A drug originally developed for spinal cord injury has shown a surprising second act: it repairs DNA damage and reduces inflammation in a mouse model of Alzheimer’s disease — and it is already known to be safe in humans.
KCL-286 (also known as C286) is a first-in-class, orally bioavailable small molecule that selectively activates retinoic acid receptor beta (RAR-beta), a nuclear receptor transcription factor in the vitamin A signaling pathway. In a study published in FEBS Open Bio, researchers at King’s College London’s Institute of Psychiatry, Psychology and Neuroscience showed that the drug reduces DNA double-strand breaks — essentially, complete severing of the DNA molecule — in the brains of aged mice with Alzheimer’s-like pathology.
DNA damage and Alzheimer’s
Accumulating evidence over the past decade has linked DNA double-strand breaks to the cognitive decline of Alzheimer’s disease. Neurons, which do not divide, are particularly vulnerable: unrepaired breaks disrupt gene expression, trigger inflammation, and can push cells into senescence or death. In the Tg2576 mouse model, which carries a human mutation that causes amyloid plaque accumulation, the researchers found significantly elevated levels of gamma-H2AX — a standard marker of DNA double-strand breaks — in the hippocampus and frontal cortex.
KCL-286 treatment for three months, starting at 15 months of age when pathology was already established, significantly reduced these breaks. The drug also upregulated BRCA1, a key protein in the homologous recombination repair pathway, and normalized the morphology of microglia and astrocytes, the brain’s immune cells, bringing them closer to the appearance of healthy, disease-free mice.
“This is a fundamentally different approach from most Alzheimer’s drug development,” said Jonathan Corcoran, senior author and professor of neuroscience at King’s College London. “Rather than targeting amyloid or tau, we are addressing what may be an upstream driver of neurodegeneration — the failure of the brain’s own DNA repair machinery.”
Already human-safe
What makes KCL-286 unusual is its existing safety data. A double-blind, randomized, placebo-controlled Phase 1 trial published in the British Journal of Clinical Pharmacology in 2023 tested the drug in 109 healthy male volunteers. The maximum tolerated dose was 100 mg daily, with no severe adverse events. Side effects — dry skin, rash, skin exfoliation, elevated liver enzymes, and eye disorders — were consistent with the known class effects of retinoid drugs and were manageable.
The researchers are now seeking to move directly into Alzheimer’s clinical trials, potentially bypassing some early-phase work because Phase 1 safety data already exist. A Phase 2a trial in spinal cord injury has been planned but has not yet started recruitment.
Caveats
Several important limitations apply. The Alzheimer’s study used only three mice per group — a very small sample. The results are biomarker-based (DNA damage, inflammation) with no cognitive or behavioral testing to show functional improvement. The Phase 1 trial tested healthy men for a different indication; Alzheimer’s patients are typically older, have comorbidities, and take multiple medications, which could change the drug’s safety profile. Finally, while BRCA1 upregulation is the intended mechanism, long-term safety monitoring is needed given BRCA1’s role as a tumor suppressor.
Sources
- Hill N, AlMuallim HYO, Maddock E, et al. “Treatment with KCL-286, a first-in-class retinoic acid receptor-beta agonist, ameliorates neuronal DNA damage and inflammation in a mouse model of Alzheimer’s disease.” FEBS Open Bio, 2026. DOI: 10.1002/2211-5463.70284
- Goncalves MB, Mant T, Taubel J, et al. “Phase 1 safety, tolerability, pharmacokinetics and pharmacodynamic results of KCL-286.” British Journal of Clinical Pharmacology 89(12):3573-3583, 2023. DOI: 10.1111/bcp.15854
- King’s College London press release via ScienceDaily