Packard Center’s 23rd Annual Symposium brings together established luminaries in ALS research and rising stars from around the world.

Hundreds of people in the ALS community gathered in person and online for the 23^rd Annual Packard Center Symposium. The meeting was a chance for researchers funded by Packard and others in the scientific world to come together and share their latest research to move the field forward as quickly as possible. More than just a research meeting, the annual symposium is a chance for scientists to share their victories and challenges with full transparency, so that we can work towards better therapies for ALS with greater speed and precision.

This openness and sharing of results isn’t an afterthought. It forms the backbone of what the Packard does. The collaboration that is required from Packard grantees breaks down the silos that can form in academia and helps scientists improve the molecular and genetic basis of ALS to create new therapies. Because much of the results shared are not yet published—and therefore have not undergone peer review—the Packard symposium is a closed meeting. This means that specific details of discoveries cannot be shared until after the subsequent research paper is published. 

As in previous years, the Packard symposium brought together established luminaries in ALS research and rising stars from around the world. Similar to the last two years, this year’s meeting could also be attended virtually. Excitement was in the air surrounding the FDA’s approval of Relyvrio in September, and about the promising results from an open label extension study of the antisense oligonucleotide (ASO) tofersen for individuals with ALS caused by mutations in SOD1. Tofersen (brand name Qalsody) was subsequently approved by the FDA in April 2023.

While the field has made great strides in understanding much of the biology that underpins ALS, plenty more remains to be elucidated. Take the TDP43 protein. Scientists first linked mutations in TARDBP (which encodes TDP-43 protein) to ALS and frontotemporal dementia (FTD) in 2006. Since then, several lines of inquiry have converged to reveal that dysregulation and mislocalization of TDP43 is related to many aspects of ALS/FTD. Some researchers have focused on how and why the protein misfolds and how this leads to the buildup of solid aggregates in the cytoplasm. Whereas some labs have used optogenetics, others have turned to model organisms such as Drosophila melanogaster. Newer work is looking at how mutant or misfolded TDP43 impacts proteostasis, autophagy, and lysosomal biology. All of this work points to TDP43 as playing a significant role in ALS/FTD, especially early in disease, perhaps even before symptoms are apparent. The pathobiology of TDP43 also provides opportunities for therapeutics, and scientists are studying how to best rescue this pathology in a targeted, precision medicine approach. The challenge is to target only those neurons with TDP43 misfolding and loss to prevent side effects and off-target toxicity. Several scientists are studying precisely that aspect of therapeutic development.

Now, as scientists better understand some of the usual activities of TDP43, they are beginning to understand what happens when TDP43 is locked in the cytoplasm. The discovery that TDP43 suppresses the inclusion of so-called cryptic exons was a major leap forward, and numerous labs are studying the downstream implications of this finding. Other researchers are finding links between TDP43 mislocalization and an emerging area of inquiry in ALS: impaired transport of proteins and other biomolecules between the nucleus and cytoplasm.

First noted at a Packard conference several years ago, impaired nucleocytoplasmic transport has been identified as one of the earliest molecular processes in ALS and has been linked to individual proteins that make up the nuclear pore. Much of that work has focused on a specific nuclear pore protein called Nup50. Animal models, ’omics studies, and more have shown that Nup50 plays an important role in ALS, and work is ongoing to determine when in the disease process they happen, what causes them, and what are the downstream effects.

Other aspects of ALS research were also present at this year’s symposium, including mutations in SOD1 and C9ORF72. In recent years, scientists have made massive strides in understanding how these mutations cause ALS and FTD, but work remains to understand how ALS-linked mutations interact with other molecular pathways in the development of disease. While these genes will remain a mainstay of ALS research for the indefinite future, researchers have continued to identify new genetic variants that also contribute to disease. At the same time, scientists have been testing new approaches to help them make sense of the incoming data tsunami and are looking to use artificial intelligence and machine learning to separate informative insights from the noise.

Scientific advances in our understanding of ALS, combined with FDA approvals of new therapies, promise to make the coming year exciting for everyone in the field. And next year’s symposium will provide an opportunity to find out just how much we’ve learned.