Researchers based at the King Abdullah University of Science & Technology in Saudi Arabia have developed a gene silencing tool that could help develop better therapeutics for genetic diseases.
Piwi-interacting RNA (piRNA) is the largest type of small non-coding RNA that is expressed in animal cells and these molecules act to suppress gene activity. Working in a preclinical model in nematode worms, researchers have managed to develop a method to silence genes of interest using piRNAs.
The team managed to silence more than one gene at once, something not achieved with other methods, and the changes were inherited by the offspring of the worms with silenced genes. The researchers also developed a method of stopping the gene silencing so it could be regulated if required.
Gene silencing is currently being developed by several biotechs for use in medical therapies. One of the most advanced using this type of technology is Alnylam Pharmaceuticals, which uses small interfering (si)RNAs to bind to disease causing mRNAs and stop their translation into pathogenic proteins. The company already has three therapeutics on the market—patisiran, givosiran, and lumasiran to treat various rare diseases, as well as inclisiran (later development external to the company) to treat hypercholesterolemia.
Other companies such as Silence Therapeutics and AUM LifeTech, among others, are also working on gene silencing treatments to target disease. While there has been a lot of success in this area in recent years, not all genes can be silenced using currently available technology.
Christian Frøkjær-Jensen, a researcher at the King Abdullah University and lead author of the study describing the work in Nature Methods, and colleagues designed ‘guide piRNAs’ to test their silencing method against two genes involved in programming worm sex. This meant the results were easier to follow as they used sex skewing as a measure of efficacy.
They found the method was effective at silencing these genes and others either alone or in a multiplexed way. “piRNA-mediated interference (‘piRNAi’) is more efficient than RNAi and can be multiplexed, and auxin-mediated degradation of the piRNA-specific Argonaute PRG-1 allows conditional gene silencing,” write the researchers.
Notably the gene silencing they programmed into the worms was inherited for up to six generations and no obvious off-target effects were seen.
“We have reprogrammed a pathway that normally guards the organism’s genome,” Frøkjær-Jensen commented in a press statement. “Our technique is an important step in enabling precise and scalable biological engineering of a very simple living organism.”
While this study is very early-stage work, the team thinks it has the potential to add new options for gene silencing therapeutics in humans. “It is interesting to consider whether piRNAi could be used as a potential therapeutic in people,” says Frøkjær-Jensen.