New therapeutic targets for treating primary open-angle Glaucoma identified

Glaucoma News: A groundbreaking study led by researchers from China Medical University and Shandong First Medical University-China has identified several promising protein targets that could lead to novel treatments for primary open-angle glaucoma (POAG), the most common form of glaucoma globally. By using a unique approach known as proteome-wide Mendelian randomization, the research team was able to link several proteins to the risk of developing POAG. This Glaucoma News report explores the study’s findings, shedding light on how these proteins may offer new therapeutic opportunities.
 

New therapeutic targets for treating primary open-angle Glaucoma identified

The Scope of Glaucoma
Glaucoma is a significant cause of irreversible blindness worldwide, with POAG being the most prevalent form, accounting for 75% - 90% of all cases. The disease is marked by a progressive loss of vision due to damage to the retinal ganglion cells and optic nerve fibers. As the global population ages, the number of people affected by glaucoma is expected to rise dramatically, with estimates suggesting 111.8 million cases by 2040.
 
Currently, treatments for POAG largely focus on lowering intraocular pressure (IOP), which is the only modifiable risk factor. However, these treatments are not always effective, and about 10% of patients eventually develop resistance to available therapies. As a result, there is an urgent need for new therapeutic approaches that target the underlying causes of the disease.
 
Identifying New Protein Targets
To address this need, the research team employed Mendelian randomization (MR), a genetic research method that uses summary statistics to identify potential causal relationships between genetic variants and diseases. The study used plasma protein data from large-scale genetic studies, including the Icelandic Decoding Genetics Study and the UK Biobank Pharma Proteomics Project. The data from these studies were combined with genome-wide association studies (GWAS) data for POAG from the FinnGen consortium and the UK Biobank.
 
The key objective was to identify plasma proteins that could serve as potential therapeutic targets for POAG. The researchers identified eight circulating proteins with strong genetic associations with the disease. Of these, three - ROBO1, FOXO3, and ITIH3 - were considered tier-one targets with the strongest evidence of involvement in POAG. The other five - NCR1, NID1, TIMP3, SERPINF1, and OXT - were categorized as tier-two targets.
 
The Proteins Involved
-ROBO1: This protein plays a role in neural development and retinal function. The study found that elevated levels of ROBO1 were associated with an increased risk of POAG, making it a prime candidate for further research. This article emphasizes the need for developing small molecule inhibitors targeting ROBO1, which could have significant therapeutic potential.
 
-FOXO3: Known for its involvement in an tioxidant defense and cell proliferation, FOXO3 was identified as a protective factor against POAG. The study suggested that compounds like resveratrol and syringaresinol, which activate FOXO3, could reduce oxidative stress and improve retinal health. These natural compounds could potentially be developed into novel treatments for glaucoma.
 
-ITIH3: This protein is involved in extracellular matrix (ECM) regulation, which plays a critical role in the drainage of aqueous humor from the eye. Polymorphisms in ITIH3 have been linked to mental health conditions like schizophrenia and depression, but this is the first study to suggest a role in POAG. Drugs targeting ITIH3, such as clozapine and zinc, could be explored for their therapeutic effects in glaucoma.
 
-NCR1 and NID1: These proteins are involved in immune responses and ECM organization. Although their roles in glaucoma are not fully understood, their genetic associations with POAG suggest that they may be involved in disease progression. Further studies are needed to explore their potential as therapeutic targets.
 
-TIMP3: A well-known inhibitor of matrix metalloproteinases (MMPs), TIMP3 is critical in regulating ECM remodeling. The study found that overexpression of TIMP3 could disrupt the balance between ECM synthesis and degradation, leading to increased IOP and worsening POAG. Pimagedine, a drug that targets TIMP3, could offer neuroprotective effects and help slow disease progression.
 
-SERPINF1 and OXT: These proteins are involved in neuroprotection and stress regulation, respectively. The study suggests that copper, which targets SERPINF1, could play a protective role in glaucoma by mitigating oxidative stress. Meanwhile, oxytocin (OXT) has been linked to various physiological processes, including stress regulation and immune response. However, more research is needed to confirm its role in POAG.
 
The Implications of These Findings
The discovery of these eight protein targets opens the door to the development of new treatments that go beyond simply lowering IOP. By targeting the underlying mechanisms of the disease, such as oxidative stress, ECM remodeling, and immune responses, these proteins could provide more effective treatments for POAG. The use of natural compounds like resveratrol, syringaresinol, and zinc in combination with existing therapies could also improve patient outcomes.
 
This study is particularly significant because it highlights the importance of personalized medicine in treating complex diseases like POAG. By targeting specific proteins that are linked to genetic variations, it may be possible to develop therapies that are tailored to individual patients, increasing the likelihood of success.
 
Limitations and Future Directions
While the findings of this study are promising, there are several limitations that need to be addressed. First, the study used plasma protein data, which may not fully reflect the specific changes occurring in ocular tissues like the retina or aqueous humor. Future studies should aim to use protein data derived from these tissues to confirm the findings. Additionally, the biological roles of many of the identified proteins in glaucoma are not yet fully understood, and further research is needed to elucidate their mechanisms.
 
Another limitation is the focus on European populations. The data used in this study were primarily derived from individuals of European ancestry, which may limit the generalizability of the findings to other populations. Future studies should aim to include more diverse populations to ensure that the results are applicable to a broader range of patients.
 
Despite these limitations, the study represents a significant step forward in our understanding of the genetic and molecular mechanisms underlying POAG. By identifying new protein targets, the research paves the way for the development of more effective and personalized treatments for this debilitating disease.
 
Conclusion
This study has identified eight plasma proteins that are genetically linked to the development of POAG, offering new insights into the disease’s underlying mechanisms. These proteins play important roles in neuroprotection, ECM regulation, and oxidative stress, making them promising therapeutic targets. Further research is needed to explore the potential of these proteins as drug targets and to develop new treatments that can effectively combat POAG.
 
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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