What’s happening in the world of ALS research at this point in the year? Read about the progress researchers have made in developing new and better models to study ALS in the lab, insights gained into the progression of ALS on a cellular level, new compounds identified as potential treatment strategies for ALS and the results of a promising Phase 2/3 clinical trial.
New insights into the progression of ALS on a cellular level
ALS symptoms typically first appear in one area of the body and eventually progress leading to widespread paralysis. For the first time, researchers have been able to track this progression throughout the body on a cellular level using an innovative new approach called spatial transcriptomics.
It is well established that genetic factors play a role in the development of ALS. On a cellular level, scientists can determine whether certain genes are activated, or “expressed,” by looking for the substances that gene creates, called RNA. Using a precise new technology, researchers at the New York Genome Center analyzed gene expression in animal models of ALS throughout disease progression.
In this study, researchers collected 76,000 gene expression measurements from 1,200 mouse spinal cord sections. Samples were taken from different regions of the spinal cord and at various stages of disease (pre-symptomatic, onset, symptomatic and end-stage), allowing researchers to track changes over time.
Researchers also collected 60,000 gene expression measurements from 80 post-mortem spinal cord sections donated from seven ALS patients. These samples were representative of the end-stage of disease but were taken from different sections of the spinal cord, enabling researchers to detect differences between distinct areas of the human spinal cord.
The large amount of data provided researchers with numerous insights into the progression of ALS. For example, researchers found that specialized cells called microglia, which are the primary immune cells of the brain and spinal cord, became dysfunctional before ALS symptoms appeared. The work helped to provide researchers with a map of disease-related changes in many cell types and revealed ways in which the various cells communicate with one another.
Further research is required to determine whether the changes observed were part of the root cause of ALS, or rather a part of the body’s response to the disease. However, this work greatly increases our understanding of the nervous system on a cellular level and researchers believe the information garnered from these types of studies may one day lead to the development of biomarkers, which are needed to help diagnose ALS earlier and test new ALS treatments.
AB Science announces results of Phase 2/3 clinical trial of masitinib in ALS
Pharmaceutical company AB Science recently published positive results from their Phase 2/3 clinical trial of masitinib in ALS that showed that the drug was able to slow functional decline. The study enrolled 394 participants and lasted 48 weeks.
Masitinib is a drug that targets cells within the body that play an important role in the immune system. Preclinical studies suggest that masitinib may reduce inflammation within the nervous system, which is believed to be a factor in the progression of ALS.
The study achieved its main goal, with participants who received the higher dose of masitinib (4.5 mg/kg/day) in combination with riluzole showing a 27% slowing of functional decline (as measured by the ALSFRS-R). This masitinib and riluzole combination also delayed decline in quality of life by 29% (as measured by the ALSAQ-40 survey) and respiratory function by 22% (as measured by forced vital capacity).
Similar to other treatments, such as the recently approved edaravone, subsequent analyses showed that masitinib has the largest effect for those who are earlier in their disease progression.
Overall, researchers are encouraged by these early results. A global Phase 3 clinical trial of masitinib is set to begin to confirm the drug’s effectiveness, and will be led by Canadian researcher Dr. Angela Genge at the Montréal Neurological Institute. This new study is expected to enroll 495 participants from Canada, the US and Europe. Please speak to your neurologist to find out if the study will be recruiting in an area near you.
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Researchers develop a model to study ALS-resistant motor neurons in the laboratory
It is common for people with ALS who have progressed to the point of advanced paralysis to retain the ability to move their eyes, yet researchers still don’t know exactly why. For some reason the motor neurons that control eye movements, called oculomotor neurons, are more resistant in ALS.
Studying oculomotor neurons in animals or humans can be difficult due to the relatively low abundance of this cell type in the brain. As a result, researchers from the Karolinska Institute in Sweden set out to develop a way to better model oculomotor neurons in the laboratory.
In the June 2019 study, researchers used stem cell technology to generate a high proportion of oculomotor neurons from mouse embryonic stem cells. After thorough analysis, the researchers were able to confirm that the cells generated in the lab were in fact oculomotor neurons with very similar properties to those found in the human brain.
Preliminary studies of the oculomotor neurons revealed that a specific survival-enhancing signaling pathway, referred to as Akt, was boosted in these cells. This led the researchers to conclude that Akt signaling may in part underlie the oculomotor neurons’ resistance in ALS.
Researchers are hopeful that further studies using these oculomotor neurons, a new ALS-resistant model, will provide a better understanding of the mechanisms responsible for the resistance, as well as important insights that could be used to help slow or stop degeneration in other, more vulnerable cell types.
The ALS Canada Research Program is currently funding a project led by Dr. Richard Robitaille, a researcher and professor at the Université de Montréal, investigating the resistance of oculomotor neurons in ALS, specifically in a region called the neuromuscular junction.
Small-molecule compounds identified that can reduce TDP-43 clumping in cells
In a study recently published in the journal Neuron, researchers from UC San Diego School of Medicine set out to identify small-molecule compounds that may be able to reduce the accumulation of stress granules within cells. Researchers are hopeful that the compounds identified in this study can provide a starting point for the development of new ALS therapies.
Stress granules are structures that form within cells in response to various stresses (such as being exposed to high/low temperatures, toxins or disease) in order to protect important cellular components. Stress granules are only meant to form temporarily; however, in ALS these structures often do not disassemble and proteins, such as TDP-43, can become trapped.
When caught in these stress-induced clumps, proteins liked TDP-43 are unable to complete their normal function which can be detrimental to the cell’s health. Thus, researchers believe that strategies aimed at restoring stress granule dynamics in cells may be an important avenue to explore for the treatment of ALS.
Using motor neurons derived from the stem cells of ALS patients with either a TDP-43 or FUS mutation as a model, researchers exposed the motor neurons to a toxin called puromycin to induce stress. They then screed thousands of small-molecule compounds for their ability to change the stress granule dynamics observed and found that several compounds were able to reduce the size and number of clumps formed.
Since TDP-43 displays abnormal behaviour in cells in 97% of all ALS cases, treatment strategies aimed at restoring the normal function and dynamics of the protein, such as the one described in this study, could have broad implications for the treatment of ALS. The researchers recognize, however, that the therapeutic benefit of the small molecules identified still needs to be confirmed in model organisms (such as mice) before a potential therapy could one day be tested in patients.
Researchers develop a new animal model to better understand C9orf72-linked ALS
A team of researchers based in China has developed a new mouse model of ALS that allows them to study the movement impairments linked to the most common genetic mutation in ALS.
Mutations in a gene called C9orf72 represent the most common genetic cause of ALS and frontotemporal dementia (FTD). 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.
Within cells, mutations in C9orf72 lead to the production of five different small proteins, referred to as dipeptide repeat proteins (DPRs). It is believed that these DPRs contribute to the neurodegeneration seen in ALS. Previous studies looking at the effects of DPR proteins in cell lines and fruit fly models of ALS indicate that one of these proteins, referred to as poly-PR, is exceptionally toxic. The exact role that poly-PR plays in human C9orf72 linked-ALS is unclear.
To better understand the role that poly-PR may play in ALS, researchers developed an ALS mouse model where the mice produce poly-PR specifically in neurons. The researchers found that these mice display the movement impairments, loss of motor neurons, and inflammation in the brain and spinal cord that is typical of ALS.
This newly developed mouse model will help researchers to study the mechanisms that underlie the movement impairments seen in C9orf72-linked ALS. In previous mouse models, the animals would often only display the behavioural/cognitive impairments that are common in FTD. Thus, these mouse models provide a new tool for ALS researchers to gain a more comprehensive view of the symptoms associated with C9orf72 mutations.
