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Investigation of the safety and feasibility of AAV1/SERCA2a gene transfer in patients with chronic heart failure supported with a left ventricular assist device – the SERCA-LVAD TRIAL

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Title: Investigation of the safety and feasibility of AAV1/SERCA2a gene transfer in patients with chronic heart failure supported with a left ventricular assist device – the SERCA-LVAD TRIAL
Authors: Lyon, A
Babalis, D
Morley-Smith, AC
Hedger, M
Suarez Barrientos, A
Foldes, G
Couch, LS
Chowdhury, RA
Tzortzis, KN
Peters, NS
Rog-Zielinska, EA
Yang, YH
Welch, S
Bowles, CT
Rahman Haley, S
Bell, AR
Rice, A
Sasikaran, T
Johnson, NA
Falaschetti, E
Parameshwar, J
Lewis, C
Tsui, S
Simon, A
Pepper, J
Rudy, JJ
Zsebo, KM
MacLeod, KT
Terracciano, CM
Hajjar, RJ
Banner, N
Harding, SE
Item Type: Journal Article
Abstract: The SERCA-LVAD trial was a phase 2a trial assessing the safety and feasibility of delivering an adeno-associated vector 1 carrying the cardiac isoform of the sarcoplasmic reticulum calcium ATPase (AAV1/SERCA2a) to adult chronic heart failure patients implanted with a left ventricular assist device. Enrolled subjects were randomised to receive a single intracoronary infusion of 1x1013 DNase-resistant AAV1/SERCA2a particles or a placebo solution in a double-blinded design, stratified by presence of neutralising antibodies to AAV. Elective endomyocardial biopsy was performed at 6 months unless the subject had undergone cardiac transplantation, with myocardial samples assessed for the presence of exogenous viral DNA from the treatment vector. Safety assessments including ELISPOT were serially performed. Although designed as a 24 subject trial, recruitment was stopped after five subjects had been randomised and received infusion due to the neutral result from the CUPID 2 trial. Here we describe the results from the 5 patients, which confirmed that viral DNA was delivered to the failing human heart in 2 patients receiving gene therapy with vector detectable at follow up endomyocardial biopsy or cardiac transplantation. Absolute levels of detectable transgene DNA were low, and no functional benefit was observed. There were no safety concerns in this small cohort. This trial identified some of the challenges of performing gene therapy trials in this LVAD patient cohort, which may help guide future trial design.
Issue Date: 15-Jul-2020
Date of Acceptance: 25-Jun-2020
URI: http://hdl.handle.net/10044/1/78835
DOI: 10.1038/s41434-020-0171-7
ISSN: 0969-7128
Publisher: Springer Nature [academic journals on nature.com]
Start Page: 579
End Page: 590
Journal / Book Title: Gene Therapy
Volume: 27
Copyright Statement: © The Author(s) 2020. This article is published with open access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Sponsor/Funder: British Heart Foundation
Celladon Corporation
British Heart Foundation
British Heart Foundation
Funder's Grant Number: SP/09/007/27920
Keywords: Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Biotechnology & Applied Microbiology
Genetics & Heredity
Medicine, Research & Experimental
Research & Experimental Medicine
06 Biological Sciences
11 Medical and Health Sciences
Publication Status: Published
Online Publication Date: 2020-07-15
Appears in Collections:National Heart and Lung Institute
Faculty of Medicine
School of Public Health

This item is licensed under a Creative Commons License Creative Commons