New Cell Atlas Poised to Support Development of Migraine Therapies

Young woman gripping head in pain from migraine, in home office

Researchers at Brigham and Women’s Hospital have mapped out a group of cells in the trigeminal ganglia (TG) that contribute to migraine pain, allowing them to further characterize the cells in a way that holds promise for the development of new therapeutics.

The research, published in Neuron, was led by William R. Renthal, MD, PhD, director of headache research at the Brigham and Women’s Faulkner Hospital’s John R. Graham Headache Center. As migraine is one of the most common neurological disorders, Dr. Renthal says that improved treatments are needed to counter the significant impact it has on society, both in terms of disability and economic loss.

“Migraine takes a real toll on adults and teens,” he says. “Unfortunately, most of the treatments we have today are not very specific for migraine symptoms and often have side effects. And while newer therapies have been transformative for some patients, many patients are still looking for relief.”

Identifying Gene Expression Patterns

In their research, Dr. Renthal and his colleagues transcriptionally and epigenomically profiled human and mouse TG at single-cell resolution. The data they developed describe evolutionarily conserved and human-specific gene expression patterns within each TG cell type, as well as the transcription factors and gene regulatory elements that contribute to cell-type-specific gene expression. The research team then leveraged the data to identify TG cell types implicated both by human genetic variation associated with migraine and two mouse models of headache.

“This is one of the first studies of its kind to compare nociceptor cell types and gene expression in mouse models and human pathology,” Dr. Renthal says. “We found that from a big-picture perspective, similar cell types exist in both mice and humans, suggesting that the mouse models could be useful for screening new migraine therapeutics.”

While the mice and human TGs have many similarities, the research team did uncover clear species differences as well. For example, they found that the gene CALCA, which encodes the neuropeptide CGRP, is expressed by different types of TG neurons in mice and humans. As CGRP is the target of newly FDA-approved migraine treatments, understanding more about the human TG cells that express these cells may offer new opportunities for treating migraine.

“Understanding genes expressed in the TG neurons that transmit pain signals during migraine, especially genes preferentially expressed within those cells, may help scientists design new treatment strategies to inhibit these neurons selectively without impacting other cells and creating negative side effects as opioids do,” Dr. Renthal says.

More work is needed to develop these treatments, he adds, including developing higher-resolution data to determine which genes in ganglia nociceptors are druggable targets. He is in the process of developing the next version of the cell atlas, which will include studying more cells from more human samples to better understand variability across human ganglia.

Exploring the Mystery of Why Migraine Runs in Families

Migraine is known to run in families, but the cell types that are affected by this genetic risk have been difficult to understand. “Our work provides new insight into the TG cell types that may be affected by having a high genetic risk for migraine,” Dr. Renthal says.

Dr. Renthal notes that he is driven to continue his research, in part, by the motivation of his patients and own family member with migraine. “I too often see the disability up close that poorly controlled migraine can cause, so I’m working hard to offer new ways to help,” he says.

“I am fortunate to practice medicine with some of the best headache doctors in the world and then go to the lab and conduct research with some of the most forward-thinking scientists in the world,” Dr. Renthal concludes. “The Brigham provides a truly unique setting for this type of interaction, and I am optimistic it will yield better treatments for our patients in the near future.”

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