Plakophillin-2 gene therapy methods and compositions
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).
1. A method for treating arrhythmogenic right ventricular cardiomyopathy (ARVC) or arrhythmogenic cardiomyopathy (ACM) in a mammal with ARVC or ACM, the method comprising administering a composition to the mammal intravenously, intracardially, pericardially, or intraarterially such that the ARVC or ACM is treated in the mammal, wherein the composition comprises (a) a viral vector comprising a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 2 encoding a plakophilin 2 (PKP2) polypeptide having the amino acid sequence of SEQ ID NO: 8 operatively linked to a cardiac specific promoter and a 3′ element; and (b) a pharmaceutically acceptable carrier or excipient.
2. The method of claim 1 , wherein the viral vector comprises a viral vector selected from the group consisting of an adeno-associated virus, an adenovirus, a lentivirus, a pox virus, a vaccinia virus, and a herpes virus.
3. The method of claim 1 , wherein the viral vector is an adeno-associated virus.
4. The method of claim 3 , wherein the adeno-associated virus is selected from the group consisting of an AAV6, an AAV8, an AAV9, and an AAV.rh74.
5. The method of claim 4 , wherein the adeno-associated virus is an AAV9.
6. The method of claim 1 , 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 3′ element comprises a Woodchuck Hepatitis Virus Posttransciptional Regulatory Element (WPRE), a bovine growth hormone polyadenylation (bGH polyA) sequence, or a combination thereof.
8. The method of claim 1 , wherein the viral vector further comprises a cardiac specific enhancer.
9. The method of claim 1 , wherein the nucleic acid sequence has a size less than or equal to about 4.7 kb.
10. The method of claim 1 , wherein the pharmaceutically acceptable carrier or excipient comprises a buffer, a polymer, a salt, or a combination thereof.
11. The method of claim 1 , wherein the method reverses or reduces 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 the heart disease.
13. The method of claim 12 , 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 mammal 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 nucleic acid sequence is at least 95% identical to SEQ ID NO: 2.