ALS research is at a time of unprecedented advancement and Canada’s world-class ALS research community – along with international ALS researchers and experts – are accomplishing more than ever before. With new advancements being announced daily, the ALS Canada Research Program team regularly summarizes what we believe are the most significant research discoveries. We’re excited to share our third 2018 update with you.

Since you’re interested in the world of ALS research, you may also be interested in ALS Canada’s 2018 Virtual Research Forum. On October 17th, join us for a free, half-day online event where you’ll gain access to live presentations from the ALS research community. Please note that attendance is limited to the first 1,000 registrants. Secure your space today.

Researchers identify a molecular link between aging and neurodegeneration

Aging is the main risk factor for developing a neurodegenerative disorder such as ALS. For example, those born with a genetic mutation known to cause ALS can live most of their lives symptom free, with the average onset of the disease occurring between 50 and 65 years of age. This has led researchers to investigate how aging interacts with genetic and environmental risk factors to cause neurodegeneration. 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 study revealed that mutations in TBK1 prevent the protein from completing its normal functions within cells and therefore 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 block the activity of RIPK1. Taken together, mutations in TBK1 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. This study identifies a unique molecular link between aging and neurodegeneration and suggests that recent advancements in the development of RIPK1 inhibitors may be a promising avenue to explore for treatment of ALS.

Similarities between genetically-linked and sporadic ALS suggest a common disease mechanism

In 2011, mutations in a gene called C9ORF72 were identified as 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. Previously, researchers found that a specific protein called hnRNP H attaches to these repeats in C9ORF72-linked ALS cases causing it to clump together in cells. In a July 2018 study, researchers found that a similar dysfunction of hnRNP H is also observed in sporadic ALS cases (i.e. cases with no family history of disease). Although the underlying mechanism as to why hnRNP H clumps together in sporadic ALS cases still remains to be determined, the similar behavior of the protein in both forms of ALS suggests a common disease mechanism. This result is promising to researchers as it indicates that therapies aimed to restore the normal balance of hnRNP H and similar proteins within cells may prove to be an effective treatment strategy for both genetic and sporadic forms of ALS. Further, this study highlights that therapies discovered using laboratory models of genetic ALS could result in treatment options for the sporadic form as well.

A laboratory model of sporadic ALS helps to identify a potential drug treatment

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 created by modifying the cell or animal to carry a mutant gene that is known to cause the disease in humans and allow researchers to study the biology of ALS in ways they could not in people. 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 that 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. Using these cellular models of sporadic ALS, the researchers then screened 1,000 approved medications to see if any could suppress cell death. From the library of medications tested researchers found that one, Requip, had a protective effect. Requip is a drug currently used to treat Parkinson’s disease and is thought to play a role in nerve cell function. The results of this study highlight the success of using stem cells to generate cellular models of sporadic ALS and identified a new drug candidate to explore for the treatment of ALS.

A clinical trial to study the safety and effectiveness of stem cell treatment in ALS

Researchers in Korea recently published the results from a Phase 2 clinical trial designed to test the safety and effectiveness of mesenchymal stem cell treatment in ALS. Of the 64 people who participated in the trial, approximately half were assigned to the group that received treatment while the other half were assigned to the control group. Participants who received treatment had stem cells taken from their bone marrow, which were then multiplied and purified under strict laboratory care, before being mixed with the individual’s spinal fluid and reinjected into the area around their spinal cord. Each participant received two injections, one month apart. The effectiveness of the treatment was measured primarily using the ALS Functional Rating Score Revised (ALSFRS-R), a 12-item questionnaire that assesses function in certain daily activities. Overall, the results showed that mesenchymal stem cell treatment appears safe and the study suggests it might be effective at slowing functional decline in ALS using this method. The authors note that no difference in survival was observed meaning that the results did not indicate treatment will extend lifespan. A larger Phase 3 clinical trial is required to confirm the long-term safety and effectiveness of mesenchymal stem cell treatment in ALS, however, the preliminary results reported in this study are promising.

Studies like these, where clinical practices are subjected to peer review prior to publication of their findings, are key to understanding whether stem cells have any value in ALS treatment. It is important to note that while the research community remains cautiously optimistic about the potential of stem cell treatments in ALS, to date there remains no definitive proof that any protocol works. We look forward to the results of clinical trials coming up in the months and years ahead.

Researchers develop a new tool to assess quality of life in people living with ALS

Quality of life (QoL) assessment tools are often used by clinicians to help inform care decisions for people living with ALS. These tools take into consideration how ALS and its treatment affect various factors such as physical and mental health, relationships, finances and spirituality. A common tool used to measure QoL in the clinical setting is a 59-item questionnaire called the ALS Specific Quality of Life Instrument (ALSQOL). This questionnaire takes approximately 15-25 minutes to complete by interview. Previous studies show that the long length of visits at ALS multidisciplinary clinics can be burdensome to people living with the disease and the length of the ALSQOL assessment can cause fatigue. For this reason, researchers in a July 2018 study set out to develop a shorter QoL assessment tool that still provides clinically useful and valid information. During the development of this new tool, the researchers collected data from 389 people living with ALS and validated its effectiveness by assessing an additional 162 patients. The newly developed tool is a 20-item questionnaire that takes only 2-5 minutes to complete while still providing valid, disease-specific information on QoL. Researchers hope that implementation of this new tool will provide a method for clinicians to more routinely screen QoL allowing for more informed decision making, better care and reduced time in clinic.

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

For more information see past updates from February and June.

Posted in: Research