Can seaweed mend a broken heart?

A drug development company from Jerusalem is testing whether injecting a substance extracted from algae into the heart can prevent further damage to the heart muscle of people who have had a heart attack

By Cynthia Graver

Doctors have been trying for a long time to find ways to prevent further damage to the heart tissue of patients who have had a heart attack. They tried everything, from drugs to cell therapy, but with little success. Innovative and promising research conducted in Israel suggests that a biological gel produced from algae, called alginate, may enable the healing ability that has so far eluded them. The study showed that alginate helps the heart heal itself when injected into animals. The Jerusalem Pharmaceutical Development Company Bioline R. Ex. It recently began to conduct the first clinical tests of the treatment in humans, and Alligant was successfully tested on the first patient.

The treatment is to be tested during 2008 in 30 patients who have had an extensive heart attack in Germany, Belgium and Israel. Meanwhile, the first patient treated successfully passed the clinical tests and no negative side effects were detected. If the tests are successful, the trial will be expanded to include several hundred heart patients in the US, and the experimental biological gel will reach the market by 2011.

"This could revolutionize the treatment of patients recovering from an extensive heart attack," says Yonatan Lior, director of the Henry Neufeld Heart Research Institute at the Sheba Medical Center, who participated in the development of the drug that may help save the heart.

A heart attack, or myocardial infarction, occurs when blood flow to the heart is blocked, and part of the muscle dies due to a lack of oxygen. The severity of the damage depends on the time that passes until the blood supply is restored. Once damaged, heart muscle tissue never regenerates. If the patient survives, the dead tissue is replaced by scar tissue.

The scarred heart wall is thinner than the healthy tissue surrounding it. The damage to the area worsens and spreads because inflammatory cells (which invade the area as part of the body's inflammatory response) secrete enzymes that break down the intercellular material that provides natural support to the heart cells. As the scar spreads it becomes thinner and weaker.

To compensate for the injury, the remaining healthy muscle works harder to pump blood, and in the process thickens. In 20-10% of the people who survived the heart attack, this excessive activity may cause arrhythmias, future heart attacks, heart failure and even death, according to Lior.

For fifteen years, Lior has been researching possible ways to prevent this deterioration of the heart. He first looked at treatments involving the injection of stem cells, hoping that they would develop into new heart cells or encourage the damaged hearts to produce cells themselves. The results were disappointing: most of the stem cells died, and those that survived were unable to cause the growth of new tissue.

At that time he discovered that the damage was also related to the intercellular substance. That is, the constant erosion of this natural scaffold put a strain on healthy areas of the heart. Restoring the extracellular support would not only help the remaining heart cells, he realized, but also provide a substrate on which cells could live and reproduce. "I thought that maybe we could prevent [the deterioration] by using a biological material to replace the lost natural tissue," says Lior.

At the same time, Samder Cohen, head of the Department of Biotechnology Engineering at Ben-Gurion University of the Negev, investigated the potential of a biological material to repair damaged hearts, after successfully using it to repair liver tissue [see Repair Broken Hearts, by Samder Cohen and Yonathan Lior, Scientific American Israel, February -March 2005].

Cohen wanted to design a scaffold where cells derived from the healthy tissue around the damaged area could be placed. She believed that once the cells settled down, they would be able to secrete extracellular skeletal proteins that would thicken the scar tissue and prevent it from spreading. First, Cohen considered using polymers composed of natural human proteins such as collagen, or synthetic polymers made of polyester that degrades in the body. But these materials were not up to the task, so she considered using alginate, a polymer derived from algae. This polymer has a molecular structure similar to the natural intercellular substance, especially after its crosslinking with calcium ions, and is used by the food, pharmaceutical and medical device industries.

Cohen froze the alginate gel in a controlled manner in order to create water crystals of controlled size and shape and then she removed the ice crystals in the mirroring process while creating a spongy material with pores whose shape is a mirror image of the shape of the ice crystals. The spongy structure of the alginate had an effect on the degree of success of the cells and blood vessels to penetrate into the sponge, grow and exist there while they react and bind to each other. Cohen designed the alginate sponge as a sort of plaster that Cohen and Lior placed directly on the calves of rats (and later pigs) that had suffered a heart attack.

Blood vessels grew into the alginate sponge, and heart cells from nearby areas settled into it and proliferated, secreting extracellular material that thickened the scar. After six weeks, the alginate broke down and its remains were excreted in the urine. Instead of the polymer, much healthier tissue remained than similar tissue in rats and pigs that were not treated with a graft. The problem was that the patch can only be inserted with the help of heart surgery that requires full anesthesia and opening the chest. This increases the risk of treatment, says Lior.

In an attempt to reduce the risk, Cohen made a change in the structure of the material: she cross-linked the alginate molecules, but kept its solubility in water. The solution created in this way can be injected into the damaged area of ​​the heart muscle, where it comes into contact with the calcium ions concentrated in the damaged area and turns into a solid gel.

The gel was shown to be especially promising in experiments on rats, so in 2005, the Bioline company chose R. Ex. In the treatment of Cohen and Lior among hundreds of other possible treatments. The company went on to test the biogel, which it called BL-1040, in pigs (which are anatomically similar to humans). These experiments were successful, similar to the experiments conducted by Cohen and Lior with the alginate plaster.

"The start of clinical studies is an important milestone in the development of Bioline R's most innovative drug. X., and the first treatment in the world intended to treat damage to heart tissue as a result of an attack. We believe and hope that the tests will prove that this new approach to treating people whose heart tissue has been damaged is an effective and safe approach," says Dr. Maurice Lester, CEO of the company. "This is the first product developed as part of the Bioline Innovations Jerusalem Incubator to reach the stage of clinical trials in humans. The greenhouse is operated by Beauline R. Ex. With the support of the Chief Scientist of the Ministry of Industry and Trade."

Lior says that no side effects were observed after injecting the substance into a patient after a myocardial infarction, as was expected from the experiments in the laboratory. As for the effectiveness of the treatment, the results must be awaited because in the laboratory experiments the animals were young and healthy (until the moment when the researchers caused them to have a myocardial infarction), while most of the people suffering from a heart attack are older people and many of them are sick with other diseases and complications. "The challenge is to show that our approach is also effective in real patients," says Lior.

Timothy Gardner, president-elect of the American Heart Association and medical director of the Center for Cardiovascular Health at Christiana Health System in Delaware, expresses cautious optimism. "The treatment addresses a real problem, and if [the human trials] are successful, it will be an important addition to treatment options."

Treatment with BL-1040 (alginate) prevents further damage to heart tissue after a heart attack. In the picture you can see a section of a pig's heart two months after an untreated myocardial infarction (left). The wall of the heart is too thin and as a result the left ventricle of the heart has expanded, which can cause heart failure. In contrast, after treatment with BL-1040 (right) the heart wall remains normal and the left ventricle maintains its original shape.

Because from Jerusalem came Mazor

Bioline R. Ex. Engages in the development of medicines and medical products from the early stages of development, through the stages of pre-clinical trials to the advanced clinical tests. The company's leading drugs are drugs for the treatment of schizophrenia and myocardial infarction. Other drugs under development are intended for the treatment of cancer, diseases of the central nervous system, the heart, metabolism, inflammatory and autoimmune diseases. Through collaboration with researchers, universities and biotechnology companies, Bioline R. Ex. To enrich the drug pipeline of global pharmaceutical companies. The company was founded in 2003 by leading parties in the field of life sciences in Israel, including Teva, the venture capital funds Giza and Pitango, Hadassit and the Jerusalem Development Authority.

From the August-September 2008 issue of Scientific American-Israel