New research paves the way for more effective RNAi-based drugs to treat diseases

RNA interference therapy (RNAi) therapies have attracted great interest in clinical trials due to their potential to treat a variety of diseases, such as genetic disorders, viral infections, and cancer. These therapies can precisely target and suppress disease-causing genes, minimizing unwanted effects and improving treatment outcomes.

As research into RNAi-based therapies increases, questions arise about how long their benefits might last and whether they can be fine-tuned. Scientists at the University of Maryland used microscopic worms as a model to investigate the mechanisms underlying RNAi and how it could be optimized for medical use in humans.The team published their findings in the journal eLife.

«In recent years, RNAi has made a real impact on the scientific world because it can be used to develop drugs that selectively suppress genes that cause diseases.“We’re already seeing it in action in sectors like agriculture, and some RNAi therapies have already been approved for use in humans,” said senior study author Anthony Jose, an assistant professor of cell biology and molecular genetics at UMD. “RNAi is very promising, but there are still a lot of fundamental questions about how to make RNAi more effective.”

In the eLife studio, Jose and his team They used quantitative models, simulations and experiments with roundworms to further understand this process. The researchers found that the gene silencing effects could wear off over time, but they were surprised to learn that the effects eventually disappeared even in non-dividing cells (cells that do not reproduce or multiply).

«It makes sense to expect that constantly dividing cells could lead to dilution of the RNAi-based drug.” explains Jose. “But what’s really surprising is how the drug’s effectiveness is lost even in cells that aren’t dividing. Surprisingly, this happens even in worms that amplify their RNA, meaning they produce more of the drug. “Our work suggests that there must be some mechanism that makes RNAi less effective over time, and researchers need to take this into account when designing dosing schedules for RNAi drugs so they can maintain their effectiveness for as long as they’re needed.” he adds.

These results highlight the need to consider drug resistance when developing RNAi-based therapies.According to Jose, just as bacteria can become resistant to antibiotics, we too can become resistant to silence over time.

“If we don’t take into account factors like the longevity of our RNA interventions, we will always create treatments that will eventually stop working“Instead, we need to take resistance into account from the start of drug development and think more about which genes to target so that the drug remains effective for as long as it needs to be,” he says.

The study also provided new information about how various regulatory proteins in worm cells work together to control gene silencing.Jose’s team identified three important regulatory proteins that influence gene silencing and found that they provide multiple, interconnected pathways to control specific target genes. For researchers, better understanding these networks of interactions could be a breakthrough in refining RNAi therapies to maximize impact on human patients.

“Losing some proteins can make it harder to silence some genes but not others,” explains Jose.Knowing how these proteins work together to influence genes could have implications when it comes to developing drugs tailored to a specific individual.“Jose adds. Looking ahead, Jose’s team plans to continue to study the RNAi degradation process and identify key features that make some genes more susceptible to silencing than others. They hope their research will pave the way for improvements to this new but promising class of therapy.

«Our ultimate goal is to accelerate progress towards more powerful, long-lasting and tailored treatments for a wide range of gene-silencing diseases.“If we don’t take into account factors like the longevity of our RNA interventions, we’ll always end up creating treatments that will eventually stop working,” Jose said. “Instead, we need to consider resistance early in drug development and think more about which genes to target so that a drug remains effective for as long as it needs to.

The study also provided new information about how various regulatory proteins in worm cells work together to control gene silencing.Jose’s team identified three important regulatory proteins that influence gene silencing and found that they provide multiple, interconnected pathways to control specific target genes. For researchers, better understanding these networks of interactions could be a breakthrough in refining RNAi therapies to maximize their impact on human patients.

«“The loss of certain proteins can make it harder to suppress some genes but not others,” explains Jose. “Knowing how these proteins work together to affect genes “This could have implications when it comes to developing drugs tailored to the individual.” Looking ahead, Jose’s team plans further study of the RNAi degradation process and identification of key features that make some genes more susceptible to silencing than others. They hope their research will pave the way for improvements to this new but promising class of therapy. “Our ultimate goal is to accelerate progress toward more powerful, long-lasting, and tailored gene silencing therapies for a broad range of diseases,” concludes Jose.

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