Singapore National Eye Centre, Singapore, Singapore,Singapore Eye Research Institute, Singapore, Singapore,Duke-NUS Graduate Medical School, Ophthalmology and Visual Sciences Academic Clinical Programme, Singapore, Singapore,School of Material Science and Engineering, Nanyang Technological University, Singapore, Singapore,Yong Loo Lin School of Medicine, Department of Ophthalmology, National University of Singapore, Singapore, Singapore,Edited by:Jesse Sengillo, University of Miami Health System, United StatesThis article was submitted to Human and Medical Genomics, a section of the journal Frontiers in GeneticsEdited by:Jesse Sengillo, University of Miami Health System, United StatesReviewed by:Jiaxing Wang, Emory University, United StatesQingnan Liang, Baylor College of Medicine, United States
This article was submitted to Human and Medical Genomics, a section of the journal Frontiers in GeneticsReceived 2021 Oct 14; Accepted 2021 Dec 14.Copyright © 2022 Fenner, Tan, Barathi, Tun, Yeo, Tsai, Lee, Cheung, Chan, Mehta and Teo.This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Abstract
Inherited retinal diseases (IRDs) are a heterogenous group of orphan eye diseases that typically result from monogenic mutations and are considered attractive targets for gene-based therapeutics. Following the approval of an IRD gene replacement therapy for Leber’s congenital amaurosis due to RPE65 mutations, there has been an intensive international research effort to identify the optimal gene therapy approaches for a range of IRDs and many are now undergoing clinical trials. In this review we explore therapeutic challenges posed by IRDs and review current and future approaches that may be applicable to different subsets of IRD mutations. Emphasis is placed on five distinct approaches to gene-based therapy that have potential to treat the full spectrum of IRDs: 1) gene replacement using adeno-associated virus (AAV) and nonviral delivery vectors, 2) genome editing via the CRISPR/Cas9 system, 3) RNA editing by endogenous and exogenous ADAR, 4) mRNA targeting with antisense oligonucleotides for gene knockdown and splicing modification, and 5) optogenetic approaches that aim to replace the function of native retinal photoreceptors by engineering other retinal cell types to become capable of phototransduction.
Keywords: inherited retinal diseases (IRDs), gene tharapy, adeno-associated virus, RNA editing, CRISPR, optogenetic, antisense oligonucleotides, retina
