METHODS AND COMPOSITIONS FOR TREATING BRAIN DISEASES

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.

19 . A method of treating a brain disease in a mammal in need thereof, comprising administering to the mammal:

(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, and

a therapeutic agent, 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, and

a therapeutic agent;

wherein the viral vector and/or cell is administered to deliver a therapeutically effective dose of the therapeutic agent.

20 . A method of identifying amino acid sequences that specifically target a specific area of the central nervous system (CNS), comprising:

transducing CNS cells in vitro by combining recombinant AAV virions containing a DNA of interest with the CNS cells in appropriate media, and

screening for CNS cells harboring the DNA of interest.