Driving Discovery: Canada’s role in the journey to Qalsody’s approval

In a significant moment for the ALS community, Qalsody (tofersen) has been approved in Canada for the treatment of ALS in adults who have a pathogenic variant (also known as a mutation) in the superoxide dismutase 1 (SOD1) gene. This achievement is built on decades of scientific dedication and research — to which Canada has played a crucial role, and with ALS Canada providing support to the initial discovery of SOD1 being linked to ALS. After the genetic discovery, several Canadians funded by the ALS Canada Research Program played an important part in establishing SOD1’s dysfunction in ALS and providing further insights into its abnormal biology, which opened a therapeutic avenue for therapies like Qalsody. 

Stories like this illustrate the downstream impact that each research grant can have in the field, and the importance of global collaboration. Each achievement today in ALS research took years of dedication, and we look forward to continuing to support grants, big and small, that are building momentum for the next ALS breakthrough.  

The journey that led to Qalsody’s approval began decades ago. In the early 1980s, connecting genetics to diseases was a challenging task, as technologies used to analyze DNA were still in their infancy. This made it difficult to analyze genes associated with diseases like ALS. 

One of the earliest genetic advancements came from Dr. James Gusella, a Canadian researcher who made significant strides in mapping and identifying genes. Dr. Guy Rouleau, a Canadian neurologist, studied under his mentorship. Dr. Rouleau would go on to play a pivotal role in ALS genetic research and has received numerous prestigious awards, including being recognized with a King Charles III Coronation Medal by ALS Canada.  

In the early 1990s, Dr. Guy Rouleau, currently the Director of the Montreal Neurological Institute, was part of a collaborative effort that included Dr. Gusella, Dr. Denise Figlewicz, who led research at ALS Canada from 2006 to 2012, and other researchers. The group, led by Dr. Robert Brown, a renowned ALS researcher at University of Massachusetts, aimed to identify a genetic variant in a family with multiple members affected by ALS. Their work led to the landmark discovery described in the paper Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis, where pathogenic variants in the SOD1 gene were identified for the first time as being causative of ALS. ALS Canada is proud to have helped provide funding and support to this monumental finding.  

The discovery of the first ALS gene, SOD1, represented a significant achievement that propelled ALS research forward, as researchers could now try to replicate ALS in the lab. Initially, it made sense, given the role of SOD1 as a protective, antioxidant protein, that these genetic variants could cause ALS through a loss-of-function mechanism. This meant that variants in the gene would cause the loss of SOD1’s normal role in the brain, making motor neurons vulnerable to disease onset and progression. However, when scientists created SOD1 knock-out mice in the lab — mice that didn’t produce the SOD1 protein at all — the animals did not develop ALS-like symptoms. This contradicted the loss-of-function theory, and further work was needed to understand SOD1-ALS.  

The breakthrough came when researchers developed a different mouse model. The model, called SOD1G93A, replicated one of the human SOD1 variants that cause ALS in people, and ended up displaying the motor neuron degeneration characteristic of ALS. This was a crucial step in further understanding SOD1 pathology, creating an unexpected theory that variants in SOD1 would produce a toxic form of the protein that contributes to disease.  

Another Canadian researcher whose work significantly impacted SOD1-ALS research early on was Dr. Heather Durham, who also received a King Charles III Coronation Medal for her work in ALS. In 1997, Dr. Durham and Dr. Figlewicz published a paper, Aggregation of mutant Cu/Zn superoxide dismutase proteins in a culture model of ALS, that demonstrated that SOD1 proteins would aggregate in motor neurons in vitro (in a laboratory dish). This finding, along with the creation of the G93A mouse model, provided compelling evidence of SOD1’s toxic gain-of-function. Dr. Neil Cashman, from the University of British Columbia, also contributed insights into protein propagation, further solidifying the hypothesis. 

Other prominent Canadian contributors to our understanding of SOD1-ALS biology — who have been funded by the ALS Canada Research Program since then — include Dr. Avi Chakrabartty, Dr. François Gros-Louis, Dr. Jean-Pierre Julien, Dr. Elizabeth Meiering, Dr. Steve Plotkin, and Dr. Christine Vande Velde. Work by other grant awardees such as Dr. Jasna Kris, Dr. Janice Roberson, and Dr. Michael Strong further highlighted the downstream toxic effects of pathogenic variants in SOD1 in a way that continues to contribute to the field. 

Alongside global efforts, Canadian researchers played a significant role in solidifying SOD1 as having a toxic gain-of-function in ALS and deepening insights into its pathology. This collective work opened a path for SOD1 to be targeted directly for reduction as a therapeutic strategy. Insights into the SOD1 gene have also contributed to all forms of ALS, as genetic models have greatly improved our understanding of the disease and the development of therapeutic targets. 

These early essential discoveries set the stage for the development of antisense oligonucleotides (ASOs) targeting SOD1. ASOs are short, synthetic strands of DNA or RNA designed to bind to specific RNA molecules in the body. This blocks the ability of the RNA to make a protein or work in other ways. 

Building on this foundational research from Canadian scientists and others globally, Dr. Don Cleveland, Dr. Timothy Miller, Dr. Richard Smith, and Dr. Frank Bennett, from the biotech company Ionis Pharmaceuticals (known as Isis at the time), led the critical discoveries that enabled the development of an ASO as a therapeutic strategy for SOD1-ALS.  

Early preclinical work started in 2004, with a clinical trial launching in 2007. However, the initial ASO showed limited efficacy in humans, requiring extensive testing and modifications, as well as further understanding of SOD1. Eventually in 2018, Biogen acquired the compound and a new version of the ASO emerged—one that would become tofersen and be approved as Qalsody. By targeting the mRNA of the SOD1 gene, Qalsody lowers the levels of toxic SOD1 proteins, aiming to reduce damage in the motor neurons, the brain cells responsible for voluntary movement. 

The approval of Qalsody is a decades-long achievement by the renowned investigators working on the therapy, with Canadian researchers playing a pivotal role in understanding the genetic underpinnings of ALS.  

However, the work continues. Although Qalsody represents hope for SOD1-ALS, it is still not a cure for the disease. Researchers are still working toward the global understanding of SOD1 biology and importantly, learning what Qalsody can tell us for other forms of ALS. This new treatment can provide insights into ASOs optimization for different genes, the importance of presymptomatic studies, and help us establish biomarkers for ALS, such as neurofilament light (NfL).  

ALS Canada is grateful to have played a role throughout this journey by supporting SOD1 foundational work. We continue to advocate for research funding and foster collaborations between researchers. It is only through generous donations from our community, and our ongoing research commitment, that we can contribute to treatments like Qalsody becoming accessible to Canadians living with ALS.  

In our blog series, Driving Discovery, we showcase stories of the ALS Canada Research Program. Thanks to generous donations, our funding has provided foundational support in several areas of ALS research and clinical care.