Nikhil Prasad Fact checked by:Thailand Medical News Team Aug 17, 2024 3 months, 5 days, 6 hours, 20 minutes ago
Glaucoma News: Glaucoma remains the leading cause of irreversible blindness globally, with primary open-angle glaucoma (POAG) being the most prevalent type, accounting for up to 90% of all glaucoma cases. This condition, characterized by the progressive degeneration of retinal ganglion cells (RGCs) and optic nerve fibers, is expected to affect over 111 million people by 2040. While current treatments primarily focus on reducing intraocular pressure (IOP), there is an ongoing need to discover novel therapeutic targets to slow disease progression and preserve vision. Researchers from China Medical University, Liaoning Province's Key Lens Research Laboratory, and Shandong First Medical University have conducted a multicenter study using proteome-wide Mendelian randomization to identify potential protein targets for new POAG treatments. This
Glaucoma News report delves into their findings and explores the promising implications for future glaucoma therapies.
Breakthrough study identifies protein targets in glaucoma treatment
Understanding Primary Open-Angle Glaucoma (POAG)
POAG is a complex disease influenced by multiple factors, including age, genetics, diabetes, and hypertension. However, the most critical modifiable risk factor is elevated IOP, which significantly increases the risk of glaucoma. Current treatment strategies focus on reducing IOP through medications, surgical interventions, and laser treatments. Despite these efforts, many patients continue to experience vision loss due to the irreversible nature of RGC and optic nerve damage. This highlights the urgent need for new therapeutic approaches that target the underlying mechanisms of the disease.
The Role of Proteins in Glaucoma
Proteins play a crucial role in the pathological processes of POAG, making them valuable targets for new treatments. For instance, stress-induced changes in the trabecular meshwork (TM) cells lead to the release of abnormal collagens and fibronectins, contributing to the buildup of extracellular matrix (ECM) proteins around the TM and increasing IOP. Identifying proteins involved in these processes can provide insights into potential drug targets that could modify the disease's progression.
The Multicenter Study: A Comprehensive Approach
To uncover new therapeutic targets, the research team employed a novel study design involving multicenter proteome-wide Mendelian randomization. This approach integrates genetic data with plasma protein levels to identify proteins causally linked to POAG. The study utilized plasma protein quantitative trait loci (pQTLs) data from the Icelandic Decoding Genetics Study and the UK Biobank Pharma Proteomics Project, combined with genome-wide association studies (GWAS) data for POAG from the FinnGen consortium and the UK Biobank.
Key Findings: Eight Promising Protein Targets
After rigorous analysis, the researchers identified eight circulating proteins as potential therapeutic targets for POAG. These proteins were categorized into two tiers based on the stren
gth of evidence linking them to POAG:
Tier One Targets (Strong Evidence):
-ROBO1 (Roundabout 1): Associated with a 38% increased risk of POAG. ROBO1 plays a role in RGC axon guidance and ocular neovascularization, making it a promising target for developing small molecule inhibitors.
-FOXO3 (Forkhead Box O3): Associated with a 65% reduced risk of POAG. FOXO3 is involved in oxidative stress regulation, and its activation may protect TM cells from oxidative damage, a key factor in glaucoma progression.
-ITIH3 (Inter-alpha-trypsin Inhibitor Heavy Chain 3): Associated with an 11% reduced risk of POAG. ITIH3 plays a role in ECM stabilization, and its involvement in other diseases suggests potential therapeutic benefits for glaucoma.
Tier Two Targets (Moderate Evidence):
-NCR1 (Natural Cytotoxicity Triggering Receptor 1): Associated with a 25% increased risk of POAG. NCR1 is involved in immune responses and may influence glaucoma through inflammation-related mechanisms.
-NID1 (Nidogen 1): Associated with a 29% increased risk of POAG. NID1 is a key component of the basement membrane and may impact AH turnover, a critical factor in IOP regulation.
-TIMP3 (Tissue Inhibitor of Metalloproteinases 3): Associated with a 9% reduced risk of POAG. TIMP3 regulates ECM remodeling, and its overexpression may contribute to increased IOP.
-SERPINF1 (Serpin Family F Member 1): Associated with a 19% reduced risk of POAG. SERPINF1, also known as pigment epithelium-derived factor (PEDF), has neuroprotective properties and may protect RGCs from glaucoma-related damage.
-OXT (Oxytocin): Associated with a 20% increased risk of POAG. Oxytocin has broad physiological roles, including stress regulation and antioxidant effects, which could impact glaucoma pathophysiology.
Exploring the Therapeutic Potential
The identification of these eight proteins opens new avenues for developing targeted glaucoma treatments. The study's druggability assessment revealed several compounds with potential therapeutic applications:
-Pimagedine: Targets TIMP3 and has shown promise in reducing RGC loss in animal models of glaucoma.
-Resveratrol: An activator of FOXO3, Resveratrol has antioxidant and neuroprotective properties, making it a potential candidate for glaucoma therapy.
-Syringaresinol: Also targeting FOXO3, Syringaresinol may alleviate oxidative stress and protect retinal cells, offering another potential treatment option.
-Clozapine: Targets ITIH3 and OXT, with potential effects on IOP regulation and retinal blood flow.
-Zinc and Copper: Target ITIH3 and SERPINF1, respectively, with potential antioxidant benefits that could mitigate glaucoma progression.
Conclusion: A Step Forward in Glaucoma Treatment
This study represents a significant step forward in the search for new glaucoma treatments. By identifying proteins causally linked to POAG, the researchers have provided a foundation for developing targeted therapies that address the underlying mechanisms of the disease. While further research is needed to confirm these findings and explore their clinical applications, the study's results offer hope for more effective glaucoma treatments in the future.
The study findings were published in the peer-reviewed journal: Frontiers in Pharmacology.
https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1428472/full
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