Aav/xbp1s-ha virus, gene therapy method and use thereof in the optimisation and improvement of learning, memory and cognitive capacities

Abstract

This invention presents a sequence of the virus AAV/XBP1s-HA, method and its use in the improvement of cognitive functions, of memory and of learning, as presented in the in vivo studies in FIG. 12/17 right panel.

1 . A method of treating a disease related to the memory, cognitive or learning capacity in a mammal subject in need thereof, said method comprising administering a therapeutically efficient amount of a viral vector that induces neuronal overexpression of XBP1 in the brain, wherein said viral vector comprises an expression cassette with a nucleotide sequence encoding the neuronal transcription factor XBP1. 
     
     
         2 . The method of  claim 1 , wherein said neuronal overexpression of XBP1 improves the performance of the memory, cognitive or learning capacities in said mammal. 
     
     
         3 . The method of  claim 1 , wherein said XBP1 is XBP1s. 
     
     
         4 . The method of  claim 1 , wherein the viral vector is of the adeno-associated type (AAV). 
     
     
         5 . The method of  claim 1 , wherein the viral vector is administered into the hippocampus. 
     
     
         6 . The method of  claim 1 , wherein said viral vector is an AAV vector comprising a recombinant genome with the expression cassette including a transcriptional regulating region specific of hippocampal tissue operatively linked to the nucleotide sequence encoding XBP1 s. 
     
     
         7 . The method of  claim 1 , wherein the virus is an AAV vector comprising an insert of a nucleotide encoding XBP1 s as contained in the plasmid deposited at the ATCC under deposit number PTA-121708. 
     
     
         8 . The method according to  claim 1 , wherein the viral vector is an AAV vector selected from AAV6, AAV7, AAV8 and AAV9. 
     
     
         9 . The method according to  claim 6 , wherein the serotype of the AAV is AAV6. 
     
     
         10 . The method according to  claim 1 , wherein the nucleotide sequence encoding XBP1 is operably linked to the regulating region of the specific transcription of neuronal tissue selected from Pgkl, Cam 2 and Thy 1. 
     
     
         11 . The method according to  claim 1 , wherein the expression cassette comprises a regulatory post-transcriptional region. 
     
     
         12 . The method according to  claim 11 , wherein the posttranscriptional regulatory region is the American woodchuck hepatitis virus post-transcriptional regulatory element (WPRE). 
     
     
         13 . The method according to  claim 1 , wherein the vector is an adeno-associated virus and further comprises one or more Inverted Terminal Repeats (ITRs) derived from AAV6, AAV7, AAV8 and AAV9. 
     
     
         14 . The method according to  claim 1 , wherein the vector is administered via the intranasal route or by direct intraventricular or intrathecal injection. 
     
     
         15 . The method according to  claim 1 , wherein a dose of the viral vector is in a range between 10 9  to 10 30  viral units per/kg. 
     
     
         16 . The method according to  claim 1 , wherein the mammal is a human. 
     
     
         17 . A method for optimizing memory or cognitive processes in a mammal in need thereof comprising administering to the mammal a pharmaceutical composition comprising an adeno-associated vector (AAV) and a pharmaceutically acceptable excipient, wherein said AAV comprises a recombinant viral genome and an expression cassette with a regulating region operatively linked to a polynucleotide that encodes a protein comprising X-box protein 1 (XBP1). 
     
     
         18 . The method of  claim 17 , wherein said XBP1 is XBP1s. 
     
     
         19 . An AAV vector comprising a recombinant genome with an expression cassette that induces neuronal overexpression of XBP1 in the brain of a mammal, wherein said neuronal overexpression of XBP1 improves the performance of the memory, cognitive or learning capacities in said mammal. 
     
     
         20 . The AAV vector of  claim 19 , wherein said XBP1 is XBP1s.