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

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

Science advances (2021-03-21)
Susanne Wegmann, Sarah L DeVos, Bryan Zeitler, Kimberly Marlen, Rachel E Bennett, Marta Perez-Rando, Danny MacKenzie, Qi Yu, Caitlin Commins, Riley N Bannon, Bianca T Corjuc, Alison Chase, Lisa Diez, Hoang-Oanh B Nguyen, Sarah Hinkley, Lei Zhang, Alicia Goodwin, Annemarie Ledeboer, Stephen Lam, Irina Ankoudinova, Hung Tran, Nicholas Scarlott, Rainier Amora, Richard Surosky, Jeffrey C Miller, Ashley B Robbins, Edward J Rebar, Fyodor D Urnov, Michael C Holmes, Amy M Pooler, Brigit Riley, H Steve Zhang, Bradley T Hyman
ABSTRACT

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.

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