Abstract
Purpose :
Angiogenic factors are valuable therapeutic targets but traditionally identified on a case-by-case basis with technical challenges. Proteomics and transcriptomics have been adopted for drug target discovery but with limited success. We developed ligandomics to globally profile endothelial ligands, including angiogenic factors, in mice with diabetic retinopathy (DR) and choroidal neovascularization (CNV). The purpose of this study is to compare different omics technologies to identify therapeutic targets, including angiogenic factors.
Methods :
We compared ligandomics with other omics for global mapping of therapeutic targets. Criteria for target selection and technical capabilities for target validation are also compared.
Results :
We applied ligandomics to mice with or without DR or CNV and globally mapped endothelial ligands with binding activity quantification. Identified ligands were independently validated by four assays: in vivo binding quantification, functional immunohistochemistry, function-first and therapy-first assays. Secretogranin III (Scg3) was identified and verified as a disease-selective angiogenic factor, and anti-Scg3 therapy was developed to treat DR and CNV in mice with optimal safety and efficacy. In contrast, RNA-seq (transcriptomics), single-cell RNA-seq and expression proteomics profile only gene/protein expression but not function. Differential expression as a quantitative criterion for target selection is overly inclusive and lacks stringency. Functional proteomics to globally map protein interactomes is incapable of comparing diseased vs. healthy cells, quantifying protein binding activity and providing a quantitative criterion for target selection. Functional characterization of targets identified by transcriptomics and proteomics is technically challenging.
Conclusions :
The validity and utility of ligandomics are demonstrated by the discovery of Scg3 as a disease-selective angiogenic factor for anti-angiogenic therapy of DR and CNV in mice. Ligandomics has the following advantages for drug target discovery: a) global mapping of cellular ligands with high intrinsic therapeutic potential; b) profiling of protein function instead of expression; and c) binding selectivity as a quantitative functional criterion for target selection. Ligandomics broadly applicable to any cell and disease is a powerful tool for disease mechanism research and drug target discovery.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.