Scientists at King’s College London have identified a potential new approach to treating Alzheimer’s disease using KCL-286, an experimental drug originally developed for spinal cord injuries. In mouse models of Alzheimer’s-like disease, the orally administered drug helped repair DNA double-strand breaks and reduce inflammation—two processes that may begin early in the disease. KCL-286 has already completed Phase 1 safety and tolerability testing in humans, but its effectiveness against Alzheimer’s disease has not yet been established.
A broader approach to Alzheimer’s disease
KCL-286 produced promising results in mice with Alzheimer’s-like disease. Rather than focusing primarily on the buildup of toxic proteins in the brain, the drug targets additional biological processes that can occur before the disease reaches an advanced stage.
Because KCL-286 is a small molecule that can be taken by mouth, it may be more convenient to administer than treatments requiring injections or infusions. Its previous Phase 1 safety and tolerability testing could also shorten the path to further clinical trials, although new studies will be needed to assess its safety and effectiveness in people with Alzheimer’s disease.
“KCL-286 is a first-in-class orally bioavailable small molecule that has already successfully completed 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.
Why Alzheimer’s disease is difficult to treat
Alzheimer’s disease involves a complex combination of changes in the brain. Two of its best-known features are abnormal accumulations of amyloid beta and tau proteins.
Amyloid beta can form sticky deposits between nerve cells, while abnormal tau can form tangles inside them. These changes interfere with normal brain function and are associated with the progressive loss of neurons, the specialized cells that transmit information throughout the brain.
Much of the effort to develop Alzheimer’s treatments has focused on these two proteins. Although drugs that remove amyloid beta have shown modest but measurable clinical benefits, they do not address all of the biological processes involved in the disease.
Researchers are therefore investigating other contributors, including DNA damage and inflammation in the brain. Both processes can occur early in the disease, making them potential targets for treatments intended to slow progression.
In the new study, KCL-286 helped repair DNA breaks and reduce inflammation in mice with Alzheimer’s-like disease. The results suggest that targeting several harmful processes at the same time could provide a broader strategy than focusing only on amyloid beta 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 project managed the drug’s development.
How the vitamin A pathway is involved
KCL-286 works by activating specific proteins involved in the retinoic acid pathway, a biological system that helps the body process and use vitamin A.
Vitamin A is widely known for its role in healthy vision, but it also contributes to cell development, gene regulation and nervous system function. Retinoic acid, a substance derived from vitamin A, helps regulate genes involved in several important biological processes.
Earlier studies found that disruption of this pathway was associated with the formation of amyloid beta deposits in rat brains. These deposits resemble important pathological features of Alzheimer’s disease, suggesting that the pathway may be relevant to the condition.
By activating particular proteins in this system, KCL-286 gives researchers a way to influence biological processes involved in brain health and cellular repair.
The drug had previously been shown to promote the repair of DNA double-strand breaks in early studies of neuropathic pain, which is caused by damage or dysfunction in the nervous system. That finding led scientists to investigate whether the same mechanism could help address DNA damage associated with Alzheimer’s disease.
Repairing dangerous DNA damage
DNA contains the genetic instructions cells need to function. Although cells have natural systems for repairing damaged DNA, some forms of damage are especially serious.
DNA double-strand breaks occur when both strands of the DNA molecule are cut. If they are not repaired properly, they can disrupt normal cellular activity and threaten cell survival.
“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 facilitates the repair of these breaks, making it possible to target key hallmarks of Alzheimer’s disease,” Professor Corcoran said.
The researchers had additional reasons to investigate KCL-286 as a potential Alzheimer’s treatment. Previous work by the same King’s College London team identified molecular pathways shared by acute spinal cord injury and Alzheimer’s disease.
Because the two conditions overlap in some biological mechanisms, the researchers proposed that drugs developed to address nervous system damage after spinal cord injury might also improve certain neuronal changes associated with Alzheimer’s disease.
The new findings support that possibility, showing that KCL-286 can influence several cellular pathways involved in the disease.
What happens next
The results point to a potential shift in Alzheimer’s research toward treatments that address multiple, interconnected causes of brain damage rather than a single feature of the disease.
KCL-286 is of particular interest because it targets DNA damage and inflammation, two processes that may arise early in Alzheimer’s disease. Its previous safety testing in humans could also give it an advantage over entirely new drug candidates that have not yet entered clinical development.
However, research into KCL-286 for Alzheimer’s disease remains at the preclinical stage. Further studies and human clinical trials will be needed to determine whether the drug can safely slow disease progression or improve outcomes for patients.
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.”
Source: www.sciencedaily.com
