Scientists at King’s College London have identified KCL-286, an experimental oral drug originally developed in research into spinal cord injuries, as a potential treatment for Alzheimer’s disease. In mouse models, the drug helped repair DNA damage and reduce inflammation—biological processes that can emerge early in the disease. KCL-286 has also completed Phase 1 safety and tolerability testing in humans, although its effectiveness against Alzheimer’s disease has not yet been established in people.
A broader approach to Alzheimer’s disease
KCL-286 produced promising results in mice with Alzheimer’s-like disease. Unlike treatments that mainly target the buildup of toxic proteins in the brain, the drug acts on additional processes that may begin before the disease reaches an advanced stage.
Because KCL-286 has already completed Phase 1 safety and tolerability testing in humans during its early development, it could potentially move toward further clinical trials more quickly than a completely new drug candidate. However, previous human testing did not establish whether it can treat 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,” said Professor Jonathan Corcoran, Professor of Neuroscience at the Institute of Psychiatry, Psychology and Neuroscience at King’s College London.
As a small molecule that can be taken by mouth, KCL-286 may also be more convenient to administer than treatments requiring injections or infusions.
Why Alzheimer’s disease is difficult to treat
Alzheimer’s disease involves a complex series of changes in the brain. Two of its best-known features are abnormal accumulations of the proteins amyloid beta and tau.
Amyloid beta can form sticky deposits between nerve cells, while abnormal tau can create 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 produced modest but measurable clinical benefits, they do not address all of the biological processes involved in the disease.
Researchers are therefore investigating other changes that may contribute to Alzheimer’s disease, 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 its progression.
In the new study, KCL-286 helped repair DNA breaks and reduce inflammation in mice with Alzheimer’s-like disease. The findings suggest that targeting several harmful processes at once 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 may help
KCL-286 works by activating certain proteins involved in the retinoic acid pathway, a biological system that helps the body process and use vitamin A.
Vitamin A is best known for supporting 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 could be relevant to the condition.
KCL-286 activates specific proteins within the pathway, allowing researchers to influence biological processes involved in brain health and cellular repair.
In early studies of neuropathic pain—a type of pain caused by damage or dysfunction in the nervous system—the drug had already been shown to promote the repair of DNA double-strand breaks. This led scientists to investigate whether the same mechanism could help address DNA damage associated with Alzheimer’s disease.
Repairing severe 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.
One example is a DNA double-strand break, which occurs when both strands of the DNA molecule are cut. If these breaks are not repaired correctly, 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 also had other reasons to suspect that KCL-286 could be relevant to Alzheimer’s disease. 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 affect several cellular pathways involved in the disease.
What comes next for KCL-286
The results point to a potential shift in Alzheimer’s research: instead of focusing on a single feature of the disease, scientists are exploring treatments that address multiple, interconnected causes of brain damage.
KCL-286 is of particular interest because it targets DNA damage and inflammation, two processes that can appear early in the progression of Alzheimer’s disease. Previous human safety testing may 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