Maximal muscle strength (MMS) is a key measure of how well a person’s muscles are working People affected by neuromuscular disorders have weaken muscle strength amongst others. Moreover, in some types of NMDs like myotonic dystrophy type 1 we have shown that strength training leads to lasting improvements in muscle strength (Roussel 2019). In order to be able to know if a person’s maximal muscle strength is “normal” we need a comparison or reference chart of what would be expected of a healthy individuals of similar age, sex, weight and height. This chart will be necessary to identify muscle weakness in order to accurately measure changes overtime and treatment efficacy. To develop this chart this research team will use standardized protocols using high quality, accessible and user-friendly handheld dynamometers (HHD) which can measure in clinic , rapid, accurate, valid, reliable and sensitive MMS value of 300 healthy participants (30 men/30 women in each decade from 18 to 69) using a standardized HHD protocol In addition to provide descriptive statistics of MMSs, predictive equation models will be established from data collected, which will allow clinicians to compare MMS measured to the expected MMS values for the same age and sex.
Such reference values will allow documenting muscle strength changes, assessing intervention effectiveness and guide prognosis in order to optimize healthcare for people living with NMD.
Genetic changes or mutations in the NEFL gene cause severe pediatric forms of Charcot-Marie-Tooth disease type 2E. Recent progresses of genetics points to an increasing contribution of genes involved in neurofilaments (NF) homeostasis as a cause of Hereditary Motor Sensory Neuropathies (HMSN). The NF network provides an excellent biomarker for the development of therapies targeting the mechanism of sensory motor degeneration. Kinases, small molecules in our bodies, like the casein kinase 1 (CK1), play a crucial role in the complex assembly process of NFs and our preliminary data point to a role of CK1 in the development (or )of these HMSN. Our proposal aims to determine the role of CK1 in the pathogenesis of HMSN and the therapeutic potential of a brain permeant CK1 agonist.
We aim:
1) To demonstrate that CK1 is involved in proper assembly of CMT2E-causing mutants NEFL in vitro and in vivo.
2) To demonstrate that CK1 is involved in the pathogenic cascade caused by mutations in GAN, HSPB1 and SACS in cellular models.
3) To Test the therapeutic potential of the CK1 agonist and demonstrate the proof of concept. We expect to identify the contribution of CK1 in the pathogenic cascades of these HMSN and the therapeutic potential of a CK1 agonist. The proposal includes a close collaboration with clinicians (Drs Massie, McGill university) for developing a therapy translatable to human and to identify patient’s populations who will benefit of this therapy.
One group of neuromuscular disorders are caused by inflammation, which is the body’s response to injury or external threats, like bacteria or viruses. An abnormally elevated inflammatory response, however, can result in an attack on the body’s own muscle and/or nerve cells, disrupting their normal function. Presently, individuals with inflammatory neuromuscular disease are subjected to non-specific, ineffective treatments with considerable side effects. The goal of our proposal is to identify novel, disease-modifying therapeutic targets that offer a safer, more effective alternative to alleviate disease symptoms. Granzymes are proteins that are key to the body’s normal inflammatory response. This team of scientists and physicians have shown that these granzymes are active and found at elevated levels in many inflammatory and autoimmune diseases, like skin diseases, asthma, lupus, and multiple sclerosis. Recently, other researchers have found preliminary evidence that granzymes can also be detected at high levels in some neuromuscular disease patients. In our current proposed project, we aim to comprehensively examine 3 different types of inflammatory muscular diseases to assess their granzyme levels, and their relationship to disease severity. These are Inflammatory myopathies; (Myositis; Polymositis, dermatomyositis; inclusion-body myositis); Chronic inflammatory demyelinating polyneuropathy, and Myasthenia gravis.
This study will allow us to better understand if novel therapies can be designed against granzymes to alleviate the symptoms of inflammatory neuromuscular disease.
Nemaline myopathy (NM) is a severe disorder associated with muscle weakness that results in impairments in motor functions such as mobility, speech and eating. Genetic changes also called mutations in at least 10 genes are known to cause NM, with changes in the NEB gene the most common cause. Despite advancing knowledge of what causes the disease and how these causes affect muscle function, there are currently no therapies. Genome editing with the CRISPR Cas9 system is revolutionizing science and also holds great potential as a strategy for treating genetic disease. NM is an ideal candidate disease for CRISPR based gene editing as most of the gene mutations that cause it are well known and restoring the normal working of the mutated gene should result in functional and clinical improvements. This research project aims to use the CRISPR system to correct the NEB exon 55 deletion mutation, the most common single mutation associated with NM, by re-introducing exon 55. So far preliminary data shows NEB exon 55 can be reintroduce into patient muscle cells and thereby restore NEB RNA and protein. Based on these data, the group will examine this therapeutic approach in a mouse model of NM to test if they can restore Nebulin in a living animal and whether such restoration rescues disease in this model. This is a critical study that is essential for developing this strategy for patients.
If successful, it will represent a first potential therapy for NM. The approach will also provide a road map for developing similar approaches for other NM subtypes.
Myotonic dystrophy type 1 (DM1) amongst others includes symptoms like excessive fatigue and sleepiness, lack of motivation, peculiar personality traits and cognitive deficits including organization, decision-making, and interpersonal difficulties. All these features greatly affect an individual’s daily living autonomy, health management as well as individuals’ and caregivers’ social participation. Furthermore, misunderstanding of these unapparent symptoms often bring family and social conflicts. Briefly, most DM-patients and caregivers highlight these neurobehavioral symptoms than the muscular symptoms that are the hallmark of the condition. This project aims to develop and transfer information and practical advices into numeric educational materials to support caregivers regarding neurobehavioral symptoms of DM1. These products would take the form of guides, video capsules and cartoons. The innovative aspect of this project lies on the fact that products will be based on challenging day-to-day life situations experienced by patients and caregivers called “partners”, as they are part of the research team in all study steps. A better understanding/management of neurobehavioral symptoms through personalized multimedia products using patients and caregivers’ experience may improve the patient-caregiver relationship, provide a greater and longer patients’ autonomy, and increase social participation.
Myasthenia Gravis (MG) is a rare condition where individuals impacted experience muscle weakness. This can affect their arms and legs, but also the muscles needed for eating, speaking and breathing, with the risk of dying. With modern treatments, individuals with MG have better health outcomes and reduced risk of death; However, despite current treatments, only 1 in 5 patients are completely symptom-free.
The goal of treatment is to achieve a minimal amount of symptoms with as little side effects as possible. The problem is that currently, we define minimal symptoms and tolerable side effects based on physicians’ and experts’ opinions. We know from other disorders that clinicians’ and patients’ views are often different; however, the preferences of people with myasthenia have not been studied. Given the increasing number of new treatments that are becoming available for this disease, it is important to understand how their use in routine care will improve outcomes that are relevant to patients.
In this project, we will study how people living with MG make decisions regarding new interventions (potential treatments, surgeries etc.), considering the trade-offs between potential side effects, efficacy, and accessibility. We will compare the views of individuals with MG to the views of the physicians who treat them. This study will also serve as a model for other neuromuscular diseases, to understand how patients make decisions regarding new interventions.
Duchenne Muscular Dystrophy (DMD) and LAMA2-related Muscular Dystrophy (LAMA2 MD) are rare and devastating genetic disease of childhood manifested by progressive skeletal muscle wasting and ultimately death. In both diseases, muscle undergoes constant cycles of degeneration-regeneration exacerbated by intrinsic muscle stem cell (MuSC) dysfunction and their impaired ability to support long-term regeneration. The overall goal of the project is to use a combination of single-cell transcriptomics (RNA-sequencing) and proteomics (mass cytometry, CyTOF) to define the cellular composition of diseased muscle tissues at the single-cell resolution. We will delineate the different cell populations that pre-exist and arise during disease progression and classify the novel cellular subsets involved in this process.
This data, in combination with genetic lineage tracing will allow reconstruction of the MuSC lineage hierarchy. We will further characterize cellular subpopulations associated with human muscle dystrophies by performing 3-Dimensional intact-tissue RNA sequencing on patient biopsies. The unbiased elucidation of the cellular events underlying the different steps of muscle disease progression at the single-cell level represents crucial missing information, which will push forward our current knowledge on muscle dystrophies. Ultimately, our goal is to develop new biomarkers and eventually new pharmacological approaches to enhance therapy by stimulating intrinsic muscle tissue repair and capitalize on our single cell expertise to uncover disease-related subsets in human biopsies.
The number of people that use a ventilator (a machine that supports breathing) at home is increasing in Canada and around the world. These individuals have complex health problems, require a lot of care and they use the healthcare system often. Unfortunately, the care for individuals using mechanical ventilators isn’t coordinated which results in frequent visits to the hospital and stress on the patient and family. Virtual care is a way to improve healthcare for individuals using ventilators. Virtual care is a good idea for individuals using ventilators because it can bring “the right people with the right expertise at the right time” into the homes of these complex patients. A newly developed virtual care platform called aTouchAway™ is now developed. It is sophisticated enough to meet the needs of individuals using ventilators and their care needs. This study will test a virtual care intervention using the aTouchAway™ platform for children and adults newly going home with ventilators in Ontario, Canada. We are studying the effect on the following: visits to the Emergency Department, patient and families’ experience and if they like using it, the costs on the healthcare system and healthcare provider time and if they like using the intervention. We have worked closely with individuals using ventilators at home and their families to design this study and make sure the results are important to them. Our study is testing a promising virtual care intervention for individuals newly going home with ventilators. Our results will help to improve the quality of life for individuals using ventilators at home by making their healthcare better.
Duchenne Muscular Dystrophy is a devastating genetic disorder manifested by progressive muscle wasting and ultimately death around the second decade of life. Injection of a secreted protein called Wnt7a greatly enhances muscle regeneration resulting in amelioration of dystrophic progression. However, based on the its chemical nature Wnt7a cannot be delivered via the blood circulation. We have discovered that Wnt7a is normally secreted on the surface of small vesicles called exosomes during muscle regeneration.
Exosomes have been demonstrated to effectively deliver cargo through the circulation to muscle. We will compare the activity of free Wnt7a versus exosomal Wnt7a, we will investigate the mechanism that targets Wnt7a to exosomes, and we will test the ability of exosomal Wnt7a to be delivered to muscle through the circulation. These experiments have the potential to significantly increase the efficacy of Wnt7a for treating Duchenne Muscular Dystrophy, especially when used in combination with gene correction therapies.
Genetic muscle diseases are a heterogeneous group of disorders, that for the greater part, do not currently have any disease-modifying therapies. Many of these conditions cause abnormal swallowing and/or ventilatory function, which has a major effect on quality of life, morbidity, and mortality. Expiratory muscle strength training (EMST) is a rehabilitative approach that can be performed using a handheld device, that provides a customisable amount of resistance to expiration. It is customisable to individual needs, and has preliminary evidence in other neurodegenerative conditions showing it can result in improved swallowing and respiratory function. It has not yet been studied in patients with hereditary muscle diseases.
The objective is to perform an open-label, interventional study of 20 participants with hereditary muscle disease, who have respiratory and/or swallowing impairment. Obtain preliminary data indicating whether EMST has benefit for respiratory/swallowing function.
