Does Electrophysiological Toxicity Limit the Therapeutic Window of Serca2a Gene Therapy?
DC Field | Value | Language |
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dc.contributor.author | Xie, Chaoqin | - |
dc.contributor.author | Hu, Jun | - |
dc.contributor.author | Jeong, Dongtak | - |
dc.contributor.author | Kohlbrenner, Erik | - |
dc.contributor.author | Najjar, Roger J. | - |
dc.contributor.author | Akar, Fadi G. | - |
dc.date.accessioned | 2021-06-22T22:04:47Z | - |
dc.date.available | 2021-06-22T22:04:47Z | - |
dc.date.issued | 2014-11 | - |
dc.identifier.issn | 0009-7322 | - |
dc.identifier.issn | 1524-4539 | - |
dc.identifier.uri | https://scholarworks.bwise.kr/erica/handle/2021.sw.erica/21117 | - |
dc.description.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. | - |
dc.language | 영어 | - |
dc.language.iso | ENG | - |
dc.publisher | Lippincott Williams & Wilkins Ltd. | - |
dc.title | Does Electrophysiological Toxicity Limit the Therapeutic Window of Serca2a Gene Therapy? | - |
dc.type | Article | - |
dc.publisher.location | 미국 | - |
dc.identifier.doi | 10.1161/circ.130.suppl_2.20347 | - |
dc.identifier.wosid | 000209790206114 | - |
dc.identifier.bibliographicCitation | Circulation, v.130 | - |
dc.citation.title | Circulation | - |
dc.citation.volume | 130 | - |
dc.type.docType | Meeting Abstract | - |
dc.description.isOpenAccess | N | - |
dc.description.journalRegisteredClass | sci | - |
dc.description.journalRegisteredClass | scie | - |
dc.relation.journalResearchArea | Cardiovascular System & Cardiology | - |
dc.relation.journalWebOfScienceCategory | Cardiac & Cardiovascular Systems | - |
dc.relation.journalWebOfScienceCategory | Peripheral Vascular Disease | - |
dc.subject.keywordAuthor | Gene therapy | - |
dc.subject.keywordAuthor | Gene transfer | - |
dc.subject.keywordAuthor | Arrhythmias, treatment of | - |
dc.subject.keywordAuthor | Heart failure | - |
dc.identifier.url | https://www.ahajournals.org/doi/10.1161/circ.130.suppl_2.20347 | - |
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