Breakthrough Against Blindness: Discovery Paves The Way For New Eye Drugs

Scientists have discovered that a protein called PRL3, already studied in cancer treatment, is also linked to serious eye diseases that cause vision loss, such as macular degeneration and diabetic retinopathy. This protein helps form defective blood vessels in the eye. A new drug that blocks PRL3 has shown promising results in animal trials and may be a more effective and safer alternative to current eye injection treatments.

Angiogenesis is the biological process responsible for forming new blood vessels from existing ones. This mechanism is normal and essential for functions such as wound healing and tissue growth. However, in some diseases, angiogenesis occurs in a disordered and exaggerated manner, resulting in the formation of abnormal blood vessels that do not function properly.

These vessels are fragile, tortuous, and leak fluid and blood, which can cause inflammation and damage to surrounding tissues. In the human eye, this uncontrolled vessel growth leads to serious complications, such as progressive vision loss.

Two of the main eye diseases caused by this type of abnormal angiogenesis are Age-Related Macular Degeneration (neovascular form) and Diabetic Retinopathy, including Diabetic Macular Edema.

Both involve the formation of abnormal blood vessels in the retina, the layer of tissue responsible for capturing light and sending images to the brain. When these vessels leak, the accumulation of fluid in the retina distorts its structure and function, compromising vision.

Schematic comparison of normal mature blood vessels and naive hyperpermeable blood vessels (created in BioRender71).

With the aging population and the rise in diabetes, these diseases have become increasingly common, affecting millions of people worldwide.

Since the 1990s, it has been known that a protein called Vascular Endothelial Growth Factor (VEGF) plays a central role in this process. In situations of low oxygenation (hypoxia) in the retina, as occurs with aging and diabetes, retinal cells release VEGF to attempt to restore oxygen supply by creating new vessels.

However, this stimulation is excessive and poorly regulated, resulting in fragile and leaky vessels. To address this problem, anti-VEGF drugs, which block this protein, have emerged. These medications are injected directly into the eye, into the so-called vitreous space, and have shown good results in many patients, reducing leakage and even improving vision in some cases.

However, not everyone benefits from these therapies. Studies show that between 37% and 45% of patients with macular degeneration and about 40% with diabetic retinopathy do not respond well to treatment. In some cases, even with regular applications, the disease continues to progress.

Furthermore, anti-VEGF treatments require frequent ocular injections, which cause discomfort, risk of serious infections (such as endophthalmitis), and complications such as retinal detachment, hemorrhages, or traumatic cataracts.

Furthermore, because VEGF also plays important roles in other parts of the body, such as the heart and brain, there are concerns about long-term side effects, especially in people who already have cardiovascular disease.

Given these limitations, researchers have been searching for alternative targets to VEGF, aiming to find more effective and less invasive therapies. One such target is a protein called PRL3, originally studied in the context of cancer.

PRL3 is an enzyme (phosphatase) that regulates several cellular processes and has been found to be highly active in several types of cancer, helping tumor cells grow, invade other tissues, and form new blood vessels. Previous studies have shown that blocking PRL3 in tumors with specific antibodies can reduce cancer growth and prevent its recurrence after treatment.

Recently, scientists have observed that PRL3 is also present at increased levels in diseased ocular tissues, such as the retina and choroid, especially in experimental models of neovascular eye disease. This suggests that, beyond cancer, PRL3 may also participate in ocular pathological angiogenesis.

In animal studies, intravenous administration of antibodies that block PRL3 (directly into the bloodstream) significantly reduced leaky blood vessels in the retina. Interestingly, this effect was even stronger than that obtained with traditional intravitreal administration, possibly because the dose administered intravenously can be higher and better distributed throughout the body.

Studies have also shown that when retinal endothelial cells (which form blood vessels) are exposed to VEGF, they increase PRL3 production. Furthermore, when PRL3 is overactivated, these cells begin to multiply and migrate more rapidly, as well as become more permeable—all characteristics of abnormal vessels.

When PRL3 is "silenced" in cells, even the presence of VEGF is not sufficient to produce these effects. This indicates that PRL3 is a kind of intermediary or facilitator of VEGF's action; that is, even if VEGF is present, it requires PRL3 to fully exert its role.

Given this, the prospect arises of repurposing PRL3-zumab, a humanized monoclonal antibody against PRL3, already in experimental use for the treatment of cancer, to combat eye diseases caused by abnormal angiogenesis.

This experiment was done with human retinal cells (HRMECs), which are important for vision health. Scientists wanted to understand what happens when a protein called PRL3 is introduced into these cells. HRMECs: These are blood vessel cells from the human retina (Human Retinal Microvascular Endothelial Cells). PRL3: This is a cancer-associated protein being studied here for its role in eye diseases. GFP: This is a green fluorescent protein used as a marker to determine whether the experiment worked (the cells that glow green correctly received the DNA with PRL3 or the control vector). ZO-1: This is an important protein that keeps cells stuck together, like a "seal" or "barrier." The more ZO-1 visible, the better the integrity of the cell layer. Vector: This is the control group, the cells that did not receive the PRL3 protein. A and C (left side): Control cells (without PRL3). They show strong red staining for ZO-1 at the cell edges (light lines between the blue nuclei), indicating that the cell barrier is well formed. B and D (right side): Cells with the PRL3 protein. ZO-1 is less visible (weaker red lines), indicating that the integrity of the cell barrier is compromised. The white arrows point: In images A and B: where ZO-1 is most clearly visible (better in cells without PRL3). In images D: where PRL3 is located in cells (mainly in membranes and within cells). E, the graph shows the amount of ZO-1 (the barrier protein) in cells with and without PRL3. Cells with PRL3 have significantly less ZO-1 (lower bars), suggesting that this protein weakens the cell barrier.

This antibody has demonstrated an excellent safety profile in Phase II human clinical studies, with no serious side effects. If proven effective in ocular diseases, it could represent a new class of treatment, potentially safer, less invasive, and effective even for patients who do not respond to anti-VEGF medications.

This type of advancement represents a paradigm shift in the treatment of blindness caused by retinal vascular diseases. More than blocking a single factor like VEGF, new therapies like PRL3-zumab offer the possibility of interrupting an entire cellular signaling network that supports disorganized vessel growth.

Furthermore, the use of intravenous therapies can avoid the direct risks associated with intraocular injections, expanding access and safety for millions of patients around the world.

READ MORE:

PRL3-zumab as an anti-angiogenic therapy in neovascular eye diseases

Koon Hwee Ang, Min Thura, Queenie Shu Woon Tan, Abhishek Gupta, Kam Yew Kuan, Jie Li, Pei Ling Chia, Beiying Qiu, Jimmy Ming Hong, Ke Guo, Xiaomeng Wang, Xinyi Su, and Qi Zeng 

Nature Communications, volume 16 : 4791 (2025)

https://doi.org/10.1038/s41467-025-59929-2

Abstract: 

Neovascular eye diseases represent a major cause of irreversible blindness. Here, we report the specific upregulation of endogenous PRL3 protein in diseased choroid-RPE in choroidal neovascularization (CNV) mouse model (male), and diseased retina in oxygen-induced retinopathy (OIR) mouse model (mixed gender), indicating PRL3’s role in neovascularization. Intravenous (IV) delivery of anti-PRL3 antibody in CNV model demonstrates superior efficacy in reducing vascular leakage compared to intravitreal (IVT) route due to larger dose permitted by IV. VEGF treatment upregulates endogenous PRL3 protein in human retinal microvascular endothelial cells (HRMECs). Retroviral PRL3 overexpression in HRMECs promotes endothelial proliferation, migration and permeability by facilitating the phosphorylation of ERK1/2, AKT, Paxillin and SRC. However, VEGF-induced proliferation is absent in PRL3-knockout HRMECs. PRL3-zumab, an anti-PRL3 humanized monoclonal antibody, has shown a strong safety profile in ongoing multi-national Phase II trials as an intravenous-administered cancer immunotherapeutic. PRL3’s involvement in ocular pathological angiogenesis suggests the potential of repurposing PRL3-zumab to treat neovascular eye diseases.