HTRA1 x Serine protease

To investigate the safety, tolerability, and efficacy of intravitreal injection of galegenimab, an anti-HtrA1 FAb, in patients with geographic atrophy (GA) secondary to age-related macular degeneration (AMD).

Phase 2, single-masked, randomized clinical trial.

Eligible GA patients with BCVA letter scores of ≥ 24 letters and baseline GA lesion size 2.54∼25.4 mm² in the study eye were enrolled. Patients were randomized 2:1:2 to receive 20 mg galegenimab every 4 (Q4W) or 8 weeks (Q8W), or sham Q4/8 W. The primary endpoint was mean change in GA area from baseline to Week 72 measured by fundus autofluorescence. A data monitoring committee (DMC) conducted periodic unmasked review of cumulative safety/limited efficacy data of the ongoing study.

Among 337 patients who received ≥ 1 dose and have at least one postbaseline GA area measurement, the adjusted mean change in GA area from baseline to Week 72 was 2.67, 2.50, and 2.38 mm² for the galegenimab Q4W, galegenimab Q8W, and pooled sham arms, respectively. Differences between the treated and sham groups were not statistically significant. However, the rate of intraocular inflammation was high (7.1%, 16/224 patients) among treated patients. The DMC recommended early termination of the study based on an early benefit/risk analysis.

Galegenimab administration did not show a difference in mean change in GA area from baseline to Week 72 compared with sham. Inhibition of HtrA1 with a Fab did not slow down GA progression.

To identify genetic determinants specific to reticular pseudodrusen (RPD) compared with drusen.

Genome-wide association study (GWAS) SUBJECTS: Participants with RPD, drusen, and controls from the UK Biobank (UKBB), a large, multisite, community-based cohort.

Participants with RPD, drusen, and controls from the UK Biobank (UKBB), a large, multisite, community-based cohort, were included. A deep learning framework analyzed 169,370 optical coherence tomography (OCT) volumes to identify cases and controls within the UKBB. Five retina specialists validated the cohorts using OCT and color fundus photographs. Several GWAS were undertaken utilizing the quantity and presence of RPD and drusen. Genome-wide significance was defined as P < 5e-8.

Genetic associations were examined with the number of RPD and drusen within 'pure' cases, where only RPD or drusen were present in either eye. A candidate approach assessed 46 previously known AMD loci. Secondary GWAS were conducted for number of RPD and drusen in mixed cases, and binary case-control analyses for pure RPD and pure drusen.

The study included 1787 participants: 1037 controls, 361 pure drusen, 66 pure RPD, and 323 mixed cases. The primary pure RPD GWAS identified four genome-wide significant loci: rs11200630 near ARMS2-HTRA1 (P = 1.9e-09), rs79641866 at PARD3B (P = 1.3e-08), rs143184903 near ITPR1 (P = 8.1e-09), and rs76377757 near SLN (P = 4.3e-08). The latter three are uncommon variants (minor allele frequency <5%). A significant association at the CFH locus was also observed using a candidate approach (P = 1.8e-04). For pure drusen, two loci reached genome-wide significance: rs10801555 at CFH (P = 6.0e-33) and rs61871744 at ARMS2-HTRA1 (P = 4.2e-20).

The study highlights a clear association between the ARMS2-HTRA1 locus and higher RPD load. Although the CFH locus association did not achieve genome-wide significance, a suggestive link was observed. Three novel associations unique to RPD were identified, albeit for uncommon genetic variants. Further studies with larger sample sizes are needed to explore these findings.

Streptococcus mutans is a primary cariogenic pathogen involved in dental biofilm formation, a major virulence factor in the development of dental caries. In S. mutans , the competence-stimulating peptide (CSP), encoded by comC , plays a critical role in environmental stress response, growth regulation, and virulence expression. In this study, we performed transcriptome analysis to investigate the role of SMU.1147, a unique core gene in S. mutans , in biological pathways related to transport, defense responses, and environmental sensing. The deletion of SMU.1147 led to the upregulation of genes involved in carbohydrate uptake and metabolism, particularly phosphotransferase system (PTS) transporters, thereby enhancing the sugar transport capacity. However, despite increased sugar uptake, the mutant strain did not show significant changes in growth rate or ATP production and displayed slightly reduced organic acid production. Additionally, the mutant exhibited significantly reduced cell viability after an 8-h incubation compared to the parental strain. Notably, genes associated with CSP-dependent signal transduction and stress defense, such as comX , comR , htrA , scnRK , and ciaRH , were downregulated in the mutant strain. Furthermore, stress-related genes, including spxA2 , clpP , and clpX , were significantly downregulated, suggesting compromised protein quality control and oxidative stress responses. Our findings suggest that SMU.1147 plays a critical role in regulating peptide-mediated signaling, metabolic coordination, and environmental adaptation in S. mutans , positioning it as a key integrator of the metabolic and stress response networks that are essential for pathogenicity and survival.

Understanding the regulatory mechanisms that govern virulence and environmental adaptation in Streptococcus mutans is essential for developing strategies to mitigate dental caries. This study reveals the critical role of the SMU.1147 gene in S. mutans in metabolic regulation, stress response, and cell viability. Our results demonstrate how the deletion of this gene affects sugar uptake and organic acid production, leading to imbalances in carbon metabolism and reduced long-term survival. These findings provide valuable insights into the ability of S. mutans to adapt to stressed conditions and highlight the role of SMU.1147 in modulating biofilm formation and virulence, contributing to our understanding of regulatory pathways in dental pathogens.