At present there are no approved treatments for Duchenne muscular dystrophy (DMD) in Canada. One current gap is that we do not have effective and sensitive tools in place to evaluate new therapies to see if they do in fact improve health.
Our research aims at understanding if an epigenetic profile of DMD would be a potential biomarker of the muscle damage that can measure how severe the disorder is, its progression over time and if we can potentially use in the testing of new treatments. To do this we will screen blood from children impacted by DMD of different stages to see if epigenetic signatures are unique to DMD and if they change over time.
In addition to identifying potential marker for evaluating new therapies, the findings from this study could result in a faster, less expensive diagnostic screening test for DMD, and would be useful in scenarios of diagnostic uncertainty for disorders impacting the DMD gene (dystrophinopathies) like Duchenne and Becker muscular dystrophy.
Chronic inflammatory demyelinating polyneuropathy (CIDP) is a condition whereby the body’s own immune system mounts an attack against the nerves in the arms and legs. This causes muscle weakness, loss of sensation and pain. One of the biggest challenges facing people with CIDP is loss of balance, which can lead to an increased risk of falls. In fact, people with CIDP report that loss of balance is the symptom they would most like to cure, of all the possible symptoms of CIDP.
Our project will address three main questions about balance in CIDP: 1) What are the causes of balance problems in CIDP?; 2) When a person is treated for CIDP, does it improve their balance?; 3) Can we measure balance in a way that is easy and quick for people with CIDP? In order to answer these questions, we will use a combination of special, highly detailed balance tests that have rarely been used for people with CIDP. We will also test whether patients’ balance is different before and after treatment. Finally, we will test whether the results from our specialized balance tests can be measured using simpler tests at the bedside.
The results of our project will promote the study of balance in CIDP. By improving knowledge about the causes of balance problems, we can design better treatments. After this study we will also be able to use balance as a tool to measure the response to different treatments for CIDP.
Myotonic Dystrophy type 1 (DM1) is a disorder affecting many organs of the body. There is currently no cure or effective treatment for the disorder. In DM1, muscles are weaker, painful and have difficulties to relax. On the molecular level multiple signaling pathways have been reported to be altered including the AMPK signaling, which is important for energy in cells. In our recent work, we found that in cell models of DM1, AMPK signaling is repressed and when it is stimulated, it improves the pathology of these cells. AMPK can be stimulated pharmacologically and physiological (i.e. through exercise.) However, it remains unknown if there is any therapeutic benefit for persons living with DM1.
In this study, we therefore propose to take our findings from cell models to further investigate the role of AMPK in persons living with DM1 and test whether endurance training has the same beneficial effects on AMPK signaling. In addition, while exercise has been shown to be beneficial for DM1 mouse models and for DM1 patients, the impact of training programs on the disorder has not been assessed.
This study will help us better understanding myotonic dystrophy, the role of exercise in muscle health and shed light on potential targets that can be developed as novel therapies for DM1.
Steroid drugs and creatine are used for muscle weakness in people living with Duchenne muscular dystrophy. Steroid drugs can also cause problems with weakening mitochondria, which are the energy producing parts of muscle cells. Duchenne also makes it harder for mitochondria to use creatine for energy. This means that both treatments may not be doing the best job possible if they are also weakening mitochondria.
We discovered that two specific drugs can offset the poor metabolism that may prevent steroid drugs and creatine from helping people as much as possible. This means that these new drugs might help the other drugs work better in people with Duchenne. This study will determine if these new drugs help muscle cells from people with Duchenne produce more energy. We will also test these drugs in mice with this disorder.
We believe the results of this study will help create new drugs that will improve current treatments. If true, this could mean that people with Duchenne will have a better quality of life.
Spinal muscular atrophy (SMA) is a rare disorder that causes muscle weakness. It is caused by low levels of a protein called survival motor neuron (SMN). Treatments that boost SMN protein make a big difference to people if started soon after they are born. For everyone else who gets treated after their muscles became weak, we need to find more ways to help them get stronger. Not much is known about how the brain is wired in SMA. The brain’s wiring depends on our movements when we are very young. Since most people with SMA become weak at a young age, their brain is probably wired differently. In other disorders, we have effective ways to help people learn and get stronger if their brain wiring is different.
In this study, we will look at the brain wiring of kids and adults with SMA and compare it with that of people without SMA to see if they are different. We will take a series of specialized brain pictures in a single session and analyze them. We will also get information about them from their medical chart such as their age and level of ability. The pictures will look both at how the brain looks and how the brain is wired. We will take the pictures exactly the same way in people with SMA as we already did for people without SMA, so we can compare them. If people with SMA have a difference in their brain wiring, it will open the door another ways of helping them reach their best potential.
Individuals impacted by neuromuscular disorders require specialized care and services which are generally offered outside of the neurological/neuromuscular clinics. Our clinic is one of the largest in Canada with more than 1600 patients under active follow-up using a health management approach and the presence of a team of internationally recognized research (Interdisciplinary Research Group on Diseases neuromuscular (GRIMN). Our clinical experience and previous research have raised questions about how well patients and their families understand research including therapeutic trials and the extent of their consent to participate in certain research initiatives such as international registers.
The objectives of this pilot project are to: 1) Create an interactive waiting room in a university clinic subspecialized in neuromuscular care aimed at informing patients and their families about various topics in research; and 2) To assess the effects of using an interactive waiting room and viewing information products to increasing patient’s knowledge.
Facioscapulohumeral muscular dystrophy (FSHD) is the most prevalent muscle disease that afflicts both children and adults regardless of their gender. FSHD is caused by aberrant gain of expression of the double homeobox 4 (DUX4) gene causing toxic effects in muscle cells. Despite the consensus on the pivotal role of DUX4 and several clinical trials, there is currently no cure or an effective therapeutic approach for FSHD patients. In our studies, we identified a novel regulator of DUX4 expression. Targeting this factor allows to block DUX4 expression and rescues the pathogenic behavior of muscle cells from FSHD patients. The treatment is safe to healthy muscle cells. Based on our results, we will use cellular and animal models of the disease to investigate a novel pharmacological approach that could represent a promising therapeutic option for FSHD patients.
Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common kinds of muscular dystrophy. It is a genetic problem that results in weakening and wasting of muscle in the face, shoulders, and limbs. FSHD is equally common in women and men. It can start at different ages, but most people with FSHD begin to show symptoms as teenagers. A childhood form of FSHD starts as early as 10 years of age—this type of FSHD is much more severe, with a high risk of patients developing problems with hearing and vision. Once FSHD starts, people with it experience a lifetime of disability. There is currently no cure for FSHD. Our proposed research aims to develop a new treatment for FSHD. FSHD is caused by abnormal production of a protein called DUX4 in muscle cells. Healthy muscle cells do not have DUX4. We plan on using small-DNA-like molecules called gapmers to decrease the amount of DUX4 protein in muscle cells. Gapmers are able to do this by specifically finding and destroying the gene products responsible for making DUX4. In addition, we will use lipid nanoparticles (LNPs) to enhance the effectiveness of gapmers. The ultimate result of this work will be to identify a possible gapmer-LNP that can be tested in clinical trials for treating FSHD. Developing a new therapy for FSHD will positively impact the lives of people with the disease.
One way to cure Duchenne muscular dystrophy (DMD) is to use stem cells to repair muscle. These stem cells, called satellite cells, can restore dystrophin expression to DMD muscle, reversing the muscle mass loss and weakness. However, when we isolate healthy satellite cells from muscle for transplant, they change in the dish, making them less efficient at repairing muscle when transplanted and less likely to make new satellite cells in the diseased muscle. New satellite cells from donor tissue are necessary for long-term repair of DMD muscle. My lab has discovered that a protein called C/EBPbeta helps satellite cells keep their stem cell potential. Treatment of donor satellite cells with a drug called IBMX before transplantation increases C/EBPbeta levels and keeps the cells more like satellite cells, essentially reprogramming them into more potent stem cells. When transplanted into dystrophic muscle, IBMX-treated muscle cells repair better and make new muscle stem cells in mice. We propose experiments to determine if (i) IBMX-treated cells can be delivered to all the skeletal muscles of the body through the blood; (ii) IBMX-treated cells can persist long term and make muscle function better; (iii) IBMX can also improve human satellite cells for transplant. This project aims to generate strong preclinical data necessary to advance new therapies for muscle wasting diseases like Duchenne Muscular Dystrophy into the clinic.
Myotonic dystrophy type 1 is one of the most frequent genetic muscle diseases in humans. The disease is characterized by muscle weakness and atrophy. Moreover, the regenerative capacity of muscle stem cells, the engine of muscle repair, is reduced in the disease. Therefore, there is a high therapeutic potential for strategies targeting muscle stem cells in myotonic dystrophy type 1; however, this avenue remains unexplored. Our goal is to investigate a new therapeutic strategy aiming to target defective muscle stem cells and restore their regenerative potential. To do so, we will use a preclinical animal model of myotonic dystrophy type 1 to validate the efficacy of these novel therapeutic molecules on muscle regeneration and physical function. Improving muscle regeneration could help to mitigate disease progression and improve the quality of life of the patients. Overall, this project will explore a novel therapeutic avenue for patients that currently have limited therapeutic options.
