Chunk #12 — Therapeutic approaches to toxic tau gain of function — Approach 1: reduce tau gene expression (gene therapy) — Anti-sense Oligonucleotides (ASOs)
Based on the above rationale, Ionis developed BIIB080 (IONISMAPT Rx), an ASO delivered intrathecally that reduces total tau gene expression. In P301S transgenic mice that express human tau, 50% reduction in tau mRNA levels by BIIB080 reversed tau aggregation, with a concomitant decrease in the rate of hippocampal atrophy, neuronal loss, and nesting behavioral deficits. [37] These encouraging preclinical findings led to an ongoing Phase 1/2 in 46 mild AD patients, who will be treated with BIIB080 for 36 weeks (NCT03186989). Additional studies support the hypothesis that 4R-tau may be a particularly pathologic species, especially in 4R-tauopathies such as PSP and CBD, leading to development of ASOs for the selective knockdown of 4R-tau, though this approach remains in preclinical development [38].
