Researchers are testing a new, genetic therapy for Alzheimer’s disease. New clinical trial results, which represent the first time that a “gene silencing” approach has been taken in dementia and Alzheimer’s disease, suggest that the method is able to safely and successfully lower levels of the harmful tau protein known to cause the disease.

Tau plays a key role in Alzheimer’s disease. The pathophysiology of the disease, according to some evidence, may be reduced by lowering tau. The team’s goal was to inhibit microtubule-associated protein tau (MAPT) expression with a tau-targeting antisense oligonucleotide (ASO) called BIIB080 (/IONIS-MAPTRx). This, they hypothesized, would reduce tau levels in patients with mild Alzheimer’s disease. The Phase I results published here—with results from 46 patients—are the first indication that this method has a biological effect.

This work is published in Nature Medicine in the paper, “Tau-targeting antisense oligonucleotide MAPTRx in mild Alzheimer’s disease: a Phase Ib, randomized, placebo-controlled trial.

There are currently no treatments targeting tau. The drugs aducanumab and lecanemab— recently approved for use in some situations by the FDA—target a separate disease mechanism in Alzheimer’s disease, the accumulation of amyloid plaques.

The Phase I trial looked at the safety of BIIB080, what it does in the body, and how well it targets the MAPT gene. Forty-six patients, with an average age of 66, were enrolled in the trial which took place from 2017 to 2020. The trial looked at three doses of the drug given by intrathecal injection (into the nervous system via the spinal canal), compared with the placebo.

Results show that the drug was well tolerated, with all patients completing the treatment period and over 90% completing the post-treatment period.

Patients in both the treatment and placebo groups experienced either mild or moderate side effects—the most common being a headache after injection of the drug. However, no serious adverse events were seen in patients given the drug.

The research team also looked at two forms of the tau protein in the central nervous system (CNS)—a reliable indicator of disease—over the duration of the study. They found a greater than 50% reduction in levels of total tau and phosphor tau concentration in the CNS after 24 weeks in the two treatment groups that received the highest dose of the drug.

“We will need further research to understand the extent to which the drug can slow progression of physical symptoms of disease and evaluate the drug in older and larger groups of people and in more diverse populations,” noted Catherine Mummery, MD, PhD, consultant neurologist at the National Hospital for Neurology and Neurosurgery (NHNN) and clinical lead for the NHNN Cognitive Disorders Clinic. “But the results are a significant step forward in demonstrating that we can successfully target tau with a gene silencing drug to slow—or possibly even reverse—Alzheimer’s disease, and other diseases caused by tau accumulation in the future.”

Previous articleDriving the CAR: The Road Ahead for Cell Therapy
Next articleCarl Icahn States His Case for Change at Illumina on “Close to the Edge”