462-P: AT-001, a Next Generation Aldose Reductase Inhibitor with Improved Selectivity and Specificity, Protects from Cellular Damage Associated with Hyperglycemia

• DOI: 10.2337/db20-462-p
• Publication Date: 2020-06-15T16:29:52Z
• Authors: RICCARDO PERFETTI; GAUTHAM YEPURI; NOSIRUDEEN A. QUADRI; RAVICHANDRAN RAMA...; AMEEN F. GHANNAM; SHOSHANA SHENDELMAN
• Keywords: Polyol pathway; Mitochondrial ROS

The generation of Reactive Oxygen Species (ROS) and Advanced Glycation Endproducts (AGE’s) resulting from chronic tissue exposure to elevated levels glucose has been identified as a key modulator diabetic complications including cardiomyopathy. Abnormal activation the polyol pathway converts excess sorbitol, generating ROS AGEs. This conversion is catalyzed by enzyme Aldose Reductase. Inhibition Reductase, rate limiting in pathway, reduces production attenuates increases NADH, down-regulates synthesis ROS. Methods Results: Cultured human adult cells (NHK) were exposed [25mM] simulate hyperglycemic conditions presence/absence Reductase inhibitor AT-001 [0.18nM]. dose selection was based on previous response studies. Cytosolic oxidative stress evaluated quantified using dihydroethidium (DHE) staining quantitated via colorimetric assessment. Mitochondrial-specific MitoSOX staining. prevented accumulation assessed both DHE quantitation staining, demonstrating effective inhibition associated damage these cells. Conclusions: effectively cellular caused under warranting further investigation treatment complications. currently being pivotal phase 2/3 study (ARISE-HF NCT 04083339) treat cardiomyopathy prevent progression overt heart failure also includes sub-analyses for retinopathy peripheral neuropathy. Disclosure R. Perfetti: Stock/Shareholder; Self; Applied Therapeutics. G. Yepuri: None. N.A. Quadri: Ramasamy: Consultant; A.F. Ghannam: Employee; Therapeutics Inc. Sanofi US. S. Shendelman: Funding (NCT04083339)