Polynucleotide therapy

Abstract

This invention provides a method of treating or preventing a disease in an animal associated with one or more self-protein(s), -polypeptide(s), or -peptide(s) that is present or involved in a non-physiologic process in the animal comprising administering to the animal a self-vector comprising a polynucleotide encoding the self-protein(s), -polypeptide(s) or -peptide(s) associated with the disease. Administration of the self-vector comprising a polynucleotide encoding the self-protein(s), -polypeptide(s) or -peptide(s) modulates an immune response to the self-protein(s), -polypeptide(s) or -peptide(s) expressed from administration of the self-vector. The invention also provides a composition comprising a polynucleotide encoding one or more self-protein(s), -polypeptide(s), or -peptide(s) that is present non-physiologically in a treated animal useful in treating or preventing a disease associated with the self-protein(s), -polypeptide(s), or -peptide(s) present in and/or the target of a non-physiologic process in the animal.

1 . A method of reducing disease severity in a subject afflicted with insulin dependent diabetes mellitus (IDDM), the method comprising
 (a) administering intramuscularly a therapeutically effective amount of a DNA plasmid vector comprising a polynucleotide encoding an autoantigen targeted in insulin dependent diabetes mellitus (IDDM); and   (b) administering an immune modulatory sequence selected from the group consisting of 5′-Purine-Pyrimidine-[X]-[Y]-Pyrimidine-Pyrimidine-3′ and 5′-Purine-Purine-[X]-[Y]-Pyrimidine-Pyrimidine-3′ wherein X and Y are any naturally occurring or synthetic nucleotide, except that X and Y cannot be cytosine-guanine, so as to reduce the severity of IDDM in the subject.   
     
     
         2 . The method of  claim 1 , wherein a reduction in the severity of IDDM in the subject is indicated by one or more measures selected from the group consisting of decreased hyperglycemia, increased plasma insulin, decreased glucosuria, decreased insulitis, decreased destruction of beta-cells, and decreased presence of autoantibodies. 
     
     
         3 . The method of  claim 1 , wherein the autoantigen is selected from the group consisting of tyrosine phosphatase IA2, IA-2β, glutamic acid decarboxylase (65 and 67 kDa forms), carboxypeptidase H, insulin, insulin B chain, proinsulin, pre-proinsulin, heat shock proteins, glima 38, islet cell antigen 69 KDa, p52, and islet cell glucose transporter GLUT-2. 
     
     
         4 . The method of  claim 1 , wherein the autoantigen is selected from the group consisting of insulin, insulin B chain, proinsulin and pre-proinsulin. 
     
     
         5 . The method of  claim 1 , wherein the immune modulatory sequence is incorporated into the DNA plasmid vector. 
     
     
         6 . The method of  claim 1 , wherein the autoantigen is a self-protein. 
     
     
         7 . The method of  claim 1 , wherein the autoantigen is a polypeptide. 
     
     
         8 . The method of  claim 1 , wherein the autoantigen is a peptide. 
     
     
         9 . The method of  claim 1 , wherein the DNA plasmid vector comprises a polynucleotide encoding a second autoantigen targeted in IDDM. 
     
     
         10 . The method of  claim 1 , wherein the second autoantigen is selected from the group consisting of tyrosine phosphatase IA2, IA-2β, glutamic acid decarboxylase (65 and 67 kDa forms), carboxypeptidase H, insulin, insulin B chain, proinsulin, pre-proinsulin, heat shock proteins, glima 38, islet cell antigen 69 KDa, p52, and islet cell glucose transporter GLUT-2. 
     
     
         11 . The method of  claim 1 , wherein the subject is a human. 
     
     
         12 . The method of  claim 1 , wherein the therapeutically effective amount of the DNA plasmid vector is in the range of about 0.001 micrograms to about 1 gram. 
     
     
         13 . The method of  claim 1 , wherein the therapeutically effective amount of the DNA plasmid vector is in the range of about 10 micrograms to about 5 milligrams. 
     
     
         14 . The method of  claim 1 , wherein the therapeutically effective amount of the DNA plasmid vector is in the range of about 0.025 milligrams to about 5 milligrams. 
     
     
         15 . The method of  claim 1 , wherein the DNA plasmid is administered as a one-time administration or in multiple administrations. 
     
     
         16 . The method of  claim 15 , wherein the multiple administrations are selected from the group consisting of daily, weekly, monthly, yearly or every other month. 
     
     
         17 . The method of  claim 16 , wherein the multiple administrations are administered over a period selected from the group consisting of six months followed by a maintenance dose administered every three to twelve months or twelve months followed by a maintenance dose administered every three to twelve months.