Vectors for tissue-specific replication

Abstract

The invention generally relates to targeted gene therapy using recombinant vectors and particularly adenovirus vectors. The invention specifically relates to replication-conditional vectors and methods for using them. Such vectors are able to selectively replicate in a target tissue to provide a therapeutic benefit from the presence of the vector per se or from heterologous gene products expressed from the vector and distributed throughout the tissue. In such vectors, a gene essential for replication is placed under the control of a heterologous tissue-specific transcriptional regulatory sequence. Thus, replication is conditioned on the presence of a factor(s) that induces transcription or the absence of a factor(s) that inhibits transcription of the gene by means of the transcriptional regulatory sequence with this vector; therefore, a target tissue can be selectively treated.

What is claimed is:  
     
         1 . A vector capable of tissue-specific replication comprising: 
 a tissue-specific transcriptional regulatory sequence operably linked to the coding region of a gene that is essential for replication of said vector.    
     
     
         2 . The vector of  claim 1 , wherein the transcriptional regulatory sequence is selected from the group consisting of promoters and enhancers.  
     
     
         3 . The vector of  claim 2 , wherein said promoter is selected from the group consisting of α-fetoprotein, DF3, tyrosinase, CEA, surfactant, and ErbB2.  
     
     
         4 . The vector of  claim 1 , wherein said vector is a DNA tumor viral vector.  
     
     
         5 . The vector of  claim 4 , wherein said DNA tumor viral vector is selected from the group consisting of Herpesvirus, Papovavirus, papillomavirus, hepatitis virus, and parvovirus.  
     
     
         6 . The vector of  claim 4 , wherein said DNA tumor viral vector is an adenovirus vector.  
     
     
         7 . The vector of  claim 6 , wherein said coding region is selected from the group consisting of E1a, E1b, and E2 and E4 coding regions.  
     
     
         8 . The vector of  claim 1 , wherein said vector contains a heterologous coding sequence that is capable of being expressed from said vector.  
     
     
         9 . A method for distributing a polynucleotide in a tissue in vivo, comprising introducing a replication-conditional vector containing said polynucleotide into said tissue, wherein said vector contains a gene essential for vector replication, the coding region of which gene is operably linked to a transcriptional regulatory sequence that functions specifically in said tissue so that replication of the vector occurs in said tissue and not in a tissue in which said transcriptional regulatory sequence does not function.  
     
     
         10 . The vector of  claim 9 , wherein the transcriptional regulatory sequence is selected from the group consisting of promoters and enhancers.  
     
     
         11 . The vector of  claim 10 , wherein said promoter is selected from the group consisting of α-fetoprotein, DF3, tyrosinase, CEA, surfactant, and ErbB2.  
     
     
         12 . The method of  claim 9 , wherein said tissue is tumor tissue.  
     
     
         13 . The method of  claim 9 , wherein said vector is a DNA tumor viral vector.  
     
     
         14 . The method of  claim 13 , wherein said DNA tumor viral vector is selected from the group consisting of Herpesvirus, Papovavirus, papillomavirus, parvovirus, and hepatitis virus.  
     
     
         15 . The method of  claim 14 , wherein said vector is an adenovirus vector.  
     
     
         16 . The method of  claim 15 , wherein said coding region that is operably linked to said transcriptional regulatory sequence is selected from the group consisting of E1a, E1b, E2, and E4 coding regions.  
     
     
         17 . The method of  claim 9 , wherein said vector encodes a heterologous gene product, and wherein said vector expresses said heterologous gene product in the cells of said tissue.  
     
     
         18 . The method of  claim 17 , wherein said heterologous gene product provides anti-tumor activity in the cells of said tissue.  
     
     
         19 . A cell containing a vector capable of tissue-specific replication, said vector comprising 
 a tissue-specific transcriptional regulatory sequence operably linked to the coding region of a gene that is essential for replication of said vector, wherein said transcriptional regulatory sequence functions in said cell so that replication of the vector occurs in said cell.    
     
     
         20 . The cell of  claim 19 , wherein said transcriptional regulatory sequence is selected from the group consisting of promoters and enhancers.  
     
     
         21 . The cell of  claim 20 , wherein said promoter is selected from the group consisting of α-fetoprotein, DF3, tyrosinase, CEA, surfactant, and ErbB2.  
     
     
         22 . The cell of  claim 19 , wherein said cell is a tumor cell.  
     
     
         23 . The cell of  claim 19 , wherein said vector is a DNA tumor viral vector.  
     
     
         24 . The cell of  claim 23 , wherein said DNA tumor viral vector is selected from the group consisting of Herpesvirus, Papovavirus, papillomavirus, parvovirus, and hepatitis virus.  
     
     
         25 . The cell of  claim 24 , wherein said vector is an adenovirus vector.  
     
     
         26 . The cell of  claim 25 , wherein said coding region that is operably linked to said transcriptional regulatory sequence is selected from the group consisting of E1a, E1b, E2, and E4 coding regions.  
     
     
         27 . The cell of  claim 19 , wherein said vector encodes a heterologous gene product, and wherein said vector expresses said heterologous gene product in the cells of a target tissue.  
     
     
         28 . The cell of  claim 27 , wherein said heterologous gene product provides anti-tumor activity in the cells of said tissue.  
     
     
         29 . A method of producing a vector capable of tissue-specific replication, said vector comprising a tissue-specific transcriptional regulatory sequence operably linked to the coding region of a gene that is essential for replication of said vector, comprising culturing the cell of  claim 19  and recovering said vector from said cell.  
     
     
         30 . A cell containing a virion capable of tissue-specific replication, said virion comprising 
 a tissue-specific transcriptional regulatory sequence operably linked to the coding region of a gene that is essential for replication of said virion, wherein said transcriptional regulatory sequence functions in said cell so that replication of the virion occurs in said cell.    
     
     
         31 . The cell of  claim 30 , wherein said transcriptional regulatory sequence is selected from the group consisting of promoters and enhancers.  
     
     
         32 . The cell of  claim 31 , wherein said promoter is selected from the group consisting of α-fetoprotein, DF3, tyrosinase, CEA, surfactant, and ErbB2.  
     
     
         33 . The cell of  claim 30 , wherein said cell is a tumor cell.  
     
     
         34 . The cell of  claim 30 , wherein said virion is a DNA tumor viral virion.  
     
     
         35 . The cell of  claim 34 , wherein said DNA tumor viral virion is selected from the group consisting of Herpesvirus, Papovavirus, papillomavirus, parvovirus, and hepatitis virus.  
     
     
         36 . The cell of  claim 35 , wherein said virion is an adenovirus virion.  
     
     
         37 . The cell of  claim 36 , wherein said coding region that is operably linked to said transcriptional regulatory sequence is selected from the group consisting of E1a, E1b, E2, and E4 coding regions.  
     
     
         38 . The cell of  claim 30 , wherein said virion encodes a heterologous gene product, and wherein said virion expresses said heterologous gene product in the cells of a target tissue.  
     
     
         39 . The cell of  claim 38 , wherein said heterologous gene product provides anti-tumor activity in the cells of said tissue.  
     
     
         40 . A method of producing a virion capable of tissue-specific replication, said virion comprising a tissue-specific transcriptional regulatory sequence operably linked to the coding region of a gene that is essential for replication of said virion, comprising culturing the cell of  claim 30  and recovering said vinon from said cell.