Longitudinal deep multi-omics profiling in a CLN3

backgroundDevelopment of therapies for CLN3 disease, a rare pediatric lysosomal storage disorder, has been hindered by the lack of etiological insights and translatable biomarkers to clinics.

methodsWe used a deep multi-omics approach to discover blood-based biomarkers using longitudinal serum samples from a porcine model of CLN3 disease. Comprehensive metabolomics was combined with a nanoparticle-based LC-MS-based proteomic profiling coupled with TMTpro 18-plex to generate quantitative data on 769 metabolites and 2634 proteins, collectively the most exhaustive multi-omics profile conducted on serum from a porcine model. This was previously impossible due to lack of efficient deep serum proteome profiling technologies compatible with model organisms.

resultsHere we show that the presymptomatic disease state is characterized by elevations in glycerophosphodiester species and lysosomal proteases, while later timepoints are enriched with species involved in immune cell activation and sphingolipid metabolism. Cathepsin S (CTSS), Cathepsin B (CTSB), glycerophosphoinositol, and glycerophosphoethanolamine captured a large portion of the genotype-correlated variation between healthy and diseased animals, suggesting that an index score based on these analytes could have great utility in the clinic.

conclusionsThis study's findings demonstrate the potential of deep multi-omics profiling for uncovering disease-specific biomarkers, providing valuable insights for understanding disease and facilitating the identification of potential drug targets, thus offering valuable insights for therapeutic interventions.