Late Breaking Abstract - A splice-switching oligonucleotide (SSO) targeting the Receptor for Advanced Glycation End-products (RAGE) attenuates lung injury in smoke and AATD associated lung disease

RAGE activation amplifies the innate immune response, driving lung inflammation and alveolar damage in COPD, however RAGE has been an intractable therapeutic target. The rare (<5%) RAGE_v1 splice variant encodes extracellular secretory RAGE (esRAGE), a decoy receptor that inhibits RAGE signalling. Harnessing this natural antagonist, we developed an SSO that selectively increases the generation of RAGE_v1 to be the dominant splice variant (>90%) while suppressing pathogenic RAGE (<10%). In healthy mice, pulmonary delivery of our SSO increases RAGE_v1 and esRAGE in lung and plasma while reducing RAGE in the lungs. An inhaled AON modulating RAGE splicing is thus a potential therapeutic approach for COPD. As proof of concept, we demonstrate weekly intranasal dosing with an SSO targeting RAGE (3mg/kg) prevented airways inflammation, lung injury and fibrosis associated with chronic 8-week cigarette smoke (CS) exposure. In an 8-month smoke exposure model, a RAGE SSO prevented alveolar damage measured as mean linear intercept associated with CS exposure (Mean±SD: Air 36±2 um; CS 52±6 um) both as concomitant therapy (CS + SSO 43±4 um; vs CS p<0.01), or delayed intervention at 4 months despite ongoing CS exposure (CS + SSO (therapeutic) 46±3 um; vs CS p<0.01). In Serpina1a-e null mice (a model of alpha-1 antitrypsin deficiency), lung injury following a two-hit, two-week LPS challenge was also prevented by treatment with a RAGE SSO, preventing the decline in PEF and FEF50, and normalising airways resistance (Rn). Harnessing the splicing of RAGE represents a novel therapeutic modality for inflammatory lung diseases.