Can Anti-Tau Therapies Treat Neurodegenerative Disorders?

Antisense Oligonucleotide to Reduce Total Tau Expression in Mild Alzheimer’s Disease

Roger M. Lane, MD, MPH, of lonis Pharmaceuticals, Carlsbad, California, described a study that is designed to the test safety and pharmacokinetics of a tau-lowering antisense oligonucleotide (ASO) in patients with mild Alzheimer’s disease. The ASO, lonis-MAPT_RX, targets microtubule-associated protein tau (MAPT) messenger RNA to reduce the synthesis of tau in the CNS, Dr. Lane said. “In contrast, current investigational biologic or small molecule anti-tau drugs target the tau protein,” he said.

In a recent study, DeVos and colleagues identified ASOs that selectively decreased human tau mRNA and protein in mice expressing mutant P301S human tau. After a reduction of human tau in this mouse model of tauopathy, fewer tau inclusions developed, and pre-existing tau pathology was reversed. The resolution of tau pathology was accompanied by the prevention of hippocampal volume loss, neuronal death, and nesting deficits. In nonhuman primates, ASOs distributed throughout the brain and spinal cord, and reduced tau mRNA and protein in the brain and spinal cord, and tau protein in the CSF.

Based on these findings, researchers are studying lonis-MAPT_RX, a second generation 2’-O-methoxyethyl (2’-MOE) chimeric ASO identified as suitable for clinical trials. It is designed to bind and degrade the pre-mRNA transcribed from the MAPT gene and thereby reduce synthesis of tau protein.

“The first clinical trial is set up in 12 centers in Canada and five European countries,” Dr. Lane said. “Patients aged 50 to 75 with mild Alzheimer’s disease are being randomized to multiple ascending doses of lonis-MAPT_RX administered intrathecally.” The study drug will be given four times at monthly intervals, and there will be six months of follow-up. End points include CSF biomarkers, neuroimaging, and clinical outcomes. “We are expecting a 50–85% reduction in tau production in the cerebral cortex,” Dr. Lane said.

—Adriene Marshall

Suggested Reading

DeVos SL, Miller RL, Schoch KM, et al. Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy. Sci Transl Med. 2017;9(374).