Induced Pluripotent Stem Cells for Inherited Optic Neuropathies—Disease Modeling and Therapeutic Development

Abstract

Background: Inherited optic neuropathies (IONs) cause progressive irreversible visual loss in children and young adults. There are limited disease-modifying treatments, and most patients progress to become severely visually impaired, fulfilling the legal criteria for blind registration. The seminal discovery of the technique for reprogramming somatic nondividing cells into induced pluripotent stem cells (iPSCs) has opened several exciting opportunities in the field of ION research and treatment. Evidence Acquisition: A systematic review of the literature was conducted with PubMed using the following search terms: autosomal dominant optic atrophy, ADOA, dominant optic atrophy, DOA, Leber hereditary optic neuropathy, LHON, optic atrophy, induced pluripotent stem cell, iPSC, iPSC derived, iPS, stem cell, retinal ganglion cell, and RGC. Clinical trials were identified on the ClinicalTrials.gov website.Results: This review article is focused on disease modeling and the therapeutic strategies being explored with iPSC technologies for the 2 most common IONs, namely, dominant optic atrophy and Leber hereditary optic neuropathy. The rationale and translational advances for cellbased and gene-based therapies are explored, as well as opportunities for neuroprotection and drug screening. Conclusions: iPSCs offer an elegant, patient-focused solution to the investigation of the genetic defects and disease mechanisms underpinning IONs. Furthermore, this group of disorders is uniquely amenable to both the disease modeling capability and the therapeutic potential that iPSCs offer. This fast-moving area will remain at the forefront of both basic and translational ION research in the coming years, with the potential to accelerate the development of effective therapies for patients affected with these blinding diseases.

Modelling autosomal dominant optic atrophy associated with OPA1 variants in iPSC-derived retinal ganglion cells

“…The inherited optic neuropathies (IONs) comprise a range of genetically diverse disorders characterized by the preferential loss of retinal ganglion cells (RGCs), optic nerve degeneration and progressive bilateral visual loss. Autosomal dominant optic atrophy (DOA) is the most common ION, with an estimated minimum prevalence of 1 in 25 000 ( 1 ). DOA typically presents with insidious visual loss during the first two decades of life, bilateral central scotomas and optic disc pallor caused by the loss of RGCs within the papillomacular bundle ( 2 ).…”

“…A key challenge for DOA research is the inherent difficulty in obtaining patient retinal tissue samples to effectively evaluate the pathogenic disease mechanisms driving RGC loss ( 1 ). In vitro disease modelling advances have increased our ability to generate physiologically relevant DOA models to further understand OPA1 disease variants.…”

Hotspots and trends in ophthalmology in recent 5 years: Bibliometric analysis in 2017–2021

“…Development in ophthalmology is essential for the prevention and treatment of eye diseases, and relevant research is growing rapidly in breadth and depth and forming complex knowledge networks. Glaucoma, age-related macular degeneration, and some hereditary eye diseases were previously considered irreversible blindnesscausing diseases, and progress had been made to cure or alleviate them by modulating new targets or using new technologies (2)(3)(4). Cataracts and posterior capsular opacification were previously thought to be treated only with surgery, but in the recent years, there had been new developments in research into drugs that inhibit cataract formation (5,6).…”

Superoxide dismutase 2 ameliorates mitochondrial dysfunction in skin fibroblasts of Leber’s hereditary optic neuropathy patients

“…Various alternative strategies have been developed for LHON research due to the lack of access to RGCs. At present, iPS-RGC cells are a favored emerging cell model ( Peron et al, 2020 ; Harvey et al, 2022 ; Singh et al, 2022 ). Fibroblasts have been induced into RGC-like cells by reprogramming of factors stimulation ( Peron et al, 2020 ) or Sendai virus infection ( Wu et al, 2018 ) and these cells present mitochondrial damage phenotype ( Wu et al, 2018 ; Yang et al, 2020 ).…”