RT Journal Article
SR Electronic
T1 Persistent repression of tau in the brain using engineered zinc finger protein transcription factors
JF Science Advances
JO Sci Adv
FD American Association for the Advancement of Science
SP eabe1611
DO 10.1126/sciadv.abe1611
VO 7
IS 12
A1 Wegmann, Susanne
A1 DeVos, Sarah L.
A1 Zeitler, Bryan
A1 Marlen, Kimberly
A1 Bennett, Rachel E.
A1 Perez-Rando, Marta
A1 MacKenzie, Danny
A1 Yu, Qi
A1 Commins, Caitlin
A1 Bannon, Riley N.
A1 Corjuc, Bianca T.
A1 Chase, Alison
A1 Diez, Lisa
A1 Nguyen, Hoang-Oanh B.
A1 Hinkley, Sarah
A1 Zhang, Lei
A1 Goodwin, Alicia
A1 Ledeboer, Annemarie
A1 Lam, Stephen
A1 Ankoudinova, Irina
A1 Tran, Hung
A1 Scarlott, Nicholas
A1 Amora, Rainier
A1 Surosky, Richard
A1 Miller, Jeffrey C.
A1 Robbins, Ashley B.
A1 Rebar, Edward J.
A1 Urnov, Fyodor D.
A1 Holmes, Michael C.
A1 Pooler, Amy M.
A1 Riley, Brigit
A1 Zhang, H. Steve
A1 Hyman, Bradley T.
YR 2021
UL http://advances.sciencemag.org/content/7/12/eabe1611.abstract
AB 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.