Does Electrophysiological Toxicity Limit the Therapeutic Window of Serca2a Gene Therapy?
- Authors
- Xie, Chaoqin; Hu, Jun; Jeong, Dongtak; Kohlbrenner, Erik; Najjar, Roger J.; Akar, Fadi G.
- Issue Date
- Nov-2014
- Publisher
- Lippincott Williams & Wilkins Ltd.
- Keywords
- Gene therapy; Gene transfer; Arrhythmias, treatment of; Heart failure
- Citation
- Circulation, v.130
- Indexed
- SCI
SCIE
- Journal Title
- Circulation
- Volume
- 130
- URI
- https://scholarworks.bwise.kr/erica/handle/2021.sw.erica/21117
- DOI
- 10.1161/circ.130.suppl_2.20347
- ISSN
- 0009-7322
1524-4539
- Abstract
- Rescue of SERCA2a expression by gene transfer to the endstage failing heart improves its mechanical and electrophysiological (EP) function. However the safety profile of SERCA2a gene therapy as a preventive measure in patients at early stages of remodeling prior to SERCA2a downregulation is unknown. Examination of the EP consequences of SERCA2a gene therapy in non-failing hearts is imperative in determining its potential EP toxicity. Hypothesis: SERCA2a upregulation using high titer adeno associated virus type 9 (AAV9) mediated gene transfer to normal rats may promote arrhythmogenic triggers, thereby limiting the therapeutic window for this approach. Methods: Using high resolution optical action potential (AP) imaging, we investigated the EP substrate 6 weeks post gene transfer of 5E11 AAV9.SERCA2a (N=13) or AAV9.GFP (N=6) to normal rats. Arrhythmia susceptibility was determined under conditions that promoted Ca overload by burst pacing & ischemia reperfusion (IR) injury. Results: AAV9.SERCA2a hearts exhibited a 50% increase in SERCA2a expression at the mRNA and protein levels compared to AAV9.GFP. No differences in heart weight to body weight were found between groups (3.85 vs 3.74 mg/g). During baseline perfusion, AAV9.GFP hearts exhibited significantly prolonged (by 30%, p Conclusions: High titer gene transfer of AAV9.GFP but not AAV9.SERCA2a elicits adverse EP remodeling in normal rat myocardium. The lack of an EP phenotype of AAV9.SERCA2a despite 50% upregulation in SERCA2a levels is consistent with a wide safety margin for this therapy.
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