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Gene therapy creates 'biological pacemakers' in pigs

21 July 2014
Appeared in BioNews 763

Adult heart cells can be genetically reprogrammed into pacemaker cells by injecting a gene into the heart, an experiment in pigs suggests.

The reprogrammed cells were able to regulate heart rate and significantly reduce the need for an electronic pacemaker. The research team at the Cedars-Sinai Heart Institute in Los Angeles hope that the technique could be used to treat patients who have problems with conventional electronic pacemakers, or in fetal hearts where there are no other available treatment options. They aim to begin clinical trials in three years' time.

The study used pigs with complete heart block (an inability to control heart rate) that had been fitted with electronic pacemakers. The researchers injected the gene TBX18 into a small area of the heart called the sinoatrial node.

After two days, heart muscle cells near at the injection site had been reprogrammed into electrically active pacemaker cells. The cells were able to regulate the pigs' heart rate under different physiological conditions like physical exercise and sleep. The activity of the reprogrammed cells almost entirely eliminated the need for the electronic pacemaker in the pig hearts over a period of two weeks.

Dr Eduardo Marbán, director of the Cedars-Sinai Heart Institute, said: 'We have been able, for the first time, to create a biological pacemaker using minimally invasive methods and to show that the biological pacemaker supports the demands of daily life. We also are the first to reprogram a heart cell in a living animal in order to effectively cure a disease'.

TBX18 is a transcription factor gene that plays a crucial role in the growth of pacemaker cells during embryonic development. In normal mature hearts, pacemaker cells generate electrical impulses that synchronise the activity of heart muscle cells and regulate the heart rate. Heart block is a condition where the electrical signals in the heart are disrupted, affecting heartbeat rhythm.

Electronic pacemakers work by sensing and correcting the heart rate with electrical signals. The average lifespan of an electronic pacemaker is seven years. The research team hope that their technique might lead to a more permanent treatment, but more research is needed to determine if the reprogrammed cells can remain as pacemaker cells for long periods.

Dr Marbán said: 'Originally, we thought that biological pacemaker cells could be a temporary bridge therapy for patients who had an infection in the implanted pacemaker area. These results show us that with more research, we might be able to develop a long-lasting biological treatment for patients'.

Gene therapies' duration of action can often be disappointing but Dr Marbán told New Scientist that 'everything we know about the action would have us believe that this TBX18 can function as a light switch. The effects of the gene remain forever'.

The researchers also suggest that TBX18 could be used to treat fetal heart defects, but this is even more speculative.

The British Heart Foundation cautioned that any clinical application is 'a long way off'. Senior cardiac nurse Amy Thompson told the BBC: 'This study is an interesting contribution to this area of research, however it was quite small and only lasted two weeks. Pacemakers continue to be an important treatment for many abnormal heart rhythms, helping to keep hearts beating and save lives'.

The study was published in Science Translational Medicine.

Biological pacemaker created by minimally invasive somatic reprogramming in pigs with complete heart block
Science Translational Medicine |  16 July 2014
Biological pacemaker keeps a beat without the hardware
New Scientist |  16 July 2014
'Biological pacemaker' tested in lab
BBC News |  17 July 2014
Next Generation: Biological Pacemakers
The Scientist |  16 July 2014
Transplanting Gene into Injured Hearts Creates Biological Pacemakers
Cedars-Sinai Heart Institute (press release) |  16 July 2014
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