Taking aim at Bcl-xL
Scientists identify a new target for treating age-related eye diseases
SOUTH SAN FRANCISCO, Calif.—The first step to treating any disease is identifying a suitable biological or genetic target, and collaborative work between UNITY Biotechnology Inc. and the University of Montreal may have done just that for age-related ophthalmological diseases such as diabetic retinopathy and diabetic macular edema.
Specifically, researchers found that eliminating senescent cells can improve a patient’s condition, and their work was published in Cell Metabolism in a paper titled “Pathological angiogenesis in retinopathy engages cellular senescence and is amenable to therapeutic elimination via BCL-xL inhibition.”
UNITY describes senescent cells, also known as p16 INK4A-expressing cells, as “a fundamental mechanism of aging and a driver of many common age-related diseases,” explaining that “Over the arc of one’s life, cells divide until they encounter some form of biologic stress, at which point they pull a form of cellular emergency brake causing them to cease dividing—forever. The result is an accumulation of senescent cells that secrete large quantities of harmful proteins, which cause inflammation, tissue degradation and the production of growth factors that alter the tissue microenvironment, which we believe leads to several age-related diseases.”
Targeting these cells within retinal blood vessels is important in diabetic retinopathy. In this disease, small blood vessels that feed the back of the eye become damaged and regrow abnormally and they can swell or leak, causing scars in the retina and damaging vision.
“This collaboration between the MRH-RC, UdeM [University of Montreal], and UNITY Biotechnology could have an impact on the quality of life of patients with diabetic retinopathy,” said Dr. Przemyslaw (Mike) Sapieha, one of the paper’s authors, a professor in UdeM’s Department of Ophthalmology, and director of MRH-RC’s Neurovascular Eye Disease Research Unit. “With a single injection, it would potentially be possible to eliminate groups of cells that contribute to diabetic eye disease, which affects some 750,000 Canadians and is the leading cause of blindness in working-age adults.”
The research team found that diseased retinal blood vessels trigger molecular pathways associated with senescence, and specifically identified Bcl-xL, which is a member of the Bcl-2 family of apoptosis regulatory proteins and is highly expressed within these damaged blood vessels. In their paper, the authors noted that senescent cells “accumulate in retinas of patients with diabetic retinopathy and during peak destructive neovascularization in a mouse model of retinopathy.”
“Using either genetic approaches that clear p16 INK4A-expressing cells or small molecule inhibitors of the anti-apoptotic protein BCL-xL, we show that senolysis [removal of senescent cells] suppresses pathological angiogenesis,” the authors explained. “Single-cell analysis revealed that subsets of endothelial cells with senescence signatures and expressing Col1a1 are no longer detected in BCL-xL-inhibitor-treated retinas, yielding a retina conducive to physiological vascular repair. “
By treating senescent cells with UNITY’s Bcl-xL small-molecule inhibitor, the team was able to selectively eliminate diseased blood vessels.
“These findings suggest that Bcl-xL inhibition has the potential to selectively target diseased retinal blood vessels, while sparing healthy ones and promoting more functional vasculature in the eye,” commented Sapieha.
UNITY is developing UBX1325, a small-molecule inhibitor of Bcl-xL, in several ophthalmologic indications, including diabetic retinopathy, diabetic macular edema, and age-related macular degeneration.
A Phase 1 clinical trial is currently underway in diabetic macular edema to explore the compound’s safety and tolerability, with initial results expected in H1 2021. Another Bcl-xL inhibitor, UBX1967, is a “molecularly distinct backup” to UBX1325, according to UNITY’s website, and is in IND-enabling development in the same indications.
“Bcl-xL inhibition may be the key to a new class of neovascular retinal medicine, in which a targeted treatment allows the retina to repair itself while eliminating diseased vasculature,” said Anirvan Ghosh, CEO of UNITY. “These findings support the role cellular senescence plays in age-related eye diseases and that senolytic medicines may provide not only a viable strategy for promoting vasculature health, but an important new treatment option for these debilitating diseases.”
