Neuromuscular Research Partnership - 2000 to 2012

Jane A. Batt, St. Michael's Hospital (Toronto)
Skeletal muscle atrophy is a phenomenon that results from numerous acute and chronic illnesses ranging from peripheral nerve injury and denervation of muscle, to metabolic diseases such as renal failure with chronic uraemia and diabetes mellitus. Muscle atrophy increases disease morbidity and impedes independent living, can be associated with increased mortality, increases health care resource utilization and costs, and in the case of peripheral nerve injury, has been shown to cause lost workplace productivity. By studying the molecular mechanisms underlying the loss of muscle mass, we will provide knowledge to allow the development of therapeutic interventions to counteract and reverse muscle atrophy, thus improving patient function, quality of life, workplace productivity and contain health resource utilization and cost.

Margaret Fahnestock, McMaster University
Muscle denervation, particularly chronic denervation over an extended period of time, results in irreversible muscle atrophy which makes repair or recovery ineffective.  One way of maintaining muscle health and receptivity to reinnervation is "sensory protection," a surgical intervention in which a sensory nerve is used to "babysit" the muscle to prevent atrophy.  We have been studying the mechanism of sensory protection in order to understand how it works and improve effectiveness.  We have also shown that sensory protection is effective in the clinic to enhance functional recovery after peripheral nerve injury. Although we have only used sensory protection so far for peripheral nerve injury and not disease, the same problem of muscle atrophy occurs as a result of chronic denervation due to neuromuscular diseases.  Thus sensory protection may be a viable option, in conjunction with other treatments, for neuromuscular disease.  Understanding the mechanism of sensory protection will allow us to design related interventions more suited to the chronic disease state.

Michael Ferns, Montreal General Hospital Research Institute
In diseases of the NMJ like myasthenia gravis and congenital myasthenic syndromes, acetylcholine receptor levels are reduced, leading to failures in transmission and debilitating muscle weakness. Our aim is to define the molecular interactions and regulatory mechanisms that localize the receptor at the synapse; thus, we may identify novel therapeutic targets and new strategies to prevent the loss of synaptic acetylcholine receptor in these conditions.

Kenneth Hastings, Montreal Neurologic /McGill University
Basic biology research can have several distinct impacts on people suffering from disease.  In the short term, some of the mechanisms, or research reagents, can have a medical application.  In the case of our work, which involves understanding the regulatory capabilities of short DNA sequences from muscle genes, some of the DNA fragments we study could be useful for driving gene expression in muscle cells in a gene therapy setting, an approach under active clinical exploration for muscle diseases. The above-mentioned paper is an example of that.  However the biggest impact is likely farther in the future.  Because this is research into the basic cellular mechanisms that determine the specialized properties of skeletal muscle fibers, it is important both for the normal development of healthy muscle and for healthy regeneration following injury or neuromuscular disease.  Our ability to build, rebuild, and modify muscle in people with muscle disorders will ultimately depend on our knowledge of these fundamental biological mechanisms.

Berge Minassian, Hospital for Sick Kids (Toronto)
We can now diagnose patients with X-linked myopathy with excessive autophagy (XMEA) by a blood test.  Our findings apply to a wide spectrum of vacuolar myopathies, many of which are actually XMEA cases (in press).  We can now envisage gene therapy for these diseases.  Having understood these diseases, we are much better positioned to come up with treatments, which we are now working on.

Hakima Moukles, University of British Columbia
The expression of dystroglycan, a critical organizer of the neuromuscular junction, is altered in Duchenne and Becker muscular dystrophy. Both these forms of muscular dystrophy are associated with mental retardation and my work has focused on the functional role of dystroglycan in the brain. The proposed studies will enable us to further understand the role of the dystroglycan complex in the central nervous system and are therefore relevant to altered expression of dystroglycan in muscular dystrophy.

Robin Parks, Ottawa Heath Research Institute
As mentioned, gene therapy holds great promise for the treatment of neuromuscular disease and, indeed, the first trial for gene therapy of Duchenne Muscular Dystrophy is currently underway.  Many of the principles that we have established in our research can be applied to any disease system, be it muscle disease, neuronal, or any tissue.  In short, the benefit of our research is not simply in our immediate findings, but in the reagents and knowledge that we have generated.  To develop the future, novel therapies for these devastating inherited diseases.

David Picketts, Ottawa Heath Research Institute
A thorough understanding of how neural progenitors function and contribute to the production of neurons is imperative if we are going to use them for cell therapy of neuromuscular diseases.  While this work should be considered to be at a very basic biological level, it helps build the foundation of our understanding of stem cells, and ultimately, stem cell therapies which represent such a promising goal towards a treatment for neuromuscular disease.

Jean-Marc Renaud, University of Ottawa
Our ultimate objective is to find a better treatment that would eliminate the HyperKPP symptoms and this constitutes the direct benefit of our research. At the same time, there are many other neuromuscular diseases that are related to defect in ion channels. Understanding the mechanisms of HyperKPP, will indirectly help understanding the mechanism of other Chanelopathies as well as helping find better treatment.

Jacques Tremblay, CHU Laval Research Centre
My research program aims to develop a cell therapy for recessive muscular dystrophies. The cell therapy that we are trying to develop will not only permit to introduce the normal gene in the muscle fibers of patients with various recessive muscular dystrophies but will also introduce in the muscles new muscle precursor cells that will increase its regenerative capacity.