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

Abstract

Successful sequencing of the human genome and evolving functional knowledge of gene products has taken genomic medicine to the forefront, soon combining broadly with traditional diagnostics, therapeutics, and prognostics in patients. Recent years have witnessed an extraordinary leap in our understanding of ocular diseases and their respective genetic underpinnings. As we are entering the age of genomic medicine, rapid advances in genome sequencing, gene delivery, genome surgery, and computational genomics enable an ever-increasing capacity to provide a precise and robust diagnosis of diseases and the development of targeted treatment strategies. Inherited retinal diseases are a major source of blindness around the world where a large number of causative genes have been identified, paving the way for personalized diagnostics in the clinic. Developments in functional genetics and gene transfer techniques has also led to the first FDA approval of gene therapy for LCA, a childhood blindness. Many such retinal diseases are the focus of various clinical trials, making clinical diagnoses of retinal diseases, their underlying genetics and the studies of natural history important. Here, we review methodologies for identifying new genes and variants associated with various ocular disorders and the complexities associated with them. Thereafter we discuss briefly, various retinal diseases and the application of genomic technologies in their diagnosis. We also discuss the strategies, challenges, and potential of gene therapy for the treatment of inherited and acquired retinal diseases. Additionally, we discuss the translational aspects of gene therapy, the important vector types and considerations for human trials that may help advance personalized therapeutics in ophthalmology. Retinal disease research has led the application of precision diagnostics and precision therapies; therefore, this review provides a general understanding of the current status of precision medicine in ophthalmology.

Short-Term In Vitro ROS Detection and Oxidative Stress Regulators in Epiretinal Membranes and Vitreous from Idiopathic Vitreoretinal Diseases

“…Although ERM cell population deserves more investigation, our finding about ROS, iNOS, VEGF, Ang-2, NRF2, and NOX4 expression in ERMs and vitreal fluids might represent a key aspect in the developing of individualized therapies [64]. Noteworthy, ERM can slowly progress and deepen the effects on the whole macula, and the risk of developing ERMs rises with ageing and genetic/epigenetic predisposition (ocular and systemic assets) [65].…”

The potential for mitochondrial therapeutics in the treatment of primary open-angle glaucoma: a review

“…This process can involve a variety of alterations, including insertion, removal, replacement, repair, and regulation of genetic material ( Wirth et al, 2013 ). Vectors introduced to enact genetic change include viruses, nucleic acids, chemical particles, and other microorganisms ( Wirth et al, 2013 ; Panikker et al, 2022 ). Viral vectors are more commonly employed than non-viral vectors in trials and applications to introduce exogenous genetic information into target cells ( Razi Soofiyani et al, 2013 ).…”

“…This improved immune response in eyes is important to note, as concern for the immunogenicity of foreign vectors has been highlighted by the death of a gene therapy clinical trial patient in 1999 due to a massive immune response following high-dose adenovirus vector administration ( Stolberg, 1999 ; Wirth et al, 2013 ). Additionally, this same physiologic response restriction of the ocular system concentrates vectors to work in the desired area, leading to a lower required dose of vector needed to produce the desired results ( Razi Soofiyani et al, 2013 ; Panikker et al, 2022 ). Furthermore, neuronal cells of the eyes, which are the pathologic cells and targets of most gene therapies, are differentiated postmitotic cells that allow for even better retention of vectors ( Panikker et al, 2022 ).…”

“…Additionally, this same physiologic response restriction of the ocular system concentrates vectors to work in the desired area, leading to a lower required dose of vector needed to produce the desired results ( Razi Soofiyani et al, 2013 ; Panikker et al, 2022 ). Furthermore, neuronal cells of the eyes, which are the pathologic cells and targets of most gene therapies, are differentiated postmitotic cells that allow for even better retention of vectors ( Panikker et al, 2022 ).…”

Toward a personalized closed-loop stimulation of the visual cortex: Advances and challenges

“…Visual impairment has a profound impact on the lives of those who experience it ( Bourne et al, 2017 ). Although some novel clinical approaches are becoming available ( Higuchi et al, 2017 ; De Silva and Moore, 2022 ; Panikker et al, 2022 ; Van Gelder et al, 2022 ), unfortunately, there is no treatment for all causes of blindness ( Fernandez, 2018 ; Fernandez et al, 2020 ). Thus, there are many blind patients for whom there is still no medical treatment.…”