The axonal guidance signaling pathway may confer protection against progression to neovascular disease in patients with intermediate AMD

Abstract

Purpose : Age-related macular degeneration (AMD) is the leading cause of blindness in the aging population. Many variants in genes have been associated with an increased risk of AMD and a handful with protection, including C2/CFB. A systems biology approach was applied to identify pathways that were differentially expressed between the clinical stages of AMD to elucidate which genes and/or pathways may provide protection against the development of neovascular disease.

Methods : We investigated differential gene expression in the macular RPE/choroid and macular neural retina in eyes across the clinical stages of AMD. Donor eyes were rapidly autopsied, meticulously dissected, and well-phenotyped using a standardized published protocol. A total of 27 donor eyes (12 normals, 10 intermediate AMD and 5 neovascular AMD) underwent RNASeq. The resultant data were subjected to bioinformatic and statistical analysis using PCA, DESeq2, Benjamini Hockberg Analysis, and Bonferonni correction. IPA was performed to identify significant sets of genes in aggregate that differed between disease states.

Results : Significant genes/pathways were identified in neovascular AMD compared to normal eyes, and for intermediate AMD compared to normal eyes. When evaluating pathways that were statistically significantly decreased in intermediate AMD versus neovascular AMD and not present in the other comparisons, the axonal guidance signaling pathway demonstrated potential as a protective pathway within the macular RPE/choroid. A total of 23% of genes (ACE2, ADAMTS1, ADAMTS8, BMP8A, RND1, SEMA4C, and WNT16) in this pathway were significant and unique to our dataset were found to protective for developing neovascular AMD. While 10% of genes (EPHA10, LRRC4c, and SEMA4B) from our data set, associated with this pathway were found to increase risk of developing neovascular AMD. The remaining 67% of genes in this pathway were not identified as being significant within our samples.

Conclusions : Our analysis demonstrates that differential gene expression occurs among several notable pathways between the disease states of AMD. Significant downregulation of the axonal guidance signaling pathway within the macular RPE/choroid tissue in those with intermediate AMD may provide a protective effect against development to neovascular AMD possibly through a neuroprotective mechanism.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.