Despite advances in pharmacological therapy, mortality and morbidity in heart failure remain high. Numerous underlying molecular abnormalities exist in the failing myocycte, of particular importance are those leading to deranged calcium handling. Gene therapy is an approach that can target these molecular abnormalities directly and a target that has received significant interest is sarcoplasmic (endoplasmic) reticulum calcium ATPase 2a (SERCA2a) which is down regulated in heart failure. There is laboratory and early clinical evidence that SERCA2a gene therapy mediated through adeno-associated virus serotype 1 (AAV1) can improve a number of measures of cardiac function, reduce cardiac alternans and reduce ventricular arrhythmias. T wave alternans (TWA) is a non-invasive marker of arrhythmia risk and is linked to abnormalities
of calcium handling. As such, TWA may be a useful tool to assess the effect of AAV1-mediated SERCA2a gene therapy (AAV1.SERCA2a) on arrhythmia risk in a heart failure population.
I conducted a number of studies in an attempt to refine the TWA technique with the aim of using TWA as an efficacy measure of AAV1.SERCA2a. The calcium upregulation by percutaneous administration of gene therapy in cardiac disease-2 (CUPID-2) study was a multi-national, multi-centre, placebo controlled randomised study recruiting 250 patients to
assess if intracoronary AAV1.SERCA2a was effective at reducing heart failure hospitalisations in advanced heart failure. As a sub-study of the CUPID-2 trial I conducted the CUPID-2 arrhythmia sub-study in patients with an implantable cardioverter defibrillator (ICD). I investigated whether treatment with AAV1.SERCA2a reduced appropriate ICD therapies and
separately I examined if AAV1.SERCA2a reduced TWA in those patients recruited at our site. I found that gene therapy trials are challenging to set up as a result of the number of legislative, safety and governance approvals that are required. Furthermore, gene therapy studies using
AAV1 are difficult to recruit to as more than half of patients are ineligible due to the presence of neutralising antibodies to the viral vector. I found that delivering AAV1.SERCA2a could be performed safely at our site. AAV1.SERCA2a gene therapy did not reduce ICD therapy or TWA as was expected after the publication of neutral results in the main CUPID-2 trial. I found
that a refinement of the TWA technique of examining multiple leads of the ECG could alter interpretation of TWA and could be tested as an approach to improve the prognostic value of TWA.