U-M Researchers Collaborate to Identify New Therapeutics in Models of Progressive Multiple Sclerosis
Dr. Morris and his team are working to devise a more effective treatment by delving deeper into the disease’s cellular mechanisms.
A team of U-M researchers, led by Aaron Morris, Assistant Professor, Biomedical Engineering, is using a transformative approach to understanding and treating Primary Progressive Multiple Sclerosis (PPMS), a relentless form of multiple sclerosis that affects approximately 15% of MS patients. The team seeks to understand the complexities of the disease at a molecular level.
PPMS is notorious for its swift progression and lasting neurological damage, leaving many patients in need of walking aids within just a decade of diagnosis. While Ocrelizumab, the first drug approved for PPMS in 2017, offers some hope by slowing disease progression, it doesn’t deliver full remission or reverse disabilities, and it carries risks of immunosuppression. Dr. Morris and his team are working to devise a more effective treatment by delving deeper into the disease’s cellular mechanisms. They hypothesize that the development of a surrogate inflamed tissue containing both immune and stromal compartments could help identify potential cell-cell communication in PPMS that could be precisely targeted. Previous research has demonstrated the utility of implantable biomaterial scaffolds as a tool to understand dynamics in cell phenotype and regulation of both immune and stromal cells, particularly in the context of metastatic cancer.
“What I am most interested in as the takeaway from this work is using the scaffolds to monitor molecular changes in disease and as a diagnostic tool,” Dr. Morris said. These subcutaneously implantable porous biomaterials harbor both immune and stromal cells, mirroring the conditions within affected tissues in the central nervous system.
Dr. Morris highlighted the key roles all team members play in collaboration and innovation, including the foundational work that co-corresponding author Lonnie Shea, Steven A. Goldstein Collegiate Professor, Biomedical Engineering, has led for decades. As the study combines expertise from neurology and biomedical engineering, supported by key contributors such as David Irani, Professor, Neurology; and Ph.D. students Laila Rad and Sydney Wheeler, it represents a strong foundation for future research.
The team leveraged scaffolds to study cellular communication and immune function, using single-cell RNA sequencing (scRNAseq) to unravel the intricate dialogues among cells in diseased states. “We were really interested in how cells communicate with each other in disease,” Dr. Morris said. “And we could see that in disease, we had dysregulated signaling from groups of these chemokines.”
Chemokines, proteins pivotal in immune cell recruitment and communication, were found to have altered signaling in the MS-like condition, experimental autoimmune encephalomyelitis (EAE), in mice. Notably, regulatory T-cells (Tregs), crucial for moderating immune responses, showed reduced communication—a familiar story in autoimmune diseases.
Understanding these altered relationships led the team to a bold hypothesis: by targeting these dysregulated pathways, they could potentially mitigate disease progression. Dr. Shea’s work sparked the development of a novel nanoparticle therapy. These nanoparticles, crafted from poly(lactide-co-glycolide), were loaded with a disease-related antigen aimed at dampening unwanted immune responses while enhancing Treg function.
“When we treated the mice before symptoms, it totally stopped the disease from happening at all,” Dr. Morris said, highlighting the need to target multiple pathways simultaneously. In more positive news, even symptomatic mice experienced reduced disease with this therapy, offering a glimpse of hope for one day translating these findings into human treatments.
Beyond PPMS, Dr. Morris envisions the biomaterial scaffolds as invaluable tools for broader immunological investigations. “My hope is that as we move toward translating these technologies, we can learn more and more about human disease,” he said. “By providing an accessible means to study immune dynamics, these scaffolds could unlock new understandings not just in MS, but potentially in other autoimmune conditions.”
With these breakthroughs, the vision of an implant providing insights into human disease could one day become reality, paving the way toward more effective, targeted therapeutic interventions and a brighter future for those battling MS and other autoimmune disorders globally.