New approach to treating dementia using antisense oligonucleotides

In a study of mice and monkeys, NIH funded researchers showed that they could prevent and reverse some of the brain injury caused by the toxic form of a protein called tau.

Scientists used a designer compound to prevent and reverse brain damage caused by tau in mice.
Credit: Miller lab, Washington University, St. Louis, MO

The results, published in Science Translational Medicine, suggest that the study of compounds, called tau antisense oligonucleotides, that are genetically engineered to block a cell’s assembly line production of tau, might be pursued as an effective treatment for a variety of disorders. Antisense oligonucleotides are short sequences of DNA or RNA that are programmed to turn genes on or off.

In several disorders, toxic forms of tau clump together inside dying brain cells and form neurofibrillary tangles, including Alzheimer’s disease, tau-associated frontotemporal dementia, chronic traumatic encephalopathy and progressive supranuclear palsy.

Researchers tested sequences designed to turn tau genes off in mice that are genetically engineered to produce abnormally high levels of a mutant form of the human protein. Tau clusters begin to appear in the brains of 6-month-old mice and accumulate with age. The mice develop neurologic problems and die earlier than control mice.

Injections of the tau antisense oligonucleotides into the fluid-filled spaces of the mice brains prevented tau clustering in 6-9-month-old mice and appeared to reverse clustering in older mice. The compound prevented the older mice from losing their ability to build nests. Further experiments on non-human primates suggested that the antisense oligonucleotides tested in mice could reach important areas of larger brains and turn off tau. In comparison with placebo, two spinal tap injections of the compound appeared to reduce tau protein levels in the brains and spinal cords of Cynomologus monkeys. As the researchers saw with the mice, injections of the compound caused almost no side effects.

Currently, researchers are conducting early phase clinical trials on the safety and effectiveness of antisense oligonucleotides designed to treat several neurological disorders, including Huntington’s disease and amyotrophic lateral sclerosis. The U.S. Food and Drug Administration recently approved the use of an antisense oligonucleotide for the treatment of spinal muscular atrophy, a hereditary disorder that weakens the muscles of infants and children.

Citation: DeVos, Sarah L., Rebecca L. Miller, Kathleen M. Schoch, Brandon B. Holmes, Carey S. Kebodeaux, Amy J. Wegener, Guo Chen et al. “Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy.” Science Translational Medicine 9, no. 374 (2017): eaag0481.
DOI: 10.1126/scitranslmed.aag0481
Research funding: National Institutes of Health, Tau Consortium, Cure PSP.
Adapted from press release by National Institute of Neurological Disorders and Stroke.