Method for tolerizing a mammalian patient to administration of gene therapy virus vectors

Abstract

A method for tolerizing a mammalian subject to administration of a live virus carrying a gene for delivery to a cell of the subject is disclosed. The method entails administering to the subject a suitable amount of an inactivated virus prior to administration of the live virus. The prior administration of the inactivated virus suppresses anti-virus cytotoxic T cells, permitting longer transgene persistence once the live virus is administered, and permitting effective readministration of live virus.

What is claimed is:  
     
         1 . A method for tolerizing-a mammalian subject to administration of a live recombinant virus carrying a transgene for delivery to a cell of said subject comprising administering to said subject a high dosage of an inactivated virus prior to administration of said live virus.  
     
     
         2 . The method according to  claim 1  wherein said inactivated virus is administered orally.  
     
     
         3 . The method according to  claim 1  wherein said inactivated virus is administered intravenously.  
     
     
         4 . The method according to  claim 1  wherein said dosage is greater than about 10 11  viral particles/kg patient body weight.  
     
     
         5 . The method according to  claim 1  wherein said inactivated virus is a whole virus.  
     
     
         6 . The method according to  claim 1  wherein said inactivated virus is a replication-defective virus.  
     
     
         7 . The method according to  claim 6  wherein said inactivated virus is selected from the group consisting of replication-defective retrovirus, replication-defective vaccinia virus, and replication-defective canarypox virus.  
     
     
         8 . The method according to  claim 1  wherein said inactivated virus comprises the recombinant virus carrying a transgene, previously subjected to inactivation.  
     
     
         9 . The method according to  claim 1  wherein said inactivated virus has identical viral sequence to the recombinant virus carrying a transgene, but said inactivated virus does not carry said transgene.  
     
     
         10 . The method according to  claim 1  wherein said inactivated virus and said live virus have antigenically related capsid proteins or express antigenically related viral proteins.  
     
     
         11 . The method according to  claim 1  wherein said inactivated virus is administered between about 6 hours to about 28 days before administration of said live virus.  
     
     
         12 . The method according to  claim 1  wherein said inactivated virus is re-administered before second and subsequent administrations of said live virus.  
     
     
         13 . The method according to  claim 1  wherein said inactivated virus is prepared by a method selected from the group consisting of thermal inactivation, physical inactivation, chemical inactivation and combinations thereof.  
     
     
         14 . The method according to  claim 1  wherein said inactivated virus and said live virus have different viral genes but carry substantially identical transgene sequences and express in vivo substantially identical transgene products.