Tau modulators and methods and compositions for delivery thereof

Abstract

The present disclosure is in the field of diagnostics and therapeutics for Alzheimer's Disease.

What is claimed is: 
     
         1 . A genetic modulator of a microtubule associated protein tau (MAPT) gene, the modulator comprising
 a DNA-binding domain that binds to a target site of at least 12 nucleotides in the MAPT gene; and   a transcriptional regulatory domain or nuclease domain.   
     
     
         2 . The genetic modulator of  claim 1 , wherein the DNA-binding domain comprises a zinc finger protein (ZFP), a TAL-effector domain protein (TALE) or single guide RNA. 
     
     
         3 . The genetic modulator of  claim 1 , wherein the transcriptional regulatory domain comprises a repression domain or activation domain. 
     
     
         4 . A polynucleotide encoding a genetic modulator according to  claim 1 . 
     
     
         5 . A gene delivery vehicle comprising a polynucleotide according to  claim 4 . 
     
     
         6 . The gene delivery vehicle of  claim 5 , wherein the gene delivery vehicle comprises an AAV vector. 
     
     
         7 . A pharmaceutical composition comprising one or more polynucleotides according to  claim 4 . 
     
     
         8 . The pharmaceutical composition of  claim 7 , wherein the genetic modulator comprises a nuclease domain and the genetic modulator cleaves the MAPT gene. 
     
     
         9 . The pharmaceutical composition of  claim 8 , further comprising a donor molecule that is integrated into the cleaved MAPT gene. 
     
     
         10 . An isolated cell comprising a genetic modulator according to  claim 1 . 
     
     
         11 . An isolated cell comprising a polynucleotide according to  claim 4 . 
     
     
         12 . A method of modulating MAPT expression in a cell, the method comprising administering a genetic modulator according to  claim 1  to a cell. 
     
     
         13 . The method of  claim 12 , wherein MAPT expression is repressed. 
     
     
         14 . The method of  claim 13 , wherein the administration is intracerebroventricular, intrathecal, intracranial, retro-orbital (RO), intravenous or intracisternal. 
     
     
         15 . A method of treating and/or preventing a tauopathy in a subject, the method comprising repressing MAPT expression according to the method of  claim 14 . 
     
     
         16 . The method of  claim 15 , wherein the amount of tau in the subject is reduced. 
     
     
         17 . A kit comprising one or more of gene delivery vehicles according to  claim 6  and/or instructions for use.