Making heart surgery safer
What is the best way to prevent bleeding during heart surgery? A clinical trial led by Dr. Dean Fergusson and Dr. Paul Hébert recently provided a surprising answer to this question. In the largest heart surgery trial ever conducted, they compared three routinely-used anti-bleeding drugs and found that the most popular drug, aprotinin, actually increased the rate of death. Although all three drugs had been tested in patients before, this was the first major study to compare them head-to-head. The results were published in the New England Journal of Medicine and they generated a great deal of attention because aprotinin was widely considered to be the most effective drug, and it was also much more expensive. The study has led to a world-wide change in standard heart surgery practice and has been touted as an example of the importance of independent, investigator-driven clinical research. It was funded by the Canadian Institutes of Health Research.

Promising new stem cell therapy
Dr. Duncan Stewart, a world-leader in stem cell research, has set his sights on developing a treatment for Acute Respiratory Distress Syndrome (ARDS), a major killer in the intensive care unit. The condition involves severe inflammation in the lungs and affects patients with many types of infection (including sepsis), as well as those with traumatic injuries. No effective treatment exists. Dr. Stewart and his team have developed a novel therapeutic approach involving bone marrow stem cells engineered to express a gene called angiopoietin 1. In a mouse model of ARDS, they found that this therapy was able to reduce inflammation in the lung and stimulate regeneration and repair of damaged tissue. After further laboratory studies, they hope to test this promising therapy in patients. The study was published in PLoS Medicine and funded by NSERC, the Heart and Stroke Foundation of Canada and Northern Therapeutics, a company founded by Dr. Stewart.

Groundbreaking cancer trial
Cancer patients in Ottawa have access to the most advanced therapies available, thanks to clinical trials led by oncologists at The Ottawa Hospital Cancer Centre. One example involves cetuximab, a drug that blocks growth-promoting molecules on the surface of cancer cells. Ottawa oncologist Dr. Derek Jonker was the lead on a major international clinical trial of this drug in colorectal cancer patients. The results showed that patients who received the drug survived 23 per cent longer, with significant improvements in quality of life. Further research may help better predict which patients are most likely to respond, thus leading to even greater success rates. The study was funded by the National Cancer Institute of Canada, ImClone Systems and Bristol-Myers Squibb and published in the New England Journal of Medicine.

A new window into Parkinson’s
A universal feature of Parkinson’s disease is the presence of inclusions, or aggregates of a protein called alpha-synuclein in certain nerve cells in the brain. Dr. Michael Schlossmacher recently co-discovered a key molecular switch called GATA-2 that turns on the production of alpha-synuclein. The discovery opens a unique window into Parkinson’s disease and provides a potential target for developing new therapies. Genetic evidence suggests that reducing alpha-synuclein levels by just 20 to 40 per cent could have a big impact on patients. The Schlossmacher team is now trying to define how the switch works and looking for molecules that may be able to adjust it. The discovery was published in Proceedings of the National Academy of Sciences and funded by the National Institutes of Health and the Michael J. Fox Foundation.

Balancing the risks of blood thinners
A world-first research study led by Dr. Marc Rodger has identified a simple rule that may allow hundreds of thousands of women to stop taking blood thinning pills such as warfarin. The study examined 646 people with unexplained blood clots in the legs, arms and lungs (called unprovoked venous thromboembolism). These clots affect up to 2.5 per cent of people in their lifetime and are a major cause of death. Once the initial blood clot is treated, warfarin is prescribed to reduce the risk of further clotting. Currently, many patients take warfarin for the rest of their lives, despite the fact that drug has serious side effects, such as increased risk of bleeding. Dr. Rodger’s study is the first to identify a group of patients (women with four clinical characteristics) who had a very low risk of blood clot recurrence and therefore may be able to safely stop taking warfarin after six months. If the results are confirmed in further studies and this rule becomes widely used, it could help prevent many cases of major bleeding and death and also reduce the large health care costs associated with chronic warfarin therapy. The study was funded by the Canadian Institutes of Health Research and published in the Canadian Medical Association Journal.

Regenerating muscle
Dr. Michael Rudnicki has made exciting progress in understanding muscle stem cells and developing regenerative therapies for diseases such as muscular dystrophy. Over the last 15 years, several research groups around the world have attempted to treat muscular dystrophy through muscle stem cell transplantation, but the therapy hasn’t worked well yet because the stem cells die quickly after transplant. Dr. Rudnicki’s group recently showed that a modified type of stem cell that lacks the “MyoD” gene survives longer and gives rise to more muscle cells after transplantation in mice compared to unmodified cells. Further research is needed before a therapy will be ready for testing in people, but the results have generated great hope and excitement. The study was published in Proceedings of the National Academy of Sciences and funded by the Canadian Institutes of Health Research, the National Institutes of Health and the Muscular Dystrophy Association.

Reaching out to osteoporosis patients
While much of medical research focuses on developing and testing new treatments, an equally important area of research focuses on making sure that effective treatments are actually used. A perfect is example is osteoporosis drugs to prevent fractures. These drugs have been proven highly effective, yet few women with fractures take them. To address the issue, Drs. Ann Cranney, Jeremy Grimshaw and Ian Graham designed a pamphlet and reminder letter targeted at both patients and family physicians and tested it in 270 women who had a recent wrist fracture. The patients who received pamphlets were three times more likely to receive recommended treatments. This study was funded by the Canadian Institutes of Health Research and published in the journal Osteoporosis International.

Fighting cancer with viruses
Ottawa is leading the development of “oncolytic” viruses that infect and destroy many types of cancer without the usual side effects associated with chemotherapy and radiation. The oncolytic virus team includes Drs. John Bell and Harry Atkins from OHRI, as well as Dr. David Stojdl from CHEO. They recently formed a company with colleagues in the US (Jennerex Biotherapeutics) to help bring these viruses into the clinic more quickly. An early-stage international clinical trial in 14 terminal liver cancer patients generated attention around the world this year: 70 per cent of the patients responded to the virus and half survived for at least double their life expectancy, with some still alive today. The study was published in Lancet Oncology and was selected first out of more than 1,000 submissions for presentation at the Society of Gene Therapy Annual Meeting. Clinical trials are expected to begin in Canada soon.

Preventing cardiovascular disease
Cardiovascular disease is the number one killer in Canada and high cholesterol is a major risk factor. Drs. Michel Chrétien, Ajoy Basak, Majambu Mbikay and Janice Mayne are doing pioneering research on a gene that may hold the key to lowering cholesterol. Called PCSK9, the gene is a member of a family of enzymes called proprotein convertases, which were co-discovered by Dr. Chrétien in the 1990s. Research has shown that many people have mutations in the PCSK9 gene, and depending on the mutation, these people may have either very low or very high cholesterol. The group has developed a number of small molecules and peptides that can inhibit the function of PCSK9 in cell culture. They may eventually be tested as new cholesterol lowering drugs in humans. This work was funded by the Canadian Institutes of Health Research and published in FEBS Journal, BBRC and Lipids in Health and Disease.