Adenovirus vectors containing cell status-specific response elements and methods of use thereof

Abstract

The present invention provides adenoviral vectors comprising cell status-specific transcriptional regulatory elements which confer cell status-specific transcriptional regulation on an adenoviral gene. A “cell status” is generally a reversible physiological and/or environmental state. The invention further provides compositions and host cells comprising the vectors, as well as methods of using the vectors.

1 . An adenovirus vector comprising an adenovirus gene under transcriptional control of a transcriptional regulatory element (TRE) comprising a cell status-specific Tre.  
     
     
         2 . The adenovirus vector of  claim 1 , wherein the adenovirus gene is essential for viral replication.  
     
     
         3 . The adenovirus vector of  claim 2 , wherein the adenovirus gene is an early gene.  
     
     
         4 . The adenovirus vector of  claim 2 , wherein the adenovirus gene is a late gene.  
     
     
         5 . The adenovirus vector of  claim 3 , wherein the adenovirus early gene is E1A.  
     
     
         6 . The adenovirus vector of  claim 3 , wherein the adenovirus early gene is E1B.  
     
     
         7 . The adenovirus vector of  claim 3 , wherein the adenovirus early gene is E4.  
     
     
         8 . The adenovirus vector of  claim 1 , wherein the cell status-specific TRE is human.  
     
     
         9 . The adenovirus vector of  claim 1 , wherein the cell status-specific TRE comprises a hypoxia responsive element (HRE).  
     
     
         10 . The adenovirus vector of  claim 9 , wherein the HRE comprises SEQ ID NO:1.  
     
     
         11 . The adenovirus vector of  claim 1 , wherein the cell status-specific TRE comprises a cell cycle specific element.  
     
     
         12 . The adenovirus vector of  claim 11 , wherein the cell cycle-specific element is from the E2F-1 gene.  
     
     
         13 . The adenovirus vector of  claim 1 , wherein the cell status-specific TRE comprises a heat-inducible element.  
     
     
         14 . The adenovirus vector of  claim 1 , further comprising a cell type-specific TRE.  
     
     
         15 . The adenovirus vector of  claim 14 , wherein the cell type-specific TRE is prostate cell specific.  
     
     
         16 . The adenovirus vector of  claim 15 , wherein the prostate cell-specific TRE is a PSA-TRE.  
     
     
         17 . The adenovirus vector of  claim 1 , further comprising a transgene under transcriptional control of a second cell status-specific TRE.  
     
     
         18 . An adenovirus vector comprising an adenovirus gene under transcriptional control of a TRE comprising a cell status-specific TRE and a cell-type specific TRE.  
     
     
         19 . The adenovirus vector of  claim 18 , wherein the adenovirus gene is an early gene.  
     
     
         20 . The adenovirus vector of  claim 19 , wherein the adenovirus early gene is E1A.  
     
     
         21 . The adenovirus vector of  claim 20 , wherein the cell status-specific TRE comprises an HRE and the cell-type specific TRE is a PSA-TRE.  
     
     
         22 . The adenovirus vector of  claim 21 , wherein the HRE comprises SEQ ID NO:1 and the PSA-TRE comprises nucleotides about 503 to about 2086 of SEQ ID NO:3 and nucleotides about 5285 to about 5836 of SEQ ID NO:3.  
     
     
         23 . A composition comprising an adenovirus vector of  claim 1 .  
     
     
         24 . The composition of  claim 23 , further comprising a pharmaceutically acceptable excipient.  
     
     
         25 . A host cell comprising the adenovirus vector of  claim 1 .  
     
     
         26 . A method of propagating adenovirus specific for cells which allow a cell status-specific TRE to function, said method comprising combining an adenovirus according to  claim 1  with the cells, whereby said adenovirus is propagated.  
     
     
         27 . A method for conferring selective cytotoxicity on a target cell, said method comprising contacting a cell which allows a cell status-specific TRE to function with an adenovirus vector of  claim 1 , whereby the vector enters the cell.  
     
     
         28 . A method for suppressing tumor growth comprising introducing the adenovirus vector of  claim 1  into a tumor cell which allows a cell status-specific TRE to function, wherein introduction of the adenovirus vector results in suppression of tumor growth.