Despite the initial hope that gene therapy had at its inception, the failures of the clinical trials coupled with the serious adverse events brought the field close to collapse ten years ago. The well publicized complications included the death a patient with a mild form of the monogenic disorder ornithine transcarbamylase deficiency which was caused by multi-organ failure following the injection of a recombinant adenovirus (70
), and the development of new T cell lymphomas in three out of the ten children with severe combined immunodeficiency (SCID) after treatment with retroviruses (14
). However, the field of gene therapy learned valuable lessons from these failures and has rebounded recently with rigorous regulatory barriers along with a new wave of novel vectors. There is now a growing number of gene therapy trials for various diseases, most notably inherited blindness (whereby gene transfer by AAV vectors partially restored vision in a pediatric patient with Leber's Congenital Amaurocis, a major cause of congenital blindness (76
)), cancer, infectious diseases, monogenic diseases, and cardiovascular diseases.
Specifically, in heart failure, there are currently a number of trials ongoing or in the planning stages targeting various pathways for rescuing the failing myocardium (). The targets that have been taken forward towards clinical trials include SERCA2a, adenylyl cyclase type 6, and SDF-1.
The first clinical trial of gene therapy in patients with HF was launched in the United States in 2007 (77
). CUPID (Calcium Up-Regulation by Percutaneous Administration of Gene Therapy in Cardiac Disease) is a multicenter trial designed to evaluate the safety profile and the biological effects of gene transfer of the SERCA2a cDNA by delivering a recombinant AAV1 (AAV1.SERCA2a) in patients with advanced HF. Participants in this trial were administered a single intracoronary infusion of AAV1.SERCA2a in an open-label approach (77
). Cohorts 1–4 of 3 patients each received sequentially a single escalating dose of AAV1.SERCA2a. Twelve month follow-up of these patients showed an acceptable safety profile (77
). Improvement was detected in several patients, reflected by symptomatic (5 patients), functional (4 patients), biomarker (2 patients) and LV function/remodeling (6 patients) parameters. Although this was a phase 1 study involving a small number of patients, early results found that AAV1.SERCA2a treatment conferred quantitative biological benefit. In the phase 2 trial, 39 patients with advanced HF were randomized to receive intracoronary adeno-associated virus 1 (AAV1) mediated SERCA2a gene delivery (in one of 3 doses (low dose − 6 × 1011
DRP, middle dose − 3 × 1012
DRP and high dose − 1 × 1013
DRP) versus placebo. Patient’s symptoms (NYHA class, Minnesota Living With Heart Failure Questionnaire [MLWHFQ]), functional status (6 minute walk test [6MWT] and VO2 max), NT-proBNP levels and echocardiographic measures were evaluated over 6 months. Treatment success was determined by examining concordant trends in the above endpoints for group- and patient-based comparisons, as well as clinical outcomes. The AAV1.SERCA2a high-dose group met the pre-specified criteria for success at the group and individual patient levels. AAV1.SERCA2a treated patients, versus placebo, demonstrated improvement or stabilization in NYHA class, MLWHFQ, 6MWT, VO2 max, NT-proBNP levels, and LV end-systolic volumes. Significant increases in time to adjudicated CV events, and a decreased frequency of CV events per patient were observed in all patients receiving AAV1.SERCA2a. No increases in adverse events, disease-related events, laboratory abnormalities or arrhythmias were observed in AAV1.SERCA2a treated patients compared to placebo.
Two other clinical trials targeting SERCA2a are currently enrolling patients. The first trial is in patients with advanced heart failure having received left ventricular assist devices at least one month prior to treatment and who will receive either AAV6.SERCA2a or saline. This trial is being conducted in the United Kingdom. A second Phase 2 monocenter double blind randomized placebo-controled, parallel study will be held in the Institut of Cardiology Pitié-Salpêtrière, Paris, France with the primary objective to investigate the impact of AAV6-CMV-SERCA2a on cardiac remodeling parameters in patients with severe heart failure.
In a separate clinical study adenovirus-5 encoding human adenylyl cyclase type 6 (is being delivered through intracoronary injection to patients with congestive heart failure. Intracoronary delivery of Ad5.hAC6 or PBS in 3:1 randomization with dose escalation, The patients will be randomized in a dose dependent fashion starting at 3.2 × 109 viral particles to 3.2 × 10^12 viral particles in 6 dose groups using a 3:1 randomization fashion with PBS (buffered saline being used for control). The trial is currently enrolling patients.
An additional trial is examining the effects of injecting SDF-1 directly into the myocardium of patients with ischemic heart disease. An open label dose escalation study to evaluate the safety of a single escalating dose of SDF-1 administered by endomyocardial injection to cohorts of adults with ischemic heart failure is currently enrolling patients. SDF-1 naked DNA will be injected directly into the myocardium at multiple sites through a percutaneous, left ventricular approach.