Category: Research

ALS is difficult to diagnose because no single test or procedure can firmly identify the disease. Current diagnostic tests for ALS focus on ruling out other diseases that share similar initial symptoms. For example, magnetic resonance imaging (MRI) is a test typically used to eliminate a diagnosis of cancer, multiple sclerosis or pressure on the spinal cord due to arthritis. A standard MRI analysis of a person with ALS, however, usually shows normal results.

The lack of a reliable diagnostic test for ALS means that it takes on average about a year for a diagnosis to be confirmed. “The delay means we can’t help people sooner, nor identify them early enough to enter a clinical trial,” said Dr. Sanjay Kalra in an interview with ALS Canada. “This issue is actually hindering the clinical investigation of drug therapies. If we could identify people with different types and progressions of ALS more quickly, we could find a breakthrough therapy faster. A test is desperately needed that can determine if a drug is working in clinical trial.” Dr. Kalra is a professor in the department of medicine (neurology) and member of the Neuroscience and Mental Health Institute at the University of Alberta.

Looking for ALS in Brain Images

Dr. Kalra has been intrigued with finding a way to harness the power of imaging to uncover the early signs of ALS since his medical residency when he met neurologist Dr. Douglas Arnold, an MRI specialist at the Montréal Neurological Institute and Hospital. “My residency research rotation was only supposed to last six months, but after realizing the potential power of this technology in research and really enjoying working with people with ALS, I decided to continue and eventually stayed as a postdoctoral fellow specializing in MRI for ALS,” said Dr. Kalra.

Dr. Kalra has secured funding for his imaging research program from a number of sponsors including the Canadian Institutes of Health Research (CIHR), the major agency of the Canadian government responsible for funding health research in Canada. His focus has been to develop and validate advanced MRI methods that can be used as a biomarker, a biological marker that allows physicians to detect disease earlier, monitor disease progression and evaluate new therapies.

In 2013 he founded the Canadian ALS Neuroimaging Consortium (CALSNIC), a multidisciplinary team of experts from across Canada that includes neurologists, MRI scientists, computing scientists, neuropathologists and a biostatistician. Since then, the CALSNIC team has been working together on a national scale to develop advanced MRI methods to find biomarkers in people with ALS and related conditions.

Dr. Kalra and three colleagues at the University of Alberta in Edmonton conducted a preliminary study in 2014-2015 to look for biomarkers in brain images using MRI scans of 19 people with ALS and 20 healthy participants for comparison. They analyzed the images with 3D texture analysis, an advanced method that allowed them to look for statistically significant patterns of brain degeneration not normally visible to the naked eye. They examined voxels, tiny 3D spaces in the brain about a cubic millimetre in size.

The researchers found different texture features in regions of the brain affected by ALS and frontotemporal dementia in people with ALS compared to people without ALS. They also discovered that some features were associated with clinical observations, such as disease duration and differences in finger tapping speed. The study was funded in part by an ALS Canada Discovery Grant.

Going Big: The First Large Imaging Study in the World

Based on encouraging research results in this preliminary study and other work, Dr. Kalra wants to confirm the findings in a larger group of people with ALS. “The ALS field has seen an explosion of imaging studies in the last five years, but for the most part, they have been single-centre studies that used different methods in small groups of patients, so it has been difficult to draw conclusions on the best method to use,” he said. “To develop and validate the use of MRI biomarkers , especially for their potential use in clinical trials, we need to confirm that our these methods will work well on a large scale, in every clinic.”

In 2015, Dr. Kalra and a team of 13 other investigators applied for a grant from ALS Canada and were successful. The resulting ALS Canada – Brain Canada Arthur J. Hudson Translational Team Grant of $2.94 million – the largest grant awarded in ALS Canada’s history – is funding the first large multicentre imaging study focused on ALS in the world, according to Dr. Kalra. The study seeks to enroll over 700 volunteers split between people with ALS and people without ALS for comparison in seven locations: Calgary, Edmonton, Vancouver, London, Toronto, Montreal and Quebec City. Some sites are currently recruiting and others will be up and running soon. Participants receive a baseline MRI and clinical evaluation followed by two follow-up visits.

Always thinking ahead, Dr. Kalra is already considering how to expand CALSNIC further to increase the value of the network. “Another purpose of setting up the CALSNIC infrastructure is that it allows us to probe other questions. I’m excited that it has spurred other ALS research and collaborations,” said Dr. Kalra, “such as at the University of Toronto where Dr. Yana Yunusova is studying speech changes in patients across the CALSNIC network and will be able to compare the findings with our imaging data. In the future, I would like to see CALSNIC build a comprehensive resource of tissue, imaging and clinical descriptions that all scientists can access to understand the disease better.”

ALS Canada has been funding world-class research across Canada for over 30 years to enable discovery of new treatments and therapeutic interventions that have the potential to make an impact on altering the course of the disease or improving the quality of life for people with ALS.

Read more about the ALS Canada Research Program and consider donating today.

A group of ALS clinicians across the country is developing Best Practice Recommendations to set a common standard of care for Canadians living with ALS. Dr. Christen Shoesmith of the London Health Sciences Centre explains. She will be speaking about the Canadian ALS Best Practice Recommendations at the Virtual Research Forum on August 9. Read more and register here.

Why is it important to have best practices in patient care?

In Canada we really feel that it’s important that each patient, no matter whether or not they live in Nova Scotia versus Quebec or BC, all get the same type of care. And that they have the same access to that type of care.

Best practices are extremely important for advocacy for our patients, and establishing what is a standard of care across the country. Without practice guidelines in place, there may be inconsistencies about patient care across the country, or between provinces. But it’s very difficult to decide which province is doing the best. And so if we have a standard set between the provinces, it’s very easy to say a province is not providing the best care for the patients because they’re not meeting the standard that we have set. And providing these Best Practice Recommendations will allow us to know exactly what is the standard, what is the measure at which all the clinics should be measured and all the patient care should be measured against. That will help in both providing excellent care to the patients because the patients deserve the best and most appropriate care for their disease, but also to advocate, to make sure that they have the resources in place to have that best care.

Setting a baseline will make sure that patients get that standard of care for their disease. The other thing is it also speaks to the ability to change, and that we need to have a process that we can adapt and continually review to make sure that we don’t need to make changes as things change.

Right now, we only have a single medication that is approved by Health Canada, but having a guidelines process in place and a group of people that look at the guidelines regularly, will make sure that if there is a new medication that is introduced, that we can adapt that quickly, and so that we can make sure we advocate for our patients to get new treatments as they become available.

One of the big things that we’ve got within our provinces is that we do have a rural versus urban distribution, and so these guidelines will also make sure that those patients that live in northern communities, that may be remote from some of the ALS centres, will get the same type of care. Because even if that patient is unable to travel to the centre because of the geographical distance, their physicians in their local centre will know what the standard of care is so that they can try their best to provide that standard of care for the patient in their local community.

Who has been involved in developing the Best Practice Recommendations? 

We have a number of ALS clinicians across the country that have been involved. We try to do our best to have a geographical representation of clinics across the country. We have someone from Nova Scotia, from New Brunswick all the way over to Alberta. They’re all ALS clinicians in clinics, so they’re either the director of the clinic or a physician that works in the ALS clinic. So we do have a broad representation. And at this time, we have nine active clinicians on the committee that are working at these guidelines.

These guidelines are based on our real-life experiences with how we treat patients and how we manage those patients in our clinics.

How has the development of these Best Practice Recommendations been funded?

We are very, very thankful that ALS Canada has decided this is a very important endeavor, and they recognize that fact for the last few years. And they have supported our project. And we’re very grateful for their support because without it the guidelines would not have been produced.

ALS Canada Virtual Research Forum

Update: Dr. Shoesmith was one of more than 20 speakers who participated in the ALS Canada Virtual Research Forum in August. Some presentations from the forum are available online here.

ALS research is at a significant tipping point, and we can now envision a future where ALS becomes a treatable condition.

This was one of the highlights shared by Dr. David Taylor, Vice President of Research at ALS Canada, during a webinar presentation on June 13, 2017. The webinar was the first in a series of four to provide an update on the latest ALS research, clinical trials and funding programs.

In sharing the advances made in ALS research discovery over the years, Dr. Taylor recalled reading an ALS paper in 2001 that was authored by leading neuroscience researcher Dr. Don Cleveland. The paper outlined four likely contributing causes of ALS, but there was clearly still so much not known about the disease. Since then, however, the major discoveries made possible through research in Canada and around the world have led to significant and exciting progress.

During the webinar, Dr. Taylor shared the milestones of major discoveries since the 1940s and discussed exciting recent advances made possible as the pace of discovery has accelerated significantly. Today, many promising gene targets have been identified, there are several potential therapies in clinical trial, and the drug edaravone (Radicava) was recently approved in the U.S.

Here are key highlights from the webinar:

ALS Discovery Milestones

• 1940s to 1960s: Post-mortem tissue samples and clinical observation were the only tools available for researchers to be able to understand the disease from a biological perspective. By the 1960s, it was discovered that 5 to 10 per cent of ALS cases are familial, meaning they are capable of being passed on from parents to children. The scientific community realized that if the genes involved in familial ALS could be identified, those insights could shed light on the 90 per cent of sporadic cases not linked to a family history.
• 1980s: Advances in technology meant that for the first time, it was possible to identify genes involved in the development of disease. For the ALS research community, this meant a focused effort on finding genetic mutations linked to ALS, and gene-hunting efforts began in earnest.
• 1993: SOD1 was the first gene to be identified as playing a major role in the development of ALS, in about one-fifth of familial/hereditary cases. Over the next 13 years, researchers continued to study the SOD1 gene while also trying to identify other genes that might play a role in the development of ALS – these would provide researchers with the tools needed to create animal and cell models of the disease to understand how it is caused at the cellular and molecular level.
• 2006 to 2011: In 2006, TDP-43 was the second major biological player to be identified as having an important role in the development of ALS. Between 2007 and 2011, scientists discovered several more genes, including C9orf72, linked to ALS.
• 2012 to 2015: The rate of ALS gene discovery accelerated significantly. By the end of 2015, more than 20 genes had been identified and the list keeps growing today.
• Today, researchers are studying dozens of identified gene targets alone and in combination to look for common pathways that determine the mechanisms of disease. Avenues of investigation include inflammation, RNA metabolism defects, misfolded protein errors and cell trafficking mistakes.

New Technologies and Big Data

Precision medicine advances mean that it is now possible to study human ALS in a laboratory setting. Using blood samples, scientists can create stem cells, grow them into motor neurons and other important cells relevant to ALS, and then look for differences in biological signatures between people with and without ALS. The technology is expensive, so many organizations are pooling data, resources and findings. In one initiative called Project MinE, ALS Canada is collaborating with organizations in over 17 countries in to map the DNA profiles of more than 15,000 people living with ALS and 7,500 people without ALS. The goal of Project MinE is to identify the “genetic signature” that leads to the development of ALS, in order to be able to target the development of treatments.

Advanced computing platforms that use artificial intelligence and machine learning can process vast amounts of data, such as the data becoming available through Project MinE, and find connections significantly faster than humans can. Researchers in the U.S. recently used IBM Watson Health to sift through information already known up to 2014 about certain aspects of ALS, as a sort of “training test” to see if this form of machine learning could use that knowledge to predict 2015 and 2016 discoveries. When it did, Watson was given all of the information up to 2016 and asked to predict future discoveries. Watson identified five new ALS genes that are currently being validated.

Biomarkers, biological markers in blood or other tissues that indicate the presence of disease or response to treatment, are now known to be critically important for studying ALS: they could help screen people for entry into clinical trials of experimental therapies that are likely to be effective for them, and allow researchers to determine the effectiveness of experimental treatments. While there are currently few biomarkers for ALS, a 2013 Phase 2 trial of the Neuraltus drug NP001 failed to find an effective response across all participants, but on further investigation of the data, a subset of individuals with elevated signs of inflammation showed no disease progression over six months. As a result, a new trial of NP001 is underway where participants are pre-screened for C-reactive protein, a biomarker for inflammation. The identification of biomarkers for ALS will continue to be an important area of exploration.

Clinical Trials

An encouraging number of clinical trials underway are testing new therapies for ALS. In 2016 alone, there were:

• Many Phase 1/2 studies underway, or on the near horizon. Phase 1/2 studies typically have a small number of participants and their primary purpose is to test safety and determine any adverse side effects.
• A number of prominent studies in Phase 2 should have results in the near future that will tell us if they move on to Phase 3: Lunasin; Neuraltus’ NP001 (with biomarker); tocilizumab (Actemra); and ezogabine (retigabine). Brainstorm (NurOwn) will be moving to Phase 3 soon.
• Two impressive Phase 3 trials, which help to determine if the progression of ALS can be slowed:
  • Masitinib (Europe): Results showed a significant therapeutic benefit i for slowing disease progression and drug approvals were filed in Europe with a decision pending. A global clinical trial for masitinib led by a Canadian investigator will open this fall to solidify if this effect is real.
  • Tirasemtiv (VITALITY-ALS): Phase 3 results are expected this summer, following promising results in Phase 2 that showed a reduction in the loss of breathing capacity

Recent FDA Approval of Edaravone (Radicava)

The biggest news in 2017, so far, is the approval of edaravone (Radicava or Radicut) by the United States Food and Drug Administration in May. It’s the second drug to be approved by the FDA for the treatment of ALS: the first drug, riluzole, was approved more than 20 years ago. In clinical trials, edaravone showed a modest but significant slowing of disease progression among participants who were early in their ALS disease progression with mild symptoms and a large vital breathing capacity.

Fueling Future Discoveries

Dr. Taylor is not the only scientist excited about recent progress in ALS research. The same Dr. Cleveland, whose paper Dr. Taylor read back in 2001, recently co-authored a new paper that said, “There is… little doubt that the pace of discovery will continue or even accelerate in several areas of research …most importantly, there will be considerable achievements in the development of therapies for ALS.”

“We now know a wide range of the genetic mutations involved in ALS to study in order to reach the next breakthroughs — but we have more tools than resources or funding to study all of them in a quick and effective way,” said Dr. Taylor. “At ALS Canada, we believe it’s a matter of ‘when’ not ‘if,’ there will be therapies, and that ‘when’ really does depend on funding.”

Future Webinars

Please join us for the next webinars in the series:

• Clinical Trials: Thursday, June 29, 2017
• Canadian ALS Research: Tuesday, July 11, 2017
• ALS Canada Research Program: Thursday, July 20, 2017

All webinars are free, presented online at 12:00 pm Eastern time.

Read about ALS Canada’s Research and consider making a donation today.

ALS Canada and Brain Canada award $4.5 million in research funding

The ALS Society of Canada (ALS Canada), in partnership with Brain Canada, today announced $4.5 million in funding for nine new ALS research projects. This means that since the Ice Bucket Challenge became a social media phenomenon in 2014, nearly $20 million has been invested in Canadian ALS research at a time when it has the potential to make the greatest impact.

ALS, or amyotrophic lateral sclerosis, is a disease that gradually paralyzes the body, leaving people without the ability to move, talk, swallow and eventually breathe. Most people die within two to five years of being diagnosed with ALS because the disease has no effective treatment or cure. However, ALS research has advanced to a point that many ALS research experts believe effective treatments are now a matter of ‘when’ not ‘if.’

“We hear often from people and families living with ALS that the promise of research discovery is something they can be hopeful about. The challenge is that research takes time, which is exactly what people living with ALS don’t have – and why the Ice Bucket Challenge has been such a game-changer,” said Tammy Moore, CEO of ALS Canada. “Because of the increased funding that the Ice Bucket Challenge has made available, we have been able to make more significant research investments than ever before. We are grateful to Canadians who donated to the Ice Bucket Challenge, to our ALS Society partners across the country and to Brain Canada and the federal government’s Canada Brain Research Fund for making this research investment possible.”

“Brain Canada’s partnership with ALS Canada has enabled greater investment in ALS research, which will in turn accelerate progress towards the development of effective treatments,” said Inez Jabalpurwala, President and CEO, Brain Canada Foundation. “In addition, the discoveries that will result from this research funding have the potential to inform how we approach other neurodegenerative diseases with similar underlying mechanisms.”

The nine projects include two large-scale, multi-year team initiatives – one of which is using stem cell technology to better understand and potentially treat ALS, while the other is studying in a new way the gene most commonly linked to ALS development – and seven smaller studies that enable investigators to explore out-of-the-box research.

“Five years ago, the breadth of ALS research we are funding today would not have been possible simply because we didn’t know enough about the disease to be able to ask the kinds of questions that today’s researchers are investigating in their work,” said Dr. David Taylor, Vice President of Research at ALS Canada. “The fact that we now have the ability to explore ALS from different angles reflects the growing body of knowledge about the disease and the increasing likelihood of effective treatments being developed.”

A research team led by Dr. Guy Rouleau of McGill University and the Montreal Neurological Institute has been awarded $2.2 million to study motor neurons and astrocytes created from people living with different forms of ALS via stem cell technology. Dr. Rouleau and his team, which includes other collaborators at McGill University and the Montreal Neurological Institute as well as Université de Montréal and Université Laval, will study the biology of these stem cells to determine if their characteristics in the laboratory can represent different forms of human disease and further develop them as a potential screening mechanism for therapeutics. The tools and tests created in this project will be valuable for both Canadian and global ALS researchers as new resources to understand the disease and find new ways to treat it.

A research team led by Dr. Janice Robertson of University of Toronto has been awarded $1.6 million to understand whether the most common genetic abnormality in ALS, which occurs in the C90RF72 gene, causes or contributes to the disease through a loss of the gene’s normal biological function. The majority of the research community is focusing on how the genetic abnormality in C9ORF72 might lead to an extra, toxic function, but in this five-year study, the team – which includes other collaborators at the University of Toronto as well as Sunnybrook Health Sciences Centre, McGill University and the Montreal Neurological Institute, and the University of British Columbia – will comprehensively analyze the potential damage to motor neurons lacking C9ORF72, and examine if both loss and gain of function mechanisms combine to cause ALS. This knowledge could fundamentally alter how therapeutics are developed for common forms of ALS as well as frontotemporal dementia (FTD), which often occurs with ALS.

Other projects that have been awarded $100,000 each in funding are:

• Dr. Gary Armstrong at the Montreal Neurological Institute and McGill University is using a state-of-the-art technique in genetic manipulation to create new zebrafish models of ALS for the most prominent genetic cause of the disease, which relates to mutations in the C9ORF72 gene.
• Dr. Neil Cashman at the University of British Columbia is using a unique fruit fly model to study whether a key toxic ALS protein can leap between neurons to explain spread of disease throughout the body.
• Dr. Charles Krieger at Simon Fraser University is studying a substance called adducin that is critically linked to health at the site of connection between motor neurons and muscle, in order to understand whether this substance might represent a target for treatment to slow the progression of ALS.
• Dr. Éric Lécuyer at Université de Montréal is using a unique set of scientific tools to comprehensively analyze the contents of key structures in ALS called stress granules.
• Dr. Marlene Oeffinger at the Institut de recherches cliniques de Montréal is studying structures called paraspeckles to understand their content and how they function, as well as how they are altered in neuronal cells that have ALS-causing mutations.
• Dr. Alex Parker at the Université de Montreal is undertaking a study to understand how probiotics slow down the progression of ALS symptoms in worms.
• Dr. Lisa Topolnik at the Centre Hospitalier de l’Université Laval will study how certain neurons called interneurons, which connect to motor neurons in the brain, might be implicated in the early stages of ALS.

All of the research projects were selected through a competitive peer review process, regarded as the international benchmark of excellence in assessing projects for research funding. The peer review process engages a panel of international experts in ALS and other neurodegenerative diseases in evaluating and ranking all proposed research projects based on their scientific merit and on the potential to most quickly advance the field of ALS research in order to develop effective treatments. All aspects of the peer review process are executed in full partnership with Brain Canada, whose funds are provided through a partnership with Health Canada known as the Canada Brain Research Fund.

Approximately 1,000 Canadians are diagnosed with ALS each year. At any time, there are approximately 2,500 to 3,000 people living with the disease in Canada, and the average cost of caring for one person with ALS is between $150,000 and $250,000. Every day, two to three Canadians will die of ALS.

About Canada’s ALS Societies
ALS Societies across Canada fundraise on a regional basis to provide services and support to people and families living with ALS and to contribute to the funding of the ALS Canada Research Program. The ALS Canada Research Program funds peer-reviewed research grants and fosters collaboration amongst Canadian researchers, helping to nurture new ideas and build capacity. ALS Societies advocate federally, provincially and locally on behalf of people and families living with ALS for better government support and access within the healthcare system.

About Brain Canada and the Canada Brain Research Fund
Brain Canada is a national non-profit organization headquartered in Montreal, Quebec, that enables and supports excellent, innovative, paradigm-changing brain research in Canada. For more than one decade, Brain Canada has made the case for the brain as a single, complex system with commonalities across the range of neurological disorders, mental illnesses and addictions, brain and spinal cord injuries. Looking at the brain as one system has underscored the need for increased collaboration across disciplines and institutions, and a smarter way to invest in brain research that is focused on outcomes that will benefit patients and families. Brain Canada’s vision is to understand the brain, in health and illness, to improve lives and achieve societal impact.

The Canada Brain Research Fund is a public-private partnership between the Government of Canada and Brain Canada, designed to encourage Canadians to increase their support of brain research, and maximize the impact and efficiency of those investments. Brain Canada and its partners have committed to raising $120 million, which is being matched by Health Canada on a 1:1 basis for a total of $240 million. For more information, visit www.braincanada.ca.