Therapeutic targeting of cellular senescence in diabetic macular edema: preclinical and phase 1 trial results.
Sergio Crespo-GarciaFrédérik FournierRoberto Diaz-MarinSharon KlierDerek RagusaLauren MasakiGael CagnoneGuillaume BlotIkhlas HafianeAgnieszka DejdaRana RizkRachel JuneauManuel BuscarletSarah ChorfiPriyanka PatelPedro J BeltranJean-Sebastien JoyalFlavio A RezendeMasayuki HataAlex NguyenLynne SullivanJason DamianoAriel M WilsonFrédérick A MalletteNathaniel E DavidAnirvan GhoshPamela R TsurudaJamie DananbergPrzemyslaw SapiehaPublished in: Nature medicine (2024)
Compromised vascular endothelial barrier function is a salient feature of diabetic complications such as sight-threatening diabetic macular edema (DME). Current standards of care for DME manage aspects of the disease, but require frequent intravitreal administration and are poorly effective in large subsets of patients. Here we provide evidence that an elevated burden of senescent cells in the retina triggers cardinal features of DME pathology and conduct an initial test of senolytic therapy in patients with DME. In cell culture models, sustained hyperglycemia provoked cellular senescence in subsets of vascular endothelial cells displaying perturbed transendothelial junctions associated with poor barrier function and leading to micro-inflammation. Pharmacological elimination of senescent cells in a mouse model of DME reduces diabetes-induced retinal vascular leakage and preserves retinal function. We then conducted a phase 1 single ascending dose safety study of UBX1325 (foselutoclax), a senolytic small-molecule inhibitor of BCL-xL, in patients with advanced DME for whom anti-vascular endothelial growth factor therapy was no longer considered beneficial. The primary objective of assessment of safety and tolerability of UBX1325 was achieved. Collectively, our data suggest that therapeutic targeting of senescent cells in the diabetic retina with a BCL-xL inhibitor may provide a long-lasting, disease-modifying intervention for DME. This hypothesis will need to be verified in larger clinical trials. ClinicalTrials.gov identifier: NCT04537884 .
Keyphrases
- endothelial cells
- vascular endothelial growth factor
- induced apoptosis
- diabetic retinopathy
- cell cycle arrest
- small molecule
- type diabetes
- clinical trial
- high glucose
- mouse model
- oxidative stress
- optic nerve
- end stage renal disease
- optical coherence tomography
- healthcare
- chronic kidney disease
- randomized controlled trial
- endoplasmic reticulum stress
- cardiovascular disease
- cancer therapy
- dna damage
- palliative care
- peripheral blood
- risk factors
- weight loss
- prognostic factors
- cell death
- coronary artery
- chronic pain
- cell proliferation
- big data
- deep learning
- mesenchymal stem cells
- electronic health record
- glycemic control
- pulmonary artery
- adipose tissue
- health insurance
- diabetic rats
- pi k akt
- insulin resistance
- pulmonary arterial hypertension
- single molecule
- neural network
- artificial intelligence
- study protocol
- affordable care act