Hiroshi Nakato, Lihsia Chen, and James Dutton
When a patient is diagnosed with a rare genetic disease, the news often comes with a discouraging caveat: no treatment options are available. For patients and clinicians alike, this scenario is all too familiar. While these genetic conditions are individually uncommon, they collectively affect millions of people, and established treatments exist for only about 5% of them.
A new collaboration between the University of Minnesota and Mayo Clinic aims to change that. The Minnesota Functional Omics Resource, or MNFORce, brings together a multidisciplinary team of researchers and clinicians working to turn genetic discoveries into new therapeutic strategies. The collaboration was established in 2024 with funding from the Minnesota Partnership for Biotechnology and Medical Genomics and reflects a deliberate effort to bridge basic science and clinical care.
“Having both sides working together, you see how fast progress can be,” says Associate Professor Lihsia Chen, one of the researchers from the Department of Genetics, Cell Biology, and Development involved in the initiative. “It’s very synergistic.”
The work begins at the Mayo Clinic, where researchers identify clusters of patients who share rare genetic disorders and then sequence their genomes to pinpoint potential disease-causing mutations. These genetic sequences are often classified as “variants of unknown significance,” meaning it isn’t clear whether or how they contribute to the disease. To answer that question, MNFORce researchers use CRISPR-Cas9 gene editing to recreate the genetic variants in a range of preclinical models, allowing them to observe how the mutations affect development, cellular function, or other key biological processes.
“Depending on the level of evolutionary conservation of a molecule of interest—or a domain affected in a patient—the choice of the best model system is different,” explains Professor Hiroshi Nakato, a GCD faculty member whose lab uses fruit flies to investigate mutations as part of the initiative. In other words, some genes and proteins have stayed remarkably similar across species throughout evolution. The more conserved they are, the more likely it is that a mutation in a simple model organism—like a fly—will mimic its effects in humans.
Chen’s lab studies genetic variants in roundworms (also known as C. elegans). Other preclinical models used in this project include zebrafish and mice, as well as induced pluripotent stem cells (iPSCs) generated in the lab of James Dutton, a GCD associate research manager and member of the University of Minnesota Stem Cell Institute. These complementary approaches help the team choose the best system for understanding how specific gene variants might cause disease.
Now, one year into the initiative, the MNFORce researchers—including faculty from the Department of Pediatrics—have successfully generated the targeted genetic variants in their respective models. With that milestone reached, they are now preparing to begin proof-of-principle drug screening. The process will examine whether existing FDA-approved medications might help restore function, which could significantly shorten the time between discovery and clinical application. “I have now had the opportunity to be in meetings with patients, and that feels really good,” Chen says. “The responsibility I feel is even stronger.”
In medical research, speed matters, and rare genetic diseases are no exception. The MNFORce team hopes the project will not only open doors for new therapies but also demonstrate how interdisciplinary, patient-centered research can accelerate progress where it is most urgently needed. It offers a model for bringing basic research closer to clinical care—and closer to the patients who stand to benefit. — Jonathan Damery