Identification and characterization of a MAPT-targeting locked nucleic acid antisense oligonucleotide therapeutic for tauopathies

• DOI: 10.1016/j.omtn.2022.07.027
• Publication Date: 2022-08-04T15:48:24Z
• Authors: Amy Easton; Marianne L. Jensen; Congwei Wang; Peter H. Hagedorn; Yuwen Li; Michael Weed; Jere E. Meredith; Valerie Guss; Kelli Jones; Martin Gill; Carol Krause; Jeffrey M. Brown; Lisa Hunihan; Joanne Natale; Alda Fernandes; Yifeng Lu; Joe Polino; Mark Bookbinder; Greg Cadelina; Yulia Benitex; Ramola Sane; John Morrison; Dieter Drexler; Stephen E. Mercer; Charlotte Bon; Nikhil J. Pandya; Ravi Jagasia; Tai-Hsien Ou Yang; Tania Distler; Fiona Grüninger; Michael Meldgaard; Marco Terrigno; John E. Macor; Charles F. Albright; James Loy; Anja M. Hoeg; Richard E. Olson; Angela M. Cacace
• Keywords: Tau protein; Tauopathy; Tau Pathology; Pathogenesis; Antisense therapy

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