UMD Researchers Uncover Key Genetic Mechanisms That Could Lead to Better RNA-Based Medicines

RNA-based medicines have recently demonstrated their potential through COVID vaccines and double-stranded RNA (dsRNA) therapies that can accurately target and silence genes that cause certain cancers or diabetes. A major challenge remains, however: getting these potentially life-saving RNA molecules into cells efficiently.

A new University of Maryland study published Monday in the journal eLife may lead to breakthroughs in RNA-based drug development. Researchers used microscopic roundworms as a model to investigate how dsRNA molecules naturally enter cells, discovering multiple pathways—a finding that could help improve drug delivery methods in humans.

“Our findings challenge previous assumptions about RNA transport,” said the study’s senior author, Antony Jose, an associate professor of cell biology and molecular genetics at UMD.

“We’ve learned that RNA molecules can carry specific instructions not just between cells but across many generations, which adds a new layer to our current understanding of how inheritance works.”

The team found that a protein called SID-1, which acts as a gatekeeper for the transfer of information using dsRNA, also has a role in regulating genes across generations. When researchers removed the SID-1 protein, they observed that the worms unexpectedly became better at passing changes in gene expression to their offspring. In fact, these changes persisted for over 100 generations—even after SID-1 was restored to the worms.

Proteins similar to SID-1 are in other animals, including humans, and understanding its role has significant implications for human medicine.

“If we can learn how this protein controls RNA transfer between cells, we could potentially develop better targeted treatments for human diseases and perhaps even control the inheritance of certain disease states,” Jose said.

The research team also discovered a gene called sdg-1 that helps regulate “jumping genes”— DNA sequences that tend to move or copy themselves to different locations on a chromosome. While jumping genes can introduce new genetic variations that may be beneficial, they are more likely to disrupt existing sequences and cause disease. The researchers found that sdg-1 is located within a jumping gene but produces proteins that are used to control jumping genes, creating a self-regulating loop that could prevent unwanted movements and changes.

“It’s fascinating how these cellular mechanisms maintain this delicate balance, like a thermostat keeping a house at just the right temperature so it isn’t too warm or too cold,” Jose explained. “The system needs to be flexible enough to allow some ‘jumping’ activity while preventing excessive movements that could harm the organism.”

The findings provide valuable insights into how animals regulate their own genes and maintain stable gene expression across generations, Jose said. Studying these mechanisms could potentially pave the way for innovative future treatments for heritable diseases in humans.

Looking ahead, the team plans to investigate mechanisms related to the transport of different types of dsRNA, where SID-1 is localized and why certain genes are being regulated across generations while others are not.

“We’re just scratching the surface,” Jose said. “What we discovered is just the beginning of understanding how external RNA can cause heritable changes that last for generations.”