First Patient Treated in Study that Tests Stem Cell-Gene Combo to Repair Heart Damage

The first patient has been treated in a groundbreaking medical trial in Ottawa, Canada, that uses a combination of stem cells and genes to repair tissue damaged by a heart attack. The first test subject is a woman who suffered a severe heart attack in July and was treated by the research team at the Ottawa Hospital Research Institute (OHRI). Her heart had stopped beating before she was resuscitated, which caused major damage to her cardiac muscle.

The therapy involves injecting a patient’s own stem cells into their heart to help fix damaged areas. However, the OHRI team, led by cardiologist Duncan Stewart, M.D., took the technique one step further by combining the stem cell treatment with gene therapy.

“Stem cells are stimulating the repair. That’s what they’re there to do,” Dr. Stewart said in an interview. “But what we’ve learned is that the regenerative activity of the stem cells in these patients with heart disease is very low, compared to younger, healthy patients.”

Stewart and his colleagues will supply the stem cells with extra copies of a particular gene in an attempt to restore some of that regenerative capacity. The gene in question encodes an enzyme called endothelial nitric oxide synthase (eNOS). Nitric oxide is a small, gaseous molecule that is made from the amino acid arginine by the enzyme nitric oxide synthase. Nitric oxide or NO signals to smooth muscle cells that surround blood vessels to relax, which causes blood vessels to dilate and this increases blood flow. In the damaged heart, NO also helps build up new blood vessels, which increase healing of the cardiac muscle. Steward added, “That, we think, is the key element. We really think it’s the genetically enhanced cells that will provide the advantage.”

Nitric oxide synthesis

The study will eventually involve 100 patients who have suffered severe heart attacks in Ottawa, Toronto and Montreal.

Culture Media from Mesenchymal Stem Cells Heals Injured Lungs

Acute lung injury and acute respiratory distress syndrome remain major causes of death and suffering despite advances in management of these conditions. The incidence of these conditions is expected to double in the next 25 years, and treatment for it is largely supportive.

Fortunately, mesenchymal stem cells (MSCs) from bone marrow have been used in experimental models to treat lung injury in rodents. MSCs can engraft into lung tissue and become lung tissue (or at least turn into cells that sure look a whole lot like lung tissue). MSCs can also suppress the types of immune responses that tend to really chew up lung tissue. Thus, MSC administration seems to improve the condition of lungs that have been attacked by infections or damaging agents.

However, the rates at which MSCs engraft into lung tissue is rather low; too low, in fact, to account for the benefit provided by MSCs. Therefore, MSCs appear to help repair lung tissue by means of “paracrine” mechanisms. This 50-cent word simply means that MSCs repair the lung by secreting molecules that promote lung healing.

To test this hypothesis, researchers in the laboratory of Bernard Thérband from the Ottawa Hospital Research Institute in Ottawa, Canada has grown MSCs in culture, and used the growth medium after the MSCs had been removed from it to treat mice that suffered from lung injuries.

To induce lung injury, mice were treated with isolated bits of bacterial cells that are known to promote acute lung injury. Then a group of these lung-injured mice were treated with conditioned medium from bone marrow MSCs that had been grown in culture dishes.

The MSC-conditioned medium decreased lung inflammation, and disruptions of the blood vessels in the lung normally observed during lung injury. Therefore, the lungs did not fill up with liquid and pus. However, the conditioned medium did not prevent the weight loss associated with lung injury. The overall tissue architecture of the lung tissue was much more normal in the mice treated with the conditioned medium from MSCs than in the untreated mice. Conditioned medium from other cultured cells had no such sanative effect.

MSC conditioned culture media also modified the activity of white blood cells in the lung. Instead of charging forward into lung tissue and damaging it in response to damage, the white blood cells (so-called “alveolar macrophages”) worked with the lung tissue to help heal it.

Finally, when Thébaud and his colleagues examined the molecules secreted into the medium by the MSCs, they discovered that the culture medium was filled with lots of interesting molecules, but one in particular caught their eye:  Insulin-like growth factor-1 (IGF-1). This molecule has all kinds of healing properties, and it seemed to Thébaud and company that IGF-1 could be responsible for a good portion of the healing. Therefore, they infused the lung-injured mice with purified IGF-1, and, wouldn’t you know, the lungs showed rather robust healing after being damaged with bacterial bits.

Thus MSCs provide lung healing properties and they do so by means of the molecules they secrete. Many of these healing properties can be recapitulated by infusing IGF-1.

Such experiments provide hope that future clinical trials for such treatments are not far off.

Injected Wnt Protein Helps With Muscular Dystrophy

Duchenne muscular dystrophy is a genetic disease that affects one of every 3,500 newborn males. Because the DMD gene is located on the X chromosome, loss-of-function mutations that cause Duchenne muscular dystrophy (DMD) tend to occur in males.

Muscular dystrophy or MS affects skeletal muscles and causes muscle weakness and muscle loss, and unfortunately, the disease often progresses to a state were the muscles are so weak and damaged that even the diaphragm, which is a voluntary muscle, becomes nonfunctional, and the patients dies from an inability to breath.

Recently, Michael Rudnicki, a MS researcher from the Ottawa Hospital Research Institute in Canada, has led a research team that discovered that injections of a protein called “WNT7a” into muscles can increase the size and strength of muscles in MS mice.

Rudnicki is the director of the Regenerative Medicine Program at Ottawa Hospital Research Institute (OHRI), Canada. The results of this work were published on the Nov. 26, 2012, in the Proceedings of the National Academy of Sciences (PNAS).

For these experiments, Rudnicki collaborated with a San Diego-based biotechnology firm known as Fate Therapeutics. Fate Therapeutics specializes in developing pharmaceuticals that are based on stem cell biology, and Rudnicki is one of the founders of this company. Rudnicki hopes to begin a clinical trial of WNT7a for DMD in the near future.

In 2009, Rudnicki and co-workers showed that WNT7a protein is able to stimulate muscle repair by increasing the available supply of a population of muscle stem cells known as “muscle satellite cells.” Muscle satellite cells are located near muscle fibers but they are dormant until they are needed for muscle repair or muscle fiber regeneration. When the muscle is stressed or damaged, the satellite cells increase in number (proliferate) and mature (differentiate).

Muscle Satellite Cells

These newly published findings build on these earlier results. Once injected into the muscles of mice afflicted with DMD, the WNT7a-injected muscles showed significant increases in fiber strength and size. However, Rudnicki and others also found that WNT7a stimulated a two-fold increase in the number of satellite cells in the injected mouse muscles.

Rudnicki was worried that WNT7a was pushing satellite cells to differentiate prematurely, which was disconcerting because such premature differentiation would deplete the muscle satellite population. However, no evidence of premature differentiation was observed. Additionally, WNT7a-injected mouse muscles showed far less contraction-related injury, suggesting that WNT7a has a kind of protective effect on the muscle.

Even though these experiments were done in a mouse model of DMD, would WNT7a also work in a similar fashion in human muscles? To answer this questions, Rudnicki and his colleagues analyzed human muscle tissue from healthy male donors that had been treated with WNT7a. The results showed that the effects of this protein in skeletal muscle are the same in humans as in mice.

To summarize from their own paper: “Our experiments provide compelling evidence that WNT7a treatment counteracts the significant hallmarks of DMD, including muscle weakness, making WNT7a a promising candidate for development as an ameliorative treatment for DMD.”

The remarkable conclusion is that increasing muscle strength by injecting WNT7a into specific, vital muscle groups, such as those involved in breathing, should be considered as a therapeutic approach for this debilitating disease.