Researchers have identified RNA mechanisms that could enhance the effectiveness, durability, and precision of treatments for issues such as high cholesterol, liver diseases, and various cancers.
RNA interference (RNAi) therapeutics are gaining considerable attention in clinical research due to their potential in treating a variety of illnesses, including genetic disorders, viral infections, and cancer. These treatments can accurately target and silence genes that cause diseases, thus reducing unintended effects and improving patient outcomes.
With the increasing number of studies focusing on RNAi treatments, it is essential to explore how long the benefits of RNAi can last and whether it can be fine-tuned for better results. Scientists at the University of Maryland used tiny roundworms as a model to investigate the underlying mechanisms of RNAi and how they might be optimized for human medical applications. The team shared their results in the journal eLife on August 20, 2024.
“Recently, RNA interference has significantly impacted scientific research by enabling the development of drugs that can selectively silence genes responsible for diseases. We’re already witnessing its implementation in agriculture, and some RNAi treatments have received approval for human use,” explained Antony Jose, a senior author of the study and an associate professor of cell biology and molecular genetics at UMD. “RNAi shows great promise, yet numerous fundamental questions remain regarding how we can enhance its effectiveness.”
In the eLife study, Jose and his research team utilized quantitative modeling, simulations, and experiments involving roundworms to delve deeper into RNAi’s mechanisms. The results indicated that the effects of gene silencing may diminish over time. Surprisingly, the researchers discovered that these effects faded even in non-dividing cells, which do not undergo reproduction and replication.
“It is somewhat understandable that continuously dividing cells might eventually dilute the effectiveness of an RNAi-type treatment,” Jose clarified. “However, what is puzzling is the loss of efficacy even in cells that don’t divide. Remarkably, this also occurs in worms, which amplify the RNAs—essentially producing more of the treatment. Our findings suggest that there must be a degradation mechanism at play impacting RNAi over time, which researchers must factor into the dosing schedules of RNAi treatments to maintain their effectiveness for as long as required.”
These insights emphasize the importance of considering drug resistance in the development of RNAi-based therapies, Jose noted. Much like bacteria can develop resistance to antibiotics, the human body may also build resistance to gene silencing over time.
“Without taking into account the durability of our RNA interventions, we risk creating treatments that lose their effectiveness over time,” Jose emphasized. “Therefore, we need to think about resistance from the outset of drug development and carefully consider which genes to target to ensure that the treatment remains effective for as long as necessary.”
The study also provided new insights into how various regulatory proteins within the worms’ cells collaborated to manage gene silencing. Jose’s team identified three key regulatory proteins that impacted gene silencing and revealed that they offered multiple interconnected pathways for controlling specific targeted genes. Understanding these interaction networks better could lead to significant advancements in optimizing RNAi therapies for the best outcomes in human patients.
“The absence of certain proteins can complicate the silencing of specific genes but not affect others,” Jose stated. “Understanding how these proteins interact with each other can be crucial when developing drugs customized to individual patients.”
Looking forward, Jose’s team aims to examine the RNAi degradation process in more detail and pinpoint the key traits that make some genes easier to silence than others. They aspire that their findings will facilitate enhancements in this promising class of therapeutics.
“Our ultimate goal is to drive progress toward more powerful, long-lasting, and personalized gene-silencing therapies for a wide array of diseases,” said Jose.
This research was funded by the National Institutes of Health (Award Nos. R01GM111457 and R01GM124356) and the U.S. National Science Foundation (Award No. 2120895).
