KCL-286 targets multiple Alzheimer’s pathways in preclinical study

Neuroscientists at King’s College London have identified a promising drug candidate that could tackle several of the key biological processes involved in Alzheimer’s disease simultaneously.

Researchers found that KCL-286, an orally administered drug that has already successfully completed Phase I human safety and tolerability trials after originally being developed for spinal cord injury, was able to reduce several disease-related features of Alzheimer’s disease in a mouse model. 

Unlike many existing treatments that focus primarily on amyloid-beta, KCL-286 targets multiple pathways linked to the disease, including DNA damage and inflammation, both of which are believed to occur during the earliest stages of Alzheimer’s progression.

“KCL-286 is a first-in-class, orally bioavailable small molecule that has already successfully cleared Phase I human safety and tolerability trials. This will dramatically cut down the traditional multi-year timeline required for new drug development,” said Professor Jonathan Corcoran, Professor of Neuroscience at the Institute of Psychiatry, Psychology & Neuroscience at King’s College London. 

Targeting early disease mechanisms

Alzheimer’s disease is a complex neurological condition traditionally caused by the build-up of toxic proteins known as amyloid-beta and tau, which eventually lead to the death of brain cells. Although approved drugs targeting amyloid-beta have shown limited but measurable clinical benefits, researchers are now exploring other biological processes that contribute to the disease.

Alzheimer’s disease is a complex neurological condition traditionally caused by the build-up of toxic proteins known as amyloid-beta and tau

DNA strand breaks and inflammation have emerged as important potential treatment targets because they appear early in the development of Alzheimer’s disease. The King’s College London team found that KCL-286 helped repair DNA damage while also reducing inflammation, suggesting it could offer a broader therapeutic strategy than treatments aimed solely at amyloid-beta 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,” said Dr Maria Goncalves, who project managed the drug development. “This highlights its potential as a disease-modifying therapy rather than simply addressing symptoms.”

Building on previous research

KCL-286 works by activating a specific protein within the retinoic acid pathway, which is responsible for processing vitamin A in the body. Previous research has linked deficiencies in this pathway to the formation of amyloid-beta deposits in the brain similar to those found in Alzheimer’s disease.

The drug had previously been shown to promote the repair of DNA double-strand breaks in neuropathic pain, leading researchers to investigate whether it could produce similar benefits in Alzheimer’s disease.

KCL-286 works by activating a specific protein within the retinoic acid pathway, which is responsible for processing vitamin A in the body

“DNA double-strand breaks are like a rope snapping completely in two, rather than just fraying at the edges,” said Professor Corcoran. ”We found that KCL-286 promotes repair of these breaks, allowing us to target a key feature of Alzheimer’s disease.”

The study also builds on earlier work by the King’s team, which identified shared molecular pathways between acute spinal cord injury and Alzheimer’s disease, suggesting KCL-286 could reduce several markers associated with the condition.

The findings indicate that KCL-286 could become a strong disease-modifying treatment by addressing several underlying causes of Alzheimer’s disease simultaneously, potentially leading to the development of more effective therapies in the future.