US2018289757A1PendingUtilityA1

Mutant adeno-associated virus virions and methods of use thereof

69
Assignee: UNIV CALIFORNIAPriority: Jun 30, 2003Filed: Jun 18, 2018Published: Oct 11, 2018
Est. expiryJun 30, 2023(expired)· nominal 20-yr term from priority
Inventors:David V. SchafferBrian K. KasparNarendra Maheshri
A61K 48/00A61K 31/7088A61K 35/76C12N 2750/14123A61K 38/1709C12N 2750/14121C12N 2750/14132C12N 2750/14161C12N 2750/14145C12N 2750/14122C12N 2810/6027C12N 2750/14143C07K 14/005C12N 2750/14151C12N 15/86C12N 7/00
69
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Claims

Abstract

The present invention provides mutant adeno-associated virus (AAV) that exhibit altered capsid properties, e.g., reduced binding to neutralizing antibodies in serum and/or altered heparin binding and/or altered infectivity of particular cell types. The present invention further provides libraries of mutant AAV comprising one or more mutations in a capsid gene. The present invention further provides methods of generating the mutant AAV and mutant AAV libraries, and compositions comprising the mutant AAV. The present invention further provides recombinant AAV (rAAV) virions that comprise a mutant capsid protein. The present invention further provides nucleic acids comprising nucleotide sequences that encode mutant capsid proteins, and host cells comprising the nucleic acids. The present invention further provides methods of delivering a gene product to an individual, the methods generally involving administering an effective amount of a subject rAAV virion to an individual in need thereof.

Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . A recombinant adeno-associated virus (rAAV) virion comprising:
 a) a variant AAV capsid protein, wherein the variant AAV capsid protein comprises at least one amino acid substitution relative to a corresponding parental AAV capsid protein, and wherein the variant capsid protein confers increased infectivity of a stem cell compared to the infectivity of the stem cell by an AAV virion comprising the corresponding parental AAV capsid protein; and   b) a heterologous nucleic acid comprising a nucleotide sequence encoding a gene product.   
     
     
         2 . The rAAV virion of  claim 1 , wherein the rAAV virion exhibits at least 5-fold increased infectivity of a stem cell compared to the infectivity of the stem cell by an AAV virion comprising the corresponding parental AAV capsid protein. 
     
     
         3 . The rAAV virion of  claim 1 , wherein the rAAV virion exhibits at least 10-fold increased infectivity of a stem cell compared to the infectivity of the stem cell by an AAV virion comprising the corresponding parental AAV capsid protein. 
     
     
         4 . The rAAV virion of  claim 1 , wherein the rAAV virion exhibits at least 25-fold increased infectivity of a stem cell compared to the infectivity of the stem cell by an AAV virion comprising the corresponding parental AAV capsid protein. 
     
     
         5 . The rAAV virion of  claim 1 , wherein the rAAV virion exhibits at least 50-fold increased infectivity of a stem cell compared to the infectivity of the stem cell by an AAV virion comprising the corresponding parental AAV capsid protein. 
     
     
         6 . The rAAV virion of  claim 1 , wherein the variant capsid protein comprises from one to 15 amino acid sequence substitutions compared to the amino acid sequence of an AAV2 capsid protein set forth in SEQ ID NO:2. 
     
     
         7 . The rAAV virion of  claim 6 , wherein the variant capsid protein comprises an amino acid sequence having at least about 85% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:53 (hEr2.29 or hEr1.23). 
     
     
         8 . The rAAV virion of  claim 6 , wherein the variant capsid protein comprises an amino acid sequence having at least about 85% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:54 (hEr2.4). 
     
     
         9 . The rAAV virion of  claim 6 , wherein the variant capsid protein comprises an amino acid sequence having at least about 85% amino acid sequence identity to the amino acid sequence set forth in SEQ ID NO:59 (hEr3.1). 
     
     
         10 . The rAAV virion of  claim 1 , wherein gene product is an interfering RNA. 
     
     
         11 . The rAAV virion of  claim 1 , wherein the gene product is a polypeptide. 
     
     
         12 . The rAAV virion of  claim 1 , wherein the parental AAV capsid protein is wild-type AAV2 capsid protein. 
     
     
         13 . The rAAV virion of  claim 1 , wherein the parental AAV capsid protein is wild-type AAVS capsid protein. 
     
     
         14 . A method of delivering a gene product to a stem cell in an individual, the method comprising administering to the individual a recombinant adeno-associated virus (rAAV) virion according to  claim 1 . 
     
     
         15 . The method of  claim 14 , wherein the gene product is a protein. 
     
     
         16 . The method of  claim 14 , wherein the gene product is a short interfering RNA. 
     
     
         17 . The method of  claim 15 , wherein the protein is a growth factor, a morphogen, a cytokine, a receptor, a protein involved in intracellular signal transduction, or a transcription factor. 
     
     
         18 . A recombinant adeno-associated virus (rAAV) virion comprising:
 a) a variant AAV capsid protein, wherein the variant AAV capsid protein comprises at least one amino acid substitution relative to a corresponding parental AAV capsid protein, and wherein the variant capsid protein confers increased infectivity of a lung epithelial cell compared to the infectivity of the lung epithelial cell by an AAV virion comprising the corresponding parental AAV capsid protein; and   b) a heterologous nucleic acid comprising a nucleotide sequence encoding a gene product.   
     
     
         19 . The rAAV virion of  claim 18 , wherein the rAAV virion exhibits at least 5-fold increased infectivity of a lung epithelial cell compared to the infectivity of the lung epithelial cell by an AAV virion comprising the corresponding parental AAV capsid protein. 
     
     
         20 . The rAAV virion of  claim 18 , wherein the rAAV virion exhibits at least 10-fold increased infectivity of a lung epithelial cell compared to the infectivity of the lung epithelial cell by an AAV virion comprising the corresponding parental AAV capsid protein. 
     
     
         21 . The rAAV virion of  claim 18 , wherein the rAAV virion exhibits at least 25-fold increased infectivity of a lung epithelial cell compared to the infectivity of the lung epithelial cell by an AAV virion comprising the corresponding parental AAV capsid protein. 
     
     
         22 . The rAAV virion of  claim 18 , wherein the rAAV virion exhibits at least 50-fold increased infectivity of a lung epithelial cell compared to the infectivity of the lung epithelial cell by an AAV virion comprising the corresponding parental AAV capsid protein. 
     
     
         23 . The rAAV virion of  claim 18 , wherein the variant capsid protein comprises from one to 45 amino acid sequence substitutions compared to the amino acid sequence of an AAVS capsid protein set forth in SEQ ID NO:43. 
     
     
         24 . The rAAV virion of  claim 18 , wherein the variant capsid protein comprises from an A581T substitution compared to the amino acid sequence of an AAVS capsid protein set forth in SEQ ID NO:43. 
     
     
         25 . A method of delivering a gene product to a lung epithelial cell in an individual, the method comprising administering to the individual a recombinant adeno-associated virus (rAAV) virion according to  claim 17 . 
     
     
         26 . The method of  claim 25 , wherein the gene product is a protein. 
     
     
         27 . The method of  claim 25 , wherein the gene product is a short interfering RNA. 
     
     
         28 . The method of  claim 26 , wherein the protein is a cystic fibrosis transmembrane conductance regulator, an immunogen, or an antiviral protein.

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