Rashmin Savani
Co-Founder and Head, Scientific Advisory Board, Azome Therapeutics
RHAMM-derived Peptide Blocks NLRP3 Inflammasome Activation: Novel Therapy to Prevent Bronchopulmonary Dysplasia
Company Description
Background & Aims: The NLRP3 inflammasome is key in the pathogenesis of Bronchopulmonary Dysplasia (BPD), a devastating chronic lung disease in preterm infants. Hyaluronan (HA, hyaluronic acid), an endogenous danger signal, activates the inflammasome to produce IL1ß and promote inflammation. We have developed a peptide, AZM-152, derived from the HA receptor RHAMM that blocks NLRP3 inflammasome activation. We hypothesized that AZM-152 would block TLR-mediated cytokine elaboration in vitro and NLRP3 inflammasome activation in the neonatal mouse hyperoxia model of BPD.
Methods: The effect of AZM-152 on TLR-mediated activation of NFkB and IL1ß production was studied in cultured mouse and human macrophages using TLR4, TLR7, and TLR8 agonists. Neonatal wild type (WT) and RHAMM knockout (KO) mice were exposed to 95% oxygen from postnatal day (PN) 1 to PN5. WT mice were given increasing doses of AZM-152 subcutaneously on PN1. Myeloperoxidase activity (MPO, neutrophils) and N-Acetyl Glucosaminidase activity (NAG, macrophages), lung IL1ß mRNA and protein were determined. Alveolarization was determined using radial alveolar counts.
Results: RHAMM-based peptide AZM-152 inhibited all TLR-stimulated IL1ß expression. Exposure of neonatal mice to hyperoxia increased MPO and NAG activities, and IL1ß mRNA and protein. RHAMM KO mice failed to increase IL1ß and had no lung inflammation. Treatment of WT mice exposed to hyperoxia with AZM-152 resulted in dose-dependent inhibition of IL1ß and inflammation. AZM-152 treatment preserved alveolarization.
Conclusions: RHAMM is critical for NLRP3 inflammasome activation. AZM-152 prevents neonatal hyperoxia-induced increased IL1β and inflammation and preserves alveolarization. RHAMM antagonism is a potential therapeutic approach for the prevention of BPD and other inflammasome-driven diseases.
Bio
Rashmin C. Savani, MBChB, is the Chair of the Department of Pediatrics, holds the Nemours Eminent Scholar Chair at the University of Florida College of Medicine, and serves as Physician-in-Chief at the University of Florida Shands Children’s Hospital, Gainesville. Dr. Savani has an active laboratory investigating the basic mechanisms of lung development and injury in neonates with a focus on inflammation and angiogenesis as it relates to Bronchopulmonary Dysplasia, and on mechanisms of TLR activation of the NLRP3 inflammasome. He has published more than 100 peer-reviewed papers, reviews, and book chapters.