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.
Highlights
Improvements to global living standards and increased life expectancies over the past century have led to a transition in medical research to noninfectious diseases (COVID19 notwithstanding) and disabilities that impair quality of life
We review recent developments in our understanding of IRDs and their clinical outcomes before providing an outline of recent approaches taken to treat this important group in blinding retinal diseases
Among more than 300 inherited retinal disease entities caused by variations within more than 270 genes, approximately 70% are inherited in an autosomal recessive manner and 25% are autosomal dominant, with the remainder being X-linked or mitochondrial diseases (RetNet www.sph.uth.edu/retnet)
Summary
Improvements to global living standards and increased life expectancies over the past century have led to a transition in medical research to noninfectious diseases (COVID19 notwithstanding) and disabilities that impair quality of life. The societal cost of IRDs in the United Kingdom and United States were estimated at more than USD 700 million and USD 30 billion, respectively (Galvin et al, 2020; Gong et al, 2021) Much of this cost is presumably due to the profound impact that IRDs have on the economic productivity of working-age individuals, where improvements in community eye screening has seen IRDs overtake diabetic retinopathy as the leading cause of blindness among working age adults in some developed nations (Hanany et al, 2020; Heath Jeffery et al, 2021). Degenerations involving the macula usually result in symptoms of metamorphopsia, reduced visual acuity, and progressive central and paracentral scotomata, while the peripheral vision is typically spared In addition to their ocular manifestations, many IRDs are associated with systemic disease, with the most well-known being Usher syndrome, an important cause of childhood sensorineural deafness (Saihan et al, 2009; Fuster-García et al, 2021). We review recent developments in our understanding of IRDs and their clinical outcomes before providing an outline of recent approaches taken to treat this important group in blinding retinal diseases
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