31 months of Gene Therapy Benefits Advanced Heart Failure Patients

Researchers from the Cardiovascular Research Center at Icahn School of Medicine at Mount Sinai reported the long-term benefits of a single dose of their gene therapy AAV1/SERCA2a in advanced heart failure patients on Nov. 19 at the American Heart Association Scientific Sessions 2013.

The new long-term follow-up results from their initial Calcium Up-Regulation by Percutaneous Administration of Gene Therapy In Cardiac Disease (CUPID 1) clinical trial found a one-time, high-dose injection of the AAV1/SERCA2a gene therapy results in the presence of the delivered SERCA2a gene up to 31 months in the cardiac tissue of heart failure patients.

In addition, study results show clinical event rates in gene therapy patients are significantly lower three years later compared to those patients receiving placebo. Also, patients experienced no negative side effects following gene therapy delivery at three-year follow-up.

“This study shows AAV1/SERCA2a gene therapy has long-lasting and beneficial effects for congestive heart failure patients allowing us to block the downward spiral of patients with severe heart failure, ” says principal investigator Roger J. Hajjar, MD, Director of the Cardiovascular Research Center and the Arthur & Janet C. Ross Professor of Medicine at Icahn School of Medicine at Mount Sinai, who developed the gene therapy approach.

2.5 year survival rates are over 90% versus about 60% for the placebo

Long Term Follow-up of Patients With Advanced Heart Failure Following a Single Intracoronary Infusion of Aav1/serca2a

In addition, on Nov. 19 Dr. Hajjar also presented at the AHA Scientific Sessions 2013 a Plenary talk entitled, “How the Postgenome Era Will Change the Practice of Cardiology” and discussed his work on targeted gene therapy for human heart failure.

In his Plenary talk, Dr Hajjar presented his new findings just published in the journal Science Translational Medicine on Nov. 13 that show delivery of small ubiquitin-related modifier 1 (SUMO-1), an important regulator of SERCA2a, in preclinical heart failure models improves cardiac contractility and prevents left ventricular dilatation — two major aspects of heart failure. According to Dr. Hajjar, the transition of this SUMO-1 gene therapy from pigs to humans seems likely in the short-term. Also, Dr. Hajjar revealed that development of novel cardiotropic vectors may render cardiovascular gene therapy easier and less-invasive in the near future.

Dr. Hajjar is the scientific cofounder of the company Celladon, which is developing AAV1/SERCA2a gene therapy for the treatment of heart failure. He holds equity in Celladon and receives financial compensation as a member of its advisory board


The Calcium Up-Regulation by Percutaneous Administration of Gene Therapy In Cardiac Disease (CUPID) study was a phase 1/phase 2 first-in-human clinical gene therapy trial using adeno-associated type 1 vector (AAV1) carrying the cardiac sarcoplasmic reticulum ATPase pump (SERCA2a) which was injected in patients with advanced heart failure. Although improvements in clinical events were reported 12 months following a single intracoronary infusion of AAV1/SERCA2a, the long term effects of gene therapy in these patients are unknown. In the present report, the final 3-year follow-up of the patients in CUPID is presented.

A total of 39 patients with advanced HF who were on stable therapy were randomized to receive intracoronary infusion of AAV1/SERCA2a (MYDICAR®) in one of 3 doses (low dose – 6 x 1011 DRP [DNAse Resistant Particles], middle dose – 3 x 1012 DRP and high dose – 1 x 1013 DRP) versus placebo. Clinical events such as worsening heart failure, ventricular assist device (VAD) placement, cardiac transplantation, intravenous inotropic treatment, myocardial infarction and death were longitudinally tracked. Three years post-administration, 13 deaths occurred in total and the survival probability over time tended to be higher for patients in all AAV1/SERCA2a groups compared to the placebo group, but especially in the high dose AAV1/SERCA2a group, in which there was a trend for better survival versus placebo (p=0.11, log rank test) as shown in the figure. Throughout the 3 years of follow-up, the number of clinical events was high in the placebo group and high but delayed in the low and mid dose groups. Few events occurred in the high dose group where we found evidence of transgene expression. No safety concerns were noted following gene transfer of AAV1/SERCA2a.

The long term results presented here are promising and indicate that AAV1/SERCA2a gene therapy may offer a new therapeutic strategy for the treatment of HF.

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