Gene-Based Therapeutics for Inherited Retinal Diseases

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.

Deciphering the Retinal Epigenome during Development, Disease and Reprogramming: Advancements, Challenges and Perspectives

“…More recently, the advent of CRISPR-mediated gene therapy and genome editing has enabled to tentatively expand the portfolio of therapeutic approaches from monogenic to multi-factorial ocular diseases, to address aberrant gene expression and pathogenic, non-coding variants involved in choroidal neovascularization, altered vascular permeability, lipid homeostasis, neuronal apoptosis or detoxification of reactive oxygen species, and to leverage neuroprotective strategies for the restoration of the visual function [ 260 , 261 ].…”

Advancing precision medicines for ocular disorders: Diagnostic genomics to tailored therapies

“…Furthermore, two other disorders, Choroideremia and LHON, are currently in the Phase 3 trials (Table 1). Success of various gene therapy trials have increased expectations 10.3389/fmed.2022.906482 from the research and medical community, bringing hope of effective treatment for genetic diseases in the near future (2,254,255). With the sophistication of current molecular and surgical techniques, IRDs are a good target due to their well-defined and typically monogenic basis.…”

“…Ocular dystrophies or inherited retinal diseases (IRDs) are a heterogeneous group of rare ocular diseases commonly caused by gene mutations which subsequently result in degeneration of retinal photoreceptors leading to progressive visual damage (1,2). Around 300 genes have been recognized in which mutations can give rise to one or more of the clinical subtypes of ocular diseases (3).…”

Gene Therapy for Rhodopsin Mutations

“…There are several technologies for gene editing, but the most commonly used technique employs clustered regularly interspaced short palindromic repeats (CRISPR) and the Cas9 nuclease or related nucleases (Mali et al 2013;Botto et al 2021;Fenner et al 2022). More recent innovations, including base editing and prime editing, permit correction of point mutations or even small insertions or deletions without introducing doublestranded breaks in the genome (Komor et al 2016;Anzalone et al 2019;da Costa et al 2021).…”