RNA-based therapies in inherited retinal diseases

Aniz Girach; Isabelle Audo; David G Birch; Rachel M Huckfeldt; Byron L Lam; Bart P Leroy; Michel Michaelides; Stephen R Russell; Juliana M F Sallum; Katarina Stingl; Stephen H Tsang; Paul Yang

doi:10.1177/25158414221134602

RNA-based therapies in inherited retinal diseases

Ther Adv Ophthalmol. 2022 Nov 4:14:25158414221134602. doi: 10.1177/25158414221134602. eCollection 2022 Jan-Dec.

Authors

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.

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.

Publication types

Review