Gene-blocking therapy advances Alzheimer’s-like symptoms in mice

Targeting tangles of tau protein in mice with Alzheimer’s-like symptoms has reversed their brain damage, halting memory loss and extending their lives (New Scientist, 2017).

Clumps of two types of sticky protein build up in the brains of people with Alzheimer’s disease; beta-amyloid plaques, and tangles of tau. While many attempts to develop drugs to treat Alzheimer’s have targeted beta-amyloid, tau protein tangles have long been suspected to play a role in memory loss.

Tim Miller of Washington University in St Louis, Missouri, said “Tau is what correlates with memory problems, so one hypothesis is that lowering tau could be beneficial.” His team has purged tau tangles from the brains of Alzheimer’s-like mice for the first time. They used fragments of RNA called antisense oligonucleotides to sabotage the gene that makes tau, preventing it from being fully translated into protein. Once a day for four weeks, the team injected the antisense treatment, named Tau-ASO12, into the fluid at the base of each mouse’s spine. The mice had been genetically engineered to make a rogue form of tau similar to what is seen in people with Alzheimer’s, predisposing the mice to developing tau-related brain problems.

The drug successfully spread throughout the brain, and was linked to a reduction in levels of tau that was made. It also seemed to destroy existing tau tangles, and prevent tau from spreading around the brain in older mice. Overall, mice that got Tau-ASO12 lived up to fifty days longer than those that didn’t, and were able to retain important abilities, such as nest-making skills, that were lost in mice that received a sham treatment.

When Tim Miller’s team gave the antisense treatment to cynomolgus monkeys, they saw around a 20% reduction in the amount of tau detected in spinal fluid samples, with no apparent side effects, early evidence that the therapy may hold promise for treating humans.

Before testing the treatment in people, the team will further assess its safety and efficacy in larger primate animals. One concern is that lowering levels of a brain protein like tau could affect normal brain function. Michel Goedert at the Laboratory of Molecular Biology in Cambridge, said “We don’t know for sure what tau does in the brain. We believe that reducing tau levels by something like 30 per cent will not cause any ill effects, but will be beneficial in terms of preventing neurodegeneration.”

Tim Miller said any human Tau-ASO12 treatment would likely be injected into the cerebrospinal fluid at the base of the spine, and would probably have to be given around once a month. Similar antisense treatments have already been given safely to people with amyotrophic lateral sclerosis (motor neurone disease) and Huntington’s disease.

Tau is implicated in several other neurodegenerative conditions, including progressive supranuclear palsy and frontotemporal dementia, and it’s possible that such a treatment could also benefit people with these conditions.

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