Spinal injury drug shows Alzheimer’s effects in mouse study
King’s College London researchers say KCL-286 repaired neuronal DNA damage and reduced inflammation in mice, but human Alzheimer’s trials have not begun.
By Priya Raghavan · Science Reporter
3 min read
An experimental drug first developed for spinal cord injury reduced several Alzheimer’s-related changes in mice, according to researchers at King’s College London. The finding matters because the drug, KCL-286, has already completed an initial human safety and tolerability trial for another condition, which the researchers say could shorten the path to Alzheimer’s clinical testing.
The team reported in FEBS Open Bio that KCL-286 eased neuronal DNA damage and inflammation in a mouse model of Alzheimer’s disease. The researchers described the drug as a first-in-class, orally available small molecule that acts on the retinoic acid receptor-beta pathway, which is tied to how the body processes vitamin A.
A broader target than amyloid alone
Alzheimer’s disease is associated with several biological changes, including the buildup of amyloid-beta and tau proteins, according to the King’s College London team. The researchers said many approved treatments have focused on amyloid-beta and have produced limited but measurable clinical benefits.
The new work looked beyond those protein deposits. According to the study authors, DNA damage and inflammation can appear early in Alzheimer’s disease and may offer targets for drugs designed to slow disease processes rather than treat symptoms alone.
Dr. Maria Goncalves, who managed the drug development project, said the study showed KCL-286 acted on both DNA damage and inflammation, processes she described as early features of Alzheimer’s progression. She said those effects point to the drug’s potential as a disease-modifying therapy.
How the drug may work
KCL-286 activates a protein in the retinoic acid pathway, according to the King’s College London researchers. They said earlier research linked disruption in that pathway to amyloid-beta-like deposits in rat brains.
The researchers had previously studied KCL-286 in neuropathic pain and found that it could help repair DNA double-strand breaks. Based on that work, they tested whether the same mechanism could address DNA damage seen in Alzheimer’s disease.
Professor Jonathan Corcoran of the Institute of Psychiatry, Psychology & Neuroscience at King’s College London said DNA double-strand breaks resemble a rope cut fully in two rather than worn at the edges. He said the study found that KCL-286 promotes repair of those breaks, allowing researchers to target a feature of Alzheimer’s disease.
Mouse findings, human questions
The study builds on earlier work from the same research group, which identified overlapping molecular pathways in acute spinal cord injury and Alzheimer’s disease. The researchers said those shared pathways suggested that a drug developed for spinal cord injury might also affect Alzheimer’s-related changes in neurons.
Natasha Hill, one of the paper’s first authors, said effective Alzheimer’s treatment will likely need to address multiple aspects of the disease. She said KCL-286 affected several disease-relevant cellular pathways, including some that begin early in the disease course.
The findings remain preclinical. King’s College London said KCL-286 has passed Phase 1 human safety and tolerability testing, but the reported Alzheimer’s effects come from a mouse model, and the researchers have not shown that the drug benefits people with Alzheimer’s disease.
The paper, by Hill, Hassan Yousef Othman AlMuallim, Elouisa Maddock, Carl Hobbs, Earl Clarke, Goncalves and Corcoran, was published in FEBS Open Bio with the title “Treatment with KCL‐286, a first‐in‐class retinoic acid receptor‐β (RARβ) agonist, ameliorates neuronal DNA damage and inflammation in a mouse model of Alzheimer’s disease.”
This story draws on original reporting from ScienceDaily.