Method to achieve extended expression of dna infused into liver

Abstract

Materials and methods for treating a patient to express a therapeutic agent comprising administering a Kupffer cell-suppressing substance in combination with a vehicle for introducing, into the patient, an exogenous nucleic acid comprising a sequence for expression of the agent.

1 . A method of treating a patient to express a therapeutic agent comprising administering a Kupffer cell-suppressing substance in combination with a vehicle for introducing, into the patient, an exogenous nucleic acid comprising a sequence for expression of the agent. 
     
     
         2 . The method of  claim 1  wherein the Kupffer cell-suppressing substance, upon dissolution in aqueous solution, comprises a free gadolinium(III) ion. 
     
     
         3 . The method of  claim 1  wherein the Kupffer cell-suppressing substance is free of chelating agents that form three or more coordinate bonds with the gadolinium atom. 
     
     
         4 . The method of  claim 1  wherein the Kupffer cell-suppressing substance is free of all chelating agents. 
     
     
         5 . The method of  claim 1  wherein the Kupffer cell-suppressing substance comprises a gadolinium(III) salt. 
     
     
         6 . The method of  claim 5  wherein the salt comprises a halide. 
     
     
         7 . The method of  claim 6  wherein the salt comprises Gd(Cl) 3 . 
     
     
         8 . The method of  claim 1  wherein the Kupffer cell-suppressing substance is chosen from the group consisting of silibinin, dichloromethylene diphosphonate, gadolinium trichloride, and clodronate. 
     
     
         9 . The method of  claim 1  wherein the therapeutic agent is chosen from the group consisting of a protein, a blood factor, erythropoietin, clotting Factor VIII, clotting Factor IX, an antibody, an antibody fragment, an scFv, and an antigen. 
     
     
         10 . The method of  claim 1  wherein the vehicle comprises a vector. 
     
     
         11 . The method of  claim 10  wherein the vector is chosen from the group consisting of an adenovirus, a lentivirus, a retrovirus, an adeno-associated virus, an integrating phage vector, a non-viral vector, a transposon and/or transposase, an integrase substrate, and a plasmid. 
     
     
         12 . The method of  claim 1  wherein the vehicle comprises a targeted nuclease for integrating the gene. 
     
     
         13 . The method of  claim 1  wherein the vehicle is chosen from the group consisting of liposomes, microspheres, micelles, particles, microparticles, nanoparticles, fusion molecules comprising a targeting moiety, and coatings on a device disposed at or near the liver. 
     
     
         14 . The method of  claim 1  wherein the Kupffer cell-suppressing substance is administered before, during, or after administration of the expressible gene. 
     
     
         15 . The method of  claim 1  comprising administering the Kupffer cell-suppressing substance at a time between 1 and 10 days after administering the expressible gene. 
     
     
         16 . The method of  claim 1  with the Kupffer cell-suppressing substance being administered by a method chosen from the group consisting of intravenous, intramuscular, subcutaneous, and percutaneous injection, and hydrodynamically to the liver. 
     
     
         17 . A method of treating a patient for expression of a gene comprising administering a nucleic acid that expresses the gene in combination with a Kupffer cell-suppressing substance that comprises a gadolinium atom that is free of chelating agents that form three or more coordinate bonds with the gadolinium atom. 
     
     
         18 . A system for treating an animal or a human patient to express an exogenous nucleic acid, the system comprising a substance to inhibit Kupffer cells in a pharmaceutically acceptable formulation, a vehicle to administer the exogenous nucleic acid, and a medical device for administration of the exogenous nucleic acid. 
     
     
         19 . The system of  claim 18  wherein the medical device is adapted to hydrodynamically deliver the vector directly to the liver of the patient. 
     
     
         20 . The system of  claim 19  wherein the medical device comprises a catheter with a size and flexibility for placement in an inferior vena cava of a human (infant, child, adult) and at least one inflatable member for isolating a port of the device within a blood vessel, said port being fluidly connected to a lumen of the catheter.