The International Symposium on ALS/MND is an annual event organized by the Motor Neuron Disease Association. It brings together the leading experts in ALS research from around the world to share their research and foster collaboration. The 2022 Symposium, which is taking place online from Tuesday, December 6th to Friday, December 9th, will feature an extensive program of research presentations as well as virtual poster sessions.

This year, the ALS Therapy Development Institute (ALS TDI) is proud to share that five members of our science team have been selected to present their latest findings at the International Symposium on ALS/MND.

  • One scientist from ALS TDI has been given the honor of being selected to give an oral presentation at the Symposium.
  • In addition, four ALS TDI scientists were selected to present posters that showcase key highlights from our ALS research this past year and demonstrate our rigorous commitment to finding treatments.

Here are some details on ALS TDI’s upcoming science presentations for the International Symposium on ALS/MND:

Oral Presentation Highlights

Investigating the Role of C9orf72 Mutations in Causing ALS

On December 7th at 11:20 am ET, ALS TDI Associate Scientist III Therese Dane will deliver an oral presentation as part of a session covering new research in cell-based models of ALS.

Delivering a talk like this at the Symposium is a distinct honor, indicating that the organizers at MNDA believe that these findings are particularly important to the field of ALS research. Only a handful of the hundreds of posters submitted to the Symposium are selected to be included in the presentation sessions.

“It's my first time submitting a poster to the Symposium,” says Therese, “so I wasn't expecting this. But it was a great surprise. I also found out that I'm the first woman from ALS TDI to give a talk at ALS/MND, so that makes me feel proud. This will be one of only three talks in the cell-based model session, so it's humbling but exciting at the same time.”

Her talk, “Reduced C9orf72 expression exacerbates polyGR toxicity in patient iPSC-derived motor neurons” will discuss experiments she performed with her colleagues on ALS TDI’s Cell Biology team to learn more about C9orf72-related ALS.

In any healthy human cell, there are two copies of the C9orf72 gene. People with C9orf72-related ALS have a mutation in one or, in rare cases, both copies of this gene, known as a C9orf72 repeat expansion mutation. To advance our understanding of how these mutations might cause damage to motor neurons, Therese used induced Pluripotent Stem Cells (iPSCs) to create four lines of motor neurons for testing.

  • The first line, which served as a control, was from a healthy person with two normal copies of the C9orf72 gene.
  • For the second and third cell lines, Therese used gene editing techniques to remove one copy of the C9 gene in the former and both copies in the latter. This resulted in one cell line with half the regular levels of the C9 protein produced by the gene, and one with no C9 protein.
  • The fourth line was derived from samples provided by a participant in ALS TDI’s Precision Medicine Program with C9orf72-related ALS.

Therese then exposed these cells to polyGR – one of the toxic proteins known to be produced by cells with C9 repeat-expansion mutations. When measuring the effects of this protein on each cell line, she found that the first (healthy control) cell line showed the most resistance to the toxic effects of polyGR, while the second and third each suffered progressively more damage. This could imply that cells with lower levels of the C9 protein are more susceptible to damage from polyGR.

However, the cells derived from a person with C9orf72-related ALS showed similar levels of damage as the cell line with no C9 genes at all, even though they contained one healthy C9 gene and one with a repeat-expansion mutation. This finding could indicate that both the lack of normal C9 protein and the presence of toxic proteins created by a mutated C9 gene are both involved in causing motor neurons to die in cases of ALS.

Additionally, Therese found that treatment with a Type 1 PRMT Inhibitor, an enzyme that affects a drug target discovered by ALS TDI, significantly reduced the damage to control cells treated with polyGR. This supports Type-1 PRMT inhibitors' importance in finding a treatment for C9orf72-related ALS. Therese and the ALS TDI cell biology team plan to explore additional experiments to both further investigate how type I PRMTs interact with C9orf72 and test these enzymes in models of other forms of ALS.

Poster Session Highlights

In addition to Therese’s oral presentation, four ALS TDI scientists have been selected to present at the ALS/MND Symposium's virtual poster sessions. Occurring throughout the Symposium’s four days in between live talks, these poster sessions will allow attendees to explore a wide range of ALS research and learn from the researchers behind it.

Further Investigating type I PRMTs in C9orf72-Related ALS and Beyond

ALS TDI Program Manager and Associate Scientist III Anna Gill will further expand upon the potential of the type I PRMTs in her poster, “Using PRMT Inhibition to Abrogate Dipeptide Repeat Protein Toxicity in C9orf72-Related ALS: A Proteomics Assessment of Post-Translational Modifications.” It covers how Anna worked to better understand the biological reasons behind why type I PRMTs appear to demonstrate efficacy in cellular models of ALS.

To do this, Anna and her colleagues on the Discovery Biology Team conducted a proteomics study, which looked at how our drug target, type I PRMTs, modified the proteins in cell. Looking at cellular models of ALS that had been treated with type I PRMT inhibitors in comparison to controls that were untreated, they found evidence that some proteins not associated with C9orf72-related ALS may also be involved in their protective effects. This could support the possibility that type I PRMTs are a potential drug target for other, non-C9orf72-related types of ALS.

Using Imaging to Learn More about Type 1 PRMT Inhibitors

ALS TDI Senior Associate Scientist Kaly Mueller will present a poster at the Symposium, titled “Effects of arginine methylation state on the subcellular localization of C9orf72 repeat expansion associated toxic dipeptide repeat proteins.”

Type I PRMT inhibitors work to inhibit the PRMT enzymes that cause asymmetric dimethylation, a specific molecular modification to the amino acid arginine. In the past, ALS TDI researchers found these type I PRMT inhibitors could be protective against mutant proteins derived from the C9orf72 mutation. To better understand why they have this effect, Kaly conducted an experiment using an imaging technique called immunofluorescence that can help researchers visualize the components of a cell. She compared images of cells that had been exposed to toxic C9-related proteins that had undergone this asymmetric dimethylation process, to other cells had been exposed to proteins that were unmethylated.

Kaly and the Discovery Biology team can use these immunofluorescence techniques to determine differences in where toxic C9-related peptides go in the cell, and how modification by our target, type I PRMTs, might affect these behaviors. With this information, ALS TDI researchers will be able to better understand how to refine new Type I PRMT inhibitor drug targets as treatments for ALS. While these experiments are still ongoing, preliminary results have already identified some differences in the localization of these proteins in the cell. With this information, ALS TDI researchers will be able to better understand what parts of the cell they need to target as they work to develop type I PRMT inhibitors as a treatment for ALS.

Copper Complexes as a Potential Treatment for ALS

Dr. Kyle Denton, ALS TDI’s Director of Cell Biology, will present a poster entitled “Discovery of Novel Small Molecule Cu(II) Complexes Using a Genome Edited iPSC-based Phenotypic Screening Platform.” It will provide information about the Cell Biology Team’s multi-year research into copper complexes, also referred to as “redox metabolism modulators” – a group of molecules that has shown promise in preclinical studies as a treatment for ALS.

The poster covers the evolution of the project, which began when Dr. Denton and his team first found that these molecules showed promise in a unique iPSC model of ALS which they developed. They went on to develop a novel screening platform to test a large number of these copper complexes in iPSCs quickly and efficiently in order to identify the most promising candidates for further study. The best-performing molecules from this study were passed on to the ALS TDI pharmacology team, who are currently testing them in animal models of ALS to identify a lead candidate to potentially advance toward human trials.

Introducing the PMP to Potential Collaborators

The Precision Medicine Program (PMP) is a collaboration between scientists at ALS TDI and people with ALS all around the world to gather data about the disease. Alan Premasiri, Manager of Clinical Operations and Associate Scientist II at ALS TDI, will present a poster detailing the PMP, titled “ALS Precision Medicine Program: Cohort Overview of a Comprehensive Natural History and Translational Research Study for the Identification of ALS Therapeutic Targets, Biomarkers, and Targetable Patient Subsets.”

Alan’s poster will serve as a high-level introduction to the PMP for researchers unfamiliar with the program. It will lay out the PMP’s goals and methods – how we collaborate with people with ALS all over the world to gather data including ALSFRS scores, life-history surveys, biological samples, and accelerometer and voice recordings to learn more about ALS. The poster will also give a glimpse into the data we have collected, including participant demographics, gene sequencing results, and speech and limb strength data.

ALS TDI has collaborated with many outside partners through the PMP, including Duke University’s Dr. Richard Bedlack and the Google Research Artificial Intelligence team. By laying out the wealth of data available in the PMP, Alan aims to appeal to potential future collaborators at the Symposium whose work could benefit from access to the PMP’s data. To this end, the poster will also serve as an announcement of a new online platform that researchers will be able to use to easily access PMP data to be introduced in 2023.

For more information on the International Symposium on ALS/MND, visit them at: https://symposium.mndassociation.org/

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