Use of rapamycin to inhibit response and induce tolerance to gene therapy vector and encoded transgene products

Abstract

Disclosed are methods for transient co-administration of rapamycin together with a gene therapy vector encoding a transgene. The present invention is directed to inhibiting the immune response of a host to the administered gene therapy vector and encoded trans gene product, thus allowing persistent trans gene expression and repeated administration of the gene therapy product to the host. The present invention is also of relevance in genetic disease patients that mount immune responses to protein replacement therapies in which case the present invention provides for transient co-administration of rapamycin together with protein replacement therapy. In a further aspect of the invention, co-administration of rapamycin could inhibit a secondary immune response in a host that has been pre-immunized with the gene therapy vector or pre-immunized with the protein product encoded by the transgene.

1 . A method for inhibiting the immune response of a host to a protein replacement therapy, said method comprising co-administering the protein replacement therapy with an effective amount of rapamycin to said host, wherein the humoral immune response to the protein replacement therapy of the rapamycin-treated host is reduced as compared to a host treated with the protein replacement therapy alone.  
     
     
         2 . The method of  claim 1 , wherein the method further comprises administering an effective amount of an agent which blocks a co-stimulation pathway.  
     
     
         3 . The method of  claim 2 , wherein the agent which blocks a co-stimulation pathway is selected from the group consisting of CTLA4-Ig, antibodies to B7-1, antibodies to B7-2, antibodies to CD28, antibodies to CD40L; and combinations of the above.  
     
     
         4 - 12 . (canceled)  
     
     
         13 . A method for inhibiting the immune response of a host to a retrovirus gene therapy vector comprising a transgene encoding a protein of interest, said method comprising co-administering the gene therapy vector with an effective amount of rapamycin to said host, wherein the humoral immune response to the retrovirus gene therapy vector of the rapamycin-treated host is reduced as compared to a host treated with the vector alone.  
     
     
         14 . The method of  claim 13 , wherein the method further comprises administering an effective amount of an agent which blocks a co-stimulation pathway.  
     
     
         15 . The method of  claim 14 , wherein the agent which blocks a co-stimulation pathway is selected from the group consisting of CTLA4-Ig, antibodies to B7-1, antibodies to B7-2, antibodies to CD28, antibodies to CD40L; and combinations of the above.  
     
     
         16 . The method of  claim 13 , wherein the retrovirus vector is lentivirus vector.  
     
     
         17 . The method of  claim 14 , wherein the transgene encodes a protein selected from the group consisting of glucocerebrosidase, alpha-galactosidase A, beta-galactosidase, sphingomyelinase, iduronate sulfatase, alpha-glucosidase and alpha-iduronidase.  
     
     
         18 . The method of  claim 14 , wherein the transgene encodes a protein selected from the group consisting of Factor VIIA, Factor VII or Factor IX.  
     
     
         19 . A method for inhibiting the immune response of a host to a non-viral gene therapy vector comprising a transgene encoding a protein of interest, said method comprising co-administering the gene therapy vector with an effective amount of rapamycin to said host, wherein the humoral immune response to the retrovirus gene therapy vector of the rapamycin-treated host is reduced as compared to a host treated with the vector alone.  
     
     
         20 . The method of  claim 18 , wherein the non-viral gene therapy vector comprises DNA.  
     
     
         21 . The method of  claim 19 , wherein the non-viral gene therapy vector further comprises a cationic amphiphilic compound.  
     
     
         22 . The method of  claim 1 , wherein the protein replacement therapy comprises glucocerebrosidase.  
     
     
         23 . The method of  claim 1 , wherein the protein replacement therapy comprises alpha-galactosidase A.  
     
     
         24 . The method of  claim 1 , wherein the protein replacement therapy comprises sphingomyelinase.  
     
     
         25 . The method of  claim 1 , wherein the protein replacement therapy comprises iduronate sulfatase.  
     
     
         26 . The method of  claim 1 , wherein the protein replacement therapy comprises galactosamine-6-sulfatase.  
     
     
         27 . The method of  claim 1 , wherein the protein replacement therapy comprises beta-galactosidase.  
     
     
         28 . The method of  claim 1 , wherein the protein replacement therapy comprises galactosamine-4-sulfatase.  
     
     
         29 . The method of  claim 1 , wherein the protein replacement therapy comprises alpha-glucosidase.  
     
     
         30 . The method of  claim 1 , wherein the protein replacement therapy comprises alpha-iduronidase.