Molecular Surgery: Proteomics of a Rare Genetic Disease Gives Insight into Common Causes of Blindness

Abstract

Summary Rare diseases are an emerging global health priority. Although individually rare, the prevalence of rare “orphan” diseases is high, affecting approximately 300 million people worldwide. Treatments for these conditions are often inadequate, leaving the disease to progress unabated. Here, we review the clinical features and pathophysiology of neovascular inflammatory vitreoretinopathy (NIV), a rare inflammatory retinal disease caused by mutations in the CAPN5 gene. Although the prevalence of NIV is low (1 in 1,000,000 people), the disease mimics more common causes of blindness (e.g. uveitis, retinitis pigmentosa, proliferative diabetic retinopathy, and proliferative vitreoretinopathy) at distinct clinical stages. There is no cure for NIV to date. We highlight how personalized proteomics helped identify potential stage-specific biomarkers and drug targets in liquid vitreous biopsies. The NIV vitreous proteome revealed enrichment of molecular pathways associated with common retinal pathologies and implicated superior targets for therapeutic drug repositioning. In addition, we review our pipeline for collecting, storing, and analyzing ophthalmic surgical samples. This approach can be adapted to treat a variety of rare genetic diseases.

Proteomic Analysis of Autoimmune Retinopathy Implicates Neuronal Cell Adhesion Molecule as a Potential Biomarker

“…Despite the limitation of the small sample size, descriptive semi-quantitative analysis can provide insight into underlying disease pathways and uncover putative biomarkers in rare patient populations, and there are no human AIR proteomic reports to date. 40 Further studies are required to prospectively validate these candidate biomarkers and correlating autoantibodies in larger patient cohorts.…”

Proteomics in uveal melanoma

“…The aqueous humor has been well studied in the field of glaucoma to learn about the pathologic changes at the trabecular meshwork. The vitreous is an attractive subject of study, given its relatively less complex protein profile in healthy eyes [6]. The protein content of the cornea, lens, and retina have been well characterized in healthy patients, which has paved the way to identifying biomarkers and therapeutic targets in the diverse disorders that affect these tissues [7–9].…”

Peptidomimetics Therapeutics for Retinal Disease

“…The retina is the innermost component and the photographic layer of the posterior segment ( Figure 1). [21] It is composed of an internal limiting membrane (ILM), a neural retina, and the retinal pigment epithelium (RPE). [22] The neural retina contains optic nerve fibers and a variety of cells, such as retinal ganglion cells, Müller cells, amacrine cells, horizontal cells, retinal capillary endothelial cells, and photoreceptor cells.…”