A drug candidate developed at King’s College London boosts DNA repair and reduces neuronal damage, as well as lowering neuroinflammation and could become a new treatment option for people with early stage Alzheimer’s disease in the future.
Writing in the journal FEBS Open Bio, lead author Jonathan Corcoran, PhD, a professor at King’s College London, and colleagues report results of a study carried out in a mouse model of Alzheimer’s disease that tested KCL-286, a retinoic acid receptor-beta agonist, and showed it had beneficial effects in the animals.
As Alzheimer’s disease develops, amyloid-beta accumulates and suppresses the brain’s natural retinoic acid signaling. This, as well as other factors, leaves neurons increasingly unable to repair DNA damage. The unrepaired damage then triggers microglial and astrocyte overactivation, which contributes to further neuronal injury in a self-reinforcing loop.
Mice treated with KCL-286 had significantly fewer DNA double-strand breaks in neurons than untreated mice, something seen in Alzheimer’s patients. They also had increased neuronal expression of BRCA1 protein, a DNA repair and tumor suppressor protein, suggesting KCL-286 partly works by ramping up the brain’s own repair machinery. In certain cancers, a BRCA1 mutation results in reduced or absent functional protein, which increases cancer risk over time.
KCL-286 also seemed to reduce inflammation in the brain of treated mice. Microglia and astrocytes were both abnormally enlarged and activated in the animals before treatment. However, after treatment the size and shape of these cells went back towards normal, in other words, calming dangerous inflammation without getting rid of the cells.
“We think of the drug as repairing potholes in a road—once the damage is fixed, normal traffic can flow again and the system settles down. By repairing the underlying damage, we can allow the system to reset,” said Corcoran in a press statement.
This is an early stage study and still needs to be tested in humans, but KCL-286 has already completed a Phase I trial in healthy human volunteers with no drug-related adverse events and is known to cross the blood-brain barrier efficiently. This is because the drug candidate is also being tested for treatment of spinal cord injury, hence the earlier Phase I study.
Both acute spinal cord injury and chronic neurodegeneration in Alzheimer’s involve accumulation of DNA double-strand breaks in neurons. In the former this is caused by the mechanical trauma and subsequent inflammation, whereas in the latter it builds up gradually over years.
The lack of side effects seen in the Phase I study is also important for KCL-286’s development as a possible Alzheimer’s treatment, as two earlier, non-selective retinoid drugs tested for treatment of Alzheimer’s caused side effects because they hit multiple off target receptor subtypes. KCL-286’s selectivity for the retinoic acid receptor-beta is designed to avoid this.
“Together with its favorable human safety profile, the data support further investigation of selective retinoic acid receptor-beta agonism as a therapeutic strategy for modifying pathogenic processes associated with Alzheimer’s disease,” conclude the authors.
The researchers think that if KCL-286 reaches the clinic early treatment is likely to be key to success. They also note there is potential for this type of therapy to be used in combination with approved Alzheimer’s treatments like lecanemab, which act to reduce harmful amyloid beta in the brain.
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