Spatial and temporal control of gene expression using a heat shock protein promoter in combination with local heat

Abstract

The invention provides methods for using local heat to control gene expression. The heat shock protein (hsp) gene promoter is recombined with a selected therapeutic gene and expressed in selected cells. Local controlled heating is used to activate the hsp promoter, for example by using focused ultrasound controlled by MRI.

1 - 9 . (canceled).  
     
     
         10 . A method for the spatial and temporal control of the expression of a genetically engineered gene of interest operably linked to a heat shock promoter in host cells within a preselected region of a mammal, comprising: 
 selectively heating the region to non-lethal supraphysiological temperatures for a period of time by applying electromagnetic radiation to the region    thereby spatially and temporally controlling the expression of the gene of interest.    
     
     
         11 . The method of  claim 10 , wherein the heat shock gene promoter is the hsp70 promoter.  
     
     
         12 . The method of  claim 11 , wherein 
 the temperature distribution of the region by is monitored by MRI temperature imaging; and    the heating is adjusted according to the monitoring so as to provide from about a 3° C. increase to about a 5° C. increase in the temperature of the region.    
     
     
         13 . The method of  claim 10 , wherein the electromagnetic radiation is microwave radiation.  
     
     
         14 . The method of  claim 10 , wherein the electromagnetic radiation is infrared radiation.  
     
     
         15 . The method of  claim 10 , wherein the electromagnetic radiation is radiofrequency radiation.  
     
     
         16 . The method of  claim 11 , wherein the heat shock gene promoter is the human hsp70B promoter and the mammal is a human.  
     
     
         17 . The method of  claim 10 , wherein 
 the temperature distribution of the region is monitored by MRI temperature imaging; and    the heating is adjusted according to the monitoring so as to provide up to an 8° C. temperature in the focal region.    
     
     
         18 . A method of treating a mammal, the method comprising: 
 introducing a genetically engineered gene operably linked to a heat shock promoter into host cells of a region of the mammal;    selectively heating the region to non-lethal supraphysiological temperatures by applying electromagnetic radiation for a period of time to the region;    thereby spatially and temporally controlling the expression of the gene and the amount of the protein produced in the region.    
     
     
         19 . The method of  claim 18 , wherein the heat shock gene promoter is the hsp70 promoter.  
     
     
         20 . The method of  claim 19 , wherein the heat shock gene promoter is the human 70B promoter and the mammal is a human.  
     
     
         21 . The method of  claim 18 , wherein 
 the temperature distribution of the region by is monitored by MRI temperature imaging; and    the heating is adjusted according to the monitoring so as to provide from about a 3° C. increase to about a 5° C. increase in the temperature of the region.    
     
     
         22 . The method of  claim 18 , wherein 
 the temperature distribution of the region by is monitored by MRI temperature    the heating is adjusted according to the monitoring so as to provide up to an 8° C. temperature in the focal region.    
     
     
         23 . The method of  claim 18 , wherein the gene encodes cytosine deaminase, interleukins 1-10, vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and platelet derived growth factor (PDGF).  
     
     
         24 . The method of  claim 18 , wherein the region comprises part of a tumor.  
     
     
         25 . The method of  claim 23 , wherein the tumor is a member of the group consisting of prostate, glioma, ovarian, and mammary tumors.  
     
     
         26 . The method of  claim 19 , wherein the period of time is about 15 minutes.  
     
     
         27 . The method of  claim 18 , wherein the electromagnetic radiation is microwave radiation.  
     
     
         28 . The method of  claim 18 , wherein the electromagnetic radiation is infrared radiation.  
     
     
         29 . The method of  claim 18 , wherein the electromagnetic radiation is radiofrequency radiation.  
     
     
         30 . The method of  claim 18 , wherein the gene encodes a wild-type mammalian protein deficient in the mammal.