In 2013, when Dr. Clotilde Lagier-Tourenne first opened her lab at MGH, her very first research grant came from Target ALS. A decade later, she is once again at the forefront, this time contributing to one of six collaborative teams funded through our 2024 Basic Biology Consortia Program.
This new round of grants tackles the toughest questions in ALS biology, with a focus on sporadic ALS (sALS), the form of the disease that accounts for 90% of all cases yet remains the least understood.
Joining Dr. Lagier-Tourenne are Dr. Isaac Chiu, a Harvard immunologist whose expertise lies in neuroimmune interactions, Dr. Brian Wainger, a Mass General physician scientist with expertise on ALS and pain, and Dr. Mark Albers, a Mass General neurologist whose career began in Alzheimer’s research. Together, they are mapping how innate immune pathways in neurons drive cell death and inflammation in ALS.
Why Sporadic ALS?
Unlike familial ALS, which is tied to inherited genetic mutations, sporadic ALS arises without a clear family history. This makes it especially hard to model in the lab. “The heterogeneity of sporadic ALS is one of our greatest challenges,” explained Dr. Lagier-Tourenne. “But innate immune pathways appear to be a common thread across both familial and sporadic cases, which makes them powerful targets to study.”
Dr. Albers underscored the importance of anchoring the work to TDP-43 pathology, which is present in the vast majority of sporadic cases. “Understanding how TDP-43 dysfunction ties into these immune pathways could help us develop biomarkers and improve clinical trial design,” he said.
A New Lens: Neurons as Active Players in Immunity
Neuroinflammation has long been associated with ALS, but most studies have focused on support cells like microglia and astrocytes. This consortium is flipping that lens to look at neurons themselves as immune-active cells.
“Every cell has to defend itself,” said Dr. Chiu. “We’re asking what happens when the innate immune pathways inside neurons go awry. If they become chronically activated, they could trigger a destructive cascade that contributes to ALS progression. That opens up entirely new therapeutic possibilities.”
Moving Research Closer to Patients
The team is already seeing translational momentum. Dr. Albers’ lab uncovered that baricitinib, an FDA-approved arthritis drug, could rescue ALS-related defects in preclinical models. This discovery led to a small pilot basket trial at the Healy ALS Center, the results of which are now under analysis.
At the same time, Dr. Chiu’s group is advancing siRNA-based approaches that are being pioneered by RNA biologists and starting to be applied clinically to specifically target neuronal immune pathways that drive cell death.
“Because these mechanisms are already being studied in other inflammatory diseases, the translational path is faster,” noted Dr. Chiu.
Collaboration in Action
One of the hallmarks of Target ALS is our consortium model, bringing together scientists from different fields and institutions, and funding collaborations that otherwise might never happen.
Dr. Lagier-Tourenne reflected: “We’ve all known each other for years, but this grant cemented the collaboration. Now, our postdocs talk daily, share cells, run experiments together. The funding didn’t just support the science, it made the collaboration real.”
For Dr. Albers, who entered the ALS field from Alzheimer’s research, that openness was critical: “The creativity happens not just in the PIs’ offices but in the lab, where young scientists combine their expertise and surprise us with new ideas.”
Looking Ahead
The team’s ultimate goal is to map how neuronal immune pathways trigger degeneration and identify biomarkers that can guide precision therapies. With clinical studies already underway and a deeper understanding of the mechanism by which modulating neuronal immune pathways can prevent neurodegeneration, the work is moving quickly to deliver new treatment options for patients.
“This is a very exciting time,” said Dr. Lagier-Tourenne. “New technologies, stronger collaborations, and the urgency of ALS are accelerating the pace. We’re closer than ever to translating basic biology into real therapeutic opportunities.”
Key Takeaway: The Albers–Lagier-Tourenne–Chiu–Wainger consortium is shining a light on one of the least understood aspects of ALS, sporadic disease biology, through the novel lens of neuronal innate immunity. Their work embodies Target ALS’s mission: catalyzing collaboration to unlock discoveries that can change the lives of everyone living with ALS.
