Projects Funded 2017

Table of Contents

ALS Canada-Brain Canada Arthur J Hudson Translational Team Grant
ALS Canada Project Grants
ALS Canada Trainee Awards

ALS Canada-Brain Canada Arthur J Hudson Translational Team Grant

Can a promising drug combination address one of the defining biological characteristics of ALS?

Enhancing the efficacy of heat shock protein inducers by cotreatment with a histone deacetylase inhibitor – a therapeutic strategy for ALS

$1.8 million awarded to lead investigator Dr. Heather Durham, McGill University, with collaborators Dr. Josephine Nalbantoglu, McGill University; Dr. Richard Robitaille, Université de Montréal; and Dr. Chantelle Sephton, Université Laval

In ALS and many other neurodegenerative diseases, one of the defining characteristics is that proteins can become misfolded and clump together, potentially damaging nerve cells. When a healthy body responds to stress, protective mechanisms increase the production of heat shock proteins that help prevent protein misfolding. This mechanism can become impaired when healthy motor neurons are compromised by disease processes. For years, Dr. Durham has been studying drugs that might enhance heat shock protein response in motor neurons. Recently, she has found a particular drug combination that can greatly increase the production of heat shock proteins in motor neurons.

This project sets the stage for researching a promising drug combination that may one day become an important therapy for people with ALS. Dr. Durham and collaborating researchers Dr. Josephine Nalbantoglu, Dr. Richard Robitaille, and Dr. Chantelle Sephton will seek to find the optimal combination of heat shock drugs together with a histone deacetylase drug and then examine the protective capabilities of the best combination in ALS mice. They will also investigate how the drugs work, which could lead to the development of potential biomarkers for human clinical trials in the future. The team will collaborate with multiple biotech and pharmaceutical companies that own the unique heat shock and histone deacetylase drugs. If this project is successful, the next step would be for drug companies to conduct toxicity testing and ultimately clinical trials with human volunteers.

ALS Canada Project Grants

What can we learn from mice that are able to walk almost normally despite significant loss of motor neuron function?

C-bouton function in ALS

$125,000 awarded to Dr. Turgay Akay, Dalhousie University

To study ALS in the lab, many researchers create mice with the disease. In recent experiments, they have discovered that the mice can walk almost normally despite significant loss of motor neuron function. One theory about why this is possible is that C-boutons, specialized synapses that provide chemical inputs to motor neurons, may increase in size and number to compensate for the loss of motor neuron function. In this project, Dr. Akay will examine how C-boutons change the chemical input to motor neuron cells to allow ALS mice with severe motor neuron loss to move quite well and whether that effect slows or accelerates ALS progression. He will also test drugs known to change C-bouton signalling to see if motor function can be preserved in ALS mice. If targeting C-bouton function can successfully slow disease progression in mice, it may prove to be a target worth pursuing in human studies in the future to find new ways to improve mobility and possibly slow disease progression.

Could touchscreen technology help to improve testing for the cognitive impairment that occurs in some cases of ALS?

Cognitive assessment in TDP-43 ALS/FTD mouse models using automated touchscreen tasks – a translatable approach for drug development

$110,770 awarded to Dr. Flavio Beraldo, Western University with co-investigators Dr. Marco Prado and Dr. Vania Prado, Western University

A significant number of people with ALS also develop cognitive impairment that may include problems with language, thought processing and behavioural changes. A prominent protein called TDP-43 is associated with ALS and is also related to cognitive impairments in frontotemporal dementia. Over 95% of people with ALS have abnormal TDP-43 protein function. To date, researchers have not been able to effectively investigate cognitive impairment in ALS mice models with TDP-43 protein abnormalities as currently available tests for studying symptoms in ALS laboratory mice are not very sensitive and are prone to human error in measurement. Dr. Beraldo and colleagues are using a touchscreen system that resembles a box that uses iPads as the walls. By using food as a reward, they have trained mice to recognize images and touch the walls with their noses. In this project, the researchers will measure how well ALS mice complete the same tasks and hope to identify subtle levels of cognitive impairment compared to mice without ALS. The touchscreen system will allow the investigators to measure changes in cognitive impairment as motor neurons degenerate in ALS mice. If successful, this new technology could be used as a tool for measuring cognitive impairment in several other ALS mouse models or for screening drugs to find new treatments in the future.

Could targeting the activity of motor neurons in the spinal cord be a new way to diagnose and treat ALS?

Examining the role of KCC2 in maintaining the balance between excitation and inhibition in ALS

$125,000 awarded to Dr. Yves De Koninck, Université Laval

Researchers have found that before the onset of ALS there is an increase in the activity of motor neurons in the spinal cord. One theory about why this happens is that there is a decrease in KCC2, a protein that’s responsible for keeping hyperactivity in check by maintaining the right amount of chloride, a chemical that plays a role in activating neurons. Researchers have identified that people with the sporadic form of ALS have lower amounts of KCC2. Dr. De Koninck has developed two promising drugs that can increase KCC2 production. In this project, he will use ALS laboratory mice to test whether restoring KCC2 levels with these drugs – whether in upper motor neurons that originate in the brain, lower motor neurons that originate in the spinal cord, or both – can prevent neurodegeneration and motor deficits. Dr. De Koninck will also investigate whether measuring KCC2 in spinal fluid can be used as a biomarker to diagnose ALS before symptom onset. Altogether, this project has the potential to help us better understand, diagnose and treat ALS.

Can microscopic bubbles in our bodies be used to deliver ALS treatments through the bloodstream?

Exosome trafficking across the blood-brain-barrier to deliver therapeutics for ALS

$125,000 awarded to Dr. Derrick Gibbings, University of Ottawa, with co-investigators Dr. Baptiste Lacoste and Dr. Maxim Berezovski, University of Ottawa

Gene mutations leading to disease often produce toxic proteins that, in the case of the inherited form of ALS, cause motor neurons to die. One of the most significant advancements in therapy over the past several years is the ability to use technology to target genetic diseases. Scientists have developed many treatments that can reduce the amount of these toxic proteins, but one of the major challenges has been delivering treatments to central nervous system. Our bodies have a specialized barrier called the blood-brain barrier that makes it very difficult to introduce drugs into the brain or nervous system.

Exosomes are microscopic bubbles that our body uses to transport substances from cell to cell. For years, researchers have tried to use exosomes in lab experiments to deliver therapies through the bloodstream, but the amount of treatment that can fit into each exosome has been a major limitation. Dr. Gibbings and colleagues have recently discovered a system to squeeze 1,000 times more treatment into each exosome. In this study, they will first test the ability of their system to deliver treatment to the brain after injection into the bloodstream, measure how many exosomes reach the destination and determine the cellular processes that allow the therapies to cross the blood-brain barrier. Second, they will use a well-studied ALS mouse model with mutations in a gene called SOD1 to see if exosomes loaded with a SOD1-targeted treatment can effectively reduce the levels of toxic, mutant SOD1 proteins. Throughout the project, they will continue working on modifying the exosomes to further enhance their ability to move treatments across the blood-brain barrier. If successful, this initial set of tests may provide the evidence needed to advance to testing exosome-delivered treatments in human clinical trials in the future.

Can adjusting the levels of a “guardian” protein protect a protein that becomes toxic in most cases of ALS?

Regulation of TDP-43 toxicity by Hsp90/STI1

$125,000 awarded to Dr. Marco Prado, Western University with co-investigators Dr. Martin Duennwald and Dr. Flavio Beraldo, Western University

Increased levels and clumping of the protein TDP-43 occur in more than 95% of ALS cases, making it an attractive target for understanding what causes the disease and finding new ways to treat it. In normal cells, a set of proteins called heat shock proteins may act as guardians to defend against TDP-43 toxicity. Dr. Prado and colleagues have demonstrated that the amount of a heat shock protein called STI1 is lower in ALS motor neurons compared to healthy motor neurons and that these lower levels directly affect the toxicity of abnormal TDP-43. In this project, they will study mice with abnormal TDP-43 and determine whether increasing or decreasing STI1 levels can preserve motor neuron health. Understanding this mechanism of action may shed light on future potential avenues for treatment. This project could also provide the first evidence that STI1 itself might be a valuable target to test in human clinical trials.

Why are eye muscles often more resistant to ALS, and what can we learn about this that could help to preserve the function of other muscles?

Unraveling neuromuscular junction resistance in ALS

$121,048 awarded to Dr. Richard Robitaille, Université de Montréal with co-investigator Danielle Arbour

Many researchers believe that one of the earliest events in ALS is the detachment of motor neurons from muscles at a site called the neuromuscular junction (NMJ) and have discovered that some NMJs are more vulnerable than others. In both humans and ALS laboratory mice, the eye muscles preserve the connections longer, which is why many assistive technology devices for ALS use eye movements for control. Previous work by Dr. Robitaille has revealed that specialized supporting cells called Perisynaptic Schwann Cells (PSCs) are critical for maintaining the NMJ connection and that PSC function is impaired in ALS mice. In this project, Dr. Robitaille will examine PSC function in ALS mice before and after they develop disease symptoms and compare the results to normal mice. He will also compare PSC function in eye NMJs with PSC function in leg NMJs, which are known to show early impairment. Also, Dr. Robitaille will analyze the entire set of proteins in both the resistant and susceptible NMJs and compare the results to look for specific markers that might explain the preserved function in eye muscles. If successful, this project could discover new targets for treatments that might preserve NMJs all over the body by enhancing PSC function.

Could the change in communication processes between motor neurons and the immune cells of the nervous system after an ALS diagnosis help to identify new treatment targets?

Development of human iPSC-based assays to study microglia-motor neuron communication in ALS

$124,930 awarded to Dr. Stefano Stifani, McGill University

Increasing evidence shows that the communication between motor neuron cells and other cell types plays a role in disease progression. Microglia, the immune cells of the nervous system, play a role in protecting motor neurons in healthy people but during disease processes like with ALS, they can become inflammatory and contribute to motor neuron death. These communication processes are challenging to study in human volunteers. In this project, Dr. Stifani will grow human microglia and motor neurons in the laboratory from the blood cells of people with ALS and examine how the cells communicate. He will compare the communication processes with ALS cells with those from cells that do not have ALS mutations. Overall, this project may provide a new understanding of how microglia play a role in human ALS and reveal new treatment targets. Dr. Stifani is already pursuing a similar study with another glial cell type called astrocytes as part of a research project led by Dr. Guy Rouleau that was funded by ALS Canada and Brain Canada in 2016, making this latest grant an important addition to an ongoing project expected to have a significant impact on ALS research.

Can image-guided focused ultrasound technology be used safely in people living with ALS as a means of delivering future treatment?

Safety and feasibility of primary motor cortex blood-brain barrier opening using transcranial MR-guided focused ultrasound with intravenous ultrasound contrast agent in patients with amyotrophic lateral sclerosis

$124,948 awarded to Dr. Lorne Zinman, University of Toronto with co-investigators Dr. Nir Lipsman, Dr. Kullervo Hynynen, Dr. Sandra Black, Dr. Todd Mainprize, and Dr. Agessandro Abrahao, University of Toronto

Delivering promising treatments to the nervous system is challenging because our bodies have a specialized barrier called the blood-brain barrier that makes it difficult to introduce drugs into the brain or nervous system. Researchers at the Sunnybrook Health Sciences Centre and the University of Toronto have developed a new technology to deliver treatments through the blood-brain barrier using image-guided focused ultrasound that can open small spaces in the barrier to let the treatments cross into the brain. They have demonstrated the safety of this technique in people with essential tremor and are currently studying the approach in patients with Alzheimer’s disease in a clinical trial. In this project, Dr. Zinman and colleagues will test the safety of image-guided focused ultrasound in eight people living with ALS. If successful, the team hopes to use the technology to deliver promising treatments that target upper motor neurons to enhance treatments that are currently directed at lower motor neurons and are already being tested in clinical trials.

ALS Canada Trainee Awards

Could whole genome sequencing reveal new areas of genetic mutations that make some people more likely to develop ALS?

Whole genome sequencing to identify novel loci in French-Canadian ALS patients

$75,000 awarded to Jay Ross, a PhD student in Dr. Guy Rouleau’s lab at McGill University

DNA is a complex molecule containing a sequence of genes that act as the master code for building and maintaining living things. Changes in the sequence are not necessarily harmful, but a small percentage of gene mutations can result in diseases like cystic fibrosis, Huntington’s disease and ALS. Using a technology called exome sequencing that uses human blood samples to examine specific sections of DNA, scientists have discovered several genes and genetic mutations related to ALS. Newer technology, called whole genome sequencing, has provided scientists with the ability to examine the complete set of DNA, known as the genome, instead of just the sections that carry protein instructions. ALS Canada is leading Canada’s participation in Project MinE, a multinational initiative to create an open-access database of the full DNA profiles of people living with ALS that researchers around the world can use to look for insights. In this project, Jay Ross, a PhD student in Dr. Guy Rouleau’s lab at McGill University, will analyze whole genome sequencing data from the Project MinE database for a group of French Canadians living with ALS to look for new areas of genetic mutations that make some people more susceptible to developing the disease. Additionally, he will investigate how the mutations influence disease processes at the cellular level, which may lead to the identification of new targets for potential drug treatments.

How might misfolded proteins that occur in ALS cause cells to die?

RGNEF and Cellular Stress Response in ALS

$50,000 awarded to Sonja Di Gregorio, a PhD student in Dr. Martin Duennwald’s lab at Western University

Proteins are the substances responsible for almost all cellular functions and are often called the workhorses of the cell. To perform their tasks in the body correctly, proteins must first fold into the right 3D shape. Misfolded proteins, those that do not adopt the correct shape, can be harmful to cells. The body uses a variety of “quality control” mechanisms to help misfolded proteins refold into the right shape or destroy them before they can pose a threat. In some cases, however, these quality control mechanisms fail to prevent misfolded proteins from accumulating, which can cause cells to die. Protein-misfolding processes have been associated with a variety of different neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease and ALS.

Sonja Di Gregorio, a PhD student in Dr. Martin Duennwald’s lab at Western University, is studying how the misfolding of three ALS-associated proteins —TDP-43, FUS/TLS and RGNEF — affects the quality control mechanisms of cells, and why protective processes fail in ALS. Using yeast cells that have been altered with genetic mutations linked to ALS, she will investigate how accumulated misfolded proteins lead to cell death. She will also study the biological properties of RGNEF, a protein only recently linked to ALS, to identify how mutations in this protein may lead to the development of ALS. For this part of the project, Di Gregorio will use yeast models, animal cell models and post-mortem human tissue samples. Findings from this project may provide a new target for the development of ALS treatments.

Will probiotics that improve ALS symptoms in worms also work in mice?

Effect of microbiota on neurodegeneration profiles in ALS C. elegans and mouse models

$75,000 awarded to Audrey Labarre, a PhD student in Alex Parker’s lab at the Université de Montréal

Trillions of microbes including bacteria, fungi and viruses live on and in the human body in a community called the microbiota. Many of the microbes are friendly and contribute to normal, healthy functions – but others are associated with diseases. For example, changes in the collection of microbes in the respiratory tract have been linked to asthma. Recent scientific evidence has found a link between changes in the microbiota and neurodegenerative diseases like Parkinson’s disease.

To investigate whether the microbiota plays a role in ALS, Audrey Labarre, a PhD student in Dr. Alex Parker’s lab at the Université de Montréal, has been studying ALS worms. Worms are useful models for studying the biology of ALS because they have a short life span, allowing scientists to see quickly how new experimental treatments affect mobility and disease progression. When scientists alter worms by creating a genetic mutation that causes ALS, the worms develop motor neuron degeneration and paralysis. Labarre’s work to date has involved treating ALS worms with probiotics – friendly, live bacteria that are known to be beneficial to the digestive tract. She has found that certain strains of probiotics have resulted in reduced death of motor neurons as well as increased mobility in the worms. In this project, Labarre will treat ALS mice with the same probiotic strains to see if she can find similar results. This research may confirm a link between the microbiota and ALS, paving the way for future therapies that could target the bacterial population in the digestive systems of people living with ALS.