Research Updates

Batt,  Jane A.            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.

Charlton, Milton        University of Toronto
Our work on phosphoproteomics points the way to use of a specific class of drugs (phosphatase inhibitors) to reduce depression of transmitter release at neuromuscular junctions and consequent muscle weakness.

Durham, Heather        Montreal Neurologic /McGill University
This research project illustrates how basic studies of the biology of motor neurons in the context of ALS can within a short time identify important contributions to development of the disease and pathways that are targets for intervention.  We are working with two pharmaceutical companies to test drugs that boost the ability of motor neurons to produce protein chaperones in culture and mouse models of familial ALS.  If successful, these studies will lead the way for therapeutic development for treatment of ALS patients.

Fahnestock, Margaret    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.

Ferns, Michael           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.

Gordon, Tessa            University of Alberta
Our research is indicating that the normal plasticity of the neuromuscular system of the adaptive conversion of fatigable to non-fatigable motor units in response to neuromuscular activity may  be very important in promoting the survival and function of motoneurons and their muscle fibers. If this adaptive conversion is sufficient for sustaining functional motor units, exercise regimes that promote this conversion may be advocated for middle aged individuals so that motor function may be normalized in individuals who are at risk of familial ALS as well as the general population in which sporadic ALS occurs.

Hastings, Kenneth        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.
 
Julien,    Jean-Pierre        Université Laval
From our results, we propose that passive immunization strategies should be considered as potential avenues for treatment of familial ALS caused by SOD1 mutations. However, because of potential adverse immune responses, immunization strategies need to be considered cautiously before going into human clinical trials. Critical issues for development of human immunotherapy will be discussed including the routes and methods of antibody delivery, the specificity of antibodies and immune responses, the penetration through blood brain barrier and when to start the treatment. A prophylactic immunotherapy may become a conceivable approach providing that the treatment is not too invasive and at reasonable cost.

Krieger, Charles        Simon Fraser University
As a physician caring for patients with ALS I appreciate the devastating aspects of this disease.  We are trying several distinct approaches in order to deal with different features of ALS in the hope that these can be applied to treatment of patients with ALS and specifically with substances that will alter phosphorylation of proteins inside cells for the use of bone marrow derived cells. 

Meakin, Susan        University of Western Ontario
Our research is directed at understanding how Nesca improves the growth of neuronal axons.  Through this understanding, we hope to identify new approaches that may be used to increase the growth of injured neurons or to delay their loss of function in response to insults such as injury and inflammation.

Minassian, Berge        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.

Moukles, Hakima        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.

Parks,     Robin            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.

Picketts,  David        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.

Renaud, Jean-Marc        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.

Robertson, Janice        University of Toronto
Our research is aimed at understanding the mechanistic basis of motor neuron degeneration in ALS. This understanding is necessary to the development of biomarkers, to aid in earlier diagnosis and to act as surrogates for therapeutic interventions, and to the design of targeted therapeutics that will abrogate the disease.

Tremblay, Jacques        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. 

Vande Velde, Christine     CHUM, Hopital Notre-Dame
Our data has provided insight as to how mutant SOD1 protein initiates disease.  Our research will help in identifying the underlying biology that causes ALS pathogenesis.  In a long term format, information gathered by our group will contribute to the development of therapies aimed at blocking or blunting the early phases of ALS disease.