Nature-inspired IL-1 targeted therapy to treat chronic inflammatory diseases

The interleukin-1 (IL-1) pathway drives inflammation in rheumatoid arthritis (RA) and other autoinflammatory diseases. We developed a recombinant adeno-associated virus (rAAV) gene therapy that delivers a secreted human IL-1 receptor antagonist (sIL-1Ra) under an inflammation-inducible promoter. This vector responds to pro-inflammatory cytokines and BMPs enriched in inflamed joints, enabling on-demand sIL-1Ra production. In mouse models of RA and IL-1Ra deficiency, inflammation-inducible sIL-1Ra reduced IL-1 signaling, immune cell activation, inflammatory gene expression, joint swelling, and bone destruction. A single systemic dose provided long-lasting therapeutic benefit, supporting this approach as a targeted treatment for chronic inflammatory diseases. Overall design: Synovial tissue was collected from SKG mice (N=3 per group) treated systemically with either an inflammation-inducible rAAV expressing secreted human IL-1 receptor antagonist (sIL-1Ra) or a matched control vector. Total RNA was extracted, bulk RNA-seq libraries were prepared, and sequencing was performed to compare transcriptomes between sIL-1Ra and control groups.