Ice Bucket Challenge Impact of Donations

Further IBC funding to leverage this larger investment came in the 2018 PhD Studentship awarded to Abdullah Ishaque, whose work in the Kalra Lab focused on a novel addition to CALSNIC. In his studies, Abdullah did a pathological examination on brains that were generously donated by individuals who participated in the MRI imaging. The attempt to correlate observations in post-mortem brain tissue with MRI on the same living individuals added a strong layer of validation that what is seen in the imaging is reflective of actual pathology.

The IBC funding for this work has significantly impacted discoveries and process improvements for ALS imaging worldwide. Dr. Kalra is an active collaborator with other global ALS imaging experts, and the data collected will continue to have an impact for years to come.

IBC funds supported hiring the third-party company, Centre for Effective Practice, to perform the literature search and support meetings of the working group of national ALS clinician experts to focus on developing the guideline content. At the same time, ALS Canada provided the human resources to keep the project on task. After many years of diligent work, the Canadian Best Practice Recommendations for the Management of ALS were published in the prestigious Canadian Medical Association Journal (CMAJ) in 2020, and they continue to be a valuable source for clinic and organization advocacy to ensure the best possible standards of care are met. In 2023, initial discussions have begun to consider the first update.

In 2006, abnormalities in the normal biology of the TDP-43 protein were described as a hallmark of many ALS cases. As TDP-43 is an RNA-binding protein (RBP), this opened the possibility that RNA and RNA-binding protein biology may be critically important in the pathogenesis of ALS and since a subsequent discovery that mutations in the gene encoding TDP-43 also caused ALS, several newly identified ALS-causative genes were also found to be RBPs or related. As of 2023, targeting TDP-43 biology with treatments is coming closer to fruition. Normalization of TDP-43 function is seen by many as the most likely target we have to cause substantial disease-modifying effects potentially. As we reach a time when clinical trials aimed at TDP-43 are becoming a reality, foundational work to understand this very complex biology has led us to this point, and multiple studies funded by the IBC have provided some of that critical research.

Beginning with a 2015 Bridge Grant, Dr. Avi Chakrabartty at University of Toronto began working on stress granules in collaboration with Dr. Christine Vande Velde at Université de Montréal through a study that would pave the way for a 2015 Arthur J. Hudson Translational Team Grant to Dr. Vande Velde. While yielding several interesting avenues about TDP-43 and RNA biology, the Hudson Grant work led to the key discovery of G3BP1 as a critical protein massively reduced in neurons when TDP-43 biology is disrupted. As a result, Dr. Vande Velde has collaborated globally with academics and industry and received prestigious grants to examine ways for restoration of G3BP1 levels as a potential therapeutic to translate toward clinical trials.

In 2016, two more Discovery Grants to Dr. Marlene Oeffinger and Dr. Éric Lécuyer, both at Institut de recherches cliniques de Montréal (IRCM), led to impactful research on TDP-43 and RNA biology. Dr. Oeffinger examined the roles of TDP-43 and other aspects of RNA biology in the nucleus, which very few have been doing in the field. It has helped play a role in deciphering the complex normal and abnormal biology of the protein. It has led to current collaboration with Dr. Vande Velde, which has yielded funding for new key projects. Dr. Lécuyer used his Discovery funding in collaboration with well-known American researcher Dr. Gene Yeo, leading to a very high-impact publication on stress granules, a critical paper in the field.

IBC funds have made a significant foundational impact on these critical ALS pathways. They will continue to see their value propagate into eventual treatments that target TDP-43 and other RNA/RBP-related mechanisms in the days ahead.

The concept that excessive firing of cortical/upper motor neurons may be an early pathogenic mechanism in ALS has existed since the 1980s and stems largely from pioneering work by Canadian Dr. Andrew Eisen. Since then, a few key opinion leaders continue to focus on this work, but it remains an understudied area of ALS research. It has had very few attempts to target it as a therapeutic strategy. In 2014, a Discovery Grant was awarded to Dr. Melanie Woodin to test a proof-of-concept intervention in a SOD1 ALS mouse model that applying the “brakes” to increased upper motor neuron firing could affect the disease course. The work led to a delay in the onset of symptoms in the mice, which is in line with hyperexcitability being potentially an early mechanism in the disease process.

IBC funding also supported the subsequent 2018 Postdoctoral Fellowship of Dr. Sahara Khademullah to work in the lab of Dr. Yves De Koninck and continue focusing on cortical hyperexcitability by testing drugs that could do the same as the successful strategy used in the Woodin Lab. While her postdoc work has not yet been published, it has yielded exciting results with intriguing promise for potential development in the clinic. It has also led to funding for Dr. De Koninck to pursue the work and a subsequent award to support Dr. Khademullah’s academic career aspirations, hoping to develop this avenue further.

IBC funds also supported a 2015 Discovery Grant to Dr. Lisa Topolnik of Université Laval, who found increased cortical hyperexcitability in C9orf72 mouse models, correlating it to people who have not yet experienced symptoms. This extended the work to an additional, critical genetic cause of the disease and reinforced the potential for this to happen very early. As treatments in this area expand and as we get more advanced at treating people earlier, including pre-symptomatically, this work could have a tremendous impact in the years ahead.

This work, supported by IBC funds, has provided, and will continue to provide key foundational evidence in the literature that has helped stimulate ongoing clinical development of therapies, such as Quralis’ QRL-101.

Abnormal expansion mutations in the gene encoding C9orf72 were discovered in 2011 as the most commonly known cause of ALS (and Frontotemporal Dementia – FTD), and work has revealed that the toxicity to motor neurons in ALS is due to either a toxic function caused by the resulting RNA and protein(s). Most of the work to date has focused on the mechanisms explaining the gained toxicity, while relatively few have examined the normal function of the C9orf72 protein. Canada has contributed significantly to this research through IBC funding, and given recent clinical trial results where targeting an aspect of gained toxicity failed to demonstrate benefit, this work may have a greater impact than initially anticipated.

Beginning in 2014, Dr. Janice Robertson at University of Toronto was funded with a Discovery Grant to explore the proteins that interact with C9orf72. This led to a 2016 Arthur J. Hudson Translational Team Grant, with Dr. Robertson as the lead investigator, aiming to expand the understanding of C9orf72 normal function. Additional IBC-funded research on the normal function of C9orf72 was awarded to Dr. Peter McPherson at McGill University through a 2015 Bridge Grant and a 2015 Discovery Grant. A 2018 PhD Studentship to Lilian Lin at University of Toronto was also IBC-funded and furthered the understanding of C9orf72 loss of function through its interaction with TDP-43.

The collective work has made Canada a world-leading country contributing to the field of loss of function mechanisms for C9orf72. These include a better understanding of its trafficking and endolysosomal functions, its functions at the synapse, and its role in nucleocytoplasmic trafficking. The funding has also supported a very impactful understanding of the role of methylation in ALS through collaborative work with Dr. Ekaterina Rogaeva at University of Toronto and best practices, leveraging the ALS Canada co-funded ALS Reproducible Antibody Platform.

In addition to discovering new genetic causes and risk factors for ALS, the Project MinE database will help us learn why some people get ALS, and others do not or why someone might be susceptible to a particular environmental trigger while it will not lead to ALS in others. It will also significantly contribute to understanding why people experience ALS differently from person to person.

Sequencing 15,000 individuals with ALS was an egregious goal, and at the time, each whole genome sequence, as they are called, cost approximately $1,500. Furthermore, the only way we could have enough samples for a rare disease like ALS and enough funding to make it happen is through global collaboration and as of 2023, 21 countries have signed on.

In 2016, Canada decided to join Project MinE with a commitment to provide 1,000 sequences. As of 2023, we have provided approximately 750. The first 200 sequences were supported with IBC funds matched by Brain Canada.

Mutations in the Fused in Sarcoma (FUS) gene were discovered in 2009 as causative for ALS by creating a toxic form of the protein. Given the normal protein function of FUS, it has not been entirely clear if the mechanism by which it causes ALS is a loss of its normal function or some extra toxic function. In recent years, Ionis Pharmaceuticals has been developing an antisense oligonucleotide treatment to reduce the levels of FUS, banking on an extra, toxic function as the predominant cause. Preliminary data has been very intriguing.

IBC funds supported a 2015 Career Transition Award, a 2015 Bridge Grant, and a 2016 Bridge Grant to Dr. Chantelle Sephton at Université Laval to study how mutant FUS disrupts neuron communication. A 2015 Arthur J. Hudson Translational Team Grant to Dr. Peter St George-Hyslop also yielded some very high-impact publications that added to the foundation of data for the potential to target FUS-ALS by reducing abnormal protein levels.

• A 2015 Career Transition Award to Dr. Chantelle Sephton at Université Laval has supported the early years of independence for her role as an Assistant Professor. Dr. Sephton has been involved in multiple advisory programs and is the Chair of the ALS Canada Scientific & Medical Advisory Council and a member of the ALS Canada Board of Directors. She has built solid collaborations, and her initial students have published their work and graduated. She has also successfully procured multi-year grants and awards to support her work, a tremendous sign of her lab’s value and impact. This includes IBC-funded 2015 and 2016 Bridge Grants.

• A 2015 Career Transition Award to Dr. Gary Armstrong at McGill University has helped propel him into an independent Assistant Professor position and into becoming an established, contributing part of the Canadian and global ALS research communities. Dr. Armstrong’s early students have presented their work in peer-reviewed manuscripts and graduated, while others have inspiring work yet to be published. He and his lab have been presenting their work in Canada and internationally. He has built strong collaborations with other academic researchers and industry, has been involved in peer review panels, and has joined the ALS Canada Scientific & Medical Advisory Council. He has also been successful in procuring multi-year grants to support his work, which is a tremendous sign of the value and impact of his lab. This included an IBC-funded 2016 Discovery Grant.

• A 2015 Bridge Grant to Christopher Pearson at The Hospital for Sick Children led to a unique learning on the complex structure of C9orf72 DNA. Dr. Pearson’s work in this area is a niche in the field that is not being explored in the same way by anyone else and may help us better understand why C9orf72 expansions cause ALS and potentially how we might find effective treatments. This was furthered by an IBC-funded 2016 Bridge Grant as well.

• A 2015 Bridge Grant to Jasna Kriz at Université Laval led to a manuscript demonstrating high levels of an anti-inflammatory protein called IL-10 in the immune cells, called microglia, during the early stages of ALS. This was one of the early descriptions of how microglia’s normal, compensatory function should also be considered when we think about how we understand and treat the disease.

• A 2015 Arthur J. Hudson Translational Team Grant to Dr. Jean-Pierre Julien at Université Laval extended his previous work looking at how the active component of the herb Ashwagandha (Withania somnifera), called Withaferin-A can interfere in the pathogenic interaction between TDP-43 and a well-established inflammatory mediator called NF-ΚB. This grant was intended to bring forward a novel compound called IMS-088 for its potential to act on this pathway and potentially be elevated to clinical trial through collaboration with ImStar Therapeutics. Though this has not worked out to date and appears to be on hold, others in the field have used the work to form a better understanding of the potential for NF-ΚB and other inflammatory mechanisms to be harnessed for therapeutic application.

• IBC funding in 2015 supported the launch of the Clinical Management Grant program. This was driven by Scientific & Medical Advisory Council member Melanie York, who was living with ALS and frequently reminded everyone of the importance of researching to support a better quality of life. This pilot program resulted in a funded grant, but more importantly, it placed clinical management research as a focus for ALS Canada research programs moving forward and as of 2023, multiple studies focused on research aimed at improving quality of life have been supported through the Discovery Grant and Trainee Award programs.

• In 2015, funds were committed to support the Canadian Neuromuscular Disease Registry (CNDR). While funds to launch the CNDR were provided by the national Research Program over many years prior, these additional dollars helped bridge it to a time when it could achieve significant funding through a partnership with industry, leveraging its capacity to collect real-world data on Radicava and Albrioza.

• A special meeting of the Canadian ALS Research Network (CALS) became a key driver of the modernization of the network that we have in 2023. The 2015 meeting set the tone for a 2016 meeting where transformation was discussed, the new governance structure was launched in 2017, and ALS Canada administrative support was provided soon after. In 2023, CALS is a vastly different organization and functions far better than a decade ago, with the IBC funding as a catalyst to that success.