In vivo validation of a lead compound targeting tau self‐association in two mouse models of tauopathy

Background Tau self‐association is the initial step in the formation of toxic tau oligomers and larger aggregates. Our program is highly differentiated in that it targets tau self‐association with small molecules to block the formation of all forms of tau aggregates, whereas other tau aggregation inhibitor programs have largely focused on inhibiting formation and/or dissociating large and relatively inert fibrils which could generate toxic tau oligomer seeds. Relative to immunotherapeutic approaches, small molecules are agnostic to specific post‐translational modifications, conformational changes or strains of tau aggregates, and have superior access to their target in the CNS. Method Preventive and therapeutic blinded studies in htau and JNPL3 transgenic mice were performed at an independent laboratory. Mice were treated for four months by administration of our lead compound in feed. For preventive studies, treatment was from 3 to 7 months‐of‐age; for preventive studies, treatment was from 7 to 11 months‐of‐age for JNPL3 and 9 to 13 months‐of‐age for htau. To quantify levels of Sarkosyl‐insoluble tau, self‐associated tau, and phosphorylated tau in the treated and control groups of mice ELISAs were performed. Immunohistochemistry determined levels of conformationally altered and hyperphosphorylated tau. Motor and cognitive behavioral testing are being performed as part of the ongoing therapeutic studies. Result The lead compound reduced self‐associated tau and caused a statistically significant, linear, dose‐dependent reduction of the levels of sarkosyl‐insoluble tau aggregates and phosphorylated insoluble tau aggregates in relationship to the levels of compound in the brain in male htau mice. The study of female JNPL3 mice showed dose‐dependent reduction below baseline and vehicle levels of self‐associated tau, insoluble tau aggregates and phosphorylated tau. The compound was well tolerated at all therapeutic doses; there were no adverse events due to the compound. Conclusion The lead compound reduced both soluble and insoluble phosphorylated tau aggregates in the htau mouse model representing tau aggregation in AD and in the JNPL3 mouse model of inherited tauopathy. These studies validated both the screening approach against tau self‐association as a target and the in vivo efficacy of the small molecule lead compound.