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

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 × 10 13 DNase-resistant AAV1/SERCA2a particles or a placebo solution in a doubleblinded 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.

An mRNA assay system demonstrates proteasomal-specific degradation contributes to cardiomyopathic phospholamban null mutation

“…Unfortunately, the initial failure from the CUPID phase 2 clinical trial, which consisted of an adeno-associated virus based SERCA overexpression therapy, put a hold on further assessments (Jessup. 2011 ; Lyon et al 2020 ). At present, downregulation of phospholamban is being assessed as a potential therapy against heart failure and as a prospective gene therapy in R14del phospholamban mutant carriers (Doevendans et al 2019 ; Schmidt et al 2001 ; Morihara et al 2017 ; Spaeter et al 2019 ).…”

Abnormal Calcium Handling in Duchenne Muscular Dystrophy: Mechanisms and Potential Therapies

“…A single intravenous injection in 3-month-old mdx mice significantly improves whole-body muscle performance and ameliorates fatal dilated cardiomyopathy in mdx mice up to 21 months of age (Wasala et al, 2020). The AAV.SERCA2a vector has been extensively studied in heart failure patients (Zsebo et al, 2014;Lyon et al, 2020). Lessons learned from these studies will help facilitate the translation of AAV.SERCA2a therapy in DMD patients.…”

Gene therapy for ischaemic heart disease and heart failure

“…In CUPID2, the primary endpoint was the reoccurrence of clinical events, such as HF-related hospitalization and MACE. In AGENT-HF, change in left ventricular end-systolic volume was set as the primary endpoint, and SERCA-LVAD evaluated the safety and feasibility of the gene therapy [7,109,110].…”