ENHANCED DELIVERY OF VIRAL PARTICLES TO THE STRIATUM AND CORTEX
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)