Projects Funded 2020

Table of Contents

ALS Canada-Brain Canada Discovery Grant Program

ALS Canada Clinical Research Fellowship

Mitsubishi Tanabe Pharma Canada Fellowship

La Fondation Vincent Bourque-ALS Canada Career Transition Award

2020 ALS Canada-Brain Canada Discovery Grant Program

How do mutations in the CHCHD10 gene contribute to ALS disease processes?

Investigating the role of mutations in CHCHD10 using ALS cell and zebrafish genetic models

$125,000 awarded to Dr. Gary Armstrong, in collaboration with Dr. Eric Shoubridge, The Neuro (Montreal Neurological Institute-Hospital) at McGill University

In 2014, mutations in a gene called CHCHD10 were newly identified as a genetic cause of ALS. Later, in 2018, co-recipient Dr. Eric Shoubridge discovered that the role of CHCHD10 in ALS is connected to another protein, called CHCHD2.

The exact way in which mutations in CHCHD10 and its interaction with CHCHD2 lead to motor neuron loss in ALS is yet to be fully understood. However, preliminary data suggest that these mutations may lead to impaired functioning of mitochondria, structures within cells that provide the energy the cell needs to survive.

With this grant, Dr. Gary Armstrong, an ALS zebrafish expert, will collaborate with Dr. Shoubridge, a world-renowned mitochondrial expert, to better understand the roles of CHCHD10 and CHCHD2 in ALS. Using patient cells and zebrafish models in the laboratory, Dr. Armstrong will explore the biological pathways impaired by mutations in CHCHD10 that ultimately lead to the neurodegeneration seen in ALS.

This project provides a unique opportunity to study the function of both proteins, as well as the role they play in ALS, and the results could lead the way to identify new treatment targets for the disease.

How does the loss of the normal function of DNAJC7 cause ALS?

Mutations in the gene encoding the molecular chaperones DnaJC7 in amyotrophic lateral sclerosis

$125,000 awarded to Dr. Martin Duennwald, Western University in collaboration with Dr. Sali Farhan, The Neuro (Montreal Neurological Institute-Hospital) at McGill University.

In 2019, a team of scientists led by co-recipient Dr. Sali Farhan discovered a new genetic cause of ALS called DNAJC7. Subsequent work revealed that mutations in the DNAJC7 gene lead to production of a protein that is unable to perform its normal function in cells. However, it is not yet known exactly how this impaired protein contributes to the development of ALS. For this project, yeast and protein folding expert Dr. Martin Duennwald will collaborate with Dr. Farhan to better understand the role of DNAJC7 in causing ALS.

It has been previously established that the DNAJC7 protein is part of a system called the heat shock response, which helps to guide the proper folding (e.g., shape) of other proteins within cells. Here, the team will focus their efforts on understanding if the loss of DNAJC7 function affects the folding of two other prominent ALS-causing proteins, TDP-43 and FUS. These proteins are known to become misfolded in ALS and are thought to play a role in the ensuing neurodegeneration.

The team will also gather clinical information from people with DNAJC7 mutations in order to better understand the clinical characteristics of this form of the disease. In a collaborative study, led by Dr. Kevin Eggan at Harvard University, the team will analyze motor neurons and other cell types derived from these individuals.

By gaining a better understanding of the biological pathways affected by DNAJC7 mutation and the subsequent loss of function, these scientists will hopefully be able to pinpoint new targets and strategies for the treatment of ALS.

How does a new experimental treatment for ALS behave within the body?

Advanced pharmacokinetics and pharmacodynamics for phase Ib/IIa trial of repurposed enoxacin therapy for patients with ALS

$125,000 awarded to Dr. Angela Genge, The Neuro (Montreal Neurological Institute-Hospital) at McGill University, in collaboration with Dr. Eran Hornstein, Weizmann Institute of Science.

A Phase 1/2 clinical trial led by Dr. Angela Genge and co-recipient Dr. Eran Hornstein is currently underway to test the safety and tolerability of enoxacin in people living with ALS. Enoxacin is an antibiotic that on a cellular level is known to activate an enzyme called DICER, which in turn can increase the levels of specific substances called microRNA (miRNA), both of which have been shown to be reduced in people living with ALS.

With this grant, the team will conduct more in-depth analyses to further assess the value of enoxacin in ALS. Researchers will measure the ability of enoxacin to reduce miRNA levels in Cerebrospinal fluid and blood. They will also assess the levels of neurofilament light (NF-L), currently considered the best marker of neurodegeneration.

Furthermore, it has been determined that enoxacin inhibits the enzyme that breaks down riluzole in the body. Since participants in the trial will be allowed to take riluzole, this study will do the important work of understanding how riluzole dosing should be modified for participants taking enoxacin to prevent undesired side effects.

Results from this study will not only provide evidence around a potential therapy for patients with ALS but will also leverage the existing fully funded clinical trial by adding value to the study data, to ensure a clear evaluation of the effects of enoxacin in ALS.

Can embodied mindfulness improve patient and caregiver quality of life?

An interdisciplinary approach to mindfulness as a quality-of-life improvement factor for people with ALS and their primary caregivers

$121,950 awarded to Dr. Angela Genge, The Neuro (Montreal Neurological Institute-Hospital) at McGill University, in collaboration with Dr. Francesco Pagnini, Università Cattolica del Sacro Cuore and, Lana Kim McGeary, Antonietta Vitale, Nathalie Magnan, Kendra Berry, Maura Fisher, Kalyna Franko, Dr. Rami Massie, The Neuro (Montreal Neurological Institute-Hospital) at McGill University.

Mindfulness is a therapeutic technique that teaches one to focus on the present moment, while calmly acknowledging and accepting their feelings, thoughts, and bodily sensations. Previous research has demonstrated that learning mindfulness can help with navigating grief and benefit overall quality of life.

In this pilot study, the first of its kind in ALS, a specific type of mindfulness will be used. Called embodied mindfulness, this approach uses defined physical movements to enhance the ability of people living with ALS, and their caregivers, to notice variability in breathing patterns, leading to a greater sense of perceived control and in turn improved quality of life.

This six-month qualitative study will recruit 40 participants, including people living with ALS and their caregivers, to determine whether an interdisciplinary embodied mindfulness protocol that combines home and clinic exercises can improve quality of life, using multiple established measures.

The findings from this study will help to inform future care for people living with ALS. If successful, the investigators hope that mindfulness-based interventions will be considered a best-practice approach to clinical care in the future.

Is there a link between metabolism and ALS disease progression?

Crosstalk between immune response and metabolic signaling: targeting leptin/AMPK axis to restore metabolic homeostasis in ALS

$125,000 awarded to Dr. Jasna Kriz, CERVO Brain Research Center at Université Laval, in collaboration with Dr. Nicolas Dupré, CHU de Québec-Université Laval and Dr. Angela Genge, The Neuro (Montreal Neurological Institute-Hospital) at McGill University.

Increased metabolism (hypermetabolism) is a characteristic often associated with more aggressive, faster progressing cases of ALS. Recently, after studying blood plasma samples from people with more rapidly progressing disease, Dr. Jasna Kriz discovered that fast progressing individuals often have decreased levels of a hormone called leptin, and increased levels of specific immune markers called CCL16 and sTNF-RII.

With this grant, Dr. Kriz and her team will examine whether these specific blood markers are directly linked to more aggressive forms of disease and therefore whether they may be able to serve as predictors of disease progression. Using ALS cell and mice models, they will also explore whether manipulating the levels of these markers could help to mediate disease progression. Finally, it is hypothesized that the altered leptin levels result from overactivation of an enzyme called AMPK, and the team will determine if targeting this enzyme represents a potential therapeutic strategy for ALS.

This work will shed light on potential biomarkers of ALS disease progression and help researchers to understand whether correcting this abnormal signature can have beneficial effects on slowing disease course.

Can new understandings about neuroinflammatory pathways lead to new treatment targets for ALS?

Cytosolic DNA sensing in ALS-related neuroinflammation

$125,000 awarded to Dr. Honglin Luo, in collaboration with Dr. Neil Cashman, University of British Columbia

Recently, Dr. Honglin Luo, in collaboration with Dr. Neil Cashman, discovered that mutations in the ALS-linked SOD1 gene result in activation of a specific neuroinflammatory pathway called cGAS-STING. Neuroinflammation is thought to play an important role in the progression of ALS and activation of this specific pathway has been identified in laboratory animal models of two other prominent causes of ALS, C9ORF72 and TDP-43.

With this grant, Drs. Luo and Cashman will further investigate how the cGAS-STING pathway is affected in SOD1-linked ALS using mice that have ALS mutations and either the cGAS or STING genes removed. This will help to determine if these pathways are critical to the motor neuron degeneration in SOD1 mice. They will also investigate the roles of cGAS and STING in the laboratory using cells expressing mutant forms of two other ALS-linked proteins, TDP-43 and FUS.

Ultimately this work will advance our understanding of the role of the cGAS-STING pathway in ALS disease progression and may reveal a promising new target for future therapies.

Can probiotics influence the disease course of ALS?

Targeting metabolic dysfunction in ALS

$125,000 awarded to Dr. Alex Parker, Centre de recherche du CHUM at Université de Montreal in collaboration with Dr. Matthieu Ruiz, Université de Montreal.

In recent years, scientists have learned that changes in gut bacteria can influence overall health. In fact, evidence suggests that the gut microbiome can play a role in one’s susceptibility to diseases, including those of the brain. While studying probiotic bacterial strains in the laboratory, Dr. Alex Parker discovered that one specific strain, HA-114, protected motor neurons from degeneration in worm models of ALS, and subsequently confirmed this effect in mice.

It was hypothesized that this specific bacterial strain was able to protect motor neurons by working to correct problems in a cellular process that metabolizes fatty acids, called mitochondrial β-oxidation.

With this grant, Dr. Parker, will further investigate the specific mechanisms by which the HA-114 bacterial strain leads to neuroprotection in an ALS mouse model. Further, in collaboration with metabolomics expert Dr. Mattieu Ruiz, the team will examine a large-scale profile of all the metabolic changes that occur when HA-114 is fed to mice.

If the team can identify key metabolites and pathways influenced by the HA-114 probiotic strain that  are responsible for the protective effect, new therapeutic targets will be identified that could lead to intriguing treatment possibilities in the future.

Is it possible to target the root cause of C9ZORF72-linked ALS?

Modulating the ALS-associated C9ORF72 repeat expansion in a murine model for therapeutic benefit

$124,999 awarded to Dr. Christopher Pearson, The Hospital for Sick Children (SickKids), in collaboration with Dr. Ekaterina Rogaeva, University of Toronto.

Mutations in a gene called C9ORF72 are the most common genetic cause of ALS. These mutations are unique in that unlike most other ALS-linked genes, where there is often a mistake in a single piece of DNA, C9ORF72 mutations involve a section of DNA that is abnormally repeated hundreds or even thousands of times. People with these repeat mutations make less of the normal C9ORF72 protein, but also produce more toxic substances in their motor neurons.

Dr. Christopher Pearson is an expert in studying repeat DNA expansions in disease and through his recent work, he has identified a previously unobserved characteristic about the C9ORF72 expansion mutation that makes it a potentially druggable target.

In this study, Dr. Pearson will determine if treating C9ORF72 model mice with a compound called fluorodeoxyuridine (FUdR) can cause these repeated DNA sections to shrink back to a less toxic size and restore production of the normal C9ORF72 protein. In collaboration with Dr. Ekaterina Rogaeva, an expert in studying a process called DNA called methylation, which can also alter C9ORF72 production, the team will examine how this process is affected by FUdR treatment.

The results gained from this project will help researchers to better understand the unique mutations in C9ORF72 and provide insight into novel therapeutic avenues to treat this form of the disease. If successful, the researchers would embark on a larger study to confirm the potential for FUdR as a treatment for C9ORF72-linked ALS.

2020 ALS Canada Clinical Research Fellowship

How advanced brain imaging can help to support ALS clinical trial enrolment and evaluation

Bridging the Gap: MRI texture and its pathological correlates in ALS

$200,000 awarded to Dr. Collin Luk at the University of Alberta

Traditional magnetic resonance imaging (MRI) is an excellent, non-invasive tool for helping doctors diagnose and monitor the progression of diseases like brain cancer or multiple sclerosis, and researchers continue to explore ways it can prove successful in identifying and understanding ALS.

With this award, Dr. Collin Luk will seek to validate an advanced MRI technique, called texture analysis, with the goal it could one day be used as a biological marker, or “biomarker,” of the onset and progression of ALS. Using this technique, Dr. Luk can detect very subtle changes in a brain image that are not visible with a regular MRI scan.

In order to validate this method, Dr. Luk will analyze MRI scans from people living with ALS and compare those with scans of post-mortem brain tissue generously donated from people who had ALS. The brain tissue will also be examined for pathological changes to ensure that the MRI scans accurately reflect the changes happening in the brain on a cellular level. He will collaborate with the Canadian ALS Neuroimaging Consortium (CALSNIC) to validate his findings.

If this new method proves to be successful, a non-invasive MRI scan could help predict disease progression, making it possible for people living with ALS to enroll in clinical trials earlier. It could also give researchers the tools they need to better evaluate the effectiveness of promising new treatments.

While completing this fellowship work, Dr. Luk will also be actively trained to provide care for people living with ALS as a neurologist at the University of Alberta clinic in Edmonton. Combining this cutting-edge clinical research work with a first-hand experience as a care provider will undoubtedly make Dr. Luk an asset in the drive towards a better understanding of the disease and achieving better treatment options.

2020 Mitsubishi Tanabe Pharma Canada Fellowship

 How wearable sensors could help to improve ALS clinical trials

Prediction of change in ALS disease state by tracking movement with wearable sensors

$200,000, awarded by ALS Canada in partnership with Mitsubishi Tanabe Pharma Canada (MTP-CA), awarded Dr. Gordon Jewett at the University of Calgary

ALS progression is typically self-reported and evaluated only during clinic visits, which can occur months apart. This approach offers only a single snapshot of the person’s performance and is susceptible to daily fluctuations in personal factors such as stress, sleep, diet, and fatigue, which can influence the outcome. As such, tools that can continuously evaluate motor function are needed.

Wearable sensors are becoming common practice in helping people track their personal health and there have been a number of studies in recent years that have begun to evaluate their applicability to ALS. These devices usually include an accelerometer and gyroscope which can monitor a person’s movement during normal daily activities), and can connect to a computer via Wi-Fi. Thus, by placing one of these sensors on an arm or leg, researchers can capture and relay difficulties with limb movement due to ALS.

With this award, Dr. Gordon Jewett will utilize his undergraduate background in biomedical software engineering to monitor limb movement in people living with ALS using a wearable sensor and utilize machine learning techniques to develop an algorithm that can predict functional decline. The study will also utilize the Canadian Neuromuscular Disease Registry (CNDR) as a means of recruitment and comparison of wearable data with standard clinical data. Collaboration with the Canadian ALS Neuroimaging Consortium (CALSNIC), which is also supported by the ALS Canada Research Program, will help to validate his findings and provide an additional layer to his work by determining if the changes observed in MRI brain scans correlate with functional changes measured by the sensors.

The ability to accurately measure the functional status of someone living with ALS from data collected through a wearable sensor could significantly benefit the design of clinical trials. This approach could be implemented as a precise, reproducible, convenient and cost-effective outcome measure in ALS clinical trials. It would also make participation more convenient with fewer clinic visits required.

Dr. Jewett will accompany this work with additional training as a neurologist at the University of Calgary ALS clinic. The unique expertise he brings to the field, combined with his clinical duties will be a very valuable addition to the Canadian clinical and clinical research landscape.

2020 La Fondation Vincent Bourque-ALS Canada Career Transition Award

A new biological target that could represent promising new antibody treatment strategy for ALS

Extracellular PPIA: a new target for an antibody-based therapeutic approach for ALS

$250,000 awarded by ALS Canada in partnership with La Fondation Vincent Bourque to Dr. Silvia Pozzi at the CERVO Brain Research Centre, Université Laval

In recent years, scientists have observed higher levels of a specific protein, called Peptidyl-Prolyl Isomerase A (PPIA), in the fluid that surrounds the brain and spinal cord in ALS mice. This has also been observed in people living with the sporadic form of the disease (i.e. those who have no family history).

PPIA is a protein that is typically found inside cells where it completes its normal function, however, when the protein is released into the fluid outside of cells (in this case referred to as extracellular PPIA or ePPIA) there can be a negative effect. Outside of cells, ePPIA can bind to another protein, called EMMPRIN, and this interaction is thought to activate a biological pathway that eventually contributes to motor neuron death.

With this award, Dr. Silvia Pozzi will explore a new therapeutic strategy for ALS that targets this toxic protein interaction. In this study, Dr. Pozzi will further explore the effects of the interaction between ePPIA and EMMPRIN on motor neurons as well as other support cells in the brain, such as glia cells, which are thought to also play a role in the onset and progression of ALS.

In order to block the interaction between ePPIA and EMMPRIN, Dr. Pozzi will develop an antibody that specifically targets EMMPRIN. Antibodies are proteins produced by the immune system to protect the body against foreign invaders like bacteria and viruses, and work by binding to specific proteins on harmful agents and triggering their removal and/or destruction.

By designing an antibody specific for EMMPRIN, Dr. Pozzi hopes to prevent the protein interaction thought to lead to motor neuron death. The ability of the antibody to reduce inflammation and motor neuron death will then be assessed in various ALS mouse models. If the antibody proves to be successful at preventing motor neuron death in mice, the next step will be to determine if similar effects can be seen in humans.

Dr. Pozzi hopes to use this project as a start to a career based on developing antibody-based treatments in the lab that can be elevated to human clinical trials and strengthen Canada’s leadership towards a future without ALS.