A drug, that has previously been shown to be safe and tolerated by humans, reduces multiple disease-linked features of Alzheimer’s in a lab model of the disease, say neuroscientists in London.
The team from King’s College has developed an approach that targets a key protein to tackle several features of Alzheimer’s disease at the same time.
They found that KCL-286, a drug that has previously passed Phase 1 safety trials—after originally being developed for spinal cord injury—was able to lessen many disease-linked features of Alzheimer’s.
Some of the causes of Alzheimer’s disease have been characterized by toxic build-up of proteins called amyloid-beta and tau, and these have been the main targets for drug development—but these have had limited clinical success.
Other features of the disease, such as DNA strand breaks and inflammation, have only recently been investigated as potential disease-modifying targets. DNA damage and inflammation occur in the earliest stages of the disease, suggesting they may be important targets for treatment.
The new drug, KCL-286—which is a “first-in-class, orally bioavailable small molecule”—was found to repair DNA breaks and reduce inflammation in a mouse model of Alzheimer’s disease, providing a broader therapeutic strategy than approaches focused on disease hallmarks such as amyloid and tau.
“Our findings demonstrate that KCL-286 not only targets DNA damage but also reduces inflammation, two processes that occur very early in Alzheimer’s disease progression,” said Dr Maria Goncalves, a project manager of the drug development.
“This highlights its potential as a disease-modifying therapy, rather than simply addressing symptoms.”
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The drug activates a specific protein in the retinoic acid pathway, a series of chemical reactions in the body used to process vitamin A. Previous studies have linked the deficits in this molecular pathway to amyloid-beta deposits forming in rat brains, similar to those seen in Alzheimer’s disease.
KCL-286 has previously been shown to help repair DNA double-strand breaks in neuropathic pain, leading researchers to hypothesize that it might be a suitable candidate for targeting the same type of DNA damage in Alzheimer’s.
“DNA double-strand breaks are like a rope snapping completely in two, rather than just fraying at the edges,”explained Professor Jonathan Corcoran, Professor of Neuroscience at King’s College London. “We found that KCL-286 promotes repair of these breaks, allowing us to target a key feature of Alzheimer’s disease.”
Natasha Hill, one of the first authors on the recently-published paper, said: “To develop an effective treatment for Alzheimer’s disease, we need to tackle multiple aspects of the disease. KCL-286 was able to target multiple disease-relevant cellular pathways, some of which are initiated very early in the disease course.”
And, because it has already cleared Phase 1 human safety and tolerability trials, this will dramatically cut down the normal multi-year timeline required for new drug development.