Medical Update Memo
February 9, 2001
The Canadian Institutes of Health Research (CIHR) announced funding of more than $5 million over five years for a study of the role that enzymes called matrix metalloproteinases (MMPs) have in multiple sclerosis. This interdisciplinary study headed by Dr. V. Wee Yong of the University of Calgary will focus on all aspects of MMPs from the environmental, biological and therapeutic aspects and involve researchers at five different universities. Part of the study will be a Phase I clinical trial of the common acne medication minocycline in relapsing-remitting MS. The clinical trial is to evaluate safety and dose tolerance, not its effectiveness in treating MS. This interdisciplinary study grew out of work that Dr. Yong has conducted with MMPs over the past few years which has been funded by the Multiple Sclerosis Society of Canada and the Medical Research Council of Canada. The MS Society provided a strong letter of support to the CIHR recommending that the proposal by Dr. Yong and colleagues be funded.
The Canadian Institutes of Health Research (CIHR) announced January 24 that it was providing more than $5 million over five years for a study of the role that enzymes called matrix metalloproteinases (MMPs) have in multiple sclerosis. Dr. V. Wee Yong, associate professor at the University of Calgary, heads the interdisciplinary study. Various parts of the study are being carried out at the University of Calgary, the University of Alberta, the University of Manitoba, the University of Montreal and McGill University.
Previous work done by Dr. Yong and others has found increasing evidence that MMPs are involved in MS activity. Certain MMPs may be responsible for allowing immune system cells to penetrate the central nervous system and to start the attack on the protective myelin covering of nerve fibres. This work, which involves a wide range of research approaches, should provide much more insight about MMPs and whether a possible treatment should be studied further.
Enzymes are proteins that regulate chemical reactions within the body. The MMP group of enzymes are supposed to break down barriers during the body's development stage to help cells get to where they are supposed to go - to help nerve cells, for example, arrive at their final destination. However, sometimes MMPs become destructive for reasons that are still unknown. It appears in some instances MMPs are used by the white blood cells to leave the blood system and infiltrate into the brain and spinal cord to cause inflammation and damage to myelin. In addition, it is known that MMPs can have beneficial effects in myelin maintenance and repair so it is important to understand all of their roles and characteristics.
The investigators will be studying MMPs using a variety of approaches from the cellular level to population health to clinical. One study will involve trying to determine whether different cell types express specific MMPs and TIMPs (endogenous tissue inhibitors of metalloproteinases). In other work, investigators will try to identify which MMPs are prerequisite to producing signs of MS-like disease in animals. Looking at population health aspects, another research team will try to determine if increased exposure to certain viruses or if having systemic respiratory or urinary infections is associated with MS disease activity and whether this is linked to MMP alterations. Another study is focussed at assessing if outcome and treatment response and their associations with MMPs can be linked to demographic factors such as age and gender, to clinical factors such as disease duration and age at onset, MRI status such as number of MS lesions and their activity and other variables such as use of MS modifying therapies or hormone usage.
Novel therapeutic strategies will be investigated. First the efficacy of the common acne medication, minocycline, will be tested in an animal model of MS. Dr. Yong and graduate student Veronika Brundula searched for drugs that are already in use and which have the incidental property of inhibiting MMPs. They found that minocycline has this property. This led to the subsequent discovery that minocycline inhibits MMPs in human white blood cells and MS signs in an animal model. Another strategy will involve testing whether the effectiveness of beta interferon or glatiramer acetate is improved by combining them with minocycline in animal studies. A number of other drugs, based on different mechanisms of action on the MS disease process, will also be examined in animal models.
A small Phase I trial to investigate safety and dose tolerance to minocycline will also be conducted. It will involve 30 people with relapsing-remitting MS. This part of the study is being headed by Dr. Luanne Metz, associate professor at the University of Calgary, and director of the MS Clinic in Calgary. No additional details regarding the clinical trial are available at this time. It should be noted that some potential serious toxicity could occur with minocycline, even in doses used to treat acne. Also, the very long-term toxicity of minocycline is not known. Furthermore, little is known about the side effects that may occur in the doses that are being planned to treat people with MS. The initial trial with minocycline will be to address safety and tolerance issues.
The Multiple Sclerosis Society of Canada strongly recommended that the CIHR fund this innovative interdisciplinary study of MMPs and multiple sclerosis. It has grown out of Dr. Yong's previous work funded by the Multiple Sclerosis Society of Canada and the previous Medical Research Council of Canada.
This research project was one of 10 announced for funding by the CIHR in late January. A total of 31 groups were invited to submit full proposals out of an original list of 180 applications nationwide from all health-related disciplines. The MMPs in MS study was the only one funded in neurosciences. The CIHR is the major federal government funding agency of health research in Canada. It replaced the Medical Research Council of Canada in 2000.
Research Team Members