Introduction and Objective: Diabetic retinopathy (DR) is a leading cause of vision loss, but treatment relies largely on intravitreal therapies, resulting in suboptimal real-world outcomes. Hyperglycemia-driven NLRP3 inflammasome activation contributes to retinal vascular leakage, suggesting that oral NLRP3 inhibition could address this unmet need. We evaluated whether BGE-102, an oral, brain-penetrant NLRP3 inhibitor with therapeutic retinal exposure, could preserve retinal vascular integrity in a streptozotocin (STZ)-induced DR model. Methods: Male C57BL/6 mice received STZ (65 mg/kg IP × 5 days). Eleven days later, mice were randomized to vehicle, BGE-102 20 mg/kg, or BGE-102 50 mg/kg (PO QD; n=16-20/group) for 96 days alongside healthy controls. Retinal vascular permeability was assessed by fluorescein angiography (FA). Blood-retinal barrier integrity was evaluated by Claudin-5 immunohistochemistry (IHC). Fasting glucose and A1c were monitored. Data were analyzed by one-way ANOVA with Dunnett’s test. Results: All STZ groups developed sustained hyperglycemia (glucose ~300 mg/dL; A1c 8%) unaffected by BGE-102 at either dose. Despite persistent hyperglycemia, BGE-102 dose-dependently reduced retinal vascular permeability vs vehicle by 74% at 20 mg/kg and 98.7% at 50 mg/kg (both p0.0001), with the higher dose restoring FA signal to healthy control levels. Claudin-5 IHC showed STZ reduced endothelial vascular content by 46% (p0.01). BGE-102 restored tight junction integrity at both doses to 95% and 97% of healthy control levels (both p0.01 vs vehicle). Conclusion: Oral BGE-102 preserved retinal vascular integrity and restored endothelial tight junctions in a DR model, with efficacy independent of glycemic control. These findings support NLRP3 inhibition as a novel approach to DR and the planned Phase 1b/2a trial in diabetic macular edema. Disclosure A. Eblimit: Employee; Current; BioAge Labs. D. Punzalan: Employee; Current; BioAge Labs. S. Yan: Employee; Current; BioAge LAbs. A. Banicki: Employee; Current; BioAge LAbs. Y. Wang: Employee; Current; BioAge Labs. K. Wilhelmsen: Employee; Current; BioAge Labs. C. Portillo: Employee; Current; BioAge Labs. M. Banicki: Employee; Current; BioAge Labs. M. Cochran: Employee; Current; BioAge Labs. C. Rodriguez: Employee; Current; BioAge Labs. G. Hartman: Employee; Current; BioAge Labs. C. Patil: Employee; Current; BioAge Labs. J. Rebo: Employee; Current; BioAge Labs. R. Hughes: Employee; Current; BioAge Labs. R. Montgomery: Employee; Current; BioAge Labs. E. Morgen: Employee; Current; BioAge Labs. Board Member; Current; BioAge Labs. Stock/Shareholder; Current; BioAge Labs. K. Fortney: Board Member; Current; BioAge Labs. Employee; Current; BioAge Labs. Stock/Shareholder; Current; BioAge Labs. P. Rubin: Employee; Current; BioAge Labs.
Eblimit et al. (Fri,) studied this question.