Trial of gene therapy in heart failure launches following success in rats and pigs.

Heart failure is a deadly condition that affects about two out of every hundred adults in the USA, and occurs when the heart is unable to provide sufficient pump action to maintain blood flow to meet the needs of the body. Among the more common causes are heart attacks and hypertension, but less frequently it can also be caused by viral infections or autoimmune diseases.

While the therapies available for heart failure have improved a lot in recent years thanks to the development of drugs such as Ivabradine, heart failure is still a major cause of death and disability, particularly among the over 65’s. As you might expect scientists around the world are developing several innovative approaches to treating heart failure – the British Heart Foundation’s “Mending Broken Hearts” appeal is an excellent example of the concerted effort now underway – and we have highlighted on this blog and our Facebook page  techniques ranging from electrical stimulation of the vagus nerve to collagen patches that stimulate tissue repair.

To those animal research has added another: Gene Therapy!

Image courtesy of Imperial College London

Image courtesy of Imperial College London

Yesterday the BBC reported the recent launch in the UK of a Clinical trial of gene therapy for heart failure, and Professor Peter Weissberg of the British Heart Foundation, who funded much of the basic and applied research leading up to this trial, noted the promise that this approach holds:

Whilst drugs can offer some relief, there is currently no way of restoring function to the heart for those suffering with heart failure. This early clinical study is the culmination of years of BHF funded laboratory research and offers real promise.

“Gene therapy is one of the new frontiers in heart science and is a great example of the cutting edge technologies that the BHF is using to fight heart failure. Gene therapy aims to improve the function of weak heart muscle cells, whereas our Mending Broken Hearts Appeal is aimed at finding ways to replace dead heart muscle cells after a heart attack. Both approaches are novel and both offer great potential for the future.””

This trial, which is being run by researchers at Imperial College London and the Royal Brompton Hospital, is part of a multinational multicentre trial of 200 patients – CUPID-2b – which seeks to assess whether injection into heart tissue of a adeno-associated virus 1-based gene therapy vector driving expression of the enzyme SERCA2a can repair damaged heart tissue and improve cardiac function. The reasoning behind this is that as a calcium transport protein SERCA2a plays a key role in maintaining the correct balance of calcium ions in heart muscle cells, and studies in both human heart failure patients and animal models of heart failure the amount of SERCA2a is lower than normal. A combination of studies in human heart muscle tissue and animal models of heart failure over several years demonstrated that this decrease is associated with calcium overload, an abnormal heart rhythm and tissue damage, suggesting that increasing the amount of SERCA2a in the injured heart tissue may reverse the damage.

In 2010 paper was published reporting on the first clinical trial of this therapy1 (available to read for free), whose primary goal was to assess the safety of the technique, and it noted that studies in animal models of heart failure provided vital evidence underpinning the decision to move it into clinical trials.

In preclinical HF models in rodents,(20) pigs,(18) and sheep,(21) increasing the level of SERCA2a using recombinant AAV vectors was well tolerated and restoration of SERCA2a levels resulted in significant improvement in cardiac function and energetics, even when the underlying pathophysiology or insult (eg, mitral valve rupture or pacing induced heart failure) was not corrected. Based on these findings, this first-in-human Phase 1/2 Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID) trial(4) aims to restore levels of this key enzyme in HF patients via gene transfer of the SERCA2a cDNA by delivering a recombinant AAV (AAV1/SERCA2a) via percutaneous intra-coronary infusion.”

These studies, first in short- term studies in rats published in 2007 and subsequently longer duration studies in pigs and sheep published in 2008, indicated that this therapy was safe, could restore SERCA2a to normal levels, promoted heart muscle repair and improved heart function.

It’s just one more example of how animal research is contribution to the exciting field of gene therapy, and to advances in treating heart failure.

Paul Browne

1)      Jaski BE, Jessup ML, Mancini DM, Cappola TP, Pauly DF, Greenberg B, Borow K, Dittrich H, Zsebo KM, Hajjar RJ; Calcium Up-Regulation by Percutaneous Administration of Gene Therapy In Cardiac Disease (CUPID) Trial Investigators. “Calcium upregulation by percutaneous administration of gene therapy in cardiac disease (CUPID Trial), a first-in-human phase 1/2 clinical trial.” J Card Fail. 2009 Apr;15(3):171-81. doi: 10.1016/j.cardfail.2009.01.013. PMCID: PMC2752875

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