Method of gene transfer for the treatment of recessive catecholaminergic polymorphic ventricular tachycardia (CPVT)
The present invention concerns a method for the treatment of recessive Catecholaminergic Polymorphic Ventricular Tachycardia comprising delivering a gene into a cardiac cell. The methods described herein relate to the use of viral vectors, such as adeno-associated virus (AAV) vectors, for the delivery of calsequestrin 2 (CASQ2) to cells, such as cardiomyocytes, so as to treat pathologies associated with mutations in this gene.
1. A method of treating recessive catecholaminergic polymorphic ventricular tachycardia (CPVT) in a patient having a homozygous mutation in the gene encoding calsequestrin 2 protein (CASQ2), comprising introducing an AAV2/9 vector comprising a nucleic acid comprising a wild-type CASQ2 gene into a cardiomyocyte in the heart of the patient, wherein the wild-type CASQ2 gene encodes a calsequestrin protein having a sequence with 95% or more homology with the sequence of a protein encoded by the nucleotide sequence as set forth in SEQ ID NO: 1 or SEQ ID NO: 2, wherein the introduction of the AAV2/9 vector into the cardiomyocyte has an anti-arrhythmic effect, thereby treating CPVT.
2. The method of claim 1 , wherein the CASQ2 gene has a coding sequence selected from the group consisting of SEQ ID NO:1 and SEQ ID NO:2.
3. The method of claim 2 , wherein the coding sequence is SEQ ID NO:2.
4. The method of claim 1 , wherein the mutation is R33Q.
5. The method of claim 1 or 3 , wherein physiological levels of expression of CASQ2 are restored.
6. The method of claim 1 or 3 , wherein the normal and anti-arrhythmic contractile function of the heart is restored.
7. The method of claim 1 or 3 , wherein the abundance and spatial organization of triadin and junctin are restored.
8. A method of treating recessive CPVT in a patient, wherein the CPVT is characterized by deregulation of intracellular Ca 2+ , comprising introducing an AAV2/9 vector comprising a nucleic acid comprising a wild-type CASQ2 gene into a cardiomyocyte in the heart of the patient, wherein the wild-type CASQ2 gene encodes a calsequestrin protein having a sequence with 95% or more homology with the sequence of a protein encoded by the nucleotide sequence as set forth in SEQ ID NO: 1 or SEQ ID NO: 2, wherein the introduction of the AAV2/9 vector into the cardiomyocyte restores intracellular Ca 2+ storage and Ca 2+ fluxes, thereby treating CPVT.
9. A method of restoring the anti-arrhythmic contractile function of the heart in a patient having abnormal Ca 2+ signaling, comprising introducing an AAV2/9 vector comprising a nucleic acid comprising a wild-type CASQ2 gene into a cardiomyocyte in the heart of the patient, wherein the wild-type CASQ2 gene encodes a calsequestrin protein having a sequence with 95% or more homology with the sequence of a protein encoded by the nucleotide sequence as set forth in SEQ ID NO: 1 or SEQ ID NO: 2, wherein the introduction of the AAV2/9 vector into the cardiomyocyte ameliorates Ca 2+ wave fragmentation and has an anti-arrhythmic effect.