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ALS Alert Newsletter

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May 23

Annual Symposium brings exciting advances from the frontlines of ALS research

More than 230 gather in Baltimore to showcase exciting advances in ALS research.

This year’s 19thannual Packard Center Symposium brought exciting advances from the frontlines of ALS research, as well as some important changes in honor of the Center’s upcoming 20thanniversary. The most visible change to Packard is its new logo, which combines its three cornerstones (collaboration, innovation, and hope) with the Johns Hopkins School of Medicine triad. The 2019 symposium was also the largest gathering ever by the Packard Center, with more than 230 in attendance.

These changes, however, won’t alter Packard’s commitment to advancing ALS research through collaboration and the open sharing of results. The annual symposium sits at the heart of these efforts, with each and every Packard grantee summarizing their work, whether successful or not. This dedication to openness and the free exchange of ideas not only gives scientists a chance to troubleshoot experiments, it gives them the opportunity to seek out new relationships with other ALS researchers. What results is the dynamic interchange of ideas that moves the field forward more quickly. This collaborative and energetic spirit worked at its best this year. 

Over the past few years, scientists at Packard and around the world have marched ever closer to a complete understanding to how ALS develops and progresses, as well as more innovative ways to leverage these advances into new and improved therapies for the disease. The discovery of the C9orf72 repeat expansion has helped to spur new insights into ALS pathogenesis that may help explain what happens on a cellular level not just to those who carry the C9 mutation but for everyone with ALS.

One emerging theme in ALS research that has grown ever more important in the last two years is the growing awareness of the role of faulty transport of large molecules between the nucleus and the cytoplasm. To do their jobs, proteins must not only be built correctly according to their genetic code, they must also appear in the right place at the right time. Nucleocytoplasmic transport—the shuttling of proteins and other large molecules into and out of the nucleus—plays a central role in this. It’s also one of the factors disrupted by the C9orf72 repeat expansion and other ALS-linked mutations. The nuclear pores involved in this transport are one of the largest protein complexes in the cell, and Packard researchers have been trying to determine which part of the process gets disrupted in ALS, and which factors may mediate toxicity from ALS-linked genetic mutations. Already published studies by Packard scientists show that restoring the TDP43 protein to its correct location in the nucleus can help reduce the molecular and physiologic signs of ALS.

Ongoing work on the role of TDP43 in ALS—scientists have previously shown that 97% of people with ALS have TDP43 aggregates in the cytoplasm—also played a major role at this year’s symposium. Only recently have scientists begun to untangle the normal functions of TDP43. Although researchers knew that it was an RNA-binding protein (just like the ALS-linked protein FUS), more recent work revealed that TDP43 suppresses the synthesis of erroneously assembled proteins. The loss of TDP43 from the nucleus means the cell loses some of this suppression, which could factor into ALS pathogenesis. As well, combining the knowledge of toxicity from the loss of nuclear TDP43 may add to the understanding of toxicity directly from cytoplasmic TDP43 aggregates. At the symposium, researchers identified several ways to prevent the formation of these aggregates, as well as how these aggregates interact with cellular processes such as stress granule formation and autophagy (the cell’s system for recycling old and malfunctioning molecules).

Packard scientists also shared the development of new ALS animal models that will allow researchers to study different aspects of the disease. These models included both well-studied mutations such as C9orf72 as well as rarer ones such as Matrin3 and NEMF (Nuclear Export Mediator Factor). These models complemented motor neuron cell cultures, now often derived from induced pluripotent stem cells from patients. Both the cell- and animal-based models of ALS are meant to be shared throughout the research community to allow the entire field to move forward. 

Although motor neurons are the primary cells affected by ALS, other brain cells, including microglia and astrocytes which provide immune and metabolic support to neurons respectively,  may also play a role in disease. At the symposium, Packard scientists shared how actions by other brain cells may help them understand how ALS starts and spreads. Targeting these other cells may also provide new opportunities for the development of ALS therapies.

Clinician-scientists from NEALS (the NorthEastern ALS Association) shared updates on new and ongoing clinical trials. The network of 127 academic sites that makes up the NEALS network has begun to transition to a Master Trial platform that can test multiple potential ALS therapeutics under the same platform. This allows scientists to pool the placebo arms, giving patients the best chance at receiving an active drug while maintaining scientific rigor. NEALS scientists also shared updates on antisense oligonucleotide (ASO) trials for ALS caused by either C9 or SOD1 mutations (see this story in the Alert for a full update on the SOD1 ASO trial), both of which are progressing well. ASOs prevent cells from producing mutant protein, thereby directly interfering with some of the root genetic causes of ALS for specific patient subgroups.

The 19thannual symposium may be done, but the Center is already beginning work on next year’s gathering, which will include special celebrations for Packard’s 20thanniversary.