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 multiple sclerosis (MS), the method comprising
 (a) administering intramuscularly a therapeutically effective amount of a DNA plasmid vector comprising a polynucleotide encoding one or more immunodominant epitopes of an autoantigen targeted in MS; 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 MS in the subject.   
     
     
         2 . The method of  claim 1 , wherein a reduction in the severity of MS in the subject is indicated by one or more measures selected from the group consisting of a reduction in clinical relapses, a reduction in gadolinium-enhancing lesions on MRI, or a reduction in enhancing lesions on MRI. 
     
     
         3 . The method of  claim 1 , wherein the autoantigen is selected from the group consisting of proteolipid protein (PLP); myelin basic protein (MBP); myelin oligodendrocyte glycoprotein (MOG); cyclic nucleotide phosphodiesterase (CNPase); myelin-associated glycoprotein (MAG), myelin-associated oligodendrocytic basic protein (MBOP); alpha-B-crystallin (a heat shock protein); OSP (oligodendrocyte specific-protein); and citrulline-modified MBP. 
     
     
         4 . The method of  claim 1 , wherein the autoantigen is a myelin protein. 
     
     
         5 . The method of  claim 4 , wherein the myelin protein is selected from the group consisting of myelin basic protein (MBP); myelin oligodendrocyte glycoprotein (MOG); myelin-associated glycoprotein (MAG), and myelin-associated oligodendrocytic basic protein (MBOP); and citrulline-modified MBP. 
     
     
         6 . The method of  claim 5 , wherein the myelin protein is myelin basic protein (MBP). 
     
     
         7 . The method of  claim 1 , wherein the subject is a human. 
     
     
         8 . The method of  claim 1 , wherein the immune modulatory sequence is incorporated into the DNA plasmid vector. 
     
     
         9 . The method of  claim 1 , wherein the autoantigen is a self-protein. 
     
     
         10 . The method of  claim 1 , wherein the autoantigen is a polypeptide. 
     
     
         11 . The method of  claim 1 , wherein the autoantigen is a peptide. 
     
     
         12 . The method of  claim 1 , wherein the DNA plasmid vector comprises a polynucleotide encoding a second autoantigen targeted in MS. 
     
     
         13 . 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 
     
     
         14 . 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. 
     
     
         15 . The method of  claim 1 , wherein the therapeutically effective amount of the DNA plasmid vector is in the range of about 0.025 mg to about 5 mg. 
     
     
         16 . The method of  claim 1 , wherein the DNA plasmid is administered as a one-time administration or in multiple administrations. 
     
     
         17 . The method of  claim 16 , wherein the multiple administrations are selected from the group consisting of daily, weekly, monthly, yearly or every other month. 
     
     
         18 . The method of  claim 17 , 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.