A drug, that has previously been shown to be safe and tolerated by humans, reduces multiple disease-linked features of Alzheimer's in a mouse model of the disease.
Neuroscientists from King's College London have developed an approach that targets a key protein to tackle several features of Alzheimer's disease in one go. They found that KCL-286, a drug that has previously passed Phase 1 safety trials originally developed for spinal cord injury, was able to lessen many disease-linked features of Alzheimer's.
"KCL-286 is a first-in-class, orally bioavailable small molecule that has already successfully cleared Phase 1 human safety and tolerability trials. This will dramatically cut down the traditional multi-year timeline required for new drug development," commented Professor Jonathan Corcoran, Professor of Neuroscience at the Institute of Psychiatry, Psychology & Neuroscience at King's College London.
The causes of Alzheimer's disease are highly complex. It is classically characterised by toxic build-up of proteins called amyloid-beta and tau, ultimately resulting in neuron death. While amyloid-beta and tau have been the main targets for drug development, approved drugs targeting amyloid-beta alone have limited but measurable 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 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 individual 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. This highlights its potential as a disease-modifying therapy rather than simply addressing symptoms," said Dr Maria Goncalves, who project managed the drug development.
The drug used in the new study, KCL-286, 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 hypothesise that it might be a suitable candidate for targeting the same type of DNA damage in Alzheimer's disease.
DNA double-strand breaks are like a rope snapping completely in two, rather than just fraying at the edges. We found that KCL-286 promotes repair of these breaks, allowing us to target a key feature of Alzheimer's disease.
Professor Jonathan Corcoran, Professor of Neuroscience at the Institute of Psychiatry, Psychology & Neuroscience at King's College London.
Shared molecular pathways between spinal acute spinal cord injury and Alzheimer's disease, established by the same team at King's, hinted that KCL-286, may lessen some markers of Alzheimer's in neurons.
Natasha Hill, one of the first authors on the 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."
The study was funded by the Medical Research Council and the Wellcome Trust.
Treatment with KCL-286, a first-in-class retinoic acid receptor-ß (RARß) agonist, ameliorates neuronal DNA damage and inflammation in a mouse model of Alzheimer's disease (DOI: 10.1002/2211-5463.70284) (Hill, AlMuallim et al.) was published in FEBS Open Bio.
