News Release

PHILADELPHIA — An investigational drug that targets an instigator of the TDP-43 protein, a well-known hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), may reduce the protein’s buildup and neurological decline associated with these disorders, suggests a pre-clinical study from researchers at Penn Medicine and Mayo Clinic. Results were published in Science Translational Medicine.

The work shows, for the first time, how toxic poly(GR) (glycine-arginine repeat) proteins produced by the mutated C9orf72 gene stimulate the clumping of TDP-43 found in ALS, also known as Lou Gehrig’s disease, and FTD patients. In a mouse model, the researchers also show that treatment with a pipeline drug known as an antisense oligonucleotide (ASO) reduced the levels of poly(GR), TDP-43 clumps, and neurodegeneration along with it.

“A common genetic cause of ALS and FTD is a repeat expansion in the C9orf72 gene, which somehow leads to TDP-43 aggregation in degenerating neurons, but what remained unclear until now was how those two were connected,” said co-senior author James Shorter, PhD, a professor of Biochemistry and Biophysics in the Perelman School of Medicine at the University of Pennsylvania. “We found that TDP-43 aggregates much more rapidly if these toxic poly(GR) proteins are around, suggesting a direct link between the mutation, poly(GR), and TDP-43.”

ALS is the progressive degeneration of motor neurons that control people’s muscles, speech, and ability to breathe. FTD, the most common form of dementia in people under 60, results in damage to the anterior temporal and/or frontal lobes of the brain; as it progresses, it becomes increasingly difficult for people to function and even care for oneself.

“This finding presents an exciting potential therapeutic target to treat these debilitating diseases by lowering poly(GR) levels,” added Hana Odeh, PhD, a post-doctoral fellow in the Shorter lab and co-first author.

After researchers in the Shorter lab demonstrated the role of poly(GR) proteins in TDP-43 accumulation at the protein level, their colleagues at Mayo Clinic in Jacksonville, Fla., studied the interactions in both human cells and mice to support the initial bench side finding at Penn. Co-senior authors from Mayo Clinic include Yongjie Zhang, PhD, an assistant professor of Neuroscience, and Leonard Petrucelli, PhD, Ralph B. and Ruth K. Abrams Professor of Neuroscience at Mayo Clinic College of Medicine and Science.

They showed in a series of complementary experiments, including immunofluorescence staining and immuno-electron microscopy, that poly(GR) in human cells alone can sequester TDP-43 proteins, and in doing so induce the formation of dense protein clumps. This same mechanism was then demonstrated in a mouse model.

It’s worth noting, the researchers said, that the burden of both TDP-43 and poly(GR) correlate with neurodegeneration in patients observed in past studies: the higher the protein levels, the worse the neurological function, providing further evidence that the two proteins are conspiring.

Next, the team delivered an ASO drug known as c9ASO, which is being investigated in clinical trials, into the brains of three-month old mice expressing the ALS/FTD-causing repeat-expansion and found that it had diminished the levels of both poly(GR) and TDP-43 aggregates. c9ASO has been shown to switch off the repeat expansions in the C9orf72 gene and reduce poly(GR), but this is the first time it’s been shown to reduce TDP-43 clumping.

To assess the drug’s neuroprotective ability, the researchers examined the amount of neurons and plasma neurofilament light (NFL), a known biomarker of neurodegeneration in patients, in treated mice. The drug prevented the reduction of cortical neurons and decreased levels of plasma NFL, they found, suggesting the drug helped confer neuroprotection. “If that extends to patients, the plasma NFL level provides a way to track how effective your therapeutic is,” Odeh said.

The researchers plan to study in more detail how TDP-43 and poly(GR) and other similar toxic proteins associated with the mutated C9orf72 interact, and conduct further studies with ASO drugs to better understand their role in stopping the clumping of TDP-43.

“This exciting collaborative study sets the stage for continued teamwork in this space, which I see as being of great interest to the ALS and FTD community,” Shorter said.

A Penn co-author on the study includes Edward Gomes, along with Casey N. Cook, Yanwei Wu, Tania F. Gendron, Karen Jansen-West, Giulia del Rosso, Mei Yue, Peizhou Jiang, Jimei Tong, Lillian M. Daughrity, Nicole M. Avendano, Monica Castanedes-Casey, Wei Shao, Björn Oskarsson, Giulio S. Tomassy, Alexander McCampbell, Frank Rigo, and Dennis W. Dickson.

This work was supported by the National Institutes of Health (R35NS097273, P01NS084974, P01NS099114, R01NS088689, R21AG065854 and R01GM099836, Mayo Clinic Foundation , Amyotrophic Lateral Sclerosis Association, Robert Packard Center for ALS Research at Johns Hopkins, Target ALS Foundation, Biogen Idec, and AstraZeneca postdoctoral fellowship.

Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation’s first medical school) and the University of Pennsylvania Health System, which together form a $8.6 billion enterprise.

The Perelman School of Medicine has been ranked among the top medical schools in the United States for more than 20 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $494 million awarded in the 2019 fiscal year.

The University of Pennsylvania Health System’s patient care facilities include: the Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center—which are recognized as one of the nation’s top “Honor Roll” hospitals by U.S. News & World Report—Chester County Hospital; Lancaster General Health; Penn Medicine Princeton Health; and Pennsylvania Hospital, the nation’s first hospital, founded in 1751. Additional facilities and enterprises include Good Shepherd Penn Partners, Penn Medicine at Home, Lancaster Behavioral Health Hospital, and Princeton House Behavioral Health, among others.

Penn Medicine is powered by a talented and dedicated workforce of more than 43,900 people. The organization also has alliances with top community health systems across both Southeastern Pennsylvania and Southern New Jersey, creating more options for patients no matter where they live.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2019, Penn Medicine provided more than $583 million to benefit our community.

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