Today marks the 10th annual International Day of Women and Girls in Science, which serves as an opportunity to recognize the contributions of women to advancements in science, technology, engineering, and mathematics. This year, we are shining a spotlight on Alyssa Coyne, Ph.D., an assistant professor of neurology at Johns Hopkins University, and how she is accelerating the development of new ALS treatments. 

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With two ICU nurses as parents, it was easy for Dr. Alyssa Coyne to picture herself in the medical field, although she wasn’t sure what type of job she wanted to pursue at first. 

“I started out my journey as a physical therapy major when I was in college,” she said. “But when I started shadowing in a neurological rehabilitation clinic and observing the physical therapists, I quickly realized that perhaps wasn't the right fit for me.”

It was this experience that put her on the path to becoming an ALS researcher. “And I haven't turned back since,” she said. 

After graduating with a Bachelor of Science degree in biology from Springfield College, Dr. Coyne went on to earn a Ph.D. in neuroscience from the University of Arizona, focusing on TDP-43, a key protein associated with ALS development. She then continued her training as a postdoctoral researcher in Dr. Jeffrey Rothstein’s lab at Johns Hopkins University, supported by a 2018 Milton Safenowitz Postdoctoral Fellowship. 

“It was getting that fellowship that really solidified my decision to stay in academia—to be able to ask the questions that I want to ask, do the research that I want to do, and make the impact that I want to make with my research.”

 Now, as the principal investigator of her own lab at Johns Hopkins, Dr. Coyne is exploring the mechanisms that impact nuclear pore complex involvement in the changes to TDP-43 that lead to ALS. 

Nuclear pore complexes are embedded within the nuclear envelope, which serves as the protective boundary between the nucleus, where DNA and RNA are located, and the cytoplasm, the gel-like fluid that fills the rest of the cell. Essentially, the nuclear pore complex acts like an air traffic control center, directing everything that moves between these two cellular compartments. 

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“The nuclear pore complex makes sure that things are where they need to be, when they need to be there,” Dr. Coyne explained. 

One of these things is TDP-43. TDP-43 is normally found in the nucleus, where it plays critical roles in regulating gene expression and in RNA processing. However, in more than 95% of people with ALS, TDP-43 moves or “mislocalizes” from the nucleus to the cytoplasm, where it can’t perform its essential functions. It also forms clumps or aggregates in the cytoplasm. Both the loss of TDP-43 from the nucleus and the formation of aggregates damage neurons, eventually leading to the development of ALS symptoms. 

What Dr. Coyne’s lab has found is that overactivation or “inappropriately sustained activation” of the ESCRT-III pathway disrupts the nuclear pore complex and contributes to the TDP-43 mislocalization and dysfunction seen in ALS. Because this is such a complicated pathway, Dr. Coyne and her team are now trying to understand the different protein components and players involved and determine which ones might be “viable therapeutic targets” that could “ultimately restore TDP-43 function and nuclear localization.” 

The lab is building new tools to screen for small molecules that disrupt the binding of some of the proteins in the ESCRT-III pathway that contribute to nuclear pore damage. They also are leveraging targeted technologies like small interfering RNA (siRNA) and antisense oligonucleotides (ASOs). ASO technology may sound familiar, as that’s what’s behind the drug Qalsody® (tofersen), which was approved in 2023 specifically for people with ALS caused by a mutation in the SOD1 gene, also known as SOD1-ALS. 

“The ASOs for SOD1 and FUS [another ALS-linked gene] that have been recently developed have proven incredibly successful, not only at stabilizing disease, but in a subset of patients, them getting better and regaining some function,” she said. “That is the biggest source of hope that we have, and I think that's been a game changer for a lot of us in the field, myself included.”  

It is the belief that one day ALS will become a livable disease that not only drives Dr. Coyne but also unifies the entire ALS research community. 

“I think we all go into this with two common goals in mind: To understand the disease and to ultimately help patients,” she said. “Everyone has different backgrounds, and so we are tackling these questions from different perspectives, but I think we all realize that the only way we're going to reach these goals is by doing this together.” 

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