ALS researchers from around the world continue to build upon existing work and make new discoveries in the hopes of realizing a future without ALS. In the June 2022 Research Update, you’ll learn about the progress researchers have made in understanding the role of astrocytes in disease progression, gene mutations that may protect against ALS, advances in our understanding of the complex biology that underlies motor neuron loss in C9ORF72-linked ALS, and promising results from a pilot ALS clinical trial.

We recently developed a research glossary that contains a list of scientific and medical terms and definitions relevant to ALS. The glossary was created to support knowledge-sharing by helping to provide clarity around terminology that may be unfamiliar to our readers. Click here to download a copy.

New insight into the role of astrocytes in the progression of ALS

Researchers have identified a cellular pathway within astrocytes that may play a role in the spread of ALS and could serve as a target for future therapeutics.

Astrocytes are specialized support cells in the brain with a wide range of functions; you can think of them like personal assistants to the neurons. ALS research has traditionally focused on motor neurons because these are the cells lost during disease progression, but there is still much to be learned about the role of astrocytes in the disease.

In this study, researchers investigated a specific astrocyte protein, called connexin 43 (or Cx43), which plays a role in creating the open channels astrocytes use to communicate with neighboring cells. These Cx43-containing channels allow astrocytes to send signaling molecules directly into other cells. During times of stress, however, these channels may also enable potentially toxic factors to be transported to motor neurons.

As part of the study, the research team analyzed cerebrospinal fluid (CSF) and postmortem tissue samples from ALS patients and found increased Cx43 levels compared to healthy controls, with the highest levels found in those predicted to have the most rapidly progressing disease. The team also studied astrocytes created in the laboratory from patient-derived stem cells and found that these astrocytes had increased levels of Cx43 and, when mixed with motor neurons in a dish, induced motor neuron death.

On the other hand, using a mouse model of ALS the researchers showed that depleting Cx43 from astrocytes slowed disease progression and extended survival. This led the researchers to test whether adding a known blocker of Cx43-containing channels could serve as a potential treatment strategy in ALS. They found that tonabersat, a drug originally developed for treatment of migraine and epilepsy, was able to block astrocyte-induced motor neuron death in cell cultures and animal models.

Taken together, the results from this study provide additional evidence that astrocytes play a role in the progression of ALS and identify a new target for future biomarker and therapeutic development in an area of ALS biology that deserves more attention.

Genetic analyses uncover DNA mutations that may be protective against ALS

Gene sequencing reveals that mutations in the non-coding region of a gene called IL18RAP may reduce the risk of developing ALS five-fold.

Deep inside the nucleus of every cell in the body, DNA carries the master blueprint—the full set of genetic instructions needed for the body to grow, live and reproduce. DNA looks like a twisted ladder made from 3.2 billion pairs of building blocks. Technology like whole-genome sequencing gives scientists the ability to read a person’s complete set of DNA, known as the genome.

What you might find surprising is that of the 3.2 billion nucleotides found in the human genome, only about 1-2% actually code for the formation of proteins – the workhorses of the cell responsible for nearly all cellular functions required to sustain life. Until recently, the purpose of the remaining 98-99% of non-coding DNA was unclear to researchers, with these regions often referred to as “junk DNA.” However, researchers have come to learn that non-coding DNA serves important functions within the body, particularly when it comes to regulating the function (e.g., turning on and off) of protein-coding genes.

In this study, researchers analyzed the full DNA sequences of 6,139 people living with ALS and 70,403 non-ALS controls. The results showed that mutations in a non-coding region of the IL18RAP gene were extremely rare in people living with ALS, but for the few ALS patients who did carry mutations in this region the onset of disease was significantly delayed.

The protein created from the coding region of the IL18RAP gene is known to have an effect on microglia, the immune cells of the central nervous system (CNS). Microglia usually play a protective role in the CNS, but if over-activated, they can become toxic to motor neurons. One theory is that the over-activation of microglia may increase neuroinflammation in people with ALS and enhance progression of the disease.

To better understand the mechanism responsible for the reduced risk and delayed onset of ALS, researchers used gene-editing technology to replicate the effects of these protective mutations on microglia created from patient-derived stem cells in the lab. They found that the mutations caused microglia to be less toxic to surrounding motor neurons by reducing neuroinflammatory pathways.

The results of this study demonstrate the importance of analyzing the vast non-coding part of the genome as well, which in the past has often been overlooked. Here, researchers have identified a new neuroprotective pathway that could potentially be targeted therapeutically. Future studies will be needed to determine if modulating this pathway can have a positive effect in people living with ALS.

Advances in understanding the cellular pathways that contribute to C9ORF72-linked ALS

A new study details downstream effects of mutations in the C9ORF72 gene, which may contribute to some of the cellular toxicity observed in ALS.

Within cells, mutations in the C9ORF72 gene lead to the production of five different small proteins, referred to as dipeptide repeat (DPR) proteins. These DPR proteins have been shown to build up in the brains of people with C9ORF72-linked ALS.

Former studies in both cellular and animal models have shown that of the five DPR proteins produced, two are thought to be the most highly toxic (referred to as poly-PR and poly-GR). Although these and other DPR proteins have been proposed to interfere with many different cellular processes, the exact role they play in disease is currently unclear.

Researchers previously looked at the cellular interactions of poly-PR and poly-GR and found that these proteins often bind to translational machinery within the cell. This is the area within cells where genetic information is converted into proteins, a vital process for all living organisms. And this interaction is thought to interfere with the production of all proteins within the cell.

To better understand how this interaction occurs, researchers used a high-resolution technique called cryogenic electron microscopy (cryo-EM) which allowed them to view exactly how the DPR proteins block protein translation in cells, providing a structural basis for their toxicity. The researchers note, however, that this may represent just one of many pathways impacted by DPR proteins that could contribute to disease.

The results from this study advance our understanding of the complex biology that accompanies motor neuron loss in C9ORF72-linked ALS. Furthermore, the structural information obtained provides a foundation for researchers to develop alternative ways to address potential DPR toxicity in those who carry C9ORF72 mutations, the most common genetic cause of ALS.

Intriguing results from a small, early-stage ALS clinical trial

Promising clinical trial results suggest that ILB®, an experimental treatment being developed by Swedish biopharmaceutical company TikoMed, may have a clinical benefit in ALS.

ILB® contains a modified version of a compound called dextran sulphate and is believed to target multiple cellular pathways in the body that play a role in motor neuron health, self-repair, and protection.

This Phase 2 open-label clinical trial enrolled thirteen ALS patients who were given subcutaneous (under-the-skin) injections of ILB® over a five week period. Participants were then followed for an additional 70 days to determine the safety, tolerability, and possible efficacy of ILB®.

Results from the study were recently published in the peer-reviewed journal PLOS ONE. There were few side-effects and no serious safety concerns after injection of ILB®. When looking at other measures, researchers found that ALSFRS-R and Norris rating scores increased after five-weeks of treatment suggesting a functional improvement. The therapeutic benefits observed, however, decreased three to four weeks after the last dosage.

After ILB® injection, there was a subsequent increase in blood plasma levels of Hepatocyte Growth Factor (HGF), a substance naturally created by our bodies that is known to have a protective effect on motor neurons and muscle cells. Researchers believe that the functional benefit observed may, in part, be due to the increased HGF levels. The idea that HGF may be an important target in ALS is supported by a lot of preclinical data and a separate study evaluating a gene therapy, called Engensis, which aims to boost HGF levels within neurons and supporting cells and had positive results in a previous Phase 1/2 clinical trial. Engensis is now being tested in a follow-up Phase 2 study, sponsored by Korean biotech company Helixmith Co.

It is important to note the researchers stress that readers should be extremely cautious when interpreting these results due to several study limitations, including the small size, open-label nature of the study, and lack of rigorous statistical analyses. It is well-known that open label studies (where participants know they are receiving the active drug) have strong placebo effects that can influence the outcomes.

Overall, however, the data suggests that ILB® is safe, well-tolerated and has a potential disease modifying effect in ALS. Further studies to determine the optimal dosage, treatment duration and possible long-term effects of ILB® are currently in progress.

Bringing you the latest news on advancements in ALS research, the ALS Canada research team regularly summarizes the most significant discoveries throughout the year.

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

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