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Merck

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
RESUMO

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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