Researchers at King’s College London have identified a promising new strategy for tackling Alzheimer’s disease by targeting several of the disease’s earliest biological changes at the same time. Their study found that KCL-286, an experimental drug originally developed for spinal cord injury that has already passed Phase 1 safety trials, reduced multiple hallmarks of Alzheimer’s in a mouse model.
“KCL-286 is a first-in-class, orally bioavailable small molecule that has already successfully cleared Phase 1 human safety and tolerability trials. This will dramatically cut down the traditional multi-year timeline required for new drug development,” commented Professor Jonathan Corcoran, Professor of Neuroscience at the Institute of Psychiatry, Psychology & Neuroscience at King’s College London.
Looking Beyond Amyloid and Tau
Alzheimer’s disease is driven by a complex combination of biological changes. The condition is best known for the buildup of amyloid-beta and tau proteins, which eventually contribute to the loss of brain cells. Although most approved treatments have focused on reducing amyloid-beta, they have delivered only limited, though measurable, clinical benefits.
Scientists are now exploring additional processes that may play important roles much earlier in the disease. Among these are DNA damage and inflammation, both of which appear in the earliest stages of Alzheimer’s and may offer new opportunities to slow its progression.
In the new study, KCL-286 repaired damaged DNA and reduced inflammation in mice with Alzheimer’s disease. By addressing multiple disease mechanisms at once, the drug could represent a broader therapeutic approach than treatments aimed only at amyloid or tau.
“Our findings demonstrate that KCL-286 not only targets DNA damage but also reduces inflammation, two processes that occur very early in Alzheimer’s disease progression. This highlights its potential as a disease-modifying therapy rather than simply addressing symptoms,” said Dr Maria Goncalves, who project managed the drug development.
How KCL-286 Works
KCL-286 works by activating a specific protein involved in the retinoic acid pathway, which helps the body process vitamin A. Earlier research has shown that disruptions in this pathway are associated with the formation of amyloid-beta deposits in rat brains that resemble those seen in Alzheimer’s disease.
The drug had already shown an ability to repair DNA double-strand breaks in studies of neuropathic pain. Based on those findings, the researchers proposed that it might also be able to repair the same type of DNA damage found in Alzheimer’s disease.
“DNA double-strand breaks are like a rope snapping completely in two, rather than just fraying at the edges. We found that KCL-286 promotes repair of these breaks, allowing us to target a key feature of Alzheimer’s disease,” said Professor Corcoran.
A Drug With Potential Beyond Its Original Purpose
Previous work by the same King’s College London research team identified shared molecular pathways between acute spinal cord injury and Alzheimer’s disease. Those similarities suggested that KCL-286 might also reduce some Alzheimer’s related changes in neurons.
Natasha Hill, one of the first authors on the paper, said: “To develop an effective treatment for Alzheimer’s disease, we need to tackle multiple aspects of the disease. KCL-286 was able to target multiple disease-relevant cellular pathways, some of which are initiated very early in the disease course.”
While the findings are based on a mouse model, the fact that KCL-286 has already completed Phase 1 safety testing for another condition could help accelerate future clinical development as researchers investigate whether the drug can provide similar benefits for people with Alzheimer’s disease.