Anti-Lgals3 Monoclonal antibody, clone N4/49

Aims Cardiac specificity provides an advantage in correlating heart failure (HF) biomarker plasma levels with indices of cardiac function and remodelling, as shown for natriuretic peptides. Using bioinformatics, we explored the cardiac specificity of secreted proteins and investigated in more detail the relationship of Dickkopf-3 (DKK3) gene expression and DKK3 plasma concentrations with cardiac function and remodelling in (pre)clinical studies. Methods and results The cardiac specificity of secreted proteins was determined using RNAseq data for a large panel of organs and tissues. This showed that natriuretic peptides (NPPAandNPPB) are highly cardiac-specific (>99%), whereas other HF biomarkers, including galectin-3 (Gal-3,LGALS3) and growth differentiation factor-15 (GDF-15), lack cardiac specificity (<4%).DKK3was cardiac-enriched (44%), warranting further investigation. In three different HF mouse models, cardiacDkk3expression was altered, but DKK3 plasma concentrations were not. In humans, DKK3 plasma concentrations were higher in HF patients (n = 2090) in comparison with age- and sex-matched controls without HF (n = 240) (46.4 ng/mL vs. 36.3 ng/mL;P < 0.001). Multivariate regression analysis revealed that DKK3 was strongly associated with HF risk factors and comorbidities, including age, kidney function and atrial fibrillation. After correction for existing prediction models, DKK3 did not independently predict HF outcome [all-cause mortality/HF hospitalization, hazard ratio 1.13 (0.79-1.61) per DKK3 doubling;P = 0.503]. Conclusions Of actively secreted HF biomarkers, only natriuretic peptides showed high cardiac specificity. Despite a cardiac specificity of 44%, secreted DKK3 had limited additional diagnostic and prognostic value.

NiemannPick disease type C (NPC) is a lysosomal storage disorder characterized by liver disease and progressive neurodegeneration. Deficiency of either NPC1 or NPC2 leads to the accumulation of cholesterol and glycosphingolipids in late endosomes and early lysosomes. In order to identify pathological mechanisms underlying NPC and uncover potential biomarkers, we characterized liver gene expression changes in an Npc1 mouse model at six ages spanning the pathological progression of the disease. We identified altered gene expression at all ages, including changes in asymptomatic, 1-week-old mice. Biological pathways showing early altered gene expression included: lipid metabolism, cytochrome P450 enzymes involved in arachidonic acid and drug metabolism, inflammation and immune responses, mitogen-activated protein kinase and G-protein signaling, cell cycle regulation, cell adhesion and cytoskeleton remodeling. In contrast, apoptosis and oxidative stress appeared to be late pathological processes. To identify potential biomarkers that could facilitate monitoring of disease progression, we focused on a subset of 103 differentially expressed genes that encode secreted proteins. Further analysis identified two secreted proteins with increased serum levels in NPC1 patients: galectin-3 (LGALS3), a pro-inflammatory molecule, and cathepsin D (CTSD), a lysosomal aspartic protease. Elevated serum levels of both proteins correlated with neurological disease severity and appeared to be specific for NPC1. Expression of Lgals3 and Ctsd was normalized following treatment with 2-hydroxypropyl--cyclodextrin, a therapy that reduces pathological findings and significantly increases Npc1(/) survival. Both LGALS3 and CTSD have the potential to aid in diagnosis and serve as biomarkers to monitor efficacy in therapeutic trials.