Drug candidate targets DNA damage in Alzheimer's disease model

A drug candidate previously tested for safety in humans has reduced several disease-associated features in a mouse model of Alzheimer's disease.

Researchers from King's College London report that KCL-286, originally developed as a treatment candidate for acute spinal cord injury, targets cellular processes associated with early Alzheimer's disease. The research, published in FEBS Open Bio, found that KCL-286 reduced markers of DNA damage, inflammation and neuronal loss in a mouse model of the disease.

Professor Jonathan Corcoran, corresponding author of the study, said: '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.'

The previous clinical trial for acute spinal cord injury assessed the safety, tolerability and pharmacological effects of KCL-286 in healthy volunteers, rather than its effectiveness as a treatment for Alzheimer's disease. The current study provides preclinical evidence to support further investigation of the drug in neurodegeneration.

The causes of Alzheimer's disease are highly complex, but key features include the accumulation of proteins such as amyloid-beta and tau, alongside inflammation and neuronal damage. These processes have been major focuses of drug development, with recently approved amyloid-targeting therapies showing modest clinical benefits in some patients.

KCL-286 works by activating a pathway involved in controlling gene activity and cell responses. Specifically, it acts on a protein called the retinoic acid receptor-beta, which is part of the retinoic acid signalling pathway. Reduced activity of this pathway has previously been linked to Alzheimer's disease-related changes, including amyloid-beta accumulation.

When administered to a mouse model of Alzheimer's disease, KCL-286 reduced DNA double-strand breaks in neurons and increased expression of the BRCA2 protein, which is involved in DNA repair. These findings suggest that the drug may help protect neurons from damage associated with disease processes.

Dr Maria Goncalves, who project-managed the drug development, said: '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.'

However, the findings are from a mouse model and it remains unclear whether the effects of KCL-286 would translate to people with Alzheimer's disease. Further studies will be needed to determine whether these effects can be replicated in humans and whether targeting DNA damage could influence disease progression.