New research supports therapeutic potential of senolytics in DME

Publication in Nature Medicine details long-lasting, disease-modifying intervention in vision loss from diabetic macular edema.

UNITY Biotechnology, a company working on therapeutics to slow, halt or reverse diseases of aging, today announced new research published in the peer-reviewed journal Nature Medicine that supports the clearance of senescent cells in the retina as a therapeutic approach that can lead to long-term improvements in vision in patients with diabetic macular edema (DME) [1].

Longevity.Technology: Sustained hyperglycemia from diabetes induces cellular senescence which damages the retina, including the delicate vasculature in the eye. This can lead to fluid accumulation and retinal thickening – key features of DME. The study shows that the therapeutic clearance of senescent cells can potentially remove an underlying source of pathogenesis and thus allow healthy cells to regenerate and remodel retinal vasculature, ultimately leading to long-term disease modification.

Senescent cells are cells that have reached the end of their replication lifespan, or have been damaged beyond repair, but which have ‘forgotten’ to undergo apoptosis or cell death. Instead, they hang around in the body, building up in numbers, encouraging other cells to become senescent and contributing to age-related tissue and organ dysfunction and various chronic age-related diseases.

Senescent cells also secrete a toxic mix of inflammatory cytokines, growth factors and proteases (senescence-associated secretory phenotype or SASP). SASP can promote chronic inflammation, tissue remodeling and other changes that can drive the development and progression of age-related diseases.

A team of scientists at University of Montreal and UNITY Biotechnology revealed that cellular senescent pathways are triggered in the diabetic retina and are specifically activated in endothelial cells. They demonstrated that these senescent cells contribute to loss of barrier function, which can cause leaky blood vessels [2].

Researchers showed that senolysis – inducing death of senescent cells – by inhibiting an anti-apoptotic protein improved retinal barrier function in diabetic mice. The double negative can be a rather tricky concept to wrap your head around, but in a nutshell, cell death in senescent cells is a good thing, proteins that prevent cell death are bad, and inhibiting those proteins to stop cell death prevention brings us back round to the good thing of cell death.

Inhibition of the anti-apoptotic BCL-xL also modified the retinal microenvironment and reestablished tissue homeostasis. In addition, in clinical trials BCL-xL inhibition led to improvements in visual acuity and retinal structure stabilization in patients with advanced disease [1].

“This research provides compelling mechanistic evidence of the therapeutic approach of eliminating senescent cells to reduce diabetes-induced retinal vascular leakage and preserve retinal function,” said Anirvan Ghosh, PhD, CEO of UNITY and an author of the paper.

“As senescent cell burden is observed in many other diseases, this study highlights the potential benefit of senolytic drugs for various age-related and metabolic diseases.”

In preclinical studies, UNITY has demonstrated that targeting Bcl-xL with UBX1325 preferentially eliminated senescent cells from diseased tissue while sparing cells in healthy tissue.

The BCL-xL inhibitor UBX1325 has also been evaluated in a Phase 2 study; this research. demonstrated that a single injection led to statistically significant and clinically meaningful improvements in visual acuity through 48 weeks in patients with DME, while reducing anti-VEGF treatment burden.

UNITY’s goal with UBX1325 is to transformationally improve real-world outcomes for patients with retinal disease. It is now actively enrolling patients for a Phase 2b clinical trial where UBX1325 is being evaluated head-to-head versus aflibercept, with 16-week results expected in Q4 2024.

“Most therapeutic options available and in development for DME target the VEGF pathway. As a BCL-xL inhibitor, the senolytic UBX1325 targets an alternative mechanism and holds the potential to not only address the limitations of but also complement anti-VEGF agents,” said Przemyslaw (Mike) Sapieha, PhD, chief scientist at UNITY and the lead author of the paper. “A new long-lasting and disease-modifying therapy for DME would be transformative for patients. This research further supports the potential for senolytic medicines to address the significant unmet need with current standard of care.”

READ MORE: Anirvan Ghosh on getting comfortable with senotherapeutics