CIRCULAR BIFUNCTIONAL APTAMERS AND TRIFUNCTIONAL APTAMERS TARGETING TAU

摘要

The lack of blood-brain barrier (BBB) penetrating ability has hindered the delivery of many therapeutic agents for tauopathy therapeutic treatment. A circular bifunctional aptamer reported here has been able to enhance the in vivo BBB penetration for improved therapy. The circular aptamer includes one transferrin receptor (TfR) aptamer to facilitate TfR-aptamer recognition-induced transcytosis across BBB endothelial cells, and one Tau protein aptamer selected to inhibit Tau phosphorylation and other tauopathy-related pathological events in the brain. This bispecific construct exhibits strong specificity towards Tau and enhanced plasma stability in comparison to linear Tau aptamer. In vivo administration of circular Tau-TfR aptamer results in a rapid uptake into relevant brain regions after crossing the BBB, such as hippocampus and cortex. A Y-shaped trispecific aptamer including one aptamer for L1CAM, one aptamer for Tau and one aptamer for TfR reported here has enhanced BBB and neuron cell membrane permeation. Bispecific and trispecific Tau aptamer coupled to a signaling moiety (such as dodecane tetraacetic acid (DOTA) or DOTA complexed to Gd+3) for neuroimaging, and bispecific or trispecific Tau aptamer coupled to protein aggregate binding moiety (such as methylene blue) for enhanced ability to disrupt tau aggregation are also contemplated in this invention.