Introduction. The receptor for advanced glycation end-products (RAGE) is highly expressed on type I AECs and promotes pro-inflammatory signaling when activated by diverse DAMP and PAMP ligands. RAGE expression is induced by inflammation, establishing a positive feedback cycle that sustains chronic inflammation. Previous work established that silencing RAGE with lung-targeted siRNAs effectively limits pulmonary inflammation in a rat model of allergic asthma. Here, we evaluate the pharmacodynamics of a clinical stage RNAi therapeutic (ARO-RAGE) in NHP.

Method. Cynomolgus monkeys received an inhaled aerosol dose of ARO-RAGE delivered via endotracheal tube or mask. Soluble RAGE (sRAGE) protein expression was monitored in serial serum and BAL samples collected for 14 weeks. Lung tissue expression of full-length RAGE receptor protein and mRNA was assessed.

Results. 4 weeks post-dose, ARO-RAGE inhalation mediated dose-dependent RAGE silencing in the NHP lung, with the highest dose (0.47 mg/kg pulmonary deposited dose) producing deep target knockdown in both mRNA (- 72%) and full-length receptor protein (- 88%). Silencing of sRAGE protein expression (derived from full-length receptor) was also observed in BAL and serum samples, reaching nadir by 4 weeks post-dose and maintaining knockdown for an additional 5-6 weeks followed by slow recovery to baseline.

Conclusion.  Inhaled ARO-RAGE, an RNAi therapeutic in Phase 1/2a trials for pulmonary inflammation, produces dose-dependent, deep and durable reduction of RAGE expression in the NHP lung. Monitoring sRAGE in BAL or serum may offer novel approaches to monitor ARO-RAGE-mediated silencing of RAGE in the lung.