ALS research is at a time of unprecedented advancement. New information on genes linked to ALS and the downstream effects of mutations in these genes has helped researchers to develop a so-called ‘roadmap’ of biological pathways that are important in ALS and to gain a better understanding of this complex disease. With new advancements being announced almost daily, the ALS Canada Research Program team has reviewed the ALS research discoveries published so far in 2017 and highlighted some of the most significant ones.
Mutations in the protein Annexin A11 may lead to the development of ALS
In a May 2017 study, researchers performed genetic analyses on 751 people living with ALS who have a family history of the disease. The results showed for the first time that mutations in a protein called annexin A11 were associated with causing ALS. The link between annexin A11 and ALS was further supported by the finding that toxic protein clumps in the spinal cord of an ALS patient contained the mutated protein. The research team involved in the study concluded that mutations in annexin A11 may impair protein trafficking in cells, a process crucial for cell survival, providing a potential pathway to target when developing new ALS treatments. Although familial ALS only accounts for approximately five to 10 per cent of all cases, this discovery highlights a disease pathway that might also be important in people who have ALS but don’t have a family history of the disease.
ALS and schizophrenia share some common genes
A global research collaboration called Project MinE, in which Canada is participating, is currently underway with the goal to better understand the genetic basis of ALS and ultimately find a cure for this devastating disease. As a result of Project MinE, researchers have found that ALS and schizophrenia share some common genetic links. More specifically, researchers found a 14.3% overlap in genes associated with both diseases. This doesn’t mean that someone with ALS is going to develop schizophrenia or vice versa – it just means that both diseases are linked to some of the same genes suggesting some common biological processes. This genetic correlation may account for reports that prolonged use of antipsychotic medication may help to reduce some ALS symptoms. Canada’s participation in Project MinE is being coordinated and funded by the ALS Canada Research Program, which is also currently funding a clinical trial to investigate the effectiveness of Pimozide, an antipsychotic drug that has been used to treat schizophrenia, at slowing ALS progression in humans.
Expansion mutations in the ATXN2 gene can mean an increased risk of ALS
In some cases, genetic mutations can take the form of expansion mutations, meaning that segments of DNA are expanded (or lengthened) in a repeating fashion. In a March 2017 study, researchers showed that expansion mutations in the ATXN2 gene can put people at a greater risk of developing ALS. In a complimentary study using ALS mice models, researchers found that reducing the amount of ataxin-2, the protein created from the ATXN2 gene, resulted in increased muscle function and survival suggesting a possible therapeutic benefit. This study represents one of the first times a ‘modifier gene’ (a gene that is not directly linked to the development of ALS but can still influence the disease) has been targeted to treat ALS and has sparked an upcoming, landmark clinical trial that would be the first to test a gene therapy approach to treat sporadic ALS.
The important role of animal models in understanding ALS
Once scientists identify genes linked to ALS, they must then identify the biological pathways affected as a result of mutations in these genes in order to ultimately develop new treatments. One extremely useful way to investigate the downstream biological effects is through the use of animal models that replicate disease. Recently, mutations in the CCNF gene were identified as playing a role in ALS. Scientists have already developed simple animal models (zebrafish) in which they are able to mutate the CCNF gene in order to better observe and understand how ALS develops and progresses. In doing so, researchers observed that the cells in the spinal cords of the zebrafish were dying at an increased rate as a result of mutations in the CCNF gene. The rapid development of an animal model in which CCNF mutations can be created and studied is just one example of how ALS research has advanced in recent years and highlights the innovative tools researchers are using to better understand the biology of this complex disease.
Safety and effectiveness of edaravone
In a previous Phase 3 clinical trial of edaravone (also referred to as Radicava and Radicut), researchers did not find a significant slowing of ALS progression. In a subsequent analysis, however, researchers found that for a certain set of participants there may be a benefit. To validate this finding, researchers repeated the Phase 3 clinical trial of edaravone with a focus on participants who met strict inclusion criteria. To be included in the study, patients needed to be early in their ALS progression, with milder symptoms and a larger vital capacity (the maximum amount of air a person can expel from their lungs after a maximum inhalation). In this secondary Phase 3 trial, researchers found a 33% functional improvement (as measured by the Revised ALS Functional Rating Scale or ALSFRS-R) for participants who were receiving the drug. Overall, the study showed that for a certain segment of people living with ALS, treatment with edaravone may help to slow functional decline. On May 5, 2017 edaravone was approved by the United States Food and Drug Administration (FDA) for treatment of ALS.
