Recently Published Preclinical Data Show Reduction of Tau Improves Tauopathy Phenotypes in Mice

Results published in The Journal of Science Translational Medicine

Ionis scientists, in collaboration with researchers at Washington University, led by Dr. Timothy Miller and Sarah DeVos, developed antisense oligonucleotides (ASOs) targeting human tau mRNA with the goal of reducing tau expression in the brain. The tau-targeting ASOs were tested in a series of in vivo preclinical studies to characterize the potential therapeutic benefit of reducing tau mRNA and tau protein in the treatment of tauopathies.  Preclinical results from these studies were published in the Journal of Science Translational Medicine in a paper titled, “Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy,” which is now available online.1

Tau is a microtubule-associated protein found primarily in neuronal cells. The accumulation of hyperphosphorylated tau protein causes neurofibrillary tangles, which are the hallmark signal of a spectrum of diseases, known as tauopathies.  There are several tauopathies including frontotemporal dementia, progressive supranuclear palsy, and the most common being Alzheimer’s disease.  There is a strong correlation between the accumulation of hyperphosphorylated tau and cognitive decline and there is evidence that mutations in the tau protein are associated with the neurodegeneration in patients with certain tauopathies.  For these reasons, there is strong scientific rationale to explore therapeutic strategies to reduce tau expression for the treatment of tauopathies.

Tau-targeting ASO’s decreased, and even reversed phosphorylated tau pathology across the brain despite the age at treatment in a transgenic mouse model expressing mutant P301S human tau (PS19 mouse model). Reducing human tau in the PS19 mouse model also halted hippocampal volume loss, neuronal loss, and reversed pathological tau seeding activity. Additionally, PS19 mice treated with tau-targeting ASOs lived significantly longer than age-matched controls and performed substantially better on the nestlet task, a test used to assess general social behavior, cognitive performance, and motor capabilities in mouse models. In non-human primates, ASOs targeting monkey tau dose-dependently reduced tau mRNA and tau protein across the spinal cord, brain, and cerebrospinal fluid.  Taken together, these preclinical results support the case for developing an antisense drug designed to selectively reduce human tau for the treatment of tauopathies.

As a part of Ionis’ neurological disease franchise, Ionis is evaluating an antisense drug in preclinical development designed to reduce tau protein for the treatment of certain tauopathies. This is one of Ionis’ more than 25 programs in research, preclinical, and clinical stages of development for neurological diseases. Ionis has clinical experience dosing multiple drugs intrathecally in patients for the treatment of neurological and neurodegenerative diseases, including with SPINRAZATM, which is approved for the treatment of pediatric and adult patients with spinal muscular atrophy, as well as IONIS-HTTRx and IONIS-SOD1Rx, which are both currently being evaluated in clinical studies in patients with Huntington’s Disease and amyotrophic lateral sclerosis, respectively.  Ionis continues to rapidly grow and advance its neurological disease franchise with the goal of bringing transformative drugs to patients with severe diseases.


  1. DeVos et al. “Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy.” Sci. Trans. Med. Vol. 9, Issue 374, Published online January 25, 2017.