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Persistent repression of tau in the brain using engineered zinc finger protein transcription factors

Authors: Wegmann, Susanne; DeVos, Sarah L.; Zeitler, Bryan; Marlen, Kimberly; Bennett, Rachel E.; Perez-Rando, Marta; MacKenzie, Danny; Yu, Qi; Commins, Caitlin; Bannon, Riley N.; Corjuc, Bianca T.; Chase, Alison; Diez, Lisa; Nguyen, Hoang-Oanh B.; Hinkley, Sarah; Zhang, Lei; Goodwin, Alicia; Ledeboer, Annemarie; Lam, Stephen; Ankoudinova, Irina; Tran, Hung; Scarlott, Nicholas; Amora, Rainier; Surosky, Richard; Miller, Jeffrey C.; Robbins, Ashley B.; Rebar, Edward J.; Urnov, Fyodor D.; Holmes, Michael C.; Pooler, Amy M.; Riley, Brigit; Zhang, H. Steve; Hyman, Bradley T.

Online: https://advances.sciencemag.org/lookup/doi/10.1126/sciadv.abe1611

Issue: Sci Adv . 2021 Mar 19;7(12):eabe1611.


Neuronal tau reduction confers resilience against β-amyloid and tau-related neurotoxicity in vitro and in vivo. Here, we introduce a novel translational approach to lower expression of the tau gene MAPT at the transcriptional level using gene-silencing zinc finger protein transcription factors (ZFP-TFs). Following a single administration of adeno-associated virus (AAV), either locally into the hippocampus or intravenously to enable whole-brain transduction, we selectively reduced tau messenger RNA and protein by 50 to 80% out to 11 months, the longest time point studied. Sustained tau lowering was achieved without detectable off-target effects, overt histopathological changes, or molecular alterations. Tau reduction with AAV ZFP-TFs was able to rescue neuronal damage around amyloid plaques in a mouse model of Alzheimer’s disease (APP/PS1 line). The highly specific, durable, and controlled knockdown of endogenous tau makes AAV-delivered ZFP-TFs a promising approach for the treatment of tau-related human brain diseases.