Insights

Session 5A Therapeutic strategies


Developing new therapeutic strategies for treating ALS is a key goal as it presents new ways to hopefully develop new patient treatments and possibly a cure for ALS. In this session the focus was aimed on new and novel therapeutic ideas for treating ALS by targeting different cell types or by utilizing novel technologies and strategies.

The first talk by the Rivest group from Quebec was focused on his group’s findings on targeting the immune response in Alzheimer’s disease. Monocytes are a type of white blood cell called a leukocyte that is key part of the immune system. They showed that monocytes are attracted to the toxic Aβ plaques, characteristic in Alzheimer’s disease and that knockout of the type 2 monocytes led to an increase in the number of plaques. They then went on to show that by activating the microglia and monocytes they could decrease and solubilise the toxic Aβ plaques and improved the cognitive impairment of mice. This process of monocyte activation could be a potential therapeutic target for neurodegenerative disorders including ALS.

In the next talk from the Weizmann institute in Israel, activation of the choroid plexus for leukocyte trafficking was identified as a therapeutic approach in superoxide dismutase 1 (SOD1) ALS. CD4+ T cells have been shown as beneficial in reducing neuro-inflammation in G93A SOD1 mice and loss of CD4+ cells led to increased neuronal loss. The group showed that the choroid plexus of SOD1 mice showed a decreased ability to produce CD4+ cells supplying the cerebrospinal fluid and spinal cord. By immunizing the mice with a central nervous system-derived peptide, they activated the choroid plexus to allow the CD4+ cell trafficking. This led to an extension in survival of the mice by 15 days on average. This proposes the question of possibly using immunization with a self-peptide to activate the inflammatory response and protect from neurodegeneration in diseases such as ALS.

The next talk from the lab of Jan Grimm based in Switzerland, investigated the use of human-derived monoclonal antibodies to target the misfolded SOD1. Healthy human donors were screened for memory B cells that had the ability to target misfolded SOD1. In spinal cord tissue from patients, the antibody had the ability so specifically bind the misfolded SOD1 in motor neurons. Mice were then immunized with the antibody leading to reduced SOD1 pathology and rescuing of the motor neurons which led to reduced muscle atrophy and improved motor function. The antibody also led to an increased survival of 2 months. This highlights the possibility of identifying and designing antibodies that can be used in immunotherapy to treat ALS.

Wim Robberecht’s group from Leuven, Belgium highlighted the potential to use a nanobody, which are just the variable domain of the heavy chain of antibodies, targeted against SOD1 as a potential treatment. Camelids and sharks have been shown to have the ability to produce the nanobody, and in HELA cells the nanobody had the ability to stop formation of high MW aggregates. In Zebrafish it reduced mutant SOD1 levels and rescued axonal length defects while in mice it led to delayed onset and an increase in survival with increased motor neuron counts and neuromuscular junctions (NMJs). The treatment in mice was effective at pre-symptomatic stages but showed no effect after symptom onset. This raises the interesting possibility of using the nanobody as a treatment for ALS.

Finally Brian Kaspar from Ohio State University talked about using gene therapy to down regulate mutant SOD1 as a potential ALS treatment. Using the viral vector AAV9 they down regulated SOD1 specifically in motor neurons and astrocytes within the CNS of mice. When mutant SOD1 mice were treated it led to improved survival, delayed onset and decreased disease progression. The work has now progressed to a primate model in which Macaque monkeys undergo spinal cord injection leading to a reduction in SOD1 levels by 90% in the spinal cord motor neurons as well as a 60% decrease in astrocytes.  This means that by using viruses to deliver to the exact cell types affected by ALS we may be able to stop the toxic effects of mutant SOD1.

In conclusion this session highlighted a number of the many new and innovative therapeutic strategies that are being developed and tested for the treatment of ALS. By utilizing the new treatment options for other neuro-degenerative diseases such as Alzheimer’s disease as well as developing novel treatments for ALS the potential for new therapies and possibly even a cure is getting closer.

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