Enhanced delivery of viral particles to the striatum and cortex

Abstract

Provided herein are novel methods for delivering recombinant adeno-associated viral (rAAV) particles to the central nervous system of a mammal (e.g., a human). In aspects, the methods involve administering rAAV particles containing a heterologous nucleic acid to the striatum and causing expression of the heterologous nucleic acid in at least the cerebral cortex and the striatum of the mammal.

1 . A method for delivering a recombinant adeno-associated viral (rAAV) particle to the central nervous system of a mammal comprising administering the rAAV particle to the striatum, wherein the rAAV particle comprises an rAAV vector encoding a heterologous nucleic acid that is expressed in at least the cerebral cortex and striatum of the mammal. 
     
     
         2 . The method of  claim 1 , wherein the rAAV particle comprises an AAV serotype 1 (AAV1) capsid. 
     
     
         3 . The method of  claim 1 , wherein the rAAV particle comprises an AAV serotype 2 (AAV2) capsid. 
     
     
         4 . (canceled) 
     
     
         5 . The method of  claim 1 , wherein the rAAV particle is administered to the putamen and the caudate nucleus of the striatum. 
     
     
         6 . The method of  claim 5 , wherein the rAAV particle is administered to the putamen and the caudate nucleus of each hemisphere of the striatum. 
     
     
         7 . The method of  claim 5 , wherein the rAAV particle is administered to one site in the caudate nucleus and two sites in the putamen. 
     
     
         8 . The method of  claim 5 , wherein the ratio of rAAV particles administered to the putamen to rAAV particles administered to the caudate nucleus is at least about 2:1. 
     
     
         9 . The method of  claim 1 , wherein the heterologous nucleic acid is expressed in the frontal cortex, occipital cortex, and/or layer IV of the mammal. 
     
     
         10 . (canceled) 
     
     
         11 . The method of  claim 1 , wherein the rAAV particle undergoes retrograde or anterograde transport in the cerebral cortex. 
     
     
         12 . The method of  claim 1 , wherein the heterologous nucleic acid is further expressed in the thalamus, subthalamic nucleus, globus pallidus, substantia nigra and/or hippocampus. 
     
     
         13 - 14 . (canceled) 
     
     
         15 . The method of  claim 1 , wherein the rAAV vector comprises the heterologous nucleic acid flanked by one or more AAV inverted terminal repeat (ITR) sequences. 
     
     
         16 - 18 . (canceled) 
     
     
         19 . The method of  claim 15 , wherein the ITR and the capsid of the rAAV particle are derived from the same AAV serotype. 
     
     
         20 . (canceled) 
     
     
         21 . The method of  claim 15 , wherein the ITR and the capsid of the rAAV viral particles are derived from different AAV serotypes. 
     
     
         22 - 30 . (canceled) 
     
     
         31 . The method of  claim 1 , wherein the rAAV vector is a self-complementary rAAV vector. 
     
     
         32 - 33 . (canceled) 
     
     
         34 . The method of  claim 1 , wherein the heterologous nucleic acid encodes a therapeutic polypeptide or therapeutic nucleic acid. 
     
     
         35 - 45 . (canceled) 
     
     
         46 . The method of  claim 1 , wherein the rAAV particle is delivered by stereotactic delivery. 
     
     
         47 . The method of  claim 1 , wherein the rAAV particle is delivered by convection enhanced delivery. 
     
     
         48 - 53 . (canceled) 
     
     
         54 . A method of treating a disorder of the CNS in a mammal comprising administering an effective amount of a rAAV particle to the striatum of the mammal, wherein the rAAV particle comprises an rAAV vector encoding a heterologous nucleic acid that is expressed in at least the cerebral cortex and striatum of the mammal. 
     
     
         55 . The method of  claim 54 , wherein the disorder of the CNS is Huntington's Disease. 
     
     
         56 . (canceled) 
     
     
         57 . The method of  claim 54 , wherein the disorder of the CNS is Parkinson's Disease. 
     
     
         58 - 89 . (canceled) 
     
     
         90 . The method of  claim 55 , wherein the heterologous nucleic acid encodes a therapeutic polypeptide or a therapeutic nucleic acid that inhibits the expression of HTT or inhibits the accumulation of HTT in cells of the CNS of the mammal. 
     
     
         91 . (canceled) 
     
     
         92 . The method of  claim 55 , wherein the heterologous nucleic acid encodes a miRNA that targets huntingtin. 
     
     
         93 . (canceled) 
     
     
         94 . The method of  claim 57 , wherein the heterologous nucleic acid encodes a therapeutic polypeptide, wherein the therapeutic polypeptide is glial-derived growth factor (GDNF), brain-derived growth factor (BDNF), tyrosine hydroxlase (TH), GTP-cyclohydrolase (GTPCH), and/or amino acid decarboxylase (AADC). 
     
     
         95 - 106 . (canceled) 
     
     
         107 . A system for expression of a heterologous nucleic acid in the cerebral cortex and striatum of a mammal, comprising
 a) a composition comprising rAAV particles, wherein the rAAV particles comprise a rAAV vector encoding the heterologous nucleic acid; and   b) a device for delivery of the rAAV particles to the striatum.   
     
     
         108 - 156 . (canceled) 
     
     
         157 . A kit for delivering a rAAV particle to the CNS of a mammal or for treating a disorder of the CNS in a mammal, comprising rAAV particles, wherein the rAAV particles comprise a rAAV vector encoding a heterologous nucleic acid that is expressed in at least the cerebral cortex and striatum of the mammal. 
     
     
         158 - 222 . (canceled)