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.
Alexander Richard LyonDaphne BabalisA C Morley-SmithM HedgerA Suarez BarrientosG FoldesL S CouchR A ChowdhuryKonstantinos N TzortzisN S PetersE A Rog-ZielinskaH-Y YangS WelchC T BowlesS Rahman HaleyA R BellA RiceT SasikaranN A JohnsonE FalaschettiJ ParameshwarC LewisS TsuiA SimonJ PepperJ J RudyK M ZseboK T MacleodC M TerraccianoR J HajjarN BannerS E HardingPublished in: Gene therapy (2020)
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.
Keyphrases
- gene therapy
- study protocol
- phase iii
- left ventricular assist device
- clinical trial
- phase ii
- open label
- left ventricular
- double blind
- circulating tumor
- low dose
- endothelial cells
- heart failure
- coronary artery disease
- placebo controlled
- gene expression
- patients undergoing
- acute coronary syndrome
- case report
- ultrasound guided
- transcription factor
- percutaneous coronary intervention
- nucleic acid