Penn and Miami researchers launch study to detect ALS and frontotemporal dementia before symptoms appear with $26 million NIH grant

Researchers launched a major effort to identify the earliest biological and clinical changes that signal whether people with a certain genetic variant will develop amyotrophic lateral sclerosis (ALS) or frontotemporal dementia (FTD), with an eye toward potentially treating these conditions before symptoms even show up. Funded by a $26 million grant from the National Institutes of Health, the effort is led by teams from the Perelman School of Medicine of the University of Pennsylvania and the University of Miami Miller School of Medicine.

The five-year study, spanning 13 research sites across the United States, focuses on a variant in the C9orf72 gene known as a “C9 expansion,” the most common inherited cause of both ALS and FTD. By identifying markers that predict when symptoms are likely to begin, researchers aim to establish the foundation for prevention trials that would entail intervention before irreversible damage to brain and nerve cells occurs.

“One of the biggest barriers to developing effective treatments for ALS and FTD is that we may be intervening too late, after the diseases have progressed too far,” said multi-principal investigator, Michael Benatar, MD, PhD, the Walter Bradley Chair in ALS Research and professor of Neurology and Public Health Sciences at the University of Miami’s Miller School. “If we can identify biological changes that occur before symptoms start, we can begin developing therapies that prevent disease rather than treating it after it starts.”

Uniting ALS and FTD research

While the C9 expansion is the most common inherited cause of ALS and FTD, researchers cannot reliably predict whether a person carrying the C9 expansion will develop ALS, FTD, both conditions, or remain symptom-free.

Although ALS and FTD are increasingly recognized as related neurodegenerative diseases, research and clinical care have traditionally focused on one condition or the other. ALS specialists focus more on motor and muscular symptoms, while cognitive and behavioral changes may receive less attention. Conversely, FTD specialists typically monitor for changes in thinking and behavior, with less emphasis on motor function.

To address this gap, the researchers brought together expertise from both fields. The study combines neurologists or psychiatrists with motor and cognitive specializations, and neuropsychologists to evaluate participants across the full ALS-FTD spectrum.

“This disease does not fit neatly into one specialty,” said multi-principal investigator, Corey McMillan, PhD, an associate professor of Neurology, and co-director of the Penn Frontotemporal Degeneration Center. “Understanding C9-related disease requires us to study cognition, behavior, and motor function together. By breaking down those silos, we hope to unlock key understandings of how these conditions develop and how we might be able to prevent it.”

Learning from a successful model in ALS

The effort builds on lessons from recent advances in another inherited form of ALS caused by mutations in the SOD1 gene.

Research on the SOD1 gene, found in approximately 2 percent of people with ALS, showed that levels of a blood biomarker called neurofilament light chain rise approximately one year before symptoms begin. Those findings helped support the development of a prevention clinical trial called ATLAS to investigate whether the recently approved ALS treatment tofersen (Qalsody) can be used to prevent ALS symptoms before at-risk individuals begin to experience symptoms of motor dysfunction.

Researchers hope to achieve a similar breakthrough in carriers of the C9 expansion, but there is currently no equivalent single biomarker that identifies when a person carrying the variant is approaching symptom onset. While neurofilament light chain remains a key biomarker, it is also clear that it will be insufficient on its own.

“Identifying other markers is the critical missing piece,” said Benatar. “It is clear that we’ll need a panel of markers in order to identify the subset of C9 expansion carriers who are most likely to develop ALS or FTD in the near term – and this is the overarching goal of C9 ALS/FTD Prevent.”

Building the foundation for new clinical trials

Future disease prevention trials will require development of promising therapeutics that would be worthy of study in a prevention trial paradigm. However, the authors cautioned that there is much preparation to be done so that the field to initiate such trials when these experimental therapeutic candidates emerge.

“By identifying a panel of biomarkers that reliably predicts which C9 expansion carriers are at the greatest short-term risk of developing ALS or FTD, the C9 ALS/FTD Prevent study will lay the critical foundation to define the study population to be enrolled in future prevention trials,” Benetar added.

"We have an unprecedented opportunity to understand how these diseases develop in their earliest stages by focusing on the full ALS-FTD spectrum of C9-related disease," McMillan said. "The more we learn about what happens before symptoms appear, the closer we get to preventing disease rather than simply treating it after the fact."

For more information on the study, please email C9Prevent@miami.edu.

This research is supported in full by the National Institutes of Health (1R01AG103000-01).