Tau inhibitor may block self-association and fibril formation in mice

Written by Sharon Salt, Editor

Previous research has demonstrated that tau load and distribution are directly correlated with disease progression in Alzheimer’s. This has piqued the interest of researchers in the field to turn to tau as a potential therapeutic target for the disease. Although developments that are currently in the clinic focus more on intervening after tau proteins have misfolded and oligomers have formed, a new study has indicated that utilizing a tau inhibitor to target the first step of this process may be emerging.

Oligomerix (NY, USA) and the Feinstein Institutes for Medical Research (NY, USA) have announced the publication of preclinical data on a tau inhibitor, which demonstrates that the oral small molecule drug may inhibit the formation of neurotoxic tau oligomers in a mouse model of tau aggregation most relevant to Alzheimer’s disease.

The study, which has been published in the Journal of Alzheimer’s Disease, revealed that the compound blocked tau self-association and inhibited downstream events that lead to tau fibril formation.

Within their investigation, the research team demonstrated that the compound inhibited hippocampal self-associated tau in the htau mouse model of tauopathy. In addition to this, the drug also reduced the amount of insoluble tau aggregates and phosphorylated insoluble aggregates in a linear, dose-dependent fashion in relation to brain compound levels.

You might also like:

By using immunocytochemical analysis, the researchers were also able to demonstrate that the tau inhibitor decreased the accumulation of misfolded tau associated with tau aggregates.

“This study validates Oligomerix’s approach for inhibiting tau aggregation and shows that targeting tau oligomer formation at the beginning of the aggregation cascade can inhibit the entire downstream aggregation pathway,” commented James Moe, President and CEO of Oligomerix.

According to the team, the next steams of the study will include assessing whether this compound could be beneficial in an inherited form of tauopathy and whether it can ameliorate behavioral defects. The company is conducting preventive and therapeutic studies in the JNPL3 mouse model of tauopathy that expresses the human tau 4R0N isoform with the mutation P301L associated with frontotemporal dementia.

“We are also currently conducting IND-enabling studies for this compound, and plan to initiate human clinical trials in 2021,” concluded Moe.

Sources: Davidowitz EJ, Krishnamurthy PK, Lopez P et al. In vivo validation of a small molecule inhibitor of tau self-association in htau mice. J. Alzheimer’s Dis. doi:10.3233/JAD-190465 (2019) (Epub ahead of print); www.eurekalert.org/pub_releases/2019-11/nh-oaf111519.php