Bringing you the latest news on advancements in ALS research, the ALS Canada Research Program team regularly summarizes what they believe are the most significant discoveries throughout the year. This is the first update for 2019.
Researchers identify a potential new biomarker and drug target for ALS
Did you know that there is a protein known to be affected in 97% of all ALS cases? This has led researchers to investigate the protein TDP-43 to learn more about its interactions within cells and how these interactions could contribute to disease. As a result, two research groups have independently identified a protein called STMN2 as playing a role in ALS. Both groups published their findings in the February 2019 issue of Nature Neuroscience.
- In the first study led by researchers from Harvard University, scientists used motor neurons derived from stem cells to investigate what happens when TDP-43 clumps together and is no longer able to function properly, as seen in most ALS cases. The researchers analyzed a variety of interactions within cells, however, one stood out in particular. They found that when the amount of functional TDP-43 was decreased, the level of another protein, STMN2, also decreased substantially. STMN2 is known to play a role in the growth and repair of motor neurons.
- In the second study led by a team from the University of California at San Diego, patient tissues were analyzed by researchers who found that STMN2 levels are lower than expected in motor neurons from the brains and spinal cords of ALS patients with and without a family history of the disease. Also using motor neurons derived from stem cells, the researchers tested whether increasing the levels of STMN2 could help to restore motor neuron health and found that it did have a restorative effect.
Taken together, these studies suggest that STMN2 could represent a potential new biomarker for ALS, which is important for earlier and accurate diagnosis. Further, drugs designed to restore the natural levels of STMN2 in cells represent a promising new treatment avenue for researchers to explore.
How artificial intelligence is helping researchers to better understand ALS
ALS is often said to be a heterogeneous disease since every person’s journey is different. People living with the disease can have very different areas of onset, ages of onset, rates of progression and symptoms. Due to the heterogeneity seen in ALS, stratification or grouping of patients into sub-populations is very important for clinical trial planning and interpretation, as well as clinical care. Better sub-grouping of ALS patients could substantially reduce the number of patients needed for an ALS clinical trial, improve patient selection and even provide people living with ALS a more accurate prognosis.
In 2015, the DREAM Prize4Life ALS Stratification Challenge explored how a crowdsourcing approach could help researchers to better stratify or group ALS patients. The challenge used clinical data from an open-access database and drew in 31 teams of researchers from across the globe who used statistical and machine learning approaches to determine meaningful sub-groups of ALS patients. In a January 2019 study, researchers analyzed results from the DREAM Prize4Life ALS Stratification Challenge and designed a new method that could integrate patient sub-groups identified by the various teams, resulting in consistent and clinically-relevant sub-groups of ALS patients. The researchers note that the sub-grouping scheme identified here could only have been achieved through a large-scale crowdsourcing approach highlighting the power of artificial intelligence to enhance our understanding of ALS. Researchers believe that classification of ALS patients using the sub-groupings identified in this study will promote advancements in ALS clinical trials, clinical care and personalized treatment.
Could a drug previously approved to treat hepatitis be successful in treating ALS?
Proteins, the substances responsible for almost all cellular functions, consist of long chains of smaller units called amino acids. These long chains must fold into the appropriate 3D shape in order for a protein to complete its intended function within a cell. If a protein misfolds, meaning it does not fold into the correct shape, the outcome can be harmful. This is believed to be the case for SOD1, an ALS-linked protein known to misfold and clump together in cells.
Previous studies suggest that a specific amino acid, tryptophan 32, may be to blame for the bad behavior of SOD1. In an April 2019 study, researchers from the University of Alberta set out to identify a drug using computer simulations that would be able to interact with this rogue amino acid and hopefully as a result reduce the toxicity of SOD1. After narrowing down the list of drugs, the researchers identified telbivudine as a lead candidate. Telbivudine is currently approved to treat hepatitis B infections.
Moving from computer simulations to the real world, the researchers assessed the effectiveness of telbivudine using an ALS animal model (zebrafish modified to carry a disease causing SOD1 gene) and found that treatment with the drug reduced motor neuron loss. The researchers note that these findings require further validation in mouse models of ALS but the preliminary results are promising and suggest that treatments targeting this specific region of SOD1 may be successful at reducing toxicity and slowing disease progression.
Insights from the body’s natural immune response open up new treatment avenues for ALS
Researchers from Université Laval and the CERVO Brain Research Centre have generated a specialized antibody, called a single-chain antibody, that helps to correct an abnormal behavior of TDP-43, a protein known to be affected in almost all ALS cases. Antibodies are proteins that are produced by the immune system to protect the body against foreign invaders like bacteria and viruses, and work by binding to specific proteins on harmful agents and triggering their removal and/or destruction. Antibodies, however, are also commonly used as tools within the laboratory. For example, antibodies can be designed to bind to specific proteins in cells allowing researchers to visualize where and how much of the target protein is within the cell.
In a February 2019 study, researchers set out to harness the power of single-chain antibodies to battle ALS and developed one that could specifically target TDP-43. To test the effectiveness of the antibody, the researchers inserted the genetic material that directs production of the antibody into a virus that was then injected into the spinal canal of mice with ALS. This allowed the single-chain antibodies to be made inside cells, where TDP-43 is found, allowing them to have more of an effect compared to traditional antibodies that generally cannot pass through the outer barrier of cells. The results showed that when mice were treated with the antibody, the number of toxic TDP-43 clumps in cells was reduced and the mice displayed increased cognitive and motor function compared to controls (i.e. ALS mice not treated with the antibody). The results from this preclinical study support future development of immunotherapy techniques for the treatment of ALS.
Positive results from preclinical studies of a gene therapy for ALS and FTD
Researchers from an Amsterdam-based biopharmaceutical company called uniQure have released two proof-of-concept studies demonstrating the potential effectiveness of a gene therapy technique to treat two related neurodegenerative diseases. Mutations in a gene called C9orf72 represent the most common genetic cause of ALS and frontotemporal dementia (FTD). Two substances are produced in cells as a result of these mutations, commonly referred to as repeat RNAs and DPRs. These substances are thought to contribute to cellular toxicity that leads to disease.
- In the first study, researchers developed substances called microRNAs that were designed to bind to the C9orf72 repeat RNAs and reduce their toxicity in cells via a process known as “silencing.” In the laboratory, researchers added the microRNAs to human cells modified to carry the disease-causing C9orf72 gene and found that the microRNAs could successfully bind to the repeat RNAs.
- In the second study, researchers showed that the silencing process was also effective in neurons derived from the stem cells of a patient with FTD and a mouse model of ALS (i.e. a mouse that has been genetically modified to carry the disease-causing C9orf72 gene). Taken together, these preclinical studies provide evidence that gene therapy may represent a successful treatment strategy for C9orf72-liked ALS and FTD by reducing the amount of toxic substances produced in cells as a result of mutation.
Pharmaceutical companies Biogen and Ionis are currently conducting Phase 1 clinical trials of antisense oligonucleotides (a type of gene therapy) for SOD1- and C9orf72-linked ALS, and the results of the preclinical studies highlighted above make us even more hopeful that we will see positive results.
