November 2001

Adult Stem Cells

Continued from page 3

By Stephen S. Hall

Heart disease is the leading killer in the United States, and there are more than one million heart attacks a year in the United States alone. As a result, heart disease has been one of the most intense-and impressive-areas of adult stem cell research in the past year.

Last spring, two separate groups, one at Columbia University and the other a collaboration between New York Medical College in Valhalla, NY, and the National Institutes of Health, published studies showing that heart attacks in rats and mice could be repaired by injecting adult stem cells in or near the injury. Now Osiris is trying to do the same with pigs. In the first round of experiments, veterinary surgeons at Johns Hopkins performed open-heart surgery on the animals and tied off the left anterior descending coronary artery, which feeds the main pumping chamber of the heart, for one hour, triggering a heart attack. After two weeks, Osiris researchers then injected about 50 million mesenchymal stem cells directly into the hearts of five test animals. The cells were genetically tagged with a marker so they could be traced in the body, and these pigs, as well as half a dozen control animals, were closely followed for up to six months.

All the pigs that did not receive stem cells died within a month or two of their heart attacks. Autopsies showed that their hearts developed extensive scarring at the sites of injury, and that the organs had become excessively large and distorted in an attempt to compensate for diminished pumping capacity. Eventually, the wall of the heart thinned and heart failure ensued. For the pigs that received stem cells, however, it was a different story. The stem cells zeroed in on the injured cardiac muscle, took up residence in and around the scar tissue and literally remodeled the damaged heart. They seemed, in fact, to interrupt the typical progression toward a lopsided (and prognostically grim) cardiac architecture.

Here are the caveats: the stem cells that take up residence in the scar tissue have the markers of cardiomyocytes, the muscle cells unique to the heart, but they do not appear to be organized in the same way and do not exhibit the typical contractile properties of heart muscle. Still, says Martin, "we've seen such good results in terms of function that we didn't care if they were myocytes or not."

As a result of that first study, completed last December (and still unpublished), Osiris quickly initiated a second round of trials in pigs-the same pigs that Martin visited that morning in May-and the results appear to confirm the initial tests. This second trial uses universal donor cells, rather than cells extracted from each pig's own marrow, that are injected immediately after the heart attack. Echocardiograms, including the ones Martin and his colleagues gathered during the May visit, have shown a statistically significant improvement in the pumping capacity of the heart. The company is now exploring the possibility of delivering these cells to precisely the right spot in a damaged heart through a catheter similar to the type used in angiograms or angioplasties.

The ultimate aim, Martin explains, is to manufacture "a universal [human] cell, cryopreserved, which could be in the emergency room of every hospital in the country, and used in emergent situations with heart attack patients." The hope is that initiating cellular therapy as soon as possible after a heart attack could significantly reduce permanent damage to the heart. Two days after Martin visited the pigs last May, Osiris officials met with U.S. Food and Drug Administration scientists, and they hope that, if all lingering regulatory and safety concerns can be satisfactorily resolved, a preliminary safety study of adult stem cells in humans with heart disease could feasibly be launched by the end of the year.

Another barnyard animal is providing further promising results for treating a condition that afflicts more than half of all Americans over the age of 65: osteoarthritis. At a farm north of Baltimore, Osiris scientists have been putting a dozen or so goats through their paces on treadmills. What's unusual about these goats is that each has sustained severe damage to one knee. To simulate conditions that commonly cause osteoarthritis, veterinary surgeons sever a ligament in the knee and remove the inner half of the meniscus, a resilient patch of cartilage that forms a cushioning pad between the thighbone and the larger of two bones that form the lower leg. The goats then spend several weeks on an exercise program using this wobbly, unstable joint-a regimen that literally rubs and erodes the remaining cartilage off the ends of the long bones. This activity creates a harrowingly accurate model of osteoarthritis.

Osiris researchers have been using an ordinary syringe to inject approximately five to ten million adult mesenchymal stem cells into a little purse of tissue inside the knee, and the results have been encouraging. Although tested in only a handful of animals, the stem cells have not only restored the surgically removed meniscus but within 12 weeks have recarpeted the eroded, bony surface of the thigh and calf bones with new cartilage. "These cells respond to mechanical forces," Osiris's Barry explains, "and the fact that the animal is putting weight on the joint means the cells experience these dynamic forces. The second thing is that they respond to the local wound environment." Encouraged by the results in animal experiments, Osiris hopes to launch initial safety studies in humans before the end of the year.