Viral vector for the targeted transfer of genes in the brain and spinal cord

Abstract

The invention relates to novel peptides, polypeptides or proteins which specifically bind to cells of the brain and/or the spinal cord. The peptides, polypeptides or proteins can be part of a viral capsid, and they can be used for guiding a recombinant viral vector selectively to the brain and/or spinal cord after systemic administration to a subject, where it provides for a tissue-specific expression of one or more transgenes. The invention therefore also relates to a recombinant viral vector, preferably an AAV vector, comprising a capsid containing at least one of the peptides, polypeptides or proteins of the invention and at least one transgene which is packaged within the capsid. The viral vector is particularly suitable for the therapeutic treatment of a disease or functional disorder of the brain and/or the spinal cord. The invention further relates to cells and pharmaceutical compositions comprising the viral vector of the invention.

1 . A peptide, polypeptide, or protein that specifically binds to cells of the brain and/or spinal cord, characterized in that it comprises the amino acid sequence of SEQ ID NO:6. 
     
     
         2 . A peptide, polypeptide, or protein according to  claim 1 , characterized in that it comprises the following:
 (a) one of the amino acid sequences of SEQ ID NO:2-5, or   (b) an amino acid sequence which differs from the amino acid sequence of SEQ ID NO:1 by modification of one amino acid.   
     
     
         3 . The protein according to  claim 1 , which is a capsid protein of a viral vector, preferably a capsid protein of an adeno-associated virus (AAV). 
     
     
         4 . The protein according to  claim 3 , which is a capsid protein of an AAV of a serotype selected from the group consisting of serotypes 2, 4, 6, 8, and 9. 
     
     
         5 . The protein according to  claim 4 , which is a capsid protein of an AAV of serotype 2. 
     
     
         6 . (canceled) 
     
     
         7 . The protein according to  claim 1 , wherein the peptide is present in the region of amino acids 550-600 of the capsid. 
     
     
         8 . The protein according to  claim 1 , comprising the following:
 (a) an amino acid sequence having at least 80% identity to the amino acid sequence of SEQ ID NO:10 and further comprises the sequence of SEQ ID NO:1 or an amino acid sequence which differs from the amino acid sequence of SEQ ID NO:1 by modification of one amino acid; or   (b) a fragment of the amino acid sequences defined in (a).   
     
     
         9 . A viral capsid which comprises a peptide, polypeptide, or protein according to  claim 1 . 
     
     
         10 . A nucleic acid which encodes a peptide, polypeptide, or protein comprising the amino acid sequence of SEQ ID NO:6 that specifically binds to cells of the brain and/or spinal cord. 
     
     
         11 . A plasmid which comprises a nucleic acid according to  claim 10 . 
     
     
         12 . A recombinant viral vector which comprises a capsid and a transgene packaged therein, wherein the capsid comprises at least one capsid protein comprising a peptide, polypeptide, or protein comprising the amino acid sequence of SEQ ID NO:6 that specifically binds to cells of the brain and/or spinal cord. 
     
     
         13 . The recombinant viral vector according to  claim 12 , which is a recombinant AAV vector. 
     
     
         14 . The recombinant viral vector according to  claim 13 , which is an AAV vector of a serotype selected from the group consisting of serotypes 2, 4, 6, 8, and 9. 
     
     
         15 . (canceled) 
     
     
         16 . The recombinant viral vector according to  claim 12 , wherein the transgene encodes one of the following proteins: a membrane or tight junction protein, a neuraminidase, glucuronidase, a chemokine antagonist, neurotrophic factor of glia cells (GDNF), neprilysine, cholesterol 24 hydroxylase, aromatic L-amino acid decarboxylase, a tyrosine hydroxylase, GTP cyclohydrolase I, and survival of motor neuron (SMN) protein. 
     
     
         17 . The recombinant viral vector according to  claim 16 , wherein the transgene encodes a neuraminidase. 
     
     
         18 . The recombinant viral vector according to  claim 12 , wherein the transgene is in the form of an ssDNA or a dsDNA. 
     
     
         19 . A method for the targeted delivery of viral vectors to the brain and/or spinal cord in a subject, comprising administering a recombinant viral vector according to  claim 12  to the subject. 
     
     
         20 . The method of  claim 19 , wherein the vector is formulated for intravenous administration. 
     
     
         21 . A cell which comprises a peptide, polypeptide, or protein according to  claim 1 . 
     
     
         22 . A pharmaceutical composition which comprises a peptide, polypeptide, or protein according to  claim 1 .