Science
We are targeting aging biology processes that underlie chronic and inflammatory diseases.
ARVO 2024, Presented by Dante Pieramici, M.D.
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Cells can enter a state of senescence, in which they remain metabolically active in the body, yet secrete various inflammatory factors, harmful proteins and metalloproteases. These senescent cells alter the surrounding microenvironment and contribute to different cellular dysfunctions and tissue degeneration.
Over time as these senescent cells accumulate, they contribute to several diseases that take a tremendous toll on our health and quality of life.
Our Senolytic Approach
UNITY is at the forefront of developing a new class of therapeutics that aim to restore diseased tissues to a healthier state. We believe this therapeutic approach has the potential to address the root cause of many diseases, such as retinopathies, neurodegenerative disorders, fibrosis and cancer.
Targeting senescent cells in diseased tissues to neutralize SASP factors, eliminate dysfunctional cells that drive disease progression and restore tissue health
In retinal diseases, a senolytic therapy may target senescent cells to reduce retinal inflammation and leakage, remodeling the vasculature of the eye
Senescent cells uniquely rely on BCL-xL for survival and therefore is an optimal therapeutic target for senolytic therapies.
Senescent vascular units are found in pathological blood vessels
BCL-xL inhibition reduces inflammatory markers and senescent cells in diabetic eyes
Senolytic therapies promote healthy retinal vasculature after a single injection
In clinical studies, a single injection of senolytic therapy resulted in significant visual acuity gains through 48 weeks
Disease-modifying Intervention in Vision Loss
Senescent cell burden in ocular tissues is associated with ophthalmological disorders such as diabetic macular edema (DME) and age-related macular degeneration (AMD).
Cellular Senescence in DME
Sustained hyperglycemia from diabetes induces cellular senescence, which damages the retina. Senescent cells within the blood vessels of the retina are no longer able to form proper junctions with their neighbors, causing the blood vessels to leak. In addition, the senescent cell burden in the eye produces proinflammatory molecules that further aggravate the inflamed retina. As fluid accumulates and the retina thickens, the delicate vasculature of the eye is severely damaged – a key feature of DME.
Targeting Senescent Cells to Restore Tissue Health
The therapeutic clearance of senescent cells can potentially remove a significant source of pathogenesis and thus allow healthy cells to regenerate, restore vasculature to a healthier state, and ultimately lead to long-term disease modification and vision improvement in patients with DME or AMD.
Senescent Cells Rely on BCL-xL for Survival
By inhibiting BCL-xL – a member of the BCL-2 family of apoptosis regulatory proteins that is highly expressed in pathological blood vessels in the retina – diseased senescent cells are eliminated, while leaving healthy blood vessels intact.
MoA animation by Visual Science, 2023
Interplay of VEGF and Senescent Cells
One of the proinflammatory cytokines that senescent cells produce is vascular endothelial growth factor (VEGF). High levels of VEGF are essential to the progression of diabetic retinopathies, including DME, and are typically produced in a state called hypoxia – a condition when there is insufficient oxygen levels or metabolic supply in a tissue.
By eliminating senescent cells, we are eliminating a source of VEGF production in diabetic retinas. As the burden of senescent cells and VEGF levels decrease, new blood vessels are able to reform to bring more oxygen and metabolic support back to the retina.
About UBX1325
UBX1325 is a potent BCL-xL inhibitor that has been demonstrated to selectively eliminate senescent cells in vitro and to inhibit retinal neovascularization, reduce vascular leakage, and improve retinal function in preclinical disease models.
Publications
Foundational research on cellular senescence and its therapeutic potential is regularly published in high quality peer-reviewed publications.
Therapeutic targeting of cellular senescence in diabetic macular edema: preclinical and phase 1 trial results
Crespo-Garcia, et al. Nature Medicine (2024)
Pathological angiogenesis in retinopathy engages cellular senescence and is amenable to therapeutic elimination via BCL-xL inhibition
Crespo-Garcia, et al. Cell Metabolism. (2021)
Neutrophil extracellular traps target senescent vasculature for tissue remodeling in retinopathy
Binet, et al. Science. (2020)
Over the last few years, the field of cellular senescence research has blossomed as we continue to better understand the key role it plays in multiple chronic and inflammatory diseases.
Scientific Presentations
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