Editors' ChoiceGene Therapy

A Nonshocking New Way to Prevent Sudden Death

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Science Translational Medicine  02 Jul 2014:
Vol. 6, Issue 243, pp. 243ec115
DOI: 10.1126/scitranslmed.3009629

Sudden cardiac death (SCD) abruptly ends the lives of more than 200,000 Americans each year. In young people, SCD is most often caused by single-gene cardiac mutations. For some patients, life-long medical treatment paired with watchful waiting is adequate to prevent SCD. But, many rely on a surgically implanted cardioverter-defibrillator (ICD). ICDs require replacement at regular intervals and work by sensing ventricular arrhythmias and automatically delivering a strong shock to restore normal heart function. Although ICD development was a life-saving advance in the prevention of SCD, ICDs do not always work and carry their own risks and burdens. Now, Denegri et al. introduce new possibilities for prevention by studying cardiac gene therapy in a mouse model of SCD.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare cause of SCD, but the disease carries a 50% mortality risk among children and is poorly treated by ICDs. Abnormalities in one of two proteins (calsequestrin or the ryanodine receptor) that regulate intracellular handling of calcium give rise to CPVT. Cardiac myocytes that contain the protein-altering mutations become overloaded with calcium, leading to life-threatening ventricular tachycardia or ventricular fibrillation. Treatment with an ICD is not always life-saving because it can provoke untreatable ventricular arrhythmias.

Denegri et al. studied the effect of cardiac gene transfer using a recombinant adenovirus vector to transfer wild-type copies of a mutant calsequestrin gene into the hearts of mice that carried a human CPVT mutation in the calsequestrin gene. The vector successfully infected 40% of cardiac myocytes, as shown by marker gene expression. When administered at birth, the gene transfer technique prevented development of the CPVT phenotype, as evidenced by the lack of ventricular-arrhythmia inducibility and characteristic histological features. Gene transfer also rescued the phenotype when administered to adult mice with CPVT. A number of obstacles remain before application in humans, including proving efficacy across the range of mutattions that cause disease in humans. However, this therapeutic approach opens new possibilities for prevention of SCD caused by genetic arrhythmia disorders.

M. Denegri et al., 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 129, 2673–2681 (2014). [Abstract]

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