Plakophillin-2 gene therapy methods and compositions

Abstract

Provided herein are methods and compositions for plakophilin-2 gene therapy for treating heart diseases such as arrhythmogenic right ventricular cardiomyopathy (ARVC) or arrhythmogenic cardiomyopathy (ACM).

What is claimed is: 
     
         1 . A method for restoring plakophilin 2 (PKP2) mRNA expression and/or PKP2 protein expression and activity levels in an individual in need thereof, the method comprising administering an adeno-associated virus (AAV) gene therapy vector comprising a nucleic acid encoding a plakophilin 2 (PKP2) polypeptide operatively linked to a promoter, wherein the AAV is selected from the group consisting of an AAV6, an AAV8, an AAV.rh74, and an AAV9, thereby restoring PKP2 mRNA expression and/or PKP2 protein expression and activity levels in the individual. 
     
     
         2 . The method of  claim 1 , wherein the AAV is an AAV9. 
     
     
         3 . The method of  claim 1 , wherein the individual has a heart disease or disorder. 
     
     
         4 . The method of  claim 3 , wherein the heart disease or disorder is arrhythmogenic right ventricular cardiomyopathy (ARVC) or arrhythmogenic cardiomyopathy (ACM). 
     
     
         5 . The method of  claim 1 , wherein the promoter is a cardiac specific promoter. 
     
     
         6 . The method of  claim 5 , wherein the cardiac specific promoter is a PKP2 promoter, a troponin promoter, or an alpha-myosin heavy chain promoter. 
     
     
         7 . The method of  claim 1 , wherein the AAV gene therapy vector further comprises a 3′ element. 
     
     
         8 . The method of  claim 7 , wherein the 3′ element comprises a Woodchuck Hepatitis Virus Posttranscriptional Regulatory Element (WPRE), a bovine growth hormone polyadenylation (bGH polyA) sequence, or a combination thereof. 
     
     
         9 . The method of  claim 1 , wherein the AAV gene therapy vector further comprises a cardiac specific enhancer. 
     
     
         10 . The method of  claim 1 , wherein the method reduces or prevents at least one of fibrofatty tissue replacement; myocardial atrophy; predominant right ventricular dilation; ventricular arrhythmias; sudden cardiac death; exercise-triggered cardiac events; right ventricular cardiomyopathy, dilation, or heart failure; left ventricular cardiomyopathy, dilation, or heart failure; atrial arrhythmias; syncope; palpitations; shortness of breath; or chest pain. 
     
     
         11 . The method of  claim 1 , wherein the method reverses at least one of fibrofatty tissue replacement; myocardial atrophy; predominant right ventricular dilation; ventricular arrhythmias; sudden cardiac death; exercise-triggered cardiac events; right ventricular cardiomyopathy, dilation, or heart failure; left ventricular cardiomyopathy, dilation, or heart failure; atrial arrhythmias; syncope; palpitations; shortness of breath; or chest pain. 
     
     
         12 . The method of  claim 1 , wherein the method restores expression of one or more genes having a direct or indirect effect on one or more symptoms of a heart disease or disorder. 
     
     
         13 . The method of  claim 13 , wherein the one or more genes comprises one or more of Ryanodine Receptor 2 (Ryr2), Ankyrin-B (Ank2), Cacnalc (CaV1.2), triadin (Trdn), or calsequestrin-2 (Casq2). 
     
     
         14 . The method of  claim 1 , wherein the individual is identified as having at least one variation in a desmosome protein. 
     
     
         15 . The method of  claim 14 , wherein the desmosome protein is PKP2. 
     
     
         16 . The method of  claim 15 , wherein the variation comprises a deletion, an insertion, a single nucleotide variation, or a copy number variation. 
     
     
         17 . The method of  claim 1 , wherein the administering is intracardiac injection, intramyocardiac injection, endocardial injection, intracardiac catheterization, or systemic administration. 
     
     
         18 . The method of  claim 17 , wherein the administering is systemic administration. 
     
     
         19 . The method of  claim 1 , wherein the AAV gene therapy vector is administered in a composition comprising a pharmaceutically acceptable carrier or excipient.