Identification and Characterization of a MAPT-targeting Locked Nucleic Acid Antisense Oligonucleotide Therapeutic for Tauopathies II

Tau is a microtubule-associated protein (MAPT, tau) implicated in the pathogenesis of Tauopathies, a spectrum of neurodegenerative disorders characterized by accumulation of hyperphosphorylated, aggregated tau.  Because tau pathology can be distinct across diseases, a pragmatic therapeutic approach may be to intervene at the level of the tau transcript, as it makes no assumptions to mechanisms of tau toxicity. Here we performed a large library screen of locked-nucleic acid-modified antisense oligonucleotides (LNA-ASOs), where careful tiling of the MAPT locus resulted in the identification of hot spots for activity in the 3’UTR.  Further modifications to the LNA design resulted in the generation of ASO-001933, which selectively and potently reduces tau in primary cultures from hTau mice, monkey, and human neurons.  ASO-001933 was well-tolerated and produced a robust, long lasting reduction in tau protein in both mouse and cynomolgus monkey brain. In monkey, tau protein reduction was maintained in brain for 20 weeks post-injection and corresponded with tau protein reduction in the CSF.  Our results demonstrate that LNA-ASOs exhibit excellent drug-like properties and sustained efficacy likely translating to infrequent, intrathecal dosing in patients. These data further support the development of LNA-ASOs against tau for the treatment of tauopathies. Comparative gene expression profiling analysis of RNA-seq data for hiPSC-derived neurons (SA001; NIH Registration Number 0085; Cellectis, Sweden) treated with 1uM ASO-001933 or 1uM ASO-NT for 42 days