Methods and compositions for treating brain diseases

Abstract

The present disclosure provides methods of treating a disease or delivering a therapeutic agent to a mammal comprising administering to the mammal's cisterna magna and/or ventricle an rAAV particle containing a vector comprising a nucleic acid encoding a therapeutic protein inserted between a pair of AAV inverted terminal repeats in a manner such that cells with access to the cerebrospinal fluid (CSF) express the therapeutic agent and in certain embodiments secretes the therapeutic agent into the CSF for distribution to the brain.

1 . A method of delivering a therapeutic agent to the central nervous system of a mammal, comprising administering to the mammal's cisterna magna an rAAV particle comprising an AAV capsid protein and a vector comprising a nucleic acid encoding a therapeutic agent inserted between a pair of AAV inverted terminal repeats in a manner effective to infect cells that contact the cerebrospinal fluid (CSF) of the mammal such that the cells express the therapeutic agent in the mammal. 
     
     
         2 . A method of treating a disease in a mammal comprising administering to the mammal's cisterna magna an rAAV particle comprising an AAV capsid protein and a vector comprising a nucleic acid encoding a therapeutic agent inserted between a pair of AAV inverted terminal repeats in a manner effective to infect cells that contact the cerebrospinal fluid (CSF) of the mammal, wherein the cell expresses the therapeutic agent so as to treat the disease. 
     
     
         3 . A method of delivering a therapeutic agent to the central nervous system of a mammal, comprising administering to the mammal's brain ventricle, subarachnoid space and/or intrathecal space an rAAV particle comprising an AAV capsid protein and a vector comprising a nucleic acid encoding a therapeutic agent inserted between a pair of AAV inverted terminal repeats in a manner effective to infect cells that contact the cerebrospinal fluid (CSF) of the mammal such that the cells express the therapeutic agent in the mammal. 
     
     
         4 . A method of treating a disease in a mammal comprising administering to the mammal's brain ventricle, subarachnoid space and/or intrathecal space an rAAV particle comprising an AAV capsid protein and a vector comprising a nucleic acid encoding a therapeutic agent inserted between a pair of AAV inverted terminal repeats in a manner effective to infect cells that contact the cerebrospinal fluid (CSF) of the mammal, wherein the cell expresses the therapeutic agent so as to treat the disease. 
     
     
         5 . The method of  claim 1 , wherein the cell expresses the therapeutic agent and secretes the therapeutic agent into the CSF. 
     
     
         6 . The method of  claim 1 , wherein the cell is an ependymal, pial, endothelial, brain ventricle, and/or meningeal cell. 
     
     
         7 . The method of  claim 1 , further comprising additionally administering the rAAV to the mammal's brain ventricle, subarachnoid space and/or intrathecal space. 
     
     
         8 . The method of  claim 1 , wherein the mammal is a non-rodent mammal. 
     
     
         9 - 10 . (canceled) 
     
     
         11 . The method of  claim 8 , wherein the non-rodent mammal is a primate. 
     
     
         12 . The method of  claim 11 , wherein the primate is human. 
     
     
         13 . The method of  claim 1 , wherein the therapeutic agent is a therapeutic nucleic acid. 
     
     
         14 . The method of  claim 1 , wherein the therapeutic agent is a protein. 
     
     
         15 . The method of  claim 14 , wherein the nucleic acid encodes a lysosomal hydrolase. 
     
     
         16 . The method of  claim 15 , wherein the protein is TPP1. 
     
     
         17 . The method of  claim 1 , wherein the disease is a lysosomal storage disease (LSD). 
     
     
         18 . The method of  claim 17 , wherein the LSD is infantile or late infantile ceroid lipofuscinoses (LINCL), neuronopathic Gaucher, Juvenile Batten, Fabry, MLD, Sanfilippo A, Hunter, Krabbe, Morquio, Pompe, Niemann-Pick C, Tay-Sachs, Hurler (MPS-I H), Sanfilippo B, Maroteaux-Lamy, Niemann-Pick A, Cystinosis, Hurler-Scheie (MPS-I H/S), Sly Syndrome (MPS VII), Scheie (MPS-I S), Infantile Batten, GM1 Gangliosidosis, Mucolipidosis type II/III, or Sandhoff disease. 
     
     
         19 . The method of  claim 18 , wherein the disease is LINCL. 
     
     
         20 - 25 . (canceled) 
     
     
         26 . The method of  claim 1 , wherein the rAAV particle is injected at 1-5 locations in the brain. 
     
     
         27 . (canceled) 
     
     
         28 . The method of  claim 1 , wherein the rAAV particle is an rAAV2, rAAV4, rAAV5 and/or rAAV9 particle. 
     
     
         29 . The method of  claim 28 , wherein the rAAV particle is an rAAV2 particle. 
     
     
         30 . (canceled) 
     
     
         31 . The method of  claim 1 , wherein the therapeutic agent is administered in a single dose to the mammal's cisterna magna. 
     
     
         32 . The method of  claim 1 , further comprising administering an immunesuppression agent. 
     
     
         33 . The method of  claim 32 , wherein the immuesuppression agent is an anti-inflammatory agent. 
     
     
         34 . The method of  claim 33 , wherein the anti-inflammatory agent is mycophenolate. 
     
     
         35 . The method of  claim 1 , wherein the rAAV is administered at a dose of about 1-5 ml of 1×10 5 -1×10 16  vg/ml. 
     
     
         36 - 37 . (canceled) 
     
     
         38 . The method of  claim 2 , further comprising additionally administering the rAAV to the mammal's brain ventricle, subarachnoid space and/or intrathecal space.