A discovery led by scientists at Lawrence Berkeley National Laboratory could open an entirely new front in the fight against Huntington's disease — a fatal, inherited neurodegenerative condition that has resisted three decades of attempts to treat its root genetic cause.
Published in Nature Communications, the research reveals that much of the damage in Huntington's comes from a mechanism that had been overlooked: the mutated huntingtin protein suppresses the cell's ability to repair double-stranded DNA breaks. Over time, these severe breaks accumulate in the striatum — the brain region hardest hit by the disease — driving neuron dysfunction and death.
"We show that symptoms are preceded by DNA damage, and that this can be reversed using an investigational antioxidant compound, which also protects against neurodegeneration. This alleviation occurs even without altering or blocking the gene," said Aris Polyzos of Berkeley Lab, who co-led the work with Cynthia McMurray.
The team showed the disease unfolds along two parallel paths. The well-known expansion of a repetitive CAG sequence in the gene proceeds independently but, on its own, does not kill neurons. Instead, it is the faulty huntingtin protein — which binds to and suppresses DNA-repair enzymes — that lets breakage accumulate. In mice engineered so the repeat expansion was blocked entirely, the animals still developed DNA breaks, symptoms and death.
Then came the striking part: the scientists treated Huntington's mice with XJB-5-131, a synthetic antioxidant developed at the University of Pittsburgh that can cross the blood-brain barrier and concentrate in mitochondria — the source of the reactive oxygen species that damage DNA. Given as a daily infusion, the compound cut double-stranded breaks, eliminated motor deficits and reduced brain inflammation.
"It basically attenuated the disease," said McMurray. "I believe we're opening the door to a new way to treat Huntington's patients."
Because clinical agents that change these DNA breaks already exist for humans, a therapeutic strategy could be tested relatively quickly. The next step is proving the mechanism holds in human cells: Polyzos is leading a study using induced pluripotent stem cells from Huntington's patients, coaxed into neurons. A future cure might combine an antioxidant like XJB-5-131 with a gene-modifying therapy that fixes the mutation at the root.
