Researchers at King’s College London have identified a promising new strategy for tackling Alzheimer’s disease by targeting several of the disease’s early 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 features of Alzheimer’s in a mouse model.
“KCL-286 is the first orally bioavailable small molecule of its kind that has already successfully passed Phase 1 human safety and tolerability trials. This will dramatically reduce the traditional multi-year timeline required for new drug development,” commented Professor Jonathan Corcoran, Professor of Neuroscience at the Institute of Psychiatry, Psychology and Neuroscience, 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 beta-amyloid and tau proteins, which eventually contribute to brain cell loss. Although most approved treatments have focused on reducing amyloid beta, they have provided only limited, although measurable, clinical benefits.
Scientists are now exploring additional processes that may play important roles much earlier in the disease. These include DNA damage and inflammation, which appear in the early 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 targeting only 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 the progression of Alzheimer’s disease. This highlights its potential as a disease-modifying therapy rather than simply addressing symptoms,” said Dr. María Gonçalves, who managed the development of the drug.
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. Previous research has shown that alterations 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 demonstrated the ability to repair DNA double-strand breaks in neuropathic pain studies. Based on those findings, the researchers proposed that it could also repair the same type of DNA damage found in Alzheimer’s disease.
“DNA double-strand breaks are like a rope that snaps completely in two, rather than simply fraying at the edges. We found that KCL-286 promotes the repair of these breaks, allowing us to address a key feature of Alzheimer’s disease,” Professor Corcoran said.
A drug with potential beyond its original purpose
Previous work by the same research team at King’s College London 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 of the paper, said: “To develop an effective treatment for Alzheimer’s disease, we need to address multiple aspects of the disease. KCL-286 was able to target multiple cellular pathways relevant to the disease, some of which are initiated very early in the course of the disease.”
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.