Researchers at King’s College London have identified a promising new strategy to tackle Alzheimer’s disease by simultaneously targeting some of the disease’s early biological changes. Their study found that KCL-286, an experimental drug originally developed for spinal cord injuries and which has already passed Phase 1 safety testing, alleviates multiple features of Alzheimer’s disease in mouse models.
“KCL-286 is a first-in-class orally bioavailable small molecule that has already successfully passed Phase 1 safety and tolerability testing in humans. This will significantly shorten the traditional multi-year timelines required for new drug development,” commented Professor Jonathan Corcoran, Professor of Neuroscience at the Institute of Psychiatry, Psychology and Neuroscience at King’s College London.
Looking beyond amyloid and tau
Alzheimer’s disease is caused by a complex combination of biological changes. This condition is best known for the accumulation of amyloid beta and tau proteins that ultimately contribute to brain cell loss. Most approved treatments focus on reducing amyloid beta, but have only limited measurable clinical efficacy.
Scientists are currently studying additional processes that may play an important role much earlier in the disease. Among them are DNA damage and inflammation, both of which appear in the early stages of Alzheimer’s disease and may offer new opportunities to slow its progression.
In a new study, KCL-286 repaired damaged DNA and reduced inflammation in Alzheimer’s disease mice. By addressing multiple disease mechanisms at once, this drug may offer a broader therapeutic approach than treatments that target only amyloid or tau.
“Our findings show 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 the potential of KCL-286 as a disease-modifying therapy, rather than just addressing symptoms,” said Dr. Maria Goncalves, who managed the drug development project.
How KCL-286 works
KCL-286 works by activating specific proteins involved in the retinoic acid pathway, which helps the body process vitamin A. Previous studies have shown that disruption of this pathway is associated with the formation of amyloid beta deposits in rat brains similar to those seen in Alzheimer’s disease.
The drug had already shown the ability to repair DNA double-strand breaks in studies of neuropathic pain. Based on these findings, the researchers proposed that the same type of DNA damage seen in Alzheimer’s disease may also be repairable.
“Double-strand breaks in DNA are like ropes that are not just frayed at the ends, but completely cut in half. We found that KCL-286 promotes the repair of these breaks, allowing us to target key hallmarks of Alzheimer’s disease,” Professor Corcoran said.
A drug with potential beyond its original purpose
Previous work by the same King’s College London research team identified a common molecular pathway between acute spinal cord injury and Alzheimer’s disease. These similarities suggest that KCL-286 may attenuate neuronal changes associated with Alzheimer’s disease.
Natasha Hill, one of the paper’s first authors, said: “Developing effective treatments for Alzheimer’s disease requires addressing multiple aspects of the disease. KCL-286 can target multiple disease-related cellular pathways, some of which are initiated very early in the course of the disease.”
Although 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 has similar effects in Alzheimer’s patients.
