Abstract

Primary open-angle glaucoma (POAG) is a leading cause of irreversible blindness, marked by progressive optic nerve damage and often asymptomatic until significant vision loss occurs. Current treatments primarily target elevated intraocular pressure (IOP) but do not prevent retinal ganglion cell (RGC) degeneration. There is strong demand for a non-invasive, comprehensive treatment method. Our team aims to create a multi-targeted eyedrop that addresses both issues.

We developed a novel, non-invasive formulation containing two fusion peptides: FT, which lowers IOP, and BC, which protects against RGC apoptosis. This dual-therapy approach targets both key mechanisms of the disease, providing a more effective strategy to slow glaucoma progression.

Furthermore, based on integrated computational and mathematical analysis, the BC and FT fusion peptides demonstrate excellent therapeutic potential. Structurally, they show exceptional stability with low instability indices and robust disulfide bonding. Functionally, they exhibit strong target binding affinity while maintaining non-toxic and non-allergenic properties. Pharmacokinetically, modeling confirms extended half-lives and optimal dose-response characteristics. This comprehensive validation establishes BC and FT as promising candidates for further development.

Our project incorporated human practices to ensure ethical viability and societal impact. We engaged patients, clinicians, and bioethicists to refine our work. Through stakeholder dialogue and outreach, we balanced diverse needs and raised awareness about glaucoma, creating a positive feedback loop that strengthens our project's purpose and supports future innovations. We have also created tailored educational materials and outreach programs to raise awareness about glaucoma prevention and the potential of synthetic biology in ophthalmic treatments.

Through active collaboration with healthcare professionals, patient communities, and ethical advisors, we can accelerate our glaucoma management program to provide a more effective strategy for slowing disease progression and improving patient outcomes worldwide. Our approach represents a paradigm shift in glaucoma therapy, moving beyond IOP management to comprehensive optic nerve protection.

Background

Primary Open-Angle Glaucoma (POAG) stands as the most prevalent and insidious form of glaucoma, posing a formidable threat to vision worldwide. It begins with the subtle loss of peripheral vision, a change so gradual and painless that many patients remain unaware until the disease has already caused significant damage. Over time, the narrowing visual field contracts into a small tunnel of sight, severely limiting the patient’s ability to navigate daily life. As the disease progresses, individuals may experience additional symptoms such as eye discomfort, headaches, and visual disturbances like rainbow halos around lights. Ultimately, POAG leads to irreversible blindness, profoundly impacting quality of life, independence, and sensory functions.

Fig 1 Progressively worsening vision of glaucoma patients.

The global burden of POAG is staggering. In 2020 alone, an estimated 68.6 million individuals were affected by this condition, and that number is projected to rise sharply to 80 million by 2040. This surging prevalence makes POAG the leading cause of irreversible blindness worldwide after cataracts. However, unlike cataracts, where vision can be restored through surgery, the vision loss caused by POAG is permanent and irreversible. The progressive nature of the disease, combined with its silent early stages, presents a significant public health challenge that demands urgent attention and improved therapeutic strategies.

Fig 2 World map depicting global prevalence of POAG. [2]

One of the most formidable challenges with POAG is its stealthy progression. It develops slowly and without pain; many patients lose as much as 40% of their visual field before any symptoms become noticeable. This delay in diagnosis often means that by the time POAG is detected, substantial and irreversible damage to the optic nerve and retinal ganglion cells will have already occurred. The asymptomatic nature of early POAG underscores the critical need for treatments that can not only reduce intraocular pressure (IOP) but also offer direct neuroprotection to preserve retinal ganglion cells and thus prevent further vision loss.

Current treatments for POAG mainly focus on lowering intraocular pressure (IOP) through medications and surgery. Although these treatments can slow the progression of the disease, they often do not completely protect retinal ganglion cells from apoptosis, which continues to result in vision loss even when intraocular pressure (IOP) is managed. This underscores the urgent need for therapies that target both the mechanical factors and the cellular aspects of the disease.

Hence, to address this problem, our project introduces a novel dual-action therapy for POAG by combining a peptide that lowers IOP with another that provides neuroprotection to retinal ganglion cells; delivered via an advanced nanocarrier system, this dual-peptide approach targets the key pathological mechanisms of POAG, offering more comprehensive management to better slow or prevent vision loss and improve patient outcomes.

Cause of POAG

Primary open-angle glaucoma (POAG) is a progressive optic neuropathy characterized by the gradual loss of retinal ganglion cells (RGCs) and damage to the optic nerve, ultimately leading to vision loss. A primary factor in the development of POAG is elevated intraocular pressure (IOP), which is mainly caused by increased resistance to aqueous humor outflow through the trabecular meshwork (TM), despite the drainage angle between the cornea and iris remaining open. The trabecular meshwork becomes dysfunctional due to changes such as loss of trabecular endothelial cells, accumulation of extracellular matrix material, and structural alterations, which lead to inadequate drainage and elevated IOP.

Fig 3 Diagram indicating the mechanisms of primary open-angle glaucoma (POAG)

Elevated IOP exerts mechanical stress on the optic nerve head, especially on the lamina cribrosa—a sieve-like structure where retinal ganglion cell axons exit the eye. This pressure induces deformation and impairs axonal transport, which disrupts the flow of essential neurotrophic factors to RGCs, compromising their survival. The resulting mechanical and ischemic damage initiates apoptotic pathways, causing the gradual death of RGCs, which manifests as progressive visual field loss beginning peripherally and eventually affecting central vision.

It is also crucial to note that not all glaucoma cases are characterized by an elevated IOP level; normal-tension glaucoma occurs despite IOP within the average range, indicating other contributing factors such as vascular dysregulation, oxidative stress, and immune-mediated neurodegeneration. However, RGC loss remains central to the disease across all forms. Thus, glaucoma pathogenesis involves a complex interplay between elevated IOP–dependent damage and neurodegenerative processes that ultimately lead to irreversible blindness if left untreated. This understanding underscores the critical need for therapies that can both reduce IOP and protect retinal ganglion cells from degeneration.

Current Solutions

Although glaucoma is a dangerous and potentially blinding disease, it is not without treatment options. The primary approaches currently include medications and surgery, each with its own benefits and notable limitations.

Medications for open-angle glaucoma mainly target lowering intraocular pressure (IOP), the only factor proven to slow or prevent disease progression. They achieve this by either increasing drainage of the aqueous humor (fluid in the eye) or reducing its production. For example, Xalatan (latanoprost), medication that increases uveoscleral outflow, thereby lowering IOP. However, such medications have several drawbacks. Side effects such as eye redness, irritation, burning, and blurred vision are common and can affect patient compliance. [2] Moreover, these eye drops focus solely on lowering IOP but neglect the equally critical aspect of preventing retinal ganglion cell (RGC) death, which is a leading cause of vision loss in glaucoma. Many patients with glaucoma, particularly those with normal-tension glaucoma, do not have elevated IOP, rendering these drugs less effective for that subgroup. Additionally, topical treatments often struggle to penetrate deep ocular tissues to reach RGCs effectively, limiting their neuroprotective capabilities. Poor adherence to daily regimens further threatens treatment success, with studies showing that a significant portion of patients fail to persist with prescribed medications.

Fig 4 of the location of RGC in the eyes.

Surgical interventions, including trabeculectomy and newer laser therapies such as selective laser trabeculoplasty (SLT), typically provide more pronounced and consistent reductions in IOP compared to medications alone. Trabeculectomy is generally considered one of the most effective treatments for controlling IOP when medications fail. However, surgeries carry inherent risks, including complications from overfiltration, resulting in hypotony, a condition characterized by dangerously low intraocular pressure that can damage ocular tissues and cause vision problems. Other surgical risks include infections, bleeding, scarring, and, in rare cases, even permanent vision loss. Furthermore, laser treatments, while less invasive, have limited efficacy and can cause inflammation or damage to the trabecular meshwork. Many patients need to repeat procedures or adjunct medications after surgery. These invasive treatments also place additional physical and psychological burdens on patients, including discomfort and recovery time, which can negatively impact one’s quality of life. [3] [4]

Overall, while current treatments effectively manage IOP, they fall short in providing a comprehensive approach that also preserves retinal ganglion cell health. This gap highlights the need for novel therapies that combine pressure-lowering effects with neuroprotective functions. A treatment that reduces IOP without compromising safety, minimizes side effects, improves patient adherence, and protects RGCs could significantly enhance glaucoma care and vision preservation.

Our Solution to This Problem

As mentioned above, preexisting solutions to glaucoma all hold their own side effects and limitations, hence it is crucial to innovate and try to curate a drug to reduce limitations, specifically how most drugs in the market now only reduce IOP and lack protection for RGC population. So, our novel solution to this clinical challenge involves the development of a dual-peptide therapy system, consisting of FT for IOP reduction and BC for RGC neuroprotection, delivered through an advanced nanocarrier platform.

Fig 5 Visual representation of the eye, before and after using our drug

FT for Targeting IOP Reduction

The FT fusion peptide represents a sophisticated multi-target approach to enhancing aqueous humor outflow. Its design incorporates two strategically selected components, FRATtides, and TP1.

Fig 6 Alphafold design for FT fusion peptide.

FRATtides

FRATtides are synthetic peptides derived from functional domains in FRAT proteins as modulators of the glycogen synthase kinase 3 (GSK-3) and Wnt signaling pathways, which we repurposed for ocular use to influence the pathological processes in glaucoma. It upregulates Axin2 expression and stimulates matrix metalloproteinase (MMP) production, thereby promoting extracellular matrix (ECM) degradation within the TM. This ECM remodeling reduces outflow resistance and facilitates improved fluid drainage. It also modulates the trabecular meshwork and enhances aqueous humor outflow, thereby lowering elevated IOP, dedicating to the effective treatment for glaucoma. [5] [6] [7]

Fig 7 Alphafold design for FRATtide.

Fig 8 FRATtide in trabecular meshwork cells

Fig 9 FRATtide inhibits GSK3 and releases β-catenin to the nucleus

Fig 10 Axin2 and MMPs contribute to ECM degradation

Fig 11 Axin2 and MMPs degrade ECM and decrease IOP

TP1

Complementing this mechanism, we are using the TP1 peptides. TP1 has garnered attention in glaucoma research since it was shown to be a peptide with potent chaperone-like activity that may both support neuronal survival and inhibit cell death, while the biological function of TP1 is to support mitochondrial activity and suppress apoptosis, especially through mitochondrial cytochrome c oxidase subunit 6b2 (COX 6b2), it can be repurposed for glaucoma treatment.TP1 activates both the PI3K/Akt pathway and nitric oxide synthase (NOS), inducing TM lation that further enhances aqueous humor outflow. Together, these coordinated actions make FT a potent agent for IOP reduction, addressing one of the primary pathological drivers of glaucoma progression.

Fig 12 Alphafold design for TP1.

Fig 13 Normal NO production in trabecular meshwork

Fig 14 TP1 increases NO production in trabecular meshwork

Together, these coordinated actions make FT a potent agent for IOP reduction, addressing one of the primary pathological drivers of glaucoma progression. [8]

BC for Neuroprotection of RGCs

While IOP control is crucial, effective glaucoma treatment must also protect the vulnerable RGC population. Our TAT-BC fusion peptide addresses this critical need through its dual neuroprotective mechanisms, consisting of BDNF and CDR1.

Fig 15 Alphafold design for BC fusion peptide.

BDNF

BDNF is an endogenous protein produced in the retina and brain that promotes neuronal survival and is instrumental for development in the central nervous system. It is extensively dispersed throughout the central nervous system, with areas of the brain such as the cerebral cortex, amygdala, hippocampus, and cerebellum showing very high levels of its presence. It is primarily expressed by neurons and is essential for maintaining synaptic plasticity, neuronal development, and survival. It is a critical neurotrophin that supports the survival and function of retinal ganglion cells (RGCs), the neurons primarily damaged in glaucoma. BDNF also binds to the receptor TrkB, along with multiple pathways in it, with its functions greatly mediating diverse cellular responses such as neuronal survival and anti-apoptotic effects. Such pathways include TAT, MAPK/ERK, and PLCy. [9]

Fig 16 Alphafold design for BDNF.

To begin with, the TAT pathway phosphorylates downstream targets like BAD and caspase 9, and stimulates AKT. Akt activation boosts antioxidant defenses by increasing SOD and catalase to neutralize ROS, reducing oxidative stress, and also stops cell death by blocking BAD and Caspase-9. AKT phosphorylates & inactivates Caspase-9, preventing it from triggering cell death. Without active Caspase-9, the apoptotic cascade stops. It also phosphorylates BAD, such that Bcl-2 & Bcl-xL now block apoptosis and promote RGC survival. Akt effectively works to prevent apoptosis. Akt also phosphorylates CREB, increasing BDNF levels, creating a positive feedback loop for even more neuron protection.

Furthermore, the ERK pathway phosphorylates CREB, where they’d moves into the nucleus & binds to DNA. This increases transcription of the BDNF gene, so more BDNF protein is produced and secreted by neurons.

Finally, the PLCy pathway activates CaMKII & CREB, further amplifying the effects of the aforementioned CREB. CaMKII inhibits pro-apoptotic proteins, which phosphorylates BAD as Akt does, again preventing it from interacting with Bcl-2/Bcl-xL at the mitochondria. This means PLCy can increase BDNF production and prevent cell apoptosis, emphasising the effects of Akt. [10] [11]

Fig 17 BDNF in PI3K/AkT pathway

Fig 18 BDNF in PLCy pathway

Fig 19 BDNF in MAPK/ERK pathway

CDR1

Studies revealed that CDR1 specifically interacts with acidic leucine-rich nuclear phosphoprotein 32A (ANP32A), a highly expressed protein in neurological tissues known to regulate multiple cellular functions including gene expression, protein interactions, and cell signaling. It was also identified as a potential biomarker candidate in the sera of glaucoma patients, found at significantly lower levels compared to healthy controls. [12]

Fig 20 Alphafold design for CDR1

Its main function comes after inhibiting ANP32A, which means there are fewer activated apoptosomes, so that there are less active caspase 9 and caspase 3, and so RGC death rates are slowed down.

Fig 21 CDR1 contributes to RGC survival by inhibiting caspase-3

ANP32A, which means there are fewer activated apoptosomes, so that there are less active caspase 9 and caspase 3, and so RGC death rates are slowed down.

Nanocarriers

Using nanocarriers for drug delivery offers critical advantages that significantly enhance both the effectiveness and safety of treatments. Their nanoscale size allows for improved penetration through biological barriers, which is especially important in the eye’s complex and protected environment. Nanocarriers facilitate precise targeting of therapeutic agents to specific tissues or cell types, increasing drug bioavailability at the intended site while minimizing systemic exposure and off-target side effects. Moreover, nanocarriers provide controlled and sustained drug release, which maintains therapeutic concentrations over time, reducing dosing frequency and improving patient compliance. They also protect sensitive peptide-based drugs from premature degradation by enzymes in ocular fluids, thereby enhancing stability and overall potency. In glaucoma, these properties are essential to overcoming challenges related to delivering drugs through anatomical and physiological barriers, ensuring that therapy reaches and acts on key pathological sites effectively. [13] [14] [15]

The FT drug harnesses Wnt3a- and CTGF-based nanocarriers specifically designed to target damaged trabecular meshwork (TM) cells, the focal point of dysfunction in glaucoma-induced intraocular pressure elevation. [16] These nanocarriers are chosen not only for their biocompatibility but also because they mimic natural signaling molecules, facilitating efficient uptake and intracellular delivery. FT’s mechanism centers on modulating the Wnt signaling pathway by binding to Frizzled and LRP5/6 receptors on TM cells, which restores normal cellular function and promotes the regulation of aqueous humor outflow. [17] Incorporating the Tat peptide as a cell-penetrating peptide (CPP) further enhances the drug’s ability to cross cell membranes and reach intracellular targets. [18] This synergistic design ensures precise and robust intervention at the molecular level, effectively repairing TM damage and reducing intraocular pressure—addressing the root cause of glaucoma progression.

Fig 22 Mechanism of nanocarrier

Similarly, the BC drug employs mNGFb nanocarriers combined with Tat CPP to selectively deliver neuroprotective agents to retinal ganglion cells (RGCs), which are critical for visual signal transmission and highly susceptible to glaucomatous damage. The mNGFb nanocarriers improve peptide stability and prolong bioavailability, protecting the therapeutic agents from enzymatic degradation and enabling sustained release within retinal tissues. Tat CPP facilitates efficient cellular uptake by traversing biological membranes and promoting receptor-mediated targeting of RGCs. Through this targeted delivery system, BC effectively administers neurotrophic factors that activate survival signaling pathways and inhibit apoptosis in RGCs. By preserving these neurons, the BC formulation directly combats neurodegeneration, a key contributor to vision loss in glaucoma. Together, the nanocarrier platforms and targeting peptides provide a potent and highly specific therapeutic strategy, maximizing efficacy while minimizing systemic toxicity. [19]

Receptor-mediated endocytosis begins after the specific binding of the ligand-decorated liposome to its corresponding cell surface receptor. This binding triggers clustering of the receptor-ligand complexes into specialized regions of the plasma membrane called clathrin-coated pits. These pits invaginate into the cell as the clathrin coat assembles, forming a vesicle that engulfs the liposome. The vesicle then pinches off from the plasma membrane, entering the cytoplasm as an early endosome. Inside the cell, the acidic environment of the endosome facilitates the dissociation of the ligand-receptor complex, allowing the release of the drug payload into the cell. Subsequently, the receptors are often recycled back to the membrane, while the liposome contents can be trafficked to their intracellular targets, enabling efficient and selective intracellular delivery of therapeutic agents. [20]

Hypothesis

Why these peptides?

Addressing the complex pathology of glaucoma requires a multifaceted therapeutic approach that can simultaneously target multiple disease mechanisms. We selected these peptides for their unique benefits that specifically tackle the main challenges in glaucoma treatment, setting them apart from other options.

FRATtides, derived from a regulatory segment of the FRAT protein that modulates glycogen synthase kinase-3 (GSK-3), specifically target a key pathway involved in intraocular pressure (IOP) regulation. This targeted mechanism makes FRATtides particularly effective at lowering IOP, a central factor in glaucoma progression, distinguishing them from peptides without such precise biological activity.

We chose TP1 for its remarkable structural stability, which results from numerous disulfide bonds that enhance resilience to enzymatic degradation and preserve bioactivity. This robustness is essential for maintaining prolonged therapeutic effects within the challenging ocular environment. Many alternative peptides lack these well-defined structural features, resulting in reduced efficacy and shorter action, making TP1 an ideal candidate for supporting retinal health.

We incorporated BDNF-derived peptides for their ability to mimic the neuroprotective functions of full-length brain-derived neurotrophic factor while providing enhanced stability and manufacturability. Unlike larger proteins, these smaller peptides are more stable and practical for development, yet retain the precise capacity to promote RGC survival rate. This targeted neuroprotection surpasses that of generic peptides, which often lack comparable specificity and efficiency.

Lastly, CDR1 peptides, originating from antibody variable regions, bring distinct functional advantages in a compact and easily modifiable form. Their short length allows for precise synthesis and customization, enabling tailored therapeutic effects that are difficult to achieve with many other peptides. This precision makes CDR1 peptides invaluable for designing effective and specific treatments.

Together, these peptides form a strategically balanced combination of targeted biological activity, structural stability, and production feasibility. Their unique properties enable us to overcome the limitations of current therapies by simultaneously reducing intraocular pressure and protecting retinal ganglion cells, establishing them as the ideal foundation for a novel dual-peptide therapy against glaucoma.

Why use fusion peptides?

We utilized fusion peptides for our drug development due to their compelling advantages that address both therapeutic efficacy and practical challenges in treating complex diseases like glaucoma. By combining multiple functional units into a single, compact molecule, "to simultaneously address multiple pathological pathways"" to simultaneously address several pathological pathways." This multifaceted approach is particularly crucial for glaucoma, where both intraocular pressure and retinal ganglion cell degeneration drive disease progression. The integration of distinct functional domains within one molecule ensures a coordinated therapeutic effect that is unattainable with single-target agents.

One of the most significant benefits of fusion peptides lies in their enhanced tissue penetration. Compared to larger biologics such as monoclonal antibodies, their relatively small size enables efficient access to and penetration of deep ocular tissues, including the trabecular meshwork and, notably, the retinal ganglion cells. This improved bioavailability ensures that the drug reaches critical sites of action in sufficient concentrations, maximizing therapeutic impact and clinical effectiveness. Nanocarriers further enhance this effect by protecting fusion peptides from enzymatic degradation in ocular fluids, prolonging their half-life and stability. Their ability to facilitate sustained and controlled drug release helps maintain therapeutic concentrations over extended periods, reducing dosing frequency and improving patient compliance. [21]

Furthermore, fusion peptides exhibit superior specificity and affinity by incorporating domains engineered to bind precisely to target receptors. [22] In addition, fusion peptides combine multiple functional domains into a single molecule, enabling simultaneous cell penetration and targeted receptor binding, which enhances drug retention and sustained therapeutic effect in ocular tissues. Nanocarriers can be engineered to recognize and bind specific ocular cell types, thus improving targeted delivery and reducing off-target effects. This targeted interaction not only heightens treatment potency but also reduces systemic exposure and potential side effects, which is a notable concern with less selective therapies. The precision of fusion peptides, enhanced by nanocarrier-mediated delivery, thus contributes to a safer pharmacological profile—an essential consideration for chronic conditions like glaucoma, where long-term treatment is required. [23]

From a manufacturing standpoint, fusion peptides have a myriad of distinct advantages. Compared to large biologics, they are generally less immunogenic and more cost-effective to produce. [24] Their smaller size and simpler structure facilitate scalable and consistent manufacturing processes, which are critical for making innovative treatments accessible to a broader patient population. Additionally, the modular nature of fusion peptides enables rational design and optimization using advanced computational methods, allowing for the refinement of key properties such as stability, half-life, and functional versatility. When combined with nanocarrier technology, these peptides gain improved pharmacokinetics and biodistribution profiles, enhancing treatment efficacy and safety. This level of customization, which combines both peptide design and nanocarrier delivery systems, remarkably enhances the drug's overall performance and its adaptability to changing therapeutic needs.

Taken together, the proven benefits of fusion peptides—including their multifunctional targeting, enhanced penetration, high specificity, improved safety, and manufacturing efficiency—position them as an ideal platform for developing novel, targeted therapies for multifactorial diseases, i.e, glaucoma. The addition of nanocarriers amplifies these advantages by offering protection from degradation, targeted and controlled release, and improved bioavailability in ocular tissues. Their ability to combine efficacy, safety, and production feasibility makes fusion peptides with nanocarrier delivery a proficient foundation for advancing glaucoma treatment beyond the limitations of current approaches.

Conclusion

Glaucoma remains one of the leading causes of irreversible blindness worldwide, profoundly impacting the quality of life for millions and placing a significant strain on healthcare systems and economies globally. This project carries substantial societal importance by directly addressing the urgent challenge of glaucoma-related vision loss through an innovative, accessible, and effective therapeutic strategy. By developing a dual-action, non-invasive ocular treatment, we have pioneered the world’s first glaucoma eye drop specifically designed to target two principal disease mechanisms simultaneously, while also enhancing patient comfort and adherence.

The drug’s design leverages fusion peptides, which offer a streamlined manufacturing process compared to traditional biologics. Advances in peptide synthesis and recombinant technologies have dramatically reduced production costs, making large-scale manufacturing both practical and economically viable. Moreover, the eye drop formulation permits widespread distribution, minimizing the need for invasive procedures and specialized medical infrastructure. This significantly lowers barriers to treatment access, particularly in resource-limited settings.

The non-invasive, easy-to-administer delivery method encourages higher patient compliance, enabling individuals—including seniors and those with limited mobility—to consistently apply the therapy at home. This convenience is critical for maintaining long-term treatment adherence, which in turn improves clinical outcomes and helps reduce the progression toward severe vision impairment and blindness.

In summary, this project represents far more than a medical breakthrough; it marks a significant advancement in public health. By offering an effective, user-friendly therapy that can preserve vision and autonomy, it provides hope and tangible benefits to millions worldwide, improving quality of life and reducing the global burden of glaucoma.

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