UK scientists develop drug which targets Alzheimer’s on multiple fronts

Scientists at King’s College London have developed a drug that tackles several features of Alzheimer’s disease at once, and it has already cleared Phase 1 human safety trials.

The drug, KCL-286, is a first-in-class, orally available small molecule first developed to treat spinal cord injury.

In a mouse model of Alzheimer’s, it repaired DNA breaks and reduced inflammation, two processes that emerge in the earliest stages of the disease.

Jonathan Corcoran, Professor of Neuroscience at the Institute of Psychiatry, Psychology & Neuroscience at King’s College London, said the molecule’s existing safety record cut years off the standard drug-development timeline because it had already passed human safety and tolerability testing.

Alzheimer’s classically involves a toxic build-up of two proteins, amyloid-beta and tau, which eventually kills neurons. Those proteins have dominated drug development, and approved treatments that target amyloid-beta alone have delivered limited but measurable results.

KCL-286 instead goes after DNA strand breaks and inflammation, features that researchers have only recently examined as disease-modifying targets and that appear early in the disease course.

Maria Goncalves, who project-managed the drug development, said the molecule targeted both DNA damage and inflammation, marking it out as a potential disease-modifying therapy rather than a treatment that only eases symptoms.

KCL-286 activates a protein in the retinoic acid pathway, the chemical process the body uses to handle vitamin A. Earlier studies linked deficits in that pathway to amyloid-beta deposits forming in rat brains, similar to those seen in Alzheimer’s.

The same King’s team had previously shown the drug helped repair DNA double-strand breaks in neuropathic pain, which led them to test it against the same type of damage in Alzheimer’s.

Corcoran likened a double-strand break to a rope snapping fully in two rather than fraying at the edges, and said the drug promoted repair of those breaks.

Alzheimer’s is the most common cause of dementia in the UK, where around 982,000 people live with the condition, a figure projected to reach 1.4 million by 2040.

Natasha Hill, one of the paper’s first authors, said an effective treatment needs to tackle multiple aspects of the disease, and that KCL-286 hit several disease-relevant cellular pathways, some triggered very early.

The results are preclinical, drawn from cell and mouse studies, and the drug would need trials in Alzheimer’s patients before any clinical use.

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