EY030580, U54OD020351, R24EY028758, R24EY027285, R01EY018213, R01EY024698, R01EY026682), New York State (SDHDOH01-C32590GG-3450000), Research to Prevent Blindness and Alcon Research Institute, and serves as a consultant for SAB, EmendoBio, Nanoscope, and Rejuvitas. P.Y. is supported by grant from the Foundation Fighting Blindness TRAP1 Award (TA-NMT-0521-0803-OHSU-TRAP), the National Institutes of Health (Bethesda, MD) (P30 EY010572), and by unrestricted departmental funding from Research to Prevent Blindness (New York, NY); he serves as a consultant for 4D Molecular Therapeutics, Adverum, AGTC, Annexon Bio, EcoR1, ExpertConnect, Guidepoint, Janssen, MeiraGTx, Nanoscope Therapeutics, Otonomy, ProQR and Vedere and receives research support from 4D Molecular Therapeutics, Acucela, AGTC, Biogen, Editas, Foundation Fighting Blindness, Iveric bio, ProQR Therapeutics, Reneuron, Sanofi, and Spark.

Figures

**Figure 1.**
Mechanisms of action of AONs in genetic eye disease. (a) Wild-type scenario. (b) AON correcting deep-intronic mutation. (c) AON inducing exon skipping. (d) AON producing mRNA knockdown (adapted from Collin 2017).

**Figure 2.**
Mechanisms of action of (a) sepofarsen, (b) Ultevursen, and (c) QR-1123 detailing wild-type condition, mutant condition, and mechanism of action of AON.

See this image and copyright information in PMC

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RNA-based therapies in inherited retinal diseases

Affiliations

RNA-based therapies in inherited retinal diseases

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

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