Inhaled siRNA therapy targeting RAGE for pulmonary inflammation: a first-in-human randomized trial
Year: 2026
Type: article
Study designs: Randomized Controlled Trial, Clinical Trial
Abstract: The receptor for advanced glycation end products (RAGE), a multiligand receptor that is abundantly expressed by lung alveolar type-1 cells, amplifies and sustains the innate immune response in a variety of pulmonary disorders, including asthma and chronic obstructive pulmonary disease. Here we developed ARO-RAGE, an inhaled, lung-epithelium-targeted siRNA directed against pulmonary RAGE mRNA. Preclinical data from rat models of asthma, chronic obstructive pulmonary disease and acute lung injury, as well as mouse models for assessment of inflammatory responses, demonstrated deep and durable silencing of RAGE, limiting pulmonary inflammation. In macaques, ARO-RAGE produced dose-dependent reductions in membrane-bound RAGE levels in lung tissue and soluble RAGE (sRAGE) levels in serum; moreover, bronchoalveolar lavage showed post-dose decreases in sRAGE levels, consistent with robust silencing of lung membrane-bound RAGE. We then tested ARO-RAGE in a phase 1/2a, randomized, double-blinded, placebo-controlled trial designed to assess safety and tolerability (primary endpoint), pharmacokinetics (secondary endpoint) and pharmacodynamics (exploratory endpoint). In healthy volunteers (total n = 58, male n = 14) and in patients with asthma (total n = 19, male n = 6), inhaled ARO-RAGE was safe and well tolerated. No clinically relevant changes in chest x-ray findings, pulmonary function tests or systemic markers of inflammation were observed in the two cohorts. Plasma levels of ARO-RAGE were low, consistent with drug retention in the lung and minimal systemic bioavailability. Prolonged dose-responsive decreases in serum and bronchoalveolar lavage sRAGE levels indicated effective pulmonary target engagement. Together, these results demonstrate safe pulmonary delivery and target engagement of an inhaled, epithelial-targeted therapeutic siRNA, and support continued clinical development of ARO-RAGE. ClinicalTrials.gov registration: NCT05276570 .
Source: Nature Medicine
Authors: Mark O’Carroll, David Kasahara, John Huetsch, Taylor Reed, Timothy N. Perkins, Rong Zhou, Lindsey Moser, Bianca Tomasini-Johansson, Anh Ta, Tim D. Oury, Tao Pei, James Hamilton, Erik W. Bush, Nicholas J. Leeper, Matthias Salathe, John Blakely, Adrian Barnett, Eung gu Lee, Sang Heon Kim, YongChul Lee, Michelle Baker, Paul Hamilton, Iwona Kobielsz-Gembala, Zenon Siergiejko, Elzbieta Hajol, Mara Rachel, Juan Roldan Sanchez, Joaquin Sastre, David Romero, Kittipong Maneechotesuwan, Watchara Boonsawat, Kittima Bangpattanasiri, Nadwipa Yuangtrakul
Institutions: Auckland City Hospital, Auckland District Health Board, Arrowhead Pharmaceuticals (United States), University of Pittsburgh, Stanford Medicine, University of Kansas Medical Center, Institute for Respiratory Health, Mater Adult Hospital, The Catholic University of Korea Bucheon St. Mary's Hospital, Hanyang University Seoul Hospital, Jeonbuk National University Hospital, NZ Respiratory & Sleep Institute, Hospital Universitario La Paz, Siriraj Hospital, Khon Kaen University, Khon Kaen Hospital, Central Chest Institute of Thailand, Vajira Hospital
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $12,690
Funder: Arrowhead Pharmaceuticals
OpenAlex ID: W7212070288