The second quarter of 2021 continues to see progress within the field of ALS research. Some of the most notable discoveries at this point in the year include the identification of a possible link between the vascular system and ALS, identifying new treatment strategies for both genetic and sporadic forms of the disease, and gathering preclinical data that may help to support the clinical development of future ALS treatments.

Researchers identify a potential link between the vascular system and early-stage ALS

New data suggests that the cerebrovascular system, which delivers oxygen and nutrients to the brain, may show early evidence of disease onset, and contribute to the variability of progression observed in sporadic ALS.

A recent study that appeared in the journal Nature Medicine revealed that in mouse models of ALS, a type of cell found in the brain’s blood vessels, called perivascular fibroblasts, shows dysfunction in the pre-symptomatic stage of ALS – prior to the neuroinflammation and neuronal loss associated with the disease. Analysis of postmortem tissue from patients with sporadic ALS also showed increased levels of a protein marker specific for perivascular fibroblasts, called SPP1, which indicated that these cells may play a role in human ALS as well.

Researchers then went on to measure SPP1 levels in the blood of 574 patients with sporadic ALS from four different countries and identified a correlation between SPP1 levels at the time of diagnosis and disease duration. The data showed that higher SPP1 levels at the first clinic visit were often associated with more aggressive progression and shorter survival.

The results from this study are important for a variety of reasons. First, the researchers have identified cellular dysfunction that seems to occur before motor neuron loss which could make perivascular fibroblasts an important target for future ALS treatments. Second, the correlation between SPP1 levels and survival suggests that this protein could help to better predict ALS progression on an individual basis. Finally, the data suggest that SPP1 could potentially also serve as a diagnostic biomarker for ALS, which is important to enable earlier diagnosis and treatment. Given that ALS will soon have its first ever pre-symptomatic clinical trial of a gene-targeted therapy, examining SPP1 levels in carriers with known genetic mutations prior to symptom onset may soon be possible.

New study provides additional evidence to support new treatment strategy for C9ORF72-associated ALS

Researchers have developed a new type of antisense oligonucleotide (ASO) that shows promise in treating a familial form of ALS.

Mutations in the C9ORF72 gene are the most common genetic cause of ALS. These mutations are unique in that unlike most other ALS-linked genes, where there is often a mistake in a single piece of DNA, C9ORF72 mutations involve a section of DNA that is abnormally repeated hundreds or even thousands of times. These repeat mutations result in less of the normal C9ORF72 protein being produced, but also create toxic by-products, such as repeat-containing forms of RNA that can accumulate in cells.

In a study recently published in the journal Nature Communications, researchers developed stereopure ASOs that showed improved activity and were able to specifically target the toxic repeat-containing RNA molecules in multiple cellular and mouse models of ALS. After treatment with these ASOs, they found that cells produced lower levels of the disease-related by-products while still maintaining healthy production of the normal C9ORF72 protein.

Researchers are encouraged by this preclinical data, which further supports the idea that selectively targeting repeat-containing RNA may be a viable therapeutic approach for the treatment of C9ORF72-associated ALS. This foundational data provides additional hope that Biogen’s ongoing Phase 1 clinical trial evaluating BIIB078, an ASO designed to treat C9ORF72-linked ALS, may be successful. Additionally, Wave Life Science, who conducted and sponsored this study, is expected to move their experimental treatment that uses this stereopure technology, WVE-004, into a Phase 1b/2a clinical trial later this year.

New compound may help to protect upper motor neurons in ALS

Scientists have identified a new compound, called NU-9, which appears to impact key cellular deficits linked to ALS and protect against the loss of upper motor neurons in cellular and animal models.
ALS is a disease that is characterized by the loss of both upper and lower motor neurons. Upper motor neurons originate in the brain and carry signals for voluntary movement from the brain to the spinal cord. Lower motor neurons, on the other hand, originate in the spinal cord and carry these signals from the spinal cord out to the muscles. To date, much of ALS research has focused on the health of the lower motor neurons despite upper motor neurons also playing an important, but more poorly understood role in the disease.

In this study, published in the journal Clinical and Translational Medicine, researchers identified two common causes of upper motor neuron loss in both patient and mouse models of ALS. They found that upper motor neuron loss appears to stem from issues with the mitochondria, the energy-producing structures within cells, and endoplasmic reticulum, the structures where proteins are made. However, when researchers treated cells with the drug-like compound NU-9, they found that the structure and integrity of both the mitochondria and endoplasmic reticulum appear to be preserved.

The researchers used mouse models linked to two different ALS-associated proteins, SOD1 and TDP-43, which are thought to have very different underlying causes of ALS. They found that the SOD1 mice were able to perform better on one of the two functional tests conducted, compared to control mice, over the 60-day period they were studied. The TDP-43 mice appeared to do better on both functional tests, again compared to controls, up until the 120-day mark. NU-9 did not show an effect in preventing lower motor neuron degeneration in the ALS models studied.

The data from this study are promising as they show that NU-9 can delay the loss of upper motor neurons in two different ALS mouse models. Given the similarities between the upper motor neuron of mice and humans at the cellular level, the researchers are hopeful that NU-9 may be able to have a similar effect in people living with ALS. They note, however, that before moving NU-9 into clinical testing in humans, more detailed studies will need be done to further analyze the properties and toxicology of this potential new drug.

Mechanistic insights into the role of RIPK1-regulated inflammation in ALS

Previous studies in multiple mouse models of ALS have shown that inhibition of RIPK1, a protein linked to neuroinflammation and cell death, has a therapeutic benefit. New research provides insight into the mechanism by which blocking RIPK1 activity may have a protective effect.

RIPK1 is a critical protein that regulates inflammation and cell death throughout the body. A study recently published in the journal PNAS analyzed the underlying pathways by which RIPK1 may contribute to disease. Using sophisticated technology that allowed researchers to analyze individual cells with high resolution, they were able to identify a subset of microglial cells that appear to become activated as a result of RIPK1 activity. Microglia are the immune cells of the central nervous system, found throughout the brain and spinal cord. They usually play a protective role, but if over-activated, they can become toxic to motor neurons. The study findings suggest that a subset of microglial cells that become over-activated in response to RIPK1 and may play an important role in disease progression.

Inhibitors of RIPK1 have already been tested in human ALS clinical trials. In partnership with pharmaceutical company Sanofi, Denali Therapeutics previously ran a Phase 1 study testing DNL747, a small-molecule inhibitor of RIPK1, in ALS. They eventually terminated the study as it became apparent that higher doses of the drug would be needed to have a therapeutic effect but preclinical studies revealed potential safety risks with increasing the dose. Denali has now switched focus to developing a next generation RIPK1 inhibitor for ALS, DNL788, which they plan to move forward to a clinical trial.

The results from this study reveal a mechanism by which RIPK1 inhibition may be able to reduce neuroinflammation in ALS and therefore slow disease progression. The study also identifies potential biomarkers for analysis in upcoming clinical trials of RIPK1 inhibitors, which are needed to ensure the drug is having the desired effect within the body.

Reseachers identify a new cellular pathway that may be a therapeutic target in CHCHD10-linked ALS

A new study suggests that a specific cellular pathway, referred to as PINK1, may be a key player in the toxicity associated with CHCHD10 mutations in ALS.

In 2014, mutations in the CHCHD10 gene were newly identified as a genetic cause of ALS. Exactly how these mutations lead to motor neuron loss in ALS is yet to be fully understood. Previous studies suggest that CHCHD10 mutations may cause impaired functioning of mitochondria, the structures within cells that provide the energy needed to survive.

In this study, published in the journal Nature Communications, researchers sought to better understand the biology of CHCHD10-linked ALS in the lab using cellular and fruit fly (drosophila) models. Their work revealed that CHCHD10 mutations caused another protein linked to 97% of all ALS cases, TDP-43, to become more insoluble and cluster within the cells at the mitochondria. It also led to activation of a cellular pathway called PINK1, which is known to play a role in the removal of damaged mitochondria within cells.

Based on this data, the researchers then explored whether they could reverse the toxicity associated with CHCHD10 mutations by activating pathways that promote the health and proper functioning of mitochondria. Utilizing small molecules that could prevent TDP-43 from clustering at the mitochondria and inhibit activation of the PINK1 pathways, the researchers were able to reduce degeneration and restore mitochondrial health in the cellular and fly ALS models.

The results from this study suggest that restoring mitochondrial function by targeting the PINK1 pathway may represent a promising treatment strategy for CHCHD10-associated ALS and further highlight mitochondrial dysfunction as a potential therapeutic target for all forms of ALS. In partnership with Brain Canada, ALS Canada is currently funding a study aimed at better understanding the role of CHCHD10 mutations in ALS using cell and zebrafish genetic models, the results of which could help to identify new treatment targets for the disease. To read more about the study, click here.

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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