Model UBX1325 - Potent Bcl-xL Inhibitor

UBX1325 is the first senolytic approach intended to target senescent cells and selectively eliminate these cells in and around diseased vasculature in the eye, while leaving healthy blood vessels intact. UBX1325 is a novel senolytic small molecule inhibitor of Bcl-xL, a member of the Bcl-2 family of apoptosis regulatory proteins that is highly expressed in pathological blood vessels in the retina. Inhibition of Bcl-xL promotes apoptosis of diseased senescent cells, which accumulate in the retina, promoting inflammation and compromising vascular integrity. In preclinical research published in Cell Metabolism, a single dose of UNITY’s Bcl-xL small molecule inhibitor led to selective elimination of senescent cells in diseased vasculature, while enabling functional, healthy blood vessels to reorganize and regenerate.

According to the National Eye Institute, diabetic retinopathy is the most prominent complication of diabetes and the leading cause of blindness in working age individuals. NEI estimates that ~8 million Americans are afflicted by the eye disease and predicts the incidence will double over the next 15 years. In diabetic retinopathy, the small caliber blood vessels that feed the back of the eye (retina) degenerate and re-grow in an abnormal manner. These diseased vessels obstruct light and can leave scars in the retina. Diabetic macular edema is a common complication of diabetic retinopathy and the leading cause of blindness in adults with diabetes.

During the course of diabetes, cells that make up the small caliber blood vessels in the eye are more likely to become senescent. We believe these senescent vascular cells compromise the integrity of the blood vessel and release inflammatory factors that collectively compromise healthy vasculature. In DME, the damaged blood vessels leak into the retina, resulting in the accumulation of fluid in the macula – or the central part of the retina. Over time, the macula swells and may lead to severe vision loss.

One of the limitations of the current standard of care, anti-VEGF therapy, for vascular diseases of the retina is that they target both sick and healthy parts of the eye and hence can potentially impair normal remodeling of healthy vessels. Anti-VEGF agents, for example, block all blood vessel growth. Bcl-xL inhibition may be the key to a new class of neovascular treatments that provide a viable and much needed alternative to current treatment modalities.