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. The SERCA-LVAD trial was one of a program of AAV1/SERCA2a cardiac gene therapy trials including CUPID1, CUPID 2 and AGENT trials. Enroled subjects were randomised to receive a single intracoronary infusion of 1 × 1013 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 at 3 years follow up, 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.
Highlights
These authors jointly supervised this work: N
Cardiomyocytes were isolated for contraction, electrophysiology and Recruitment started at Harefield Hospital in July 2014 and was stopped after the Trial Steering Committee (TSC) reviewed the provisional results of the CUPID 2 trial in May 2015
The SERCA-Left ventricular assist devices (LVADs) trial did not complete recruitment due to the results of CUPID 2 which became available during the study and altered the risk: benefit ratio for this patient cohort leading to cessation of recruitment and inability to obtain planned endomyocardial biopsy (EMB) for 2 subjects
Summary
The initial CUPID1 trial delivering SERCA2a gene therapy via intracoronary infusion of an adeno-associated viral vector (AAV) encoding the SERCA2a gene, under regulation of a cytomegalovirus promoter, to adult HF patients was published in 2011 [10] This showed the procedure safety in a dose-response study and a potential efficacy signal in the subgroup receiving 1 × 1013 DNase-resistant particles. It had been intended to investigate the influence of prior circulating neutralising antibodies (NAbs) to AAV1 upon myocardial gene transfer, the recruitment of only one NAb positive patient meant that this question went unanswered This trial was initiated in 2014 but following the announcement of the neutral result of CUPID2 trial in April 2015, the SERCA-LVAD trial steering committee suspended recruitment after reviewing the risk:benefit balance for study subjects. We present the 3 year follow up results from the 5 subjects who were enroled, randomised and received investigational medicinal product (IMP) infusion in the SERCA-LVAD trial
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