2020 is shaping up to be another exciting year in ALS research discovery. Last year, major scientific advances in Canada and internationally led to significant and exciting progress in ALS research. As identified by the ALS Canada Research team, here are the most newsworthy research stories of 2019 that provide hope for what’s to come.

Early results show promise for tofersen, an experimental therapy aimed a treating a subtype of familial ALS

On May 1, 2019, Biogen announced interim results from their phase 1/2 study of tofersen (also referred to as BIIB067), an antisense oligonucleotide (ASO) being studied for the treatment of a familial form of ALS linked to mutations in the SOD1 gene. Tofersen is designed to bind to SOD1 mRNA (the blueprint used to create SOD1 protein in cells) and thereby block formation of the toxic protein. Tofersen is delivered directly to the spinal fluid through what is called an intrathecal injection.

Preliminary data from the phase 1/2 study showed that tofersen is safe and can reduce the levels of toxic SOD1 protein found in the central nervous system. Participants receiving tofersen showed a trend toward slowing of disease progression, as measured by the ALSFRS-R.

Positive results from the earlier phase 1/2 study supported Biogen’s decision to move tofersen forward to a phase 3 study to confirm its safety and effectiveness. The global phase 3 study is currently recruiting at two sites in Canada: the Montreal Neurological Institute and Sunnybrook Health Sciences Centre.

Results from the phase 2 study of NurOwn and full enrollment of the phase 3 study

A phase 3 study designed to confirm the safety and effectiveness of NurOwn in a larger population is now underway. In October, BrainStorm Cell Therapeutics announced that the 200-patient clinical trial is fully enrolled, and it is expected that all participants will have completed planned study visits and assessments by October 2020.

Results from the phase 2 study testing NurOwn for the treatment of ALS were published in the peer reviewed journal Neurology. The study involved 48 participants, 36 of which were treated with a single dose of NurOwn, and 12 were given placebo. The results showed that treatment with NurOwn was safe and well-tolerated by participants. Overall, the rate of disease progression for those treated with NurOwn, as measured by the ALSFRS-R, was similar to participants given placebo. However, for a subset of participants with more rapid disease progression, the results were more promising, suggesting that NurOwn may be able to positively impact disease progression.

Revolutionary clinical trial method for ALS treatments to launch in early 2020

In September 2019, the Sean M. Healey & AMG Center for ALS at Massachusetts General Hospital announced it will launch the first ever platform clinical trial in ALS. Researchers across the globe are adopting this innovative new design for ALS clinical trials. The platform trial, is a clinical trial where multiple treatments are tested and evaluated at the same time. The platform model aims to find beneficial treatments using fewer patients, in less time and with a greater probability of success. Another major advantage of this model is that the placebo groups for each therapy being tested can be shared, meaning participants will have a greater chance of receiving an active drug over a placebo.

The Sean M. Healey & AMG Center’s trial will be conducted at 54 sites across the U.S. and will evaluate five promising therapies to at the outset of the trial. Additionally, TRICALS, the largest European research initiative dedicated to finding a cure for ALS, is preparing to launch a platform trial at multiple centres testing at least three new therapies to start. Researchers are excited about this new approach as they believe it will move the global field more quickly towards our shared goal of finding a treatment for ALS.

ALS Canada awards almost $1.4 million for 16 new research projects

In November 2019, after rigorous scientific assessment by a panel of global ALS experts, ALS Canada announced nearly $1.4 million will be invested in leading-edge ALS research that will further the study of the disease. More than $850,000 is being invested in ten Project Grants, and $540,000 is being invested in six Trainee Awards that will provide momentum for the next generation of promising ALS researchers.

Funding partners for the ALS Canada Research Program’s 2019 grants and awards are the provincial ALS Societies across Canada, Orangetheory Fitness, La Fondation Vincent Bourque, and the Brain Canada Foundation (with financial support from Health Canada). Continued investment in research fuels the scientific discoveries that bring hope for a future without ALS. You can learn more about these promising new projects here, and read more about each funded project throughout the course of the year on our blog.

Canadian researchers develop a new method to deliver future ALS treatments directly to the brain

One of the most important factors for any new ALS treatment is its ability to reach the brain and spinal cord where it is needed most. For oral or intravenous (IV) treatments (i.e. those injected right into the blood stream) this means they must be able to cross the blood-brain barrier, a specialized barrier that protects the central nervous system from substances in the bloodstream. In order to bypass this challenge, a team of researchers at Sunnybrook Health Sciences Centre in Toronto have developed a creative new way to ensure that future ALS treatments can be delivered directly to the brain.

Using magnetic resonance imaging-guided focused ultrasound (MRgFUS), the researchers showed that they can temporarily and safely open small spaces in the blood-brain barrier that would allow potential treatments to cross over into the brain. The results of this first-in-human phase 1 clinical trial, funded in part by ALS Canada, were published in the peer reviewed journal Nature Communications. After 60 days, the four participants who underwent the procedure had no major adverse events. This means that using MRgFUS should allow for safe administration of treatments directly to the brain in people living with ALS, which the researchers indicate in a press release will be the next stage of the study.

Initiation of a global phase 3 study to test a new oral form of edaravone

In November 2019, Mitsubishi Tanabe Pharma America announced initiation of a global phase 3 study to test the safety and effectiveness of a new oral form of edaravone, called MT-1186. This phase 3 study will enroll 150 people living with ALS at approximately 65 sites across the U.S., Canada, Europe and Japan. All participants will be given the active drug meaning there will be no placebo group. The hope is that if this oral form of edaravone proves to be safe and is delivered to the brain and spinal cord as effectively as the current IV form, the results of this trial will be enough for approval.

Radicava is currently delivered only through intravenous (IV) infusion directly into the blood stream. Due to the relatively intensive dosing regimen recommended for Radicava, a treatment option like MT-1186 that can be taken orally could significantly improve quality of life for people living with ALS.

In October 2018, Health Canada approved Radicava (edaravone) for the treatment of ALS. Yet, more than a year later, Radicava is still not accessible through public reimbursement to Canadians living with ALS. With no defined timeframe or transparency in the public reimbursement process, advocacy efforts at the provincial level are being executed in order to communicate the urgent unmet need for access to treatment within the ALS community.

Learn more about how you can support the advocacy priority of equitable, timely and affordable access to proven ALS therapies by advocating to the Minister responsible for health in your province to reimburse Radicava without further delay.

Researchers identify new genetic modifiers of C9ORF72-linked ALS

Researchers identified three new genes that may be able to influence the progression of C9ORF72-linked ALS. Mutations in C9ORF72 represent the most common genetic cause of ALS and frontotemporal dementia (FTD). The C9ORF72 gene normally contains a short segment of DNA that, in some people living with ALS, is mutated and drastically expanded. Two substances are produced in cells as a result of these mutations, commonly referred to as RNA foci and DPR proteins. These substances are thought to contribute to the cellular toxicity that leads to disease.

Researchers have been working hard to better understand how they may be able to regulate the formation of these toxic substances and thereby increase motor neuron survival. Using modern laboratory techniques, researchers in three separate studies performed genetic screens on a variety of ALS models, from yeast cells to fruit flies to motor neurons derived from ALS patient stem cells, to look for genes that may be able to influence the formation of these toxic repeat RNAs and DPR proteins. Three different genes were identified: AFF2/FMR2, DDX3X and RPS25. These studies combined provide a deeper understanding of how these toxic substances are made in cells and insights into how researchers may be able to hinder that process when developing new treatment options for C9ORF72-linked ALS.

Important advances in both the clinical understanding and management of ALS

In addition to advances made in basic research and clinical trials, researchers are exploring ways to improve quality of life for people living with ALS. A study published in the journal Neurology analyzed the healthcare services that people living with ALS accessed in their last year of life. The researchers found that a home visit from a palliative care physician was associated with better end of life outcomes but that most people living with ALS did not access this service. Palliative care is an area of medicine aimed at improving the quality of life of patients and families facing the problems associated with a life-threatening illness. Funded entirely through the ALS Canada Research Program, Dr. Jocelyn Zwicker and Dr. Christine Watt at The Ottawa Hospital will be expanding on this work by conducting a study to better understand the benefits of early palliative care in ALS. By identifying the palliative needs of individuals and the impact of offering earlier palliative care, the researchers hope to have a positive impact on quality of life for people living with ALS and their caregivers.

Researchers have also made significant strides in 2019 to better our clinical understanding of ALS. Dr. Yana Yunusova at the Sunnybrook Research Institute in Toronto was involved in numerous studies demonstrating how changes in speech can be utilized to detect and track motor neuron degeneration in ALS. Also supported through the ALS Canada Research Program, Dr. Yunusova will continue this work leading a team of researchers that will use machine learning to train an artificial intelligence (AI) model on voice recordings from people with ALS. The goal is to create a tool that can be used to identify the subtle acoustic features of upper and lower motor neuron loss in ALS. The researchers hope this new tool will assist existing methods in providing a faster and more accurate way to diagnose people with ALS, enabling them to access clinical trials or proven therapies more quickly in the future.

Important connections formed in the understanding of ALS

Each new advancement in ALS research represents another piece of the puzzle that links our understanding of the disease. In 2019, new connections were made between cellular pathways thought to play a role in ALS, such as cellular trafficking (the mechanism by which substances are transported from one region of a cell to another) and RNA biology.

RNA carries the genetic information used to create proteins in cells. Protein formation is required in all parts of the cell, and so RNA must travel long distances in motor neurons, sometimes up to 1 metre in length, to where it is needed. How RNA is transported to these far regions however is currently not well understood. In a study published in the journal Cell, researchers found that that the ALS-linked protein ANXA11 may play an important role in attaching RNA to structures that can transport it to distant sites in the motor neuron. The researchers describe the RNA as “hitchhiking” onto other moving structures within the cell. Mutations in ANXA11 linked to ALS are thought to impair its ability to tie RNA to these moving structures. Funded in part through an ALS Canada–Brain Canada Arthur J. Hudson Translational Team Grant, this study links together two critical cellular function that may be disrupted in ALS.

In a separate study published in the journal Nature Communications, researchers found that disruption of a different cellular trafficking process, called nucleocytoplasmic transport, can be caused by mutations in PFN1. Nucleocytoplasmic transport involves the trafficking of substances between two important compartments of the cell, the nucleus and cytoplasm, and is crucial to cell survival. This newly identified role links PFN1 to C9ORF72, which has previously been implicated in nucleocytoplasmic transport, and provides a greater understanding of the pathways involved in disease. The researchers were able identify a cellular target that they hope can be modified to help restore normal nucleocytoplasmic transport. These studies are just two examples of the many studies that are linking important pathways in the biology of ALS and represents an important step forward in our ability to identify new treatment targets.

Canadians make significant contributions to better understanding of ALS biology

In 2019 Canadian researchers made significant contributions to the global understanding of ALS. Canadian scientist Dr. Sali Farhan, working out of the Broad Institute of MIT and Harvard in Boston, led a gene sequencing study that identified a new genetic cause of ALS.

Dr. Janice Robertson at the Tanz Centre for Research in Neurodegenerative Diseases at the University of Toronto identified an important function of C9ORF72 at the synapse of motor neurons, the place where the electrical signal is passed from one neuron to another or to a muscle cell. This may help to explain some of the dysfunction observed at the synapse in ALS.

Dr. Turgay Akay at the Brain Repair Center at Dalhousie University identified a compensation process that naturally occurs in our bodies that helps to maintain normal movement while losing motor neurons. Enhancing this pathway may represent a promising new avenue to explore when it comes to treatment options.

Dr. Kathryn Volkening and Dr. Michael Strong at Western University provided experimental evidence showing that the when two ALS-linked proteins are present in cells, they can work together to exacerbate disease more than each protein could alone. This finding may help to explain some of the heterogeneity observed in ALS (i.e. why one person may live with the disease for 2 years and another for 20 years).

Dr. Neil Cashman at the University of British Columbia led a study that provided insights into how a familial form of ALS, linked to mutations in the SOD1 gene, may spread through the body providing researchers with a new therapeutic target to consider when developing treatments.

These studies are just a few examples of the innovative work being done in ALS research across Canada. As the only dedicated source of funding for ALS research in Canada, the ALS Canada Research Program aims to continue to accelerate research impact by providing funding for the most promising ALS projects focused on translating scientific discoveries into treatments for ALS.

Bringing you the latest news on advancements in ALS research, the ALS Canada research team regularly summarizes the most significant discoveries throughout the year.

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Note: We have included links to the publications because we know you may be interested in the original source papers. While abstracts are always available, many journals are subscription based, and in some cases, full papers may only be accessed at a cost.