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ALS Alert Newsletter

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Jun 13
2017

17th Annual Symposium Brings Together Packard's Brightest

Packard Center's annual research symposium sets the agenda for the coming year.

For the 17th time, Packard scientists, colleagues, friends, and supporters gathered in downtown Baltimore to discuss the year’s progress in the fight against ALS. Three solid days of talks enabled researchers to share both their trials and their tribulations in understanding ALS and finding ways to stop the disease. Science might not have found a cure yet, but every year of work brings researchers closer than before. Packard’s ability to bridge basic research about motor neurons with clinical trials means that these results can move forward to help patients more quickly.

Thomas Lloyd, a researcher and clinician at Johns Hopkins, prepares to give his talk at the 17th Annual Packard Center Symposium.

The highlight of this year’s meeting was a presentation on a new drug to treat spinal motor atrophy (SMA). A neurodegenerative disease like ALS, SMA is caused by a mutation in the Survival Motor Neuron protein and predominantly affects children and teens, many of whom never get the chance to grow up. In 2016, Ionis Pharmaceuticals, which has had a long relationship with the Packard Center, finally received FDA approval for a drug called Spinraza that can treat and reverse some of the symptoms of SMA. The drug, which is injected directly into the spinal cord, uses small molecules called antisense oligonucleotides (ASOs) to increase the amount of normal, full-length SMN protein made by motor neurons. Scientists are currently testing ASOs in the treatment of SOD1 ALS, and the positive results of Spinraza bolstered their hopes that the drug will be effective, although it’s still too soon to say for sure.

Rita Sattler, a researcher at the Barrow Neurological Institute, poses a question after a session.

On the basic science front, Packard researchers continue to work towards understanding the function of various genes linked to ALS and how mutations alter their function and cause disease. Over the past year, several studies have identified ALS-linked deficits in the ability for proteins and other molecules to move from the nucleus into the cytoplasm and vice versa. This phenomenon was initially discovered with respect to the C9orf72 repeat expansion, although new work is showing that the issue may be more widespread. Other scientists are examining how non-standard RNA translation associated with the C9 repeat expansion creates toxic peptides and how it might interfere with RNA metabolism.

Although TDP43 is not a newly discovered mutation in ALS, it remains central to the disease process. As such, many Packard scientists continue to study various aspects of the protein, including its incorporation into stress granules, dense aggregations that form into the cells when they are under stress. One particular region of this protein enables it to form large clumps that also obstruct normal RNA metabolism, and various labs are working to identify how this happens and why the clumps and stress granules don’t dissolve after the stressor has passed. They are also working to understand how these clumps inhibit TDP43’s usual functions, and how this cascade affects the cell.

Throughout the three day conference, collaboration is a familiar sight.

Just as scientists have learned that TDP43 pathology and cyto-plasmatic transport play an overarching role in ALS, they have also discovered problems with autophagy in many ALS animal models and patient cells. As the cell’s primary recycling mechanism, autophagy breaks down used proteins, nucleic acids, and other molecules into their component parts. If autophagy is not functioning as it should, the cell doesn’t have enough building blocks to make the macromolecules it needs. A growing body of research, including new results presented in this year’s symposium, supports the idea that autophagy errors play a major role in ALS and other neurodegenerative diseases.

Packard scientists have also struck out in creative and innovative new ways. Deep learning and network analysis are beginning to show how many seemingly disparate aspects of ALS are actually connected at the cellular and functional level. These strategies will also help researchers make sense of the large amounts of data generated from new types of experiments, including the Answer ALS initiative. Begun in December 2015, Answer ALS will attempt to enroll 1000 ALS patients and an equal number of controls to understand the disease on a deep, molecular level. Fibroblast cells will be used to generate lines of induced pluripotent stem cells that can be used for genomics, transcriptomics, epigenomics, metabolomics, proteomics, and more. Scientists around the country will also collect information on the natural history of ALS and its progression in a variety of patient populations. Updates on Answer ALS presented at the symposium show that more than 400 patients have already been enrolled in the study, which places them ahead of schedule.

Chris Donnelly is a Packard researcher and an assistant professor of neurobiology at Pitt School of Medicine.

The annual conference isn’t just a place for scientists to provide updates. They also share difficulties they’ve had, and can consult with a room full of experts for new ideas and resources. It’s also a place to forge new collaborations, and several new lines of inquiry have begun with casual conversations over lunch or coffee. Although ALS doesn’t yet have a treatment or cure, the hope remains in the science.

Packard Research Program Coordinator and Symposium organizer Rebecca Berger (right) along with founder Jeff Rothstein (back) and science director Piera Pasinelli (left) celebrate at the conclusion of the conference.