Scholars

Li Gan, PhD

Weill Cornell Medicine

Disease Area

Neuroscience

Focus

Evolution of a Novel Human cGAS Inhibitor to Treat Tauopathy

Scholar Profile

2024 Scholar, Harrington Brain Health Medicines Center

Much of Alzheimer’s disease research has focused on anti-amyloid immunotherapy. Some newer therapies that target accumulations of amyloid-beta plaques in the brain have been shown to reduce cognitive decline by 30% in patients with very mild disease.

Although that’s a positive step, Dr. Gan says simply, “That means our job is not done. We need therapies that can improve cognitive function. Not just slow it down, but stabilize and reduce cognitive decline. And we need these therapies for more patients.” To that end, Dr. Gan and her colleagues are exploring a treatment pathway that targets tau. Tau is a protein found in brain cells that drives cognitive decline by inducing inflammation.

Dr. Gan’s team is developing small molecule inhibitors of the DNA-sensing cGAS enzyme, which plays a crucial role in maladaptive immune response and chronic neuroinflammation caused by tau tangles. According to Dr. Gan, cGAS inhibitors could complement existing beta-amyloid therapies, bringing benefits to a larger group of patients—potentially even those with moderate cognitive decline.

Dr. Gan and her team are seeking to evaluate two human cGAS inhibitors using human iPSC (induced pluripotent stem cells). They anticipate that the cGAS inhibitors will reduce tau-induced inflammation in human iPSC-derived organoids.

Dr. Gan notes that an intriguing aspect of tau research is that patients who have amyloid-beta plaques do not always experience memory loss. Patients who have memory loss, however, always have inflammation caused by tau.

“That's why I've been working on tau for the past 20 years,” Dr. Gan says. “cGAS inhibitors will temper the chronically inflamed brain. That will help the brain heal and stop the memory loss. Finding that solution is what drives me.”

"I'm a biologist, not a chemist. I study molecules, disease mechanisms and biological processes. But to turn those findings into drugs, we need chemistry expertise. That's the type of expertise the Harrington excels at providing."