Methods and compositions for treating brain diseases

Abstract

The present disclosure provides targeting peptides and vectors containing a sequence that encodes targeting peptides that deliver agents to the brain.

What is claimed is: 
     
         1 . A modified adeno-associated virus (AAV) capsid protein comprising a targeting peptide PXXPS (SEQ ID NO:1), SPXXP (SEQ ID NO:2), TLH (SEQ ID NO:3), QSXY (SEQ ID NO:4), PYFPSLS (SEQ ID NO:5), YAPLTPS (SEQ ID NO:6), PLSPSAY (SEQ ID NO:7), DSPAHPS (SEQ ID NO:8), GTPTHPS (SEQ ID NO:9), PDAPSNH (SEQ ID NO:10), TEPHWPS (SEQ ID NO:11), SPPLPPK (SEQ ID NO:12), SPKPPPG (SEQ ID NO:13), NWSPWDP (SEQ ID NO:14), DSPAHPS (SEQ ID NO:15), GWTLHNK (SEQ ID NO:16), KIPPTLH (SEQ ID NO:17), ISQTLHG (SEQ ID NO:18), QSFYILT (SEQ ID NO:19), TTQSEYG (SEQ ID NO:20), LXSS (SEQ ID NO:21), PFXG (SEQ ID NO:22), or SIXA (SEQ ID NO:23), MLVSSPA (SEQ ID NO:24), LPSSLQK (SEQ ID NO:25), PPLLKSS (SEQ ID NO:26), PXKLDSS (SEQ ID NO:27), AWTLASS (SEQ ID NO:28), GTFPFLG (SEQ ID NO:30), GQVPFMG (SEQ ID NO:31), ANFSILA (SEQ ID NO:32), GSIWAPA (SEQ ID NO:33), or SIAASFS (SEQ ID NO:34) as expressed in an amino to carboxy orientation or in a carboxy to amino orientation, wherein the targeting peptide targets a modified AAV to brain vascular endothelium. 
     
     
         2 . The capsid protein of  claim 1 , wherein the targeting peptide targets wildtype brain vascular endothelium. 
     
     
         3 . The capsid protein of  claim 1 , wherein the targeting peptide targets a diseased brain vascular endothelium. 
     
     
         4 . The capsid protein of  claim 3 , wherein the target peptide targets brain vascular endothelium in a subject that has a lysosomal storage disease. 
     
     
         5 . The viral vector of  claim 3 , wherein the target peptide targets brain vascular endothelium in a subject that does not have a lysosomal storage disease. 
     
     
         6 . The capsid protein of  claim 1 , wherein the AAV is AAV2. 
     
     
         7 . A nucleic acid sequence encoding the modified capsid protein of  claim 1 . 
     
     
         8 . An AAV virus containing the capsid protein of  claim 1 . 
     
     
         9 . A viral vector comprising a nucleic acid encoding the capsid protein of  claim 1 . 
     
     
         10 . A cell comprising the viral vector of  claim 9 . 
     
     
         11 . A method of treating a disease in a mammal comprising administering
 (a) a viral vector comprising a nucleic acid encoding a capsid protein comprising a targeting peptide PXXPS (SEQ ID NO:1), SPXXP (SEQ ID NO:2), TLH (SEQ ID NO:3), QSXY (SEQ ID NO:4), PYFPSLS (SEQ ID NO:5), YAPLTPS (SEQ ID NO:6), PLSPSAY (SEQ ID NO:7), DSPAHPS (SEQ ID NO:8), GTPTHPS (SEQ ID NO:9), PDAPSNH (SEQ ID NO:10), TEPHWPS (SEQ ID NO:11), SPPLPPK (SEQ ID NO:12), SPKPPPG (SEQ ID NO:13), NWSPWDP (SEQ ID NO:14), DSPAHPS (SEQ ID NO:15), GWTLHNK (SEQ ID NO:16), KIPPTLH (SEQ ID NO:17), ISQTLHG (SEQ ID NO:18), QSFYILT (SEQ ID NO:19), TTQSEYG (SEQ ID NO:20), LXSS (SEQ ID NO:21), PFXG (SEQ ID NO:22), or SIXA (SEQ ID NO:23), MLVSSPA (SEQ ID NO:24), LPSSLQK (SEQ ID NO:25), PPLLKSS (SEQ ID NO:26), PXKLDSS (SEQ ID NO:27), AWTLASS (SEQ ID NO:28), GTFPFLG (SEQ ID NO:30), GQVPFMG (SEQ ID NO:31), ANFSILA (SEQ ID NO:32), GSIWAPA (SEQ ID NO:33), or SIAASFS (SEQ ID NO:34), as expressed in an amino to carboxy orientation or in a carboxy to amino orientation, wherein the targeting peptide targets an AAV to brain vascular endothelium, or   (b) a cell comprising a viral vector comprising a nucleic acid encoding a capsid protein comprising a targeting peptide PXXPS (SEQ ID NO:1), SPXXP (SEQ ID NO:2), TLH (SEQ ID NO:3), QSXY (SEQ ID NO:4), PYFPSLS (SEQ ID NO:5), YAPLTPS (SEQ ID NO:6), PLSPSAY (SEQ ID NO:7), DSPAHPS (SEQ ID NO:8), GTPTHPS (SEQ ID NO:9), PDAPSNH (SEQ ID NO:10), TEPHWPS (SEQ ID NO:11), SPPLPPK (SEQ ID NO:12), SPKPPPG (SEQ ID NO:13), NWSPWDP (SEQ ID NO:14), DSPAHPS (SEQ ID NO:15), GWTLHNK (SEQ ID NO:16), KIPPTLH (SEQ ID NO:17), ISQTLHG (SEQ ID NO:18), QSFYILT (SEQ ID NO:19), TTQSEYG (SEQ ID NO:20), LXSS (SEQ ID NO:21), PFXG (SEQ ID NO:22), or SIXA (SEQ ID NO:23), MLVSSPA (SEQ ID NO:24), LPSSLQK (SEQ ID NO:25), PPLLKSS (SEQ ID NO:26), PXKLDSS (SEQ ID NO:27), AWTLASS (SEQ ID NO:28), GTFPFLG (SEQ ID NO:30), GQVPFMG (SEQ ID NO:31), ANFSILA (SEQ ID NO:32), GSIWAPA (SEQ ID NO:33), or SIAASFS (SEQ ID NO:34), as expressed in an amino to carboxy orientation or in a carboxy to amino orientation, wherein the targeting peptide targets an AAV to brain vascular endothelium.   
     
     
         12 . A method to deliver an agent to the central nervous system of a subject, comprising transducing vascular endothelial cells with the viral vector of  claim 9 , wherein the transduced vascular endothelial cells express the agent and deliver the agent to the central nervous system of the subject. 
     
     
         13 . A method to deliver a nucleic acid to the central nervous system of a subject, comprising transducing vascular endothelial cells with a nucleic acid comprising the modified AAV capsid of  claim 1 , wherein the transduced vascular endothelial cells express the nucleic acid in the central nervous system of the subject. 
     
     
         14 . A method to deliver an expression vector for expressing a heterologous gene to the central nervous system of a subject, comprising transducing vascular endothelial cells with an expression vector for expressing a heterologous gene comprising the modified AAV capsid of  claim 1  so that the transduced vascular endothelial cells express the heterologous gene in the central nervous system of the subject. 
     
     
         15 . The method of  claim 11 , wherein the mammal or subject is a human. 
     
     
         16 . The method of  claim 12 , wherein the mammal or subject is a human. 
     
     
         17 . The method of  claim 13 , wherein the mammal or subject is a human. 
     
     
         18 . The method of  claim 14 , wherein the mammal or subject is a human.