Scientists discover new Alzheimer’s drug that repairs DNA damage and reduces brain inflammation
Scientists at King’s College London have identified a promising new strategy to combat Alzheimer’s disease, which could tackle several of the disease’s harmful effects simultaneously. Their research suggests that an experimental drug originally developed for spinal cord injuries could help repair damaged DNA, reduce inflammation and target biological changes associated with the disease.
The drug, known as KCL-286, produced encouraging results in a mouse model of Alzheimer’s disease. Unlike treatments that primarily focus on the buildup of toxic proteins in the brain, this approach targets additional processes that can begin well before the disease reaches its advanced stages.
A particularly promising advantage is that KCL-286 has already completed phase 1 safety and tolerability trials in humans as part of its earlier development. This could significantly shorten the path to deeper clinical testing, although its effectiveness against Alzheimer’s disease in humans has not yet been established.
“KCL-286 is a first-in-class, orally bioavailable small molecule that has already successfully completed Phase 1 safety and tolerability trials in humans. This will significantly reduce the traditional multi-year time frame required for the development of new drugs,” commented Professor Jonathan Corcoran, Professor of Neuroscience at the Institute of Psychiatry, Psychology and Neuroscience at King’s College London.
The drug is a small molecule that can be taken orally, potentially making it more convenient to administer than treatments requiring injections or infusions.
Why Alzheimer’s disease is so difficult to treat
Alzheimer’s disease involves a complex series of changes in the brain, making it particularly difficult to develop effective treatments. Two of its best-known characteristics are the abnormal accumulation of proteins called beta-amyloid and tau.
Beta-amyloid can build up in sticky deposits between nerve cells, while abnormal tau proteins can form tangles inside them. These changes interfere with normal brain function and are associated with the progressive loss of neurons, the specialized cells responsible for transmitting information throughout the brain.
Much of the effort to develop treatments for Alzheimer’s disease has focused on these two proteins. Although drugs that eliminate beta-amyloid have demonstrated modest but measurable clinical benefits, they do not fully address the many biological processes involved in the disease.
Researchers are increasingly studying other changes that may contribute to Alzheimer’s disease, including DNA damage and inflammation in the brain. Both can appear early in the disease process, making them potentially valuable targets for treatments designed to slow its progression.
In the new study, KCL-286 helped repair DNA breaks and reduce inflammation in mice with Alzheimer’s disease. These results suggest that targeting multiple harmful processes simultaneously could offer a broader approach than focusing solely on amyloid beta or tau.
“Our results 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 treatment rather than just treating symptoms,” said Dr. Maria Goncalves, who led the drug’s development.
How Vitamin A Pathways Could Help Fight Alzheimer’s Disease
The drug works by activating a particular protein involved in the retinoic acid pathway, a biological system associated with how the body processes and uses vitamin A.
Vitamin A is best known for supporting healthy vision, but it also plays an important role in cellular development, gene regulation, and nervous system function. Retinoic acid, a substance derived from vitamin A, helps control the activity of genes involved in several essential biological processes.
Previous research found that disruptions in this pathway were associated with the formation of beta-amyloid deposits in the brains of rats. These deposits resemble a major pathological feature of Alzheimer’s disease, suggesting that this pathway may be linked to the disease.
KCL-286 activates a specific protein within this system, providing researchers with a way to influence biological processes related to brain health and cellular repair.
The drug had already been shown to promote the repair of DNA double-strand breaks in previous research investigating neuropathic pain, a type of pain caused by damage or dysfunction of the nervous system.
This discovery led scientists to study whether the same mechanism could also help address the DNA damage associated with Alzheimer’s disease.
Repairing a dangerous type of DNA damage
DNA contains the genetic instructions that cells need to function properly. Although cells have natural systems for repairing damaged DNA, some forms of damage are particularly severe.
One example is a DNA double-strand break, which occurs when both strands of the DNA molecule are severed. These breaks can disrupt normal cellular activity and threaten cell survival if not properly repaired.
“Double-strand breaks in DNA are like a rope that breaks completely in two, rather than just fraying at the edges. We found that KCL-286 promotes the repair of these breaks, allowing us to target a key feature of Alzheimer’s disease,” Professor Corcoran said.
The researchers had another reason to suspect that KCL-286 might be useful against Alzheimer’s disease. Previous work by the same team at King’s College London identified molecular pathways common to acute spinal cord injury and Alzheimer’s disease.
Because the two conditions involve overlapping biological mechanisms, scientists reasoned that a drug developed to treat nervous system damage after spinal cord injury might also improve some neuronal changes linked to Alzheimer’s disease.
Their new findings support this possibility, showing that KCL-286 can influence multiple cellular pathways involved in disease.
A promising new direction for the treatment of Alzheimer’s disease
The findings highlight a potentially important shift in Alzheimer’s disease research. Rather than 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. Its previous human safety tests also provide a potential advantage over entirely new drug candidates that have not yet entered clinical development.
However, the results on Alzheimer’s disease remain preclinical. Additional studies and human clinical trials will be needed to determine whether the drug can safely slow disease progression or improve patient outcomes.
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 several disease-relevant cellular pathways, some of which are initiated very early in the disease course. »
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