Cell-penetrating asymmetric siRNA targeting MyD88 suppresses inflammasome-driven ocular degeneration and angiogenesis.

Chronic inflammation mediated by innate immune signaling contributes to retinal degeneration, pathological angiogenesis, and ocular surface damage in age-related macular degeneration (AMD) and dry eye disease (DED). Myeloid differentiation primary response 88 (MyD88), a central adaptor downstream of Toll-like and IL-1 receptors, integrates NF-κB-dependent cytokine induction and inflammasome priming. In this study, we developed OLX10212, a chemically optimized palmitoyl-conjugated, cell-penetrating asymmetric small interfering RNA (cp-asiRNA) that silences MyD88 without an external delivery vehicle. Following intravitreal administration, OLX10212 achieved broad retinal distribution and sustained MyD88 knockdown in mice and rabbits. In sodium iodate- and Alu RNA-induced geographic atrophy models, OLX10212 preserved retinal architecture and electroretinographic function while suppressing NLRP3-associated transcripts, consistent with the inhibition of inflammasome signaling. A single intravitreal dose reduced lesion volume in laser-induced choroidal neovascularization models in mice and cynomolgus monkeys. Vascular endothelial growth factor (VEGF) expression was also decreased in mice, suggesting that OLX10212 modulates pro-angiogenic inflammatory pathways. Topical administration further ameliorated corneal epithelial injury and inflammatory cytokine expression in a benzalkonium chloride-induced DED model. A phase 1 clinical trial of intravitreal OLX10212 in patients with neovascular AMD is ongoing, and phase 2 studies are planned.