Investigational Compound Observed to Reverse Toxic Tau Tangles

In a new animal study, the authors found that a new compound was able to reverse brain injury caused by toxic tau protein, which tangles and causes dementia.

These findings suggest that tau antisense oligonucleotides, which inhibit the production of tau, may be an effective treatment for multiple cognitive disorders, according to a study published by Science Translational Medicine.

In several disorders, such as Alzheimer’s disease, tau-associated frontotemporal dementia, chronic traumatic encephalopathy, and progressive supranuclear palsy, tau aggregates in the brain and forms neurofibrillary tangles, which results in damage. Despite being involved with many disease states, there are currently no effective treatments to prevent toxic tau tangles.

"This compound may literally help untangle the brain damage caused by tau,” said senior study author Timothy Miller, MD, PhD.

Antisense oligonucleotides are sequences of DNA or RNA that have been engineered to turn genes on or off, according to the study.

The investigators analyzed sequences that would turn tau genes off in mice that were modified to create high levels of the toxic protein. In these mice, tau aggregates begin forming at 6 months, and cause neurologic problems and earlier death, compared with control animals.

In the study, the investigators injected the compound into the brains of the mice, and found it stopped tau clumps from forming in younger mice, and reversed aggregation in older mice.

The investigational compound also was observed to cause older mice to live longer and have healthier brains compared with the control group, according to the study. Older mice treated with the compound did not lose their nest building abilities, which was seen in the control group.

“These results open a promising new door,” said Margaret Sutherland, PhD, program director at the National Institute of Neurological Disorders and Stroke. “They suggest that antisense oligonucleotides may be effective tools for tackling tau-associated disorders.”

Researchers are now conducting early clinical trials to determine the safety and efficacy of antisense oligonucleotides to treat neurological disorders, such as Huntington’s disease and amyotrophic lateral sclerosis.

The FDA recently approved the use of an antisense oligonucleotide to treat patients with spinal muscular atrophy, making it the first approved treatment for the disease.

Others studies that included non-human primates suggest that the compound could reach crucial portions of the brain, and turn off tau. Compared with placebo, 2 spinal tap injections of the antisense oligonucleotides were observed to reduce tau levels in the brain and spinal cords of Cynomologus monkeys.

Throughout the various studies, nearly no side effects were experienced.

Prior to testing the compound in humans, the compound must be extensively analyzed for safety. The investigators are taking the next steps to translate these findings into a new treatment for tau-related disorders, the study concluded.