Skeletal muscles are essential to many physiological functions; yet, because myopathies are rare and heterogeneous, diagnosing and treating them can be quite difficult. This project presents an innovative approach to advance the understanding of satellite cell-opathies, a unique group of illnesses that affect the function of muscle stem cells. This project will use muscle cells and 3D tissue engineering to test the effect of rare genetic variations linked to satellite cell-opathies on myogenic cell function. This project aims to provide insight into the molecular pathways underlying these disorders and pinpoint possible targets for treatment. This project not only lays the groundwork for investigating secondary satellite cell-opathies, which will advance our understanding of the role of muscle stem cells in disease progression, but it also holds potential for offering patients with satellite cell-opathies individualized therapy options.
Clinical Fellowship Recipient
Dr Bram De Wel obtained his medical degree and completed his residency in neurology at the University Hospital Leuven in Belgium. During his residency, he obtained a PhD in neuromuscular diseases with a focus on advanced outcome measures in spinal muscular atrophy and muscular dystrophies. Dr De Wel will complete a neuromuscular medicine and EMG fellowship at the University of Calgary.
Clinical Fellowship Recipient
Dr Mark Krongold completed a bachelor’s degree in Neuroscience at the University of Calgary and medical school at Western University. He is currently completing his neurology residency at the University of Manitoba. Through his experiences in neurology, he developed an interest in electrodiagnostics and neuromuscular medicine. He looks forward to pursuing a career filled with constant learning and the chance to have a positive impact on patient’s lives. With support from the National Clinical Fellowship in Neuromuscular Medicine & Electromyography he will join the University of British Columbia for training in the upcoming year.
Clinical Fellowship Recipient
Dr Yiu-Chia Chang studied Microbiology and Immunology at McGill University. He then obtained his medical degree at University of Ottawa and matched to Western University for residency training in neurology. During his residency, he developed a keen interest in neuromuscular medicine early on and took on extra rotations in the neuromuscular clinics and EMG lab. Among different sub-specialties within the neuromuscular field, Dr Chang is particularly interested in muscle diseases. During his fellowship, he aims to expand his knowledge and skills in the management of neuromuscular diseases and electrodiagnostics, as well as to acquire expertise in muscle diseases. He also aspires to be involved in medical education, with the goal of offering well-organized curriculum in neuromuscular medicine for trainees.
Advanced human myo-fibrogenic 3D models for COL6 disease modeling and therapy development
How changes in Col6 gene lead to the various symptoms seen in Col6-RD is still a poorly understood which limits amongst others clinical trial development and identification of potential drug targets. This study will develop 3D muscles created from patient-derived iPSC- myogenic and fibrogenic cells, a critical step to further understanding this disorder as well as establishing genetically relevant models to test future COL6-RD therapies.
Further steps toward an RNA-based therapy for COL6-RD
In recent years, there has been rapid development of gene therapy tools in genetic disorders. With this project the researchers are taking the first of many steps towards establishing a potential therapy using the novel CRISPRoff technology to target dominant glycine changes causing COL6-RD.
Evaluating the impact of stop variants on MLIP’s (Muscular LMNA-Interacting Protein) function in muscle
Genes contain all of the information necessary to produce a protein. Changes in the spelling of genes can heavily change protein functions and might cause health problems. Rare neuro/muscle disorders are caused by changes in the spelling of genes important for keeping muscles healthy. With the advance of technology, we are able to diagnosis patients by identifying differences in their genetic code. We and others have shown new variants (or genetic code differences) in the gene MLIP (Muscular LMNA-Interacting Protein), thought to be liked to muscle related disorders (myopathies). Little is known yet about MLIP’s function, except that is highly expressed within the muscle. It interacts with the lamin protein, also known to be important for heart and muscles functions. We believe the altered protein is associated with a myopathy seen in children and adult patients. MLIP has only recently been linked with myopathies. Unfortunately, we do not know enough of MLIP role. As so, we will study the effect of MLIP mutations in our laboratory. More specifically, we will reproduce genetic changes found in existing patient’s genes in a cellular model. This will allow us to see how muscles are formed, maintained and affected by MLIP. We believe the study of this mutation will greatly improve our understanding of myopathies. It will also improve patient diagnosis. It will contribute to a better understanding of the role of MLIP in certain myopathies.
How genealogies (family histories) can help us understand myotonic dystrophy type 1
Myotonic dystrophy type 1 (DM1) is a disorder that occurs more frequently in some regions. It is caused by the expansion of a repeated genetic sequence in the DMPK gene. However, the link between this gene and the severity of the disorder is unclear. Other genetic changes such as modifier genes have been proposed to better explain the disorder. Modifier genes affect the expression of other (main) genes. Nevertheless, few human studies confirmed the presence of such genes in patients with DM1. Here we propose to look for modifier genes in DM1 patients from the Saguenay-Lac-Saint-Jean (SLSJ). The SLSJ region has the highest incidence of DM1 worldwide, with a frequency of ~1/630, due to its strong founder effect. For this study, we will join many types of data for 200 patients with DM1 from the SLSJ. Since patients with DM1 in SLSJ mostly come from only one ancestor, we expect to see shared regions around the disorder genes. Thus, we propose to apply statistical methods to identify new modifier genes linked to DM1 in these patients. This could be the first step in beginning therapies or treatments for patients with DM1. Additionally, finding modifier genes associated with earlier DM1 onset could lead to early preventive therapies. These new findings will have an impact on DM1 research, but also for many other rare neuromuscular disorders.
Therapy development for centronuclear myopathy caused by DNM2 gene changes
Centronuclear myopathy (CNM) is a common genetic form of childhood muscle disorders. Patients with CNM usually start experiencing symptoms starting from birth. The disorder can be extremely severe. It may require breathing and feeding tube support in some individuals, and can result in early death. Genetic changes in 5 different genes can cause CNM. Despite the fact that these are severe and life limiting disorders, there are no treatments. Our study will focus on one subtype of CNM caused by genetic changes in the DNM2 gene. DNM2-CNM is the second most common form of CNM. There are currently no therapies in development for DNM-CNM. We have identified several potential candidate treatments. These drugs have yet to be tested and validated in a suitable model of the disorder. The goal of this proposal is ultimately to bring treatments to patients with DNM2-CNM. We will accomplish this goal by testing promising candidate drugs in a recently developed mouse model of DNM2-CNM. Successful completion of our study will result in the first potential therapies for DNM2-CNM. The drugs we plan to test are all already Health Canada-approved. They thus hold great potential for direct translation to patients. Importantly, we have successfully used this strategy before for a different muscle disorder. This lends confidence that our approach will work for DNM2-CNM as well.
Pre-clinical testing of novel pharmacological inhibitors of toxic DMPK mRNA in models of myotonic dystrophy type 1
There is currently no cure for patients with myotonic dystrophy. This muscle disorder is caused by an expansion in a section of the gene – a highly repetitive sequence called CTG triplet repeats. When that happens, it can be toxic in muscles and result in defects in the alternative splicing of several transcripts. There is a great need for a drug that targets the expression of the mutant gene or its toxic product in the muscles of patients. We developed a new drug that inhibits the expression of the mutant gene. This drug corrects the mis-splicing of key transcripts in muscle cells from patients. What we want to explore in this proposal is the capacity of the drug to work in an animal model of the disorder. We will assess the activity of these drugs in a mouse model expressing a human copy of the mutant gene. We will measure how this drug reduces the expression of the toxic transcript. This project might lead to the development of new drugs for the treatment of patients with myotonic dystrophy and improve their quality of life.