| First Author | Wegmann S | Year | 2021 |
| Journal | Sci Adv | Volume | 7 |
| Issue | 12 | PubMed ID | 33741591 |
| Mgi Jnum | J:317981 | Mgi Id | MGI:6807854 |
| Doi | 10.1126/sciadv.abe1611 | Citation | Wegmann S, et al. (2021) Persistent repression of tau in the brain using engineered zinc finger protein transcription factors. Sci Adv 7(12) |
| abstractText | Neuronal tau reduction confers resilience against beta-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. |
