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Persistent repression of tau in the brain using engineered zinc finger protein transcription factorsWegmann, 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
Science advances, 03/2021, Letnik: 7, Številka: 12Journal Article
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 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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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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in: SICRIS
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