Last year, major scientific advances in Canada and internationally led to significant and exciting progress in ALS research. Discoveries that increase our understanding of ALS are happening far more often than ever before, and as a result many new experimental treatments are set to begin human clinical trials in the next few years. Due to the rapid progress of ALS research it can sometimes be hard to stay on top of the latest discoveries. To help with this, the ALS Canada Research Program team regularly summarizes what we believe are the most significant research discoveries in the field. There are three updates from 2018: February, June and October. Below you’ll find the most newsworthy research stories of 2018.
Approval of Canada’s second ALS treatment, edaravone
On October 4, 2018, Health Canada approved edaravone (also referred to as Radicava® and Radicut®) for the treatment of ALS. Edaravone is the first drug to be approved by Health Canada for the treatment of ALS since the approval of riluzole in 2000. The results of a Phase 3 clinical trial showed that for a certain segment of people living with ALS who are early in their disease progression, treatment with edaravone may help to slow functional decline. Approval from Health Canada means that edaravone can now be marketed and sold in Canada. The drug is currently being manufactured for availability sometime in 2019. Other considerations, like the price of the drug and whether it will be covered through provincial drug plans, have not yet been determined. We hope to see a positive reimbursement recommendation. It is also our hope that the approval of edaravone will build momentum for the development of additional therapies, underscoring the importance of research investment. Canadians living with ALS who are interested in learning more about edaravone should connect with a neurologist at their ALS clinic.
In partnership with ALS Societies across Canada, ALS Canada actively advocates for timely and affordable access to any potential new ALS therapies and brings a voice to how inconsistencies and gaps in the healthcare system are directly affecting Canadians living with ALS. We believe federal and provincial governments must adopt an access program that helps bring promising ALS treatments through the system in a sustainable and equitable way.
A laboratory model of sporadic ALS helps researchers to better understand the most common form of the disease
In its early stages, medical research is often conducted using disease models (ranging from nerve cells in a dish, to worms, to mice). These models are often created by modifying the cell or animal to carry a mutant gene that is known to cause the disease in humans. However, since the majority of ALS cases are sporadic in nature with no known genetic cause or family history of disease, it can be difficult for researchers to model sporadic ALS in the laboratory. For this reason, researchers have now turned to stem cell technology. This approach allows them to generate motor neurons in a dish that retain the full genetic information of the person the stem cells were derived from. In an August 2018 study, researchers generated motor neurons from the stem cells of 32 sporadic ALS patients and discovered that they were able to mimic many of the disease characteristics seen in animal models and human tissue. The results of this study highlight the success of using stem cells to generate cellular models of sporadic ALS and provide researchers with a new method to study the biology of the most common form of ALS in ways they could not in the past.
Restoring the normal function of C9ORF72 in cells may help to slow ALS progression
Mutations in a gene called C9ORF72 are the most common genetic cause of ALS. The C9ORF72 gene normally contains a short repeating segment of DNA that, in some people living with ALS, is drastically expanded with up to hundreds or thousands of repeats observed. Since C9ORF72’s identification as a major cause of ALS in 2011, researchers have been questioning whether ALS results from loss of the normal function of the gene in cells or from gain of a toxic new function. A March 2018 study revealed that it is likely a combination of both mechanisms – loss of the normal function and gain of a toxic function – that contributes to disease. By studying human motor neurons derived from iPS stem cells, the researchers found that loss of the normal C9ORF72 function reduced the motor neuron’s ability to clear toxic material from the cell that is produced as a result of mutation. The results of this study provide valuable new insights into the normal function of C9ORF72 in motor neurons and suggest that therapeutics designed to promote the normal function of the protein represent a promising new treatment avenue to explore. A team of Canadian researchers, led by Dr. Janice Roberston and funded by an ALS Canada-Brain Canada Arthur J. Hudson Translational Team Grant, are currently conducting a study to gain a more comprehensive understanding of the normal functions of C9ORF72 which we believe will ultimately enhance our ability to efficiently target C9ORF72 and its mechanisms in future treatment strategies.
A newly-discovered beneficial role of TDP-43 in muscles may hold clues for treating ALS
Abnormalities in a protein called TDP-43 are present in approximately 97 per cent of all ALS cases, making understanding this malfunction extremely important to understanding the disease. TDP-43 is normally found in the nucleus of a cell (a central compartment where our DNA is located); however, in people living with ALS it is often found in the cytoplasm (the area outside of the nucleus) where it does not belong and cannot perform its normal function to keep motor neurons healthy. It is also harmful because when TDP-43 is in the cytoplasm it forms clumps that are thought to be toxic, leading to cell death. However, a November 2018 study revealed an unexpected finding that these TDP-43 clumps may not always be toxic. In fact, the researchers found that these clumps, which they refer to as myo-granules when in muscle cells, are formed temporarily in injured muscles and promote muscle regeneration in both mice and humans. The researchers believe that when these TDP-43 clumps are formed temporarily they are beneficial to cells; however, for some reason in ALS, motor neurons are unable to dissolve these clumps and return TDP-43 to the nucleus, resulting in neurodegeneration. The researchers are hopeful because if these clumps normally form and then go away in muscle cells, something is helping them dissolve and understanding the mechanisms involved in this process could open up a new pathway to develop treatments for ALS.
A molecular link between aging and neurodegeneration
Aging is the main risk factor for developing a neurodegenerative disorder such as ALS. In a September 2018 study, researchers from Harvard Medical School found RIPK1 as a common link between aging and a genetic cause of ALS. RIPK1 is a protein known to promote inflammation and cell death, however, its activity is controlled by two other proteins, TBK1 and TAK1. Mutations in TBK1 have been linked to both ALS and frontotemporal dementia (FTD). A separate 2019 study confirmed that mutations in TBK1 prevent the protein from being able to block the toxic activity of RIPK1. In addition, researchers found that the amount of the second “checkpoint” protein, TAK1, produced in cells decreases with age indicating that as people grow older they naturally have a reduced capacity to control the activity of RIPK1. Furthermore, mutations in another ALS gene called OPTN have also been shown to cause a reduced ability to regulate RIPK1. Taken together, mutations in TBK1 or OPTN and reduced TAK1 with age, combine to promote RIPK1 activity resulting in neuroinflammation that is thought to play a role in the onset and progression of ALS. All of this suggests that drugs designed to inhibit RIPK1 may be important treatments for ALS. In a new clinical trial researchers will be testing an inhibitor drug called DNL747 that will be delivered orally to people living with ALS. Researchers will monitor participants to ensure that the drug is safe, determine the appropriate dosage and learn more about how the body breaks down the drug internally. If DNL747 is able to modify the activity of RIPK1 and is considered safe, researchers hope it will be effective at slowing the progression of ALS in later clinical trials.
Montréal announced as the location of the 31st International Symposium on ALS/MND
The International Symposium on ALS/MND is the largest medical and scientific conference specific to ALS/MND. Organized by the Motor Neuron Disease Association, each year the Symposium attracts over 1,000 delegates, representing the power and commitment of the global ALS research community. Earlier this year it was announced that the 31st International Symposium on ALS/MND will be held in Montréal, Canada in December 2020. The ALS Society of Canada will host the event along with our partners at the ALS Society of Quebec. It is our hope that by sharing new discoveries as rapidly as possible and fostering collaboration between leading researchers around the world, more treatment options with the potential to significantly improve the lives of people living with ALS will be available in the next several years.
Orangetheory Fitness campaign raises over $250,000 in support of ALS research in Canada
In 2017, Orangetheory Fitness facilities across the United States launched the #IBurnForALS campaign for the first time, raising $2 million for Augie’s Quest, an organization that raises funds for ALS research in the US. The inspiration behind the campaign is Augie Nieto, the founder of Life Fitness, who was diagnosed with ALS in 2005. In 2018, the nationwide fundraiser south of the border made its way to Orangetheory Fitness franchises across Canada. On February 15, 2018 Orangetheory Fitness launched the #IBurnForALS campaign in each of their 70+ fitness studios across the country. Over $250,000 was raised in support of the ALS Canada Research Program, which funds peer-reviewed research grants and fosters collaboration amongst Canadian ALS researchers. We look forward to partnering with Orangetheory Fitness for the #IBurnForALS campaign again in May of 2019.
ALS Canada awards $1.72 million for 14 new research projects
The ALS Canada Research Program is generously funded by Canadians committed to realizing a future without ALS. Funding is made possible through individual donations and community-based efforts, as well as partnership with ALS Societies across Canada that contribute 40 per cent of net proceeds from the WALK for ALS fundraising events. In November, after rigorous scientific assessment by a panel of global ALS experts, ALS Canada announced an investment of $1 million in eight new research projects being funded through the ALS Canada Research Program. In a separate announcement with the Brain Canada Foundation, ALS Canada announced an additional $720,000 in funding for six new Trainee Awards, which completes the investment of the last of the $20 million research partnership with the Brain Canada Foundation (with financial support from the Government of Canada) following the Ice Bucket Challenge. ALS Canada was pleased to also partner with La Fondation Vincent Bourque, which honours his legacy through financial support of an additional Trainee Award that would not have been possible without their generous contribution. You can learn more about these exciting new projects here.
Consensus guidelines developed to improve the quality of ALS clinical trials
In 1994 consensus guidelines were developed by a subcommittee of the Motor Neuron Diseases Research Group of the World Federation of Neurology (WFN) for conducting clinical trials of ALS. The purpose of these guidelines was to set a quality standard for the design, conduct, performance, analysis and reporting of ALS clinical trials globally. The guidelines were later revised and expanded in 1999, however, growing experience in clinical trials over the years since then has led researchers to once again revise the guidelines. After a rigorous review progress with input from researchers across the globe, the newly revised Consensus Guidelines for Design and Implementation of Amyotrophic Lateral Sclerosis (ALS) Clinical Trials were presented for the first time in Glasgow, Scotland at the 29th International Symposium on ALS/MND. By implementing these consensus guidelines researchers believe that substantial progress can be made in standardizing and improving the speed/quality of clinical trials in ALS globally with the aim of finding an effective treatment option for ALS as soon as possible.
Continued hope for the future
The opportunity to be involved in clinical trials for experimental ALS treatments is something that is often of interest to people who are living with ALS. Now more than ever, Canadians have greater access to participate in clinical trials as there are 13 different studies actively recruiting across Canada and many more set to begin in the next several years. Of the currently active studies, six are testing new drug treatments for ALS, five are observational studies aimed to learn more about the disease, one is evaluating a new method of delivering promising treatments to the brain and another is focused on clinical management of the disease. For more information on clinical trials available to you, please speak with your clinician (preferably at an ALS clinic). You can also learn more about the clinical trials currently being conducted at sites across Canada by visiting ALS Canada’s Clinical Trials resource, where all Canadian ALS clinical trials are listed with links to additional resources and contact information for each trial.