Single delivery of an adeno-associated viral construct to transfer the CASQ2 gene to knock-in mice affected by catecholaminergic polymorphic ventricular tachycardia is able to cure the disease from birth to advanced age

Marco Denegri, Rossana Bongianino, Francesco Lodola, Simona Boncompagni, Verónica C. De Giusti, José E. Avelino-Cruz, Nian Liu, Simone Persampieri, Antonio Curcio, Francesca Esposito, Laura Pietrangelo, Isabelle Marty, Laura Villani, Alejandro Moyaho, Paola Baiardi, Alberto Auricchio, Feliciano Protasi, Carlo Napolitano, Silvia G. Priori

Research output: Contribution to journalArticle

Abstract

Background-Catecholaminergic polymorphic ventricular tachycardia is an inherited arrhythmogenic disorder characterized by sudden cardiac death in children. Drug therapy is still insufficient to provide full protection against cardiac arrest, and the use of implantable defibrillators in the pediatric population is limited by side effects. There is therefore a need to explore the curative potential of gene therapy for this disease. We investigated the efficacy and durability of viral gene transfer of the calsequestrin 2 (CASQ2) wild-type gene in a catecholaminergic polymorphic ventricular tachycardia knock-in mouse model carrying the CASQ2R33Q/R33Q (R33Q) mutation. Methods and Results-We engineered an adeno-associated viral vector serotype 9 (AAV9) containing cDNA of CASQ2 wild-type (AAV9-CASQ2) plus the green fluorescent protein (GFP) gene to infect newborn R33Q mice studied by in vivo and in vitro protocols at 6, 9, and 12 months to investigate the ability of the infection to prevent the disease and adult R33Q mice studied after 2 months to assess whether the AAV9-CASQ2 delivery could revert the catecholaminergic polymorphic ventricular tachycardia phenotype. In both protocols, we observed the restoration of physiological expression and interaction of CASQ2, junctin, and triadin; the rescue of electrophysiological and ultrastructural abnormalities in calcium release units present in R33Q mice; and the lack of life-threatening arrhythmias. Conclusions-Our data demonstrate that viral gene transfer of wild-type CASQ2 into the heart of R33Q mice prevents and reverts severe manifestations of catecholaminergic polymorphic ventricular tachycardia and that this curative effect lasts for 1 year after a single injection of the vector, thus posing the rationale for the design of a clinical trial.

Original languageEnglish
Pages (from-to)2673-2681
Number of pages9
JournalCirculation
Volume129
Issue number25
DOIs
Publication statusPublished - Jun 24 2014

Fingerprint

Gene Knock-In Techniques
Calsequestrin
Parturition
Viral Genes
Implantable Defibrillators
Sudden Cardiac Death
Green Fluorescent Proteins
Heart Arrest
Genetic Therapy
Genes
Polymorphic catecholergic ventricular tachycardia
Cardiac Arrhythmias
Complementary DNA
Clinical Trials
Newborn Infant
Pediatrics
Calcium
Phenotype
Drug Therapy
Mutation

Keywords

  • Arrhythmias cardiac
  • Calsequestrin
  • Death sudden
  • Genetic therapy
  • Recovery of function

ASJC Scopus subject areas

  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Single delivery of an adeno-associated viral construct to transfer the CASQ2 gene to knock-in mice affected by catecholaminergic polymorphic ventricular tachycardia is able to cure the disease from birth to advanced age. / Denegri, Marco; Bongianino, Rossana; Lodola, Francesco; Boncompagni, Simona; De Giusti, Verónica C.; E. Avelino-Cruz, José; Liu, Nian; Persampieri, Simone; Curcio, Antonio; Esposito, Francesca; Pietrangelo, Laura; Marty, Isabelle; Villani, Laura; Moyaho, Alejandro; Baiardi, Paola; Auricchio, Alberto; Protasi, Feliciano; Napolitano, Carlo; Priori, Silvia G.

In: Circulation, Vol. 129, No. 25, 24.06.2014, p. 2673-2681.

Research output: Contribution to journalArticle

Denegri, M, Bongianino, R, Lodola, F, Boncompagni, S, De Giusti, VC, E. Avelino-Cruz, J, Liu, N, Persampieri, S, Curcio, A, Esposito, F, Pietrangelo, L, Marty, I, Villani, L, Moyaho, A, Baiardi, P, Auricchio, A, Protasi, F, Napolitano, C & Priori, SG 2014, 'Single delivery of an adeno-associated viral construct to transfer the CASQ2 gene to knock-in mice affected by catecholaminergic polymorphic ventricular tachycardia is able to cure the disease from birth to advanced age', Circulation, vol. 129, no. 25, pp. 2673-2681. https://doi.org/10.1161/CIRCULATIONAHA.113.006901
Denegri, Marco ; Bongianino, Rossana ; Lodola, Francesco ; Boncompagni, Simona ; De Giusti, Verónica C. ; E. Avelino-Cruz, José ; Liu, Nian ; Persampieri, Simone ; Curcio, Antonio ; Esposito, Francesca ; Pietrangelo, Laura ; Marty, Isabelle ; Villani, Laura ; Moyaho, Alejandro ; Baiardi, Paola ; Auricchio, Alberto ; Protasi, Feliciano ; Napolitano, Carlo ; Priori, Silvia G. / Single delivery of an adeno-associated viral construct to transfer the CASQ2 gene to knock-in mice affected by catecholaminergic polymorphic ventricular tachycardia is able to cure the disease from birth to advanced age. In: Circulation. 2014 ; Vol. 129, No. 25. pp. 2673-2681.
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abstract = "Background-Catecholaminergic polymorphic ventricular tachycardia is an inherited arrhythmogenic disorder characterized by sudden cardiac death in children. Drug therapy is still insufficient to provide full protection against cardiac arrest, and the use of implantable defibrillators in the pediatric population is limited by side effects. There is therefore a need to explore the curative potential of gene therapy for this disease. We investigated the efficacy and durability of viral gene transfer of the calsequestrin 2 (CASQ2) wild-type gene in a catecholaminergic polymorphic ventricular tachycardia knock-in mouse model carrying the CASQ2R33Q/R33Q (R33Q) mutation. Methods and Results-We engineered an adeno-associated viral vector serotype 9 (AAV9) containing cDNA of CASQ2 wild-type (AAV9-CASQ2) plus the green fluorescent protein (GFP) gene to infect newborn R33Q mice studied by in vivo and in vitro protocols at 6, 9, and 12 months to investigate the ability of the infection to prevent the disease and adult R33Q mice studied after 2 months to assess whether the AAV9-CASQ2 delivery could revert the catecholaminergic polymorphic ventricular tachycardia phenotype. In both protocols, we observed the restoration of physiological expression and interaction of CASQ2, junctin, and triadin; the rescue of electrophysiological and ultrastructural abnormalities in calcium release units present in R33Q mice; and the lack of life-threatening arrhythmias. Conclusions-Our data demonstrate that viral gene transfer of wild-type CASQ2 into the heart of R33Q mice prevents and reverts severe manifestations of catecholaminergic polymorphic ventricular tachycardia and that this curative effect lasts for 1 year after a single injection of the vector, thus posing the rationale for the design of a clinical trial.",
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T1 - Single delivery of an adeno-associated viral construct to transfer the CASQ2 gene to knock-in mice affected by catecholaminergic polymorphic ventricular tachycardia is able to cure the disease from birth to advanced age

AU - Denegri, Marco

AU - Bongianino, Rossana

AU - Lodola, Francesco

AU - Boncompagni, Simona

AU - De Giusti, Verónica C.

AU - E. Avelino-Cruz, José

AU - Liu, Nian

AU - Persampieri, Simone

AU - Curcio, Antonio

AU - Esposito, Francesca

AU - Pietrangelo, Laura

AU - Marty, Isabelle

AU - Villani, Laura

AU - Moyaho, Alejandro

AU - Baiardi, Paola

AU - Auricchio, Alberto

AU - Protasi, Feliciano

AU - Napolitano, Carlo

AU - Priori, Silvia G.

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N2 - Background-Catecholaminergic polymorphic ventricular tachycardia is an inherited arrhythmogenic disorder characterized by sudden cardiac death in children. Drug therapy is still insufficient to provide full protection against cardiac arrest, and the use of implantable defibrillators in the pediatric population is limited by side effects. There is therefore a need to explore the curative potential of gene therapy for this disease. We investigated the efficacy and durability of viral gene transfer of the calsequestrin 2 (CASQ2) wild-type gene in a catecholaminergic polymorphic ventricular tachycardia knock-in mouse model carrying the CASQ2R33Q/R33Q (R33Q) mutation. Methods and Results-We engineered an adeno-associated viral vector serotype 9 (AAV9) containing cDNA of CASQ2 wild-type (AAV9-CASQ2) plus the green fluorescent protein (GFP) gene to infect newborn R33Q mice studied by in vivo and in vitro protocols at 6, 9, and 12 months to investigate the ability of the infection to prevent the disease and adult R33Q mice studied after 2 months to assess whether the AAV9-CASQ2 delivery could revert the catecholaminergic polymorphic ventricular tachycardia phenotype. In both protocols, we observed the restoration of physiological expression and interaction of CASQ2, junctin, and triadin; the rescue of electrophysiological and ultrastructural abnormalities in calcium release units present in R33Q mice; and the lack of life-threatening arrhythmias. Conclusions-Our data demonstrate that viral gene transfer of wild-type CASQ2 into the heart of R33Q mice prevents and reverts severe manifestations of catecholaminergic polymorphic ventricular tachycardia and that this curative effect lasts for 1 year after a single injection of the vector, thus posing the rationale for the design of a clinical trial.

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KW - Recovery of function

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