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ALS Alert Newsletter

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May 1

Packard scientists and guests gather for 18th Symposium

Hundreds gather in Baltimore for the latest in ALS research

In the first week of March, several hundred Packard-funded scientists and guests gathered at the Baltimore Hyatt Regency to share their latest research. This gathering forms the core of Packard and makes this organization different from so many others. Grantees must share their work, challenges and all, with other Packard researchers to facilitate the open flow of ideas and knowledge. This accelerates research, bringing us closer to a treatment for ALS. This year also brought some of the very first preliminary results from Answer ALS, the largest and most comprehensive study on the disease.

Don Cleveland of the University of California San Diego and winner of this year's Breakthrough Prize opened the Symposium as the featured lecturer.

Although scientists have known about links between gene mutations in SOD1 and ALS for more than two decades, work on this and other proteins continues to yield insight into the disease. Packard researcher Don Cleveland, who won this year’s Breakthrough Prize for his work on small molecules called antisense oligonucleotides (ASOs) to treat SOD1 ALS and other motor neuron diseases, opened this year’s symposium with a history of his work. Summarizing decades of work, Cleveland explained how mutations in SOD1 contribute to ALS and how lowering levels of mutant protein have been found to reduce symptoms of the disease in animal models. Clinical trials using ASOs on SOD1 ALS are currently underway and those for C9orf72 ALS will begin shortly.

SOD1’s role as an antioxidant also opened the gateway into work on the importance of oxidative and other forms of cellular stress in ALS, including inflammation. Several researchers are working to investigate biomarkers of inflammation and oxidative stress to use in ALS clinical trials and in research, to better direct studies towards specific subtypes of ALS. It’s also guiding work into some of the fundamental disease mechanisms to show why motor neurons are affected when nearly all other cell types are fine. Packard researchers also developed new microscopy techniques to study how proteins such as TDP43 interact with stress granules, and how stress granules affect protein trafficking. This deeper understanding of ALS pathology will help guide treatment development.

Packard scientists Rita Sattler (Barrow Neurological Institute) and Giovanni Manfredi (Weill Cornell Medicine) at the 18th Annual Packard Center ALS Symposium.

The discovery of the C9orf72 repeat expansion in late 2011 changed the ALS research landscape. Many Packard scientists have shifted their work to include work on this gene, which continues to yield major insights into how ALS develops and progresses. At this year’s symposium, two main avenues of work guided C9orf72 research. The first continued the examination of the small toxic peptides created from the large segment of repeated DNA. Work in previous years has shown that these peptides cause problems by binding to other proteins and by interfering with the movement of proteins, lipids, and other molecules between the nucleus and cytoplasm. Packard scientists continued working to define in ever-more precise detail exactly how the presence of these peptides lead to disease, and whether it’s possible to disrupt this process to slow disease progression.

Sandrine Da Cruz, a neurobiologist at Ludwig Institute for Cancer Research, presented at the Symposium.

Although alterations in nucleocytoplasmic transport were first discovered in the context of the C9orf72 mutation, Packard scientists have also been investigating the phenomenon in all forms of ALS. Like defects in protein homeostasis and RNA processing, damage to nucleocytoplasmic transport may be one of the final endpoints around which many different types of ALS converge. This discovery less than two years ago has created a vigorous new area of ALS research, and many scientists presented some of their preliminary results at this year’s symposium.

Chris Donnelly of the University of Pittsburgh and colleagues meet between presentations at the annual Packard Center meeting

Lastly, Packard researchers shared some of the very first results to emerge from the Answer ALS project. Answer ALS began in 2015 as a patient- and clinician-led research project to enroll 1000 ALS patients across the United States to understand the different subtypes of ALS and how a variety of different potential causes all converge on motor neuron degeneration and death. At this year’s keynote lecture, Ernest Fraenkel provided an overview of how he intends to integrate and interpret some of the million-plus data points that will be gathered for each trial participant. This expansive dataset provides lots of information on correlations between different disease pathways, but it doesn’t indicate causality. To gather that information, Fraenkel will need a network-based approach that uses overlap between different datasets to home in on causal factors. This approach has already begun to pay off. Using early genetic sequencing results from the project, scientists from Project Mine in collaboration with Answer ALS have identified a new ALS-linked gene.  

Clive Svendsen, with Cedars-Sinai and representing Answer ALS, presented at the Packard Center's annual meeting.

Because so many new collaborations begin as the result of the Packard symposium, it’s impossible to say yet just how much impact this year’s gathering will have. But one thing is certain: by this time next year, when Packard researchers once again meet in Baltimore, the field will have edged ever closer to a better understanding of ALS.

Packard Center director Jeff Rothstein (left) and Packard Center scientific director Piera Pasinelli (2nd from left) honor Symposium organizers Rebecca Berger (center) and Jessica Lynn (right).