New Worm Study Paves Way for Better RNA-Based Drugs to Treat Human Disease

The rise of RNA interference (RNAi) therapeutics is spurring hopes for more effective ways to precisely target and “silence” the genes behind various diseases and disorders, but fundamental questions remain about how long RNAi benefits can last and whether the effects of such drugs can be fine-tuned.

In new findings published Tuesday in the journal eLife, University of Maryland researchers unveiled RNA mechanisms that may lead to more effective, durable and targeted treatments for conditions like high cholesterol, liver diseases and cancers.

In the study, cell biology and molecular genetics Associate Professor Antony Jose and his team used quantitative modeling, simulations and experiments with roundworms to dig deeper into the RNAi process. The researchers confirmed earlier research results that the effects of gene silencing could wear off over time, but they also discovered something surprising.

“It makes some sense to expect that constantly dividing cells could eventually dilute an RNAi-based drug,” Jose explained. “But the real head-scratcher is how the drug’s efficacy is lost even in cells that don’t divide.”

The work reveals that there must be some mechanism beyond dilution that degrades the effects of RNAi over time—and researchers must take that mechanism into consideration when developing dosing schedules for RNAi drugs so that they can maintain effectiveness as long as they’re needed, Antony said.

The findings highlight the need to consider drug resistance when developing RNAi-based treatments, he said. Just as bacteria can become resistant to antibiotics, humans may also become resistant to silencing over time.

“If we don’t consider factors such as the longevity of our RNA interventions, then we will forever be creating treatments that will eventually stop working,” Jose noted. “Instead, we have to consider resistance at the very beginning of drug development and think harder about what genes to target so that the drug remains as effective for as long as needed.”

The study also offered new insights into how different regulatory proteins within the worms’ cells worked together to control gene silencing. Jose’s team highlighted three important regulatory proteins that influenced gene silencing and found that they provided multiple interconnected paths for the control of certain targeted genes. For the researchers, getting a better understanding of these networks of interactions could lead to breakthroughs in fine-tuning RNAi therapies for maximum impact on human patients.

Looking ahead, Jose’s team plans to investigate the RNAi degradation process more closely and identify the key features that make some genes more susceptible to silencing than others. They hope that their research paves the way for improvements to this emerging yet promising class of therapeutics.

“Our ultimate aim is to catalyze progress toward more potent, durable and tailored gene-silencing therapeutics for a wide range of diseases,” Jose said.