Further Evidence for Cellular Senescence to Contribute Meaningfully to the Progression of Diabetic Retinopathy
Ever more of the research community is drawn to work on cellular senescence by the clear, robust, and expanding evidence for senescent cell accumulation to be a major contributing cause of aging. Clearance of senescent cells by senolytic treatments produces extension of healthy life span and rejuvenation in mice, the reversal of many different age-related conditions. Senolytics are presently in the early stages of human clinical trials, with promising results for some of the approaches taken, such as use of the dasatinib and quercetin combination.
The role of senescent cells in the progression of diabetic retinopathy was outlined in some detail five years ago or so. This form of retinopathy, and others such as macular degeneration, is characterized by the inappropriate growth of leaky blood vessels into the retina, disrupting structure and killing cells. This growth is driven in large part by the secreted signals of senescent cells.
Unity Biotechnology is focused on the development of first generation senolytic small molecule drugs derived from chemotherapeutics such as navitoclax. The company is targeting conditions of the eye for what looks to be much the same rationale as they targeted osteoarthritis of the knee: that they can use localized treatments that minimize any off-target side effects that might emerge with systemic delivery of a drug. Based on the failure of their last clinical trial for localized senolytic treatment of the knee joint, this strategy may prove to be a case of optimizing for regulatory approval at the cost of clinical efficacy. Sad to say, but a great deal of the medical landscape is defined not by what works most effectively, but instead by what the regulators are most likely to accept.
The likely problem with localized approaches to senolytic therapy is that the signals secreted by senescent cells enter the circulation and travel throughout the body. Removing the contribution of local senescent cells may well not be enough to produce reliable benefits in a patient exhibiting chronic systemic inflammation, with significant numbers of senescent cells in all tissues. The failed Unity Biotechnology trial is argued to have been a demonstration of this point. If the company also fails to produce benefits in patients for the eye via localized injection of senolytics, that would likely ensure that no group ever again tries a localized approach.
UNITY Biotechnology, Inc., a biotechnology company developing therapeutics to slow, halt, or reverse diseases of aging, today announced new preclinical research that reveals a novel mechanism for treating age-related eye diseases - such as diabetic retinopathy and diabetic macular edema - by restoring vascular health in the retina. By selectively eliminating the senescent cells accumulating in diseased blood vessels of the eye, researchers identified a way to target diseased vasculature while leaving healthy blood vessels intact, thus enabling the retina to repair itself.
Researchers demonstrated that diseased blood vessels in the retina trigger molecular pathways associated with aging, collectively termed cellular senescence. The authors used a combination of animal models and human samples to identify a molecular target, called Bcl-xL, that is highly expressed in diseased retinal blood vessels. Targeting these senescent cells with a single dose of UNITY's Bcl-xL small molecule inhibitor led to selective elimination of diseased vasculature, while enabling functional, healthy blood vessels to reorganize and regenerate.
Attenuating pathological angiogenesis in diseases characterized by neovascularization such as diabetic retinopathy has transformed standards of care. Yet little is known about the molecular signatures discriminating physiological blood vessels from their diseased counterparts, leading to off-target effects of therapy. We demonstrate that in contrast to healthy blood vessels, pathological vessels engage pathways of cellular senescence. Senescent (p16 INK4A-expressing) 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 suppresses pathological angiogenesis. 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. These findings provide mechanistic evidence supporting the development of BCL-xL inhibitors as potential treatments for neovascular retinal disease.