The University of California, San Francisco has received a USD 1.07 million National Institute on Aging R01 award to investigate whether IL-6 trans-signaling drives postoperative cognitive decline in older adults and patients with Alzheimer's disease — and whether an existing drug can prevent it.
The grant, led by principal investigators Mervyn Maze and Niccolo Terrando in UCSF's Department of Anesthesiology, targets perioperative neurocognitive disorders (PNDs), a spectrum of conditions ranging from acute delirium to longer-term cognitive deterioration following surgery. With no approved preventive therapies and estimated first-year US healthcare costs exceeding USD 33 billion annually, PNDs represent a significant and underserved clinical problem as surgical populations age.
The central hypothesis is that elevated hippocampal IL-6 trans-signaling — a pathway distinct from classical IL-6 receptor signaling — increases neuroinflammation and neurodegeneration in aged and Alzheimer's-vulnerable brains following surgical stress. Using aged and AD transgenic mouse models subjected to orthopedic surgery, the team will assess whether upregulated hippocampal STAT3 phosphorylation mediates cognitive impairment, and whether single-cell RNA sequencing can identify downstream therapeutic targets. Critically, the project will test sgp130Fc, a selective IL-6 trans-signaling blocker, both prophylactically and therapeutically, including a perioperative safety evaluation.
The translational hook is direct: sgp130Fc is the mechanism underlying olamkicept, a biologic currently under development by Ferring, in Phase II trials for inflammatory bowel disease. Positive preclinical findings here could support repurposing olamkicept for randomized trials in high-risk surgical patients — a relatively compressed path given existing clinical safety data. No approved agent currently targets IL-6 trans-signaling for neurological indications, though broad IL-6 pathway inhibitors such as tocilizumab have been explored in neuroinflammatory contexts with mixed results.