Gene Therapy Creates a New Heart Pacemaker

When a patient’s heart beats too rapidly, too slowly or erratically, and if the usual heart medicines fail to properly regulate the heart rhythm, then the patient’s cardiologist may prescribe the implantation of an electronic pacemaker to regulate the heart rhythm. Even though implanted pacemakers are widely used, their installation requires an invasive surgery, they carry some risk of infection, and they also set off metal detectors during airport security checks. However, gene therapy might soon join the electronic pacemaker as a treatment for a poorly-regulated heart. It runs out that inserting a specific gene into heart-muscle cells can allow researchers to restore a normal heart rhythm in pigs, albeit temporarily.

Electronic pacemakers restore regular function to hearts by sending small electrical currents to the heart muscle in order to stimulate a heartbeat. This function is usually donned by the sinoatrial node, which is a cluster of a few thousand cardiac cells in the upper part of the right atrium that signals the heart to initiate a heartbeat and, therefore, sets the heart rate.

Heart Conducting System.  1) is the sinoatrial node or pacemaker and 2 is the atrioventricular node that receives the beat signal from the sinoatrial node and sends it to the ventricles.
Heart Conducting System. 1) is the sinoatrial node or pacemaker and 2 is the atrioventricular node that receives the beat signal from the sinoatrial node and sends it to the ventricles.

A research team led by Eduardo Marbán, who is a cardiologist at Cedars-Sinai Medical Center in Los Angeles, California, attempted to engineer heart cells outside the sinoatrial node to act as the pacemaker of the heart. The findings from Marbán’s laboratory were reported in the journal Science Translational Medicine.

Marbán and his colleagues used 12 laboratory pigs for their laboratory experiments. In these animals, Marbán and others induced a fatal heart condition in which electrical activity that originates from the sinoatrial node cannot spread through the heart. This forces other, less capable parts of the heart to take over and act as a pacemaker. Then, Marbán’s group used high-frequency radiowaves to destroy the sinoatrial nodes in the pigs’ hearts. This caused the animals’ average heart rate to slow to about 50 beats per minute (compared to the normal rate of 100 or more beats per minute). Such animals, if they were a human, would require an electronic pacemaker.

Next, Marbán and other injected the pigs’ hearts with a genetically modified virus that carried a pig gene called Tbx18, which is involved in heart development. Within one day, infected heart cells infected with the virus began to express those genes usually found in sinoatrial node cells. These cells acted as the pacemaker and began to direct the pumping the heart at a normal rate. The animals maintained this steady beating for the two-week study period, whether resting, moving or sleeping.

In an interview, Marbán said that his method is simpler than other biological approaches to restore a normal heart rhythm to hearts. These other approaches include inducing cardiac muscle cells to a pluripotent state, then coaxing them to differentiate into pacemaker cells. However, Marbán cautioned that the effects of gene therapy might be temporary. Over time, the body’s immune system would probably recognize the virus used to deliver Tbx18 to the heart and attack and destroy the infected cells. Marbán’s team is presently monitoring pigs that have received the gene-therapy treatment for several months to measure the persistence of this pacemaker effect.

However, even if the treatment’s effects are limited, it could still prove useful, according to Marbán. For example, if a pacemaker patient suffers from an infection as a result of the pacemaker, that pacemaker must be temporarily removed. This patient could then receive a biological pacemaker that could keep the heart pumping steadily until the infection clears and a new device is implanted. The gene-therapy approach could also help unborn children with heart defects, or even children who quickly outgrow implanted pacemakers or people for whom surgery is simply too risky.

“I think it’s a truly creative idea,” says Ira Cohen, a cardiac electrophysiologist at Stony Brook University Medical Center in New York. He would like to see the therapy tested in dogs, whose average heart rate is 60-100 beats per minute, which is more similar to that of a human.

Marbán is presently in talks with the US Food and Drug Administration about developing a human trial, which he says could be just two to three years away.

Stephen Hawking Visits UCLA Stem Cell Laboratory

Stephen Hawking
Stephen Hawking

On Tuesday, Stephen Hawking toured a stem cell laboratory where scientists are studying ways to slow the progression of Lou Gehrig’s disease, a neurological disorder that has left the British cosmologist almost completely paralyzed.

After the visit, the 71-year-old Hawking urged doctors, nurses and staff at Cedars-Sinai Medical Center to support the research.

Hawking recalled how he became depressed when he was diagnosed with the disease 50 years ago and initially didn’t see a point in finishing his doctorate. But his attitude changed when his condition didn’t progress as fast and he was able to concentrate on his studies.

“Every new day became a bonus,” he said.

The hospital last year received nearly $18 million from California’s taxpayer-funded stem cell institute to study the debilitating disease also known as amyotrophic lateral sclerosis. ALS attacks nerve cells in the brain and spinal cord that control the muscles. People gradually have more and more trouble breathing and moving as muscles weaken and waste away.

There’s no cure and no way to reverse the disease’s progression. Few people with ALS live longer than a decade.

Diagnosed at age 21 while a student at Cambridge University, Hawking has survived longer than most. He receives around-the-clock care, can only communicate by twitching his cheek, and relies on a computer mounted to his wheelchair to convey his thoughts in a distinctive robotic monotone.

A Cedars-Sinai patient who was Hawking’s former student spurred doctors to invite the physicist to glimpse their stem cell work.

“We decided it was a great opportunity for him to see the labs and for us to speak to one of the preeminent scientists in the world,” said Dr. Robert Baloh, who heads the hospital’s ALS program.

Cedar-Sinai scientists have focused on engineering stem cells to make a protein in hopes of preventing nerve cells from dying. The experiment so far has been done in rats. Baloh said he hopes to get governmental approval to test it in humans, which would be needed before any therapy can be approved.

Hawking is famous for his work on black holes and the origins of the universe. His is also famous for bringing esoteric physics concepts to the masses through his best-selling books including “A Brief History of Time,” which sold more than 10 million copies worldwide. Hawking titled his speech to Cedars-Sinai employees “A Brief History of Mine.”

Despite his diagnosis, Hawking has remained active. In 2007, he floated like an astronaut on an aircraft that creates weightlessness by making parabolic dives.

Doctors don’t know why some people with Lou Gehrig’s disease fare better than others. Dr. Baloh said he has treated patients who lived for 10 years or more.

“But 50 years is unusual, to say the least,” he said.

Manipulation of a Master Molecular Switch Called 190RhoGAP May Improve Stem Cell Treatment Of Heart Attacks

New research findings have provided vitals clues as to why heart-based stem cells differentiate into muscle or blood vessels. Such a discovery might hold the key to better treatments for heart attacks in the future.

Human heart tissue lacks the capacity to heal after a heart attack and instead of reforming heart muscle; it tends to form a non-contracting heart scar. Stem cells in the heart can augment the healing process and direct the heart to make heart muscle and blood vessels rather than scars, but why this does not normally occur is unclear.

Particular physicians and their colleagues have shown that introducing heart stem cells into the heart can reduce the formation of heart scar tissue and increase the regeneration of heart muscle. However, uncovering the molecular switch that directs the fate of these cells could result in even more effective treatments for heart patients.

A recent report has shown that scientists who have manipulated a protein called “p190RhoGAP” managed to direct the differentiation of cardiac stem cells to become either blood vessels or heart muscle. Members of this research group even said that altering levels of this protein can affect the activities of these stem cells.

Andre Levchenko, a biomedical engineering professor who supervised the research effort said: “In biology, finding a central regulator like this is like finding a pot of gold.” The lead author of this paper, Kshitiz, said, “Our findings greatly enhance our understanding of stem cell biology and suggest innovative new ways to control the behavior of cardiac stem cells before and after they are transplanted into a patient. This discovery could significantly change the way stem cell therapy is administered in heart patients.”

Earlier in 2012, a medical team at Cedars-Sinai Medical Center in Los Angeles, CA reported reductions of scar tissue in heart attack patients after harvesting some of the patient’s own cardiac stem cells, growing more of these cells in the lab and then transfusing them back into the patient. Using the stem cells from the patient’s own heart prevented the rejection problems that often occur when tissue is transplanted from another person.

The goal of Levchenko’s research is to determine what directs the stem cells, at the molecular level, to change into helpful heart tissue. Answering this question could improve the results from experiments like the one done at Cedars-Sinai and boost regeneration in the heart after a heart attack to an even greater degree.
Levchenko’s team (from Johns Hopkins) tried to change the surface upon which they grew the harvested cardiac stem cells. Surprisingly, growing the cells on a surface that had a similar rigidity to that of heart tissue caused the stem cells to grow faster and to form blood vessels. The increase in growth was substantially greater than that observed with any other protocol with regard to these stem cells. The increased population growth on such a medium also gave prominent hints as to why the formation of a cardiac scar (a structure with very different rigidity), can inhibit stem cells that reside there from regenerating the heart.

By digging further into this phenomenon, the Johns Hopkins group found that the increased cell growth under these conditions was due to decreases in the levels of a protein called p190RhoGAP. This same molecule, when absent, could also direct stem cells to form blood vessels.
Levchenko explained: “It was the kind of master regulator of this process. And an even bigger surprise was that if we directly forced this molecule to disappear, we no longer needed the special heart-matched surfaces. When the master regulator was missing, the stem cells started to form blood vessels, even on glass.”

When Levchenko’s group artificially increased levels of 190RhoGAP, the stem cells formed heart muscle. According to Levchenko, “The stem cells started to turn into cardiac muscle tissue, instead of blood vessels. This told us that this amazing molecule was the master regulator not only of the blood vessel development, but that it also determined whether cardiac muscles and blood vessels would develop from the same cells, even though these types of tissue are quite different.”

Can such findings make a difference in the treatment of living beings? To get a handle on the clinical consequences of this finding, Levchenko’s group limited the production of p190RhoGAP in cardiac stem cells not within a culture dish, but inside the heart of a living animals. The cells with less 190RhoGAP integrated more smoothly into an animal’s blood vessel networks in the aftermath of a heart attack. Also, more of these transplanted heart cells survived, compared to what had occurred in earlier cell-growing procedures.

Kshitiz said that the special heart-like surface on which the cardiac stem cells were grown triggers regulation of the master molecule, and this then guides the next steps in differentiation.

“This single protein can control the cells’ shape, how fast they divide, how they become blood vessel cells and how they start to form a blood vessel network,” he said. “How it performed all of these myriad tasks that require hundreds of other proteins to act in a complex interplay was an interesting mystery to address, and one that rarely occurs in biology. It was like a molecular symphony being played in time, with each beat placed right at the moment before another melody has to start.”
See Matrix Rigidity Controls Endothelial Differentiation and Morphogenesis of Cardiac Precursors;” Kshitiz et al; Science Signaling, 2012; 5 (227): ra41 DOI: 10.1126/scisignal.2003002.