2024 Packard Symposium is Largest Ever
This year, a record number of participants joined us for the 24th annual Packard Center Symposium. Nearly 300 were on-site in Baltimore, while an additional 100 participated online. The gathering allowed Packard grantees, affiliates, and other ALS researchers to share their latest results in an open fashion to fuel new avenues of investigation and foster novel collaboration between teams.
This format—along with the monthly Packard PI meetings—is by design. By sharing results before they are published, scientists can troubleshoot problems, gain new perspectives, and leverage others’ work to advance their own findings. This prods the scientific process to move faster, taking the field closer to effective therapies for ALS, and, perhaps one day, even a cure for the disease.
This year’s meeting combined longstanding areas of interest in ALS research, such as TDP-43 and the C9orf72 repeat expansion, with newer areas of investigation, including dysfunctions of the nuclear pore and the genes and proteins that may alter the course of ALS.
Dysfunctions in the RNA binding protein TDP-43 occurs in 97% of ALS patients, as well as a substantial portion of those with Alzheimer’s and other neurodegenerative diseases. Subsequent work showed that TDP-43 was mislocalized to the cytoplasm from the nucleus in ALS, where it formed large, insoluble clumps of protein. In 2015, Packard scientist Phil Wong published a study in Science showing that one of the primary functions of TDP-43 is to suppress the expression of cryptic exons. These snippets of DNA look similar to the parts of a gene intended to be part of the final protein, but need to be silenced to ensure they are not included accidentally. This discovery opened up new avenues of research into what happens when TDP-43 is not able to perform its usual functions that are still being explored today.
Ongoing work into TDP-43 loss of function has identified several genes containing cryptic exons that may be important to the development of ALS. Packard scientists are continuing to work on links between ALS and STMN2 and UNC13A, and how TDP-43 plays a role in this linkage. Researchers are in the process of understanding whether it might be possible to design drugs to restore the normal processing of STMN2 and UNC13A after the onset of TDP-43 proteinopathy, which will require untangling the complex network of events in which the ALS disease process begins. This strategy will also help develop TDP-43-related biomarkers for ALS, which will be a key part in evaluating the efficacy of potential therapies. Other lines of inquiry related to TDP-43 include understanding how cellular stress impacts the protein’s ability to process RNA.
This year’s symposium poster session featured projects and posters from 80 participants.
More than a decade after its discovery, Packard scientists continue to interrogate the C9orf72 repeat expansion for clues to ALS. Despite being the most common genetic cause of ALS in populations of European descent, creating realistic and accurate animal models of C9-ALS has been challenging. Work creating Caenorhabditis elegans worm models and mouse models is ongoing, especially for studying the role of the toxic dipeptide protein repeats that are created as a result of the expansion. Creating effective C9-based therapies will require detailed knowledge about what parts of the repeat expansion cause disease, and the impacts of removing them.
Both C9orf72 and TDP-43 also appear to be involved in nucleocytoplasmic transport. While some small molecules can freely move between the nucleus and cytoplasm, many require transport via proteins in the nuclear pore complex. This complex is built out of many smaller protein components and is one of the largest known eukaryotic protein complexes. In recent years, scientists have discovered that the movement of proteins and other macromolecules is altered in ALS. A leading example is the mislocalization of nuclear TDP-43 to the cytoplasm. By backtracking this chain of events, scientists are identifying parts of the nuclear pore complex that are linked to ALS, such as a protein called Nup50. As new research emerges, impaired nucleocytoplasmic transport appears to be playing an increasingly larger role in our understanding of ALS, especially in the earliest phase of disease.
Even by itself, this understanding is important. But this process also opens new potential avenues for therapeutics. While any potential drugs are years away from testing, the development of nuclear pore-targeting therapies is starting to gather steam. This process will require researchers to understand the range of naturally occurring variants of proteins like Nup50, and how they contribute to disease.
New areas of inquiry continue to open as well. Immunotherapies, which are revolutionizing the treatment of many cancer types, may also have promise for treating ALS. Identification of disease modifiers, such as fatty acids and certain genetic variants, may also help steer scientists towards potential therapies. New clinical trial designs being pioneered by NEALS are also helping researchers test drugs more quickly and efficiently, allowing therapies to reach patients in a streamlined fashion.
Attendees enjoyed a networking dinner and an evening of bowling on the final night of the Symposium.
It’s this end goal that continues to drive Packard scientists—to identify therapeutics that will improve quality of life and alter the course of ALS. The collaboration and research partnerships fostered at these annual symposiums are a key strategy towards developing these breakthroughs.
Thank you to our sponsors who helped make the 24th Annual Packard Center ALS Research Symposium possible:
Mitsubishi Tanabe Pharma America
Amylyx
Biogen
The Bernardino Family
GRIP
Eikonzio Therapeutics
IONIS
Prevail Therapeutics
QurAlis
Sanofi
Capacity Bio
Muscular Dystrophy Association
OrphAI Therapeutics
By: Carrie Arnold
Photo Credits; Jon Christofersen (Johns Hopkins University) and Suzanne Connelly (Robert Packard Center)