Heart failure: Cardiac gene therapy clinically unconvincing

Cardiac gene transfer therapy is currently being developed with the aim of further improving the treatment of patients with advanced heart failure. In view of the disappointing results of the largest study to date on the benefit of this innovative therapeutic approach, this goal is now far from being achieved.

Cardiac gene therapy for heart failure is based on the discovery that there are key defects at the molecular level that contribute to the worsening of myocardial contractility and relaxation. It is hoped that these defects can possibly be corrected by gene therapy.

This hope is now disappointed by the results of the CUPID-2 study presented at the ESC Congress 2015 in London. According to the study, a special gene transfer therapy could not improve the prognosis of patients with advanced heart failure within one year.

Improvement of calcium homeostasis

The therapy aims to correct changes in calcium metabolism in cardiomyocytes, which are thought to be of central importance in the pathogenesis of heart failure. The molecular target of this therapy is the sarcoplasmic Ca2+-ATPase (SERCA2a).

This is a protein located in the membrane of the sarcoplasmic reticulum (SR). Its function is to transport calcium ions back from the cytoplasm into the SR during diastole in order to replenish the cell’s internal calcium storage.

In heart failure, SERCA2a expression and activity are limited. As a result, fewer calcium ions are transported back into the SR, which has negative effects on contractile myocardial function.

Heart failure: Cardiac gene therapy clinically unconvincing

Cardiac gene transfer therapy is currently being developed with the aim of further improving the treatment of patients with advanced heart failure. In view of the disappointing results of the largest study to date on the benefit of this innovative therapeutic approach, this goal is now far from being achieved.

Cardiac gene therapy for heart failure is based on the discovery that there are key defects at the molecular level that contribute to the worsening of myocardial contractility and relaxation. It is hoped that these defects can possibly be corrected by gene therapy.

This hope is now disappointed by the results of the CUPID-2 study presented at the ESC Congress 2015 in London. According to the study, a special gene transfer therapy could not improve the prognosis of patients with advanced heart failure within one year.

Improvement of calcium homeostasis

The therapy aims to correct changes in calcium metabolism in cardiomyocytes, which are thought to be of central importance in the pathogenesis of heart failure. The molecular target of this therapy is the sarcoplasmic Ca2+-ATPase (SERCA2a).

This is a protein located in the membrane of the sarcoplasmic reticulum (SR). Its function is to transport calcium ions back from the cytoplasm into the SR during diastole in order to replenish the cell’s internal calcium storage.

In heart failure, SERCA2a expression and activity are limited. As a result, fewer calcium ions are transported back into the SR, which has negative effects on contractile myocardial function.

Overexpression compensation

From this, the concept was derived to compensate the decreased expression and activity of SERCA2a by an overexpression of this protein in myocardial cells induced by gene transfer via catheter. To this end, appropriate DNA sequences must be introduced into the cardiac target cells as carriers of the therapeutic information.

This is done using viral vectors, in particular adenoviruses or adeno-associated viruses (AAV). AAV are taken up by the target cells and then enter the cell nucleus where the therapeutic DNA is released (transfection).

The US company Celladon has developed a cardiac

AAV/SERCA2a gene therapy (Mydicar), which initially proved promising in animal experiments. In a first clinical study (CUPID Phase IIa study) in 39 patients with advanced left heart failure, the safety of the vector and the application (intracoronary infusion) of AAV-SERCA2a was confirmed. There were also indications for a possible improvement of symptomatic and functional parameters.

Clinical effect failed to materialize

In the placebo-controlled follow-up study CUPID-2, AAV-SERCA2a therapy was then tested for efficacy and safety in 250 patients with heart failure (NYHA Class II-IV, 80 percent of whom were in stage NYHA III) and low left ventricular ejection fraction (24 percent on average).

The study hypothesis was that cardiac gene therapy would significantly reduce cardiac insufficiency-related hospitalizations and outpatient treatment required due to disease worsening (primary combined endpoint). Unfortunately, it did not:

With 104 (AAV/SERCA2a therapy) and 128 (placebo) the number of corresponding events in both groups was not significantly different, Prof. Barry Greenberg from San Diego reported at the ESC congress in London. Nor did the analysis of secondary or “exploratory” endpoints such as death, heart transplantation, need for mechanical vascular support or NYHA class reveal any significant differences between the gene therapy and placebo groups – not even in subgroups.

Many unresolved questions

The concept of cardiac gene transfer therapy is not fundamentally questioned by these results. However, according to Greenberg, their results raise new questions that need to be clarified: Was SERCA2a perhaps the wrong “target” for the study population? Is it possible that the new therapy has not been sufficiently introduced into the cardiomyocytes? Were the endpoints chosen correctly?

Sponsor
Our Facebook Page
Advertisement
Sponsor