Diabetic retinopathy (DR) and secondary macular edema (DME) persist as leading causes of vision loss and complete blindness in adults throughout the world. This is especially important because the rates of diabetes are on the rise both in the United States and globally.1
Given this concerning rise, we are now tasked with the chronic management of progressive, vision-threatening retinal disease. Current management options include anti-vascular endothelial growth factor (VEGF) therapies and laser treatments, which may still leave gaps in care and highlight the need for new, more effective therapies.
One emerging avenue for therapy is cellular senolysis, which consists of the targeted elimination of senescent cells that may be involved in the pathogenesis and progression of DR and DME.2
Brief overview of diabetic retinopathy
Over 100 million individuals globally are estimated to have been diagnosed with DR, with up to 20 to 25% of them having DME.3 In the US alone, almost a third of diabetes patients exhibit signs of DR. Dangerous comorbid conditions such as hypertension and hyperlipidemia, along with poor glycemic control, are known to worsen DR and DME risk.3,4
Figure 1: Moderate non-proliferative diabetic retinopathy in a 58-year-old female.
Figure 1: Courtesy of Kevin Cornwell, OD, FAAO.
DR and DME may severely impair daily functioning, quality of life, mobility, employment, mental health, and self-perception.5
A few symptoms of DR include:6
- Blurring of vision
- Floaters
- Color vision distortion
- Loss of central vision
The need for frequent and potentially painful treatments such as intravitreal injections and laser photocoagulation therapy may, unfortunately, reduce treatment adherence.7 This opens the door for increasing both private and system healthcare costs, and practicing reactive medicine, rather than preventive medicine.8
Pathophysiology of DR
DR is ultimately a microvascular domino effect, initially caused by nonenzymatic glycosylation, which leads to the formation of advanced glycation end products (AGEs) that accumulate in the retina. These AGEs then increase oxidative stress and weaken blood vessel integrity, promoting the leakage of fluid into the extravascular space.9
DR typically starts as non-proliferative DR (NPDR), marked by microaneurysms, hemorrhages, and exudates, leaving parts of the retina oxygen-deprived.10
Figures 2 and 3: Fundus images of a 70-year-old male with mild non-proliferative diabetic retinopathy without macular edema in the right and left eye, respectively.
Figure 2: Courtesy of Jill Gottehrer, OD, FAAO.
Figure 3: Courtesy of Jill Gottehrer, OD, FAAO.
This opens the door to progression to the more serious proliferative stage (PDR), where the growth of fragile, abnormal new blood vessels poses a serious risk to a patient’s vision.11
DR can then lead to DME, which refers to the accumulation of excess fluid within the macula, which is the most sensitive and central part of the retina. This can occur at any stage of DR and commonly causes central vision loss in patients who are living with diabetes.12
Figures 4 and 5: Fundus images from a 51-year-old male with proliferative diabetic retinopathy with macular edema in the right and left eye, respectively.
Figure 4: Courtesy of Jill Gottehrer, OD, FAAO.
Figure 5: Courtesy of Jill Gottehrer, OD, FAAO.
Chronically high blood sugar levels wreak havoc on the body’s blood vessels and compromise the blood-retina barrier, resulting in longitudinal vascular leakage, retinal ischemia, and neovascularization. Recently, studies began to implicate cellular senescence in this process.13
Cellular senescence is a process by which the cell cycle is irreversibly arrested in the G1 or G2 phase. This diversion from regular cellular programming fuels a cascade of proinflammatory signaling and oxidative stress in the retina, which leads to its ultimate degeneration.14,15
Diagnosis of DR
Diagnosing DR and related DME combines clinical examination with multimodal imaging such as optical coherence tomography (OCT) and OCT-angiography.
Traditionally, the ETDRS (Early Treatment Diabetic Retinopathy Study) scale has been used to guide DR staging and OCT, specifically by measuring subfield thickness, which informs DME staging.16 Fluorescein angiography has significant use in detecting areas of fluid leakage or ischemia in the retina.17
Current methods for managing DR and DME
The management of DR and DME begins with managing diabetes systemically by attempting to control blood sugar levels.18 This has been shown to slow the progression of DR in its early stages, but ultimately, if patients progress to late stages, the damage almost becomes irreversible.
Targeted ophthalmic treatments may slow the rapid progression of disease or mask symptoms, but are not a permanent solution. These include intravitreal anti-VEGF injections to halt retinal neovascularization, laser photocoagulation therapy, and corticosteroid implants for severe or refractory cases.19
However, current treatments still leave something to be desired because they are not enough to halt the disease. Furthermore, patients may not be highly compliant with frequent anti-VEGF injections, which can be painful or anxiety-inducing.20
Even when patients are compliant with the injections, they may later become unresponsive.21 This often occurs to patients who are diagnosed with DR later than average because of systemic barriers such as poor access to specialty care, in which the disease is left to progress inconspicuously because of the lack of early detection and interventions.22
Paradigm shift: Senolytic therapies
Cellular senescence is a self-preservation mechanism that cells employ to mitigate chronic stress in diseased individuals. This may be beneficial in the treatment of acute injury or tumor suppression; however, the longitudinal accumulation of senescent cells disrupts tissue homeostasis.23
It is hypothesized that chronic hyperglycemia triggers cellular senescence in retinal endothelial and glial cells, contributing to the pathophysiology of DR.24 According to Kirkland and Tchkonia, senolytic therapies have been successful in the treatment of multiple other systemic disorders, such as dasatinib and quercetin for idiopathic pulmonary fibrosis and diabetic nephropathy.25
Another example they discussed is navitoclax, which has been utilized in the treatment of hematologic malignancies. Importantly, dasatinib and quercetin were also used as senolytic therapies in the first-ever phase 1 clinical trial for Alzheimer’s disease.
Although the sample size was limited, the study demonstrated feasible blood-brain barrier penetration and some indications of reduced inflammatory markers, fueling further interest in senolytic treatments for neurodegenerative diseases.26
Senolytic therapy for DME
With this encouraging finding in the neighboring field of neurology, UNITY Biotechnology launched a Phase 2, randomized controlled trial to assess UBX1325 safety and activity in AMD patients.27
The results of this trial represent a paradigm shift, moving beyond symptom suppression to modifying the underlying cellular pathology. Some patients achieved sustained improvements in visual acuity after a single dose.
Furthermore, there was a reduction in central retinal thickness without the need for additional anti-VEGF rescue in some patients. Most importantly, the injection of UBX1325 was well-tolerated, with no adverse events reported to date.27
Phase 2b clinical trial data for UBX1325
Earlier this year, UNITY Biotechnology announced topline results from the ASPIRE phase 2b study of 52 patients who were randomly assigned 1:1 to receive either 10ug UBX1325 or 2mg aflibercept control injections every 8 weeks for 6 months.28
The primary efficacy endpoint was non-inferiority to aflibercept, measured by mean change in best-corrected visual acuity from baseline to the average of weeks 20 and 24.
Participants who received UBX1325 achieved vision gains comparable to aflibercept at weeks 24 and 36, with patients in the UBX1325 group achieving a mean gain of 5.2 letters at week 24 and 5.5 letters at week 36.28
While UBX1325 was non-inferior to aflibercept at week 24, it did not meet statistical noninferiority on the average of weeks 20 and 24. Instead, it reached noninferiority at an 88% confidence interval compared with a 90% threshold that was set as the primary analysis endpoint.28
The future of DR clinical trials: A precision approach
While novel mechanisms, such as senolytics, represent a paradigm shift in treating DR, a parallel evolution in clinical trial design is required to realize their full potential. The high failure rate of drug candidates, often due to an incomplete understanding of disease mechanisms in living humans, necessitates a more sophisticated strategy.
An integrated, precision-medicine approach can de-risk development, enhance data quality, and accelerate the delivery of new therapies to patients. First, we must move beyond patient selection based on classical structural staging, such as the ETDRS scale, which may not reflect the underlying molecular pathology.
Advanced techniques, such as integrating liquid biopsy proteomics with AI, enable an unprecedented view into the cellular drivers of disease in vivo. The TEMPO platform, for instance, has demonstrated that the cellular drivers of DR switch during disease progression; the early, non-proliferative (NPDR) stage is driven primarily by vascular cells, while the later, proliferative (PDR) stage is driven by immune cells.29
Future clinical trials should therefore stratify patients based on their dominant cellular and molecular signature, ensuring that the right patients are matched with the proper therapeutic mechanism.
Tracking molecular changes in DR in clinical trials
Second, trial endpoints must evolve to capture these molecular changes. Relying solely on long-term functional outcomes, like visual acuity, or structural changes on an OCT can be slow and may not tell the whole story. We can now deploy novel molecular endpoints, including the molecular "Eye Age Clock," an AI-powered model that assesses the molecular age of specific cell types.29
Crucially, this has revealed that DR is associated with accelerated aging of retinal cells. A key endpoint for senolytics and other next-generation therapies could be their ability to halt or reverse this accelerated aging process, offering a quantifiable measure of tissue rejuvenation.
This approach provides rapid molecular feedback, with the potential for go / no-go decisions in as little as 6 to 8 weeks, fundamentally accelerating the development cycle. By combining precise patient stratification with smarter, molecularly-driven endpoints and operationally excellent trial management, we can increase the probability of success, reduce trial costs, and shorten the time to market for sight-saving therapies.
This is the future of retinal therapeutic development—a future that is more precise, more efficient, and ultimately, more beneficial for patients worldwide.
Conclusion
DR and DME remain major causes of vision loss despite existing therapies. Senescent cells play a critical role in chronic retinal inflammation and dysfunction. Senolytic therapies, such as UBX1325, offer a novel, targeted approach to address the root causes of disease.
While early clinical trials are promising, further research is needed to define the long-term efficacy, safety, and optimal patient selection. Understanding the evolving landscape of retinal therapeutics, including cellular senolytics, will be crucial to delivering future-ready care.
