PMID- 27711080
OWN - NLM
STAT- MEDLINE
DCOM- 20170828
LR  - 20220129
IS  - 2041-4889 (Electronic)
VI  - 7
IP  - 10
DP  - 2016 Oct 6
TI  - Adeno-associated virus-mediated CASQ2 delivery rescues phenotypic alterations in 
      a patient-specific model of recessive catecholaminergic polymorphic ventricular 
      tachycardia.
PG  - e2393
LID - 10.1038/cddis.2016.304 [doi]
AB  - Catecholaminergic Polymorphic Ventricular Tachycardia type 2 (CPVT2) is a highly 
      lethal recessive arrhythmogenic disease caused by mutations in the 
      calsequestrin-2 (CASQ2) gene. We have previously demonstrated that viral transfer 
      of the wild-type (WT) CASQ2 gene prevents the development of CPVT2 in a 
      genetically induced mouse model of the disease homozygous carrier of the R33Q 
      mutation. In the present study, we investigated the efficacy of the virally 
      mediated gene therapy in cardiomyocytes (CMs) differentiated from induced 
      pluripotent stem cells (iPSCs) obtained from a patient carrying the homozygous 
      CASQ2-G112+5X mutation. To this end, we infected cells with an Adeno-Associated 
      Viral vector serotype 9 (AAV9) encoding the human CASQ2 gene (AAV9-hCASQ2). 
      Administration of the human WT CASQ2 gene was capable and sufficient to restore 
      the physiological expression of calsequestrin-2 protein and to rescue functional 
      defects of the patient-specific iPSC-derived CMs. Indeed, after viral gene 
      transfer, we observed a remarkable decrease in the percentage of delayed 
      afterdepolarizations (DADs) developed by the diseased CMs upon adrenergic 
      stimulation, the calcium transient amplitude was re-established and the density 
      and duration of calcium sparks were normalized. We therefore demonstrate the 
      efficacy of the AAV9-mediated gene replacement therapy for CPVT2 in a human 
      cardiac-specific model system, supporting the view that the gene-therapy tested 
      is curative in models with different human mutations of CPVT.
FAU - Lodola, Francesco
AU  - Lodola F
AD  - Molecular Cardiology, IRCCS Fondazione Salvatore Maugeri, Pavia, Italy.
FAU - Morone, Diego
AU  - Morone D
AD  - Laboratory of Inflammation and Immunology in Cardiovascular Pathologies, 
      Humanitas Research Hospital, Rozzano (MI), Italy.
FAU - Denegri, Marco
AU  - Denegri M
AD  - Molecular Cardiology, IRCCS Fondazione Salvatore Maugeri, Pavia, Italy.
FAU - Bongianino, Rossana
AU  - Bongianino R
AD  - Molecular Cardiology, IRCCS Fondazione Salvatore Maugeri, Pavia, Italy.
FAU - Nakahama, Hiroko
AU  - Nakahama H
AD  - Laboratory of Inflammation and Immunology in Cardiovascular Pathologies, 
      Humanitas Research Hospital, Rozzano (MI), Italy.
FAU - Rutigliano, Lucia
AU  - Rutigliano L
AD  - Laboratory of Inflammation and Immunology in Cardiovascular Pathologies, 
      Humanitas Research Hospital, Rozzano (MI), Italy.
AD  - Institute of Genetic and Biomedical Research (IRGB) - UOS Milan, National 
      Research Council of Italy, Milan, Italy.
FAU - Gosetti, Rosanna
AU  - Gosetti R
AD  - Laboratory of Inflammation and Immunology in Cardiovascular Pathologies, 
      Humanitas Research Hospital, Rozzano (MI), Italy.
FAU - Rizzo, Giulia
AU  - Rizzo G
AD  - Molecular Cardiology, IRCCS Fondazione Salvatore Maugeri, Pavia, Italy.
FAU - Vollero, Alessandra
AU  - Vollero A
AD  - Molecular Cardiology, IRCCS Fondazione Salvatore Maugeri, Pavia, Italy.
FAU - Buonocore, Michelangelo
AU  - Buonocore M
AD  - Unit of Clinical Neurophysiology & Neurodiagnostic Skin Biopsy, IRCCS Fondazione 
      Salvatore Maugeri, Pavia, Italy.
FAU - Napolitano, Carlo
AU  - Napolitano C
AD  - Molecular Cardiology, IRCCS Fondazione Salvatore Maugeri, Pavia, Italy.
FAU - Condorelli, Gianluigi
AU  - Condorelli G
AUID- ORCID: 0000-0003-0481-6843
AD  - Laboratory of Inflammation and Immunology in Cardiovascular Pathologies, 
      Humanitas Research Hospital, Rozzano (MI), Italy.
AD  - Institute of Genetic and Biomedical Research (IRGB) - UOS Milan, National 
      Research Council of Italy, Milan, Italy.
AD  - Humanitas University, Rozzano (MI), Italy.
FAU - Priori, Silvia G
AU  - Priori SG
AUID- ORCID: 0000-0001-6877-0288
AD  - Molecular Cardiology, IRCCS Fondazione Salvatore Maugeri, Pavia, Italy.
AD  - Department of Molecular Medicine, University of Pavia, Pavia, Italy.
FAU - Di Pasquale, Elisa
AU  - Di Pasquale E
AD  - Laboratory of Inflammation and Immunology in Cardiovascular Pathologies, 
      Humanitas Research Hospital, Rozzano (MI), Italy.
AD  - Institute of Genetic and Biomedical Research (IRGB) - UOS Milan, National 
      Research Council of Italy, Milan, Italy.
LA  - eng
GR  - 294609/ERC_/European Research Council/International
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20161006
PL  - England
TA  - Cell Death Dis
JT  - Cell death & disease
JID - 101524092
RN  - 0 (CASQ2 protein, human)
RN  - 0 (Calsequestrin)
RN  - 0 (Catecholamines)
RN  - SY7Q814VUP (Calcium)
RN  - Polymorphic catecholergic ventricular tachycardia
SB  - IM
MH  - Arrhythmias, Cardiac/metabolism/pathology
MH  - Biopsy
MH  - Calcium/metabolism
MH  - Calsequestrin/*genetics
MH  - Catecholamines/*metabolism
MH  - Cell Differentiation
MH  - Dependovirus/*metabolism
MH  - Female
MH  - *Gene Transfer Techniques
MH  - *Genes, Recessive
MH  - Humans
MH  - Induced Pluripotent Stem Cells/metabolism
MH  - Male
MH  - *Models, Biological
MH  - Myocytes, Cardiac/metabolism/pathology
MH  - Pedigree
MH  - Phenotype
MH  - Skin/pathology
MH  - Tachycardia, Ventricular/pathology/physiopathology/*therapy
PMC - PMC5133973
EDAT- 2016/10/07 06:00
MHDA- 2017/08/29 06:00
PMCR- 2016/10/01
CRDT- 2016/10/07 06:00
PHST- 2016/06/06 00:00 [received]
PHST- 2016/08/01 00:00 [revised]
PHST- 2016/08/24 00:00 [accepted]
PHST- 2016/10/07 06:00 [entrez]
PHST- 2016/10/07 06:00 [pubmed]
PHST- 2017/08/29 06:00 [medline]
PHST- 2016/10/01 00:00 [pmc-release]
AID - cddis2016304 [pii]
AID - 10.1038/cddis.2016.304 [doi]
PST - epublish
SO  - Cell Death Dis. 2016 Oct 6;7(10):e2393. doi: 10.1038/cddis.2016.304.