ALS is a devastating neurodegenerative disease, and while there is no cure, ongoing research continues to offer hope for more effective treatments. An individual at the forefront of these efforts is Dr. Kathryn Morelli, an assistant professor in the Department of Neurological Sciences at the University of Vermont’s Larner College of Medicine, whose research aims to address the complex challenges of ALS, building on work she did with her postdoctoral mentor Dr. Gene Yeo. Working closely with Abby Kirch, a PhD student in her lab, Kathy and her team are focused on developing RNA-targeted therapies for ALS, particularly for the C9ORF72 mutation, one of the most common genetic causes of the disease.
One of the critical resources that has enabled their groundbreaking work is the support from Target ALS, as an organization dedicated to accelerating the development of effective treatments for ALS. Through its Stem Cell Core and Reagents Core, Target ALS is helping researchers like Kathy and Abby push the boundaries of ALS research in ways that would be difficult—if not impossible—without these invaluable resources.
A Focus on Human Models: The Power of Stem Cells
Kathy’s research is centered on the development of novel RNA-targeting therapies, including zinc finger nucleases, for ALS. As she explains, ALS, particularly C9orf72 ALS, is driven by toxic RNA that disrupts the function of motor neurons, ultimately leading to neurodegeneration. In the quest for effective treatments, understanding the disease at the molecular level and testing new therapies in models that closely mimic human disease are crucial steps.
This is where Target ALS’s Stem Cell Core comes in. The ability to access patient-specific stem cell lines is a game-changer for researchers. “Target ALS has been amazing and has supplied our lab with not only C9orf72 stem cells, but all of their entire stem cell bank,” Kathy says. “This has opened so many doors for us because we can make many different types of human preclinical models—patient-specific models—to really look at the molecular etiology of ALS.”
These human-derived stem cells can be used to create spinal cord organoids, which are 3D models that replicate the basic structure of the human spinal cord. These organoids include motor neurons and other cell types affected in ALS, providing a more accurate model for studying the disease compared to traditional 2D cell cultures or mouse models. As Kathy explains, “Organoids are different. They have all the different cell types of an organ within one model, so they are a much better representation of what’s happening in humans versus traditional cell culture models.”
For ALS research, this is a critical advantage. While mouse models have historically been used to test therapies, they do not always capture the full complexity of human ALS, especially for mutations like C9orf72. “We don’t have the best mouse models right now for C9orf72 ALS,” Kathy admits, “so having access to human stem cells is incredibly important to test our therapies more accurately before moving to clinical trials.”
The ability to work with these models allows Kathy’s team to test the efficacy and potential toxicity of new therapies, such as the zinc finger-based RNA-targeting strategies they are developing. “We can evaluate the delivery, efficacy, and potential toxicity of this therapy in human tissue before ever stepping into a clinic,” she says.
Without Target ALS’s access to these stem cell lines, creating such models would be significantly more costly and time-consuming, potentially delaying research and innovation. “Stem cell banks are often not publicly accessible, and even when they are, each cell line can be very expensive. This is why this resource has been instrumental in advancing our research,” Kathy notes.
Reagents and Antibodies: The Critical Tools for Testing New Therapies
In addition to stem cell models, high-quality reagents—such as antibodies—are essential for evaluating the success of new therapies. Kathy and Abby emphasize the importance of having access to reliable, validated antibodies that can accurately measure whether a treatment is targeting and clearing the toxic proteins associated with ALS. “Antibodies are a really important reagent to test if a drug works or not,” Kathy explains. “They can help determine if the toxic proteins produced by the C9orf72 mutation are being recognized and cleared by the therapy.”
For ALS, particularly in the case of C9orf72, this process can be complicated. “The C9orf72 mutation produces multiple toxic proteins, that are notoriously difficult to target with antibodies,” Kathy explains. “With commercial antibodies, the results can be inconsistent, making it difficult to determine whether my drug is effective. But having access to the antibodies from Target ALS that have been validated by established ALS researchers is incredibly valuable. I trust the results I get with these antibodies.”
By providing researchers with reliable, high-quality reagents, Target ALS ensures that preclinical studies can yield accurate and reproducible data. This not only accelerates the pace of research but also helps to avoid costly setbacks that can occur when therapies fail due to poor reagent quality.
Target ALS’s Support for Early-Career Investigators
Beyond the tangible resources of stem cells and reagents, Target ALS’s role in fostering a collaborative and supportive environment for early-career researchers is also highly significant. Kathy, a Target ALS Springboard Fellow, credits the organization with helping her become more integrated into the ALS research community. “Target ALS has really helped me feel more connected to the ALS field,” she says. “It’s been daunting at times—I have so much respect for the scientists in my field and think of them as rock stars, especially my postdoctoral mentor, Gene Yeo. But giving me the opportunity to speak at the Target ALS Annual Meeting in 2024 was fantastic. The way they organized the meeting—where I could sit with different groups of scientists throughout—was great. I was able to present my work, which got me noticed, and have conversations with these scientists.”
For Kathy, these interactions have been invaluable. “I was able to meet a few scientists who actually provided some of these resources. Now we can chat about future directions or which reagents to avoid. Target ALS has been fantastic in that respect.”
Target ALS’s commitment to data sharing also stands out. As Kathy mentions, the new ALS Data Engine is an essential tool for advancing the field. “Data sharing is going to be absolutely fantastic. ALS is a rare disease, and we need lots of samples and data to understand what’s driving it, especially in sporadic forms. The more data, the better,” she says.
Kathy’s postdoctoral mentor, Gene, notes, “New researchers inject new energy and ideas, often orthogonal to the current themes and trends that established investigators in the area are already pursuing. They also sometimes bring in new techniques/technologies to enrich the field. Collaborations with new investigators should be encouraged to really introduce them to resources and facilities that they may not be aware of.” He adds that because early labs may not have the resources to pursue ambitious projects, it is imperative that Springboard Fellows and postdocs transitioning should be supported and have access to resources to “lower the activation energy to try exciting, but often risky science”.
A Personal Connection: Why ALS Research Matters
Kathy and Abby’s drive to work in ALS research is deeply personal, as residents of Vermont. Abby explains, “Northern New England has some of the highest rates of ALS occurrence in the country. While it’s often considered a rare disorder, many of us know someone affected by it. This has fueled my deep commitment to supporting research efforts, with the hope that one day we can provide resources to improve and extend the quality of life for those living with the disease.”
Kathy adds, “I hear the same thing over and over again: we have no idea what happened. It’s really scary to be diagnosed with something where you just don’t know what caused it. That’s what really drives me to continue with this field, to help figure this out. Having hands-on time with a disease that is still so unknown is powerful. A huge issue with ALS is not being able to diagnose it early. Our hope is that, through our research, we might discover new ways to diagnose ALS or find new genetic links that could lead to better treatments and outcomes.”
Embracing Failure: The Long Road to Discovery
For both Kathy and Abby, their work in ALS research goes beyond developing effective treatments—it’s about persevering through the inevitable challenges of scientific discovery. Kathy shares valuable advice for young researchers entering the field: “Therapeutic development is incredibly hard. 9 out of 10 times, your therapies are going to fail, but that’s okay. You have to accept failure as part of the process and keep innovating. If therapeutic development were easy, diseases wouldn’t exist. But when you discover that one therapy or that one biomarker that could make a difference, it makes every setback worth it.”
Her advice? “Be prepared to fail, but know one day, you’ll succeed, and it will be worth it. Along the way, you’ll gain invaluable lessons from those failures.”
Abby, who is just beginning her journey as an ALS researcher adds that what has made a difference for her has been finding a mentor like Kathy, who has made delving into such a complex field all the easier. She adds, “ALS is a hard problem to solve, which is why it’s still getting solved. There is still so much unknown about it and there are so many different directions that this could go in. This is what interests me – it’s an open-ended question.”
Gene shares that he believes it’s important that mentors help their trainees, driving a spirit of mentorship forward. He says, “When she was in my lab, Kathy’s attention to developing patient-derived organoid models to evaluate our new RNA therapeutic modalities (like our Zinc finger work or CRISPR approaches) has been invaluable to help us understand the impact in human-relevant systems. I look forward to continuing to collaborate with her as my group continues to advance technologies in the pre-clinical therapeutic arena.”
The research conducted by Kathy and her team at the University of Vermont demonstrates the critical role that well-funded, high-quality resources play in advancing ALS research when paired with dedicated scientists who want to see a world where Everyone with ALS Lives. From patient-specific stem cell lines to validated reagents, Target ALS’s commitment to supporting early-stage investigators has paved the way for meaningful advancements in the search for effective ALS treatments. While the road ahead is long, the collaboration between researchers, institutions, and organizations like Target ALS holds the promise of a brighter future for ALS patients and their families.
Support the Global ALS Research Community
Your support helps us provide essential tools to researchers around the world, ensuring that critical discoveries are within reach for all. Join us in empowering the global ALS research community and driving progress toward effective treatments. Make a difference today—every donation brings us one step closer to a world where Everyone Lives.
