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The potential of RNA-based therapies in combating diseases is increasingly evident, particularly illustrated by the recent success of RNA vaccines and double-stranded RNA (dsRNA) therapies. While the ability to create drugs that utilize dsRNA for precise targeting of harmful genes has been established, a significant hurdle remains: the effective delivery of these vital RNA molecules into cells.
A new study published in the journal eLife on February 4, 2025, holds promise for advancing RNA drug development. Researchers from the University of Maryland utilized microscopic roundworms as a model to examine how dsRNA molecules naturally penetrate cells and affect subsequent generations. Their findings revealed various pathways through which dsRNA accesses the cells of the worms, which may enhance drug delivery strategies in humans.
“Our research challenges prior beliefs regarding RNA transport,” stated Antony Jose, the senior author of the study and an associate professor at UMD’s Department of Cell Biology and Molecular Genetics. “We discovered that RNA can transmit specific information not only between cells but also across generations, which adds a new perspective to our understanding of hereditary processes.”
The research indicated that a protein named SID-1, which facilitates the transfer of dsRNA, also plays a crucial role in gene regulation across generations. When SID-1 was removed from the worms, they showed an unexpected improvement in their ability to transmit changes in gene expression to their offspring. Remarkably, these alterations were sustained for more than 100 generations, even after SID-1 was reintroduced.
“What’s particularly interesting is that related proteins are present in other species, including humans,” Jose remarked. “Gaining insights into SID-1’s function could have profound implications for human health. By understanding this protein’s role in RNA transfer, we might develop more targeted therapies for various diseases, potentially influencing the inheritance of certain conditions.”
The research team also identified a gene known as sdg-1 that helps manage ‘jumping genes,’ which are segments of DNA that can move or replicate within the genome. While these jumping genes can introduce beneficial genetic variations, they are more commonly associated with disruptions that can lead to disease. The researchers noted that sdg-1 resides within a jumping gene and generates proteins that regulate these genes, forming a self-regulatory mechanism to curtail unintended movements and modifications.
“It’s fascinating how these cellular processes maintain a balance, akin to a thermostat regulating a home’s temperature,” Jose explained. “The system requires flexibility to permit some jumping activity while also preventing excessive movements that could jeopardize the organism’s health.”
According to Jose, the insights gained from this research are crucial for understanding how living organisms manage their gene expressions and the stability of gene inheritance across generations. Studying these cellular mechanisms may lead to innovative treatments for genetic disorders in humans.
Moving forward, the team intends to explore further the mechanisms involved in transporting different dsRNA types, the localization of SID-1, and why certain genes are regulated through generations while others are not.
“We’re only beginning to uncover the complexities of this field,” Jose noted. “What we have found is merely the initial stage of understanding how external RNA can induce heritable changes over generations. This research is crucial for enhancing the design and delivery of RNA-based therapies to patients.”
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The research article, titled “Intergenerational transport of double-stranded RNA in C. elegans can limit heritable epigenetic changes,” was published in the journal eLife on February 4, 2025.
Co-authors from the University of Maryland include lead author Nathan Shugarts (Ph.D. ’21, biological sciences), along with biological sciences Ph.D. student Aishwarya Sathya, Andrew L. Yi (B.S. ’19, biological sciences; B.S. ’22, psychology), Winnie M. Chan (B.S. ’19, biological sciences; B.S. ’22, psychology), and Julia A. Marré (B.S. ’09, Ph.D. ’17, biological sciences).
This work received support from the National Institutes of Health (Award Nos. R01GM111457 and R01GM124356) and the U.S. National Science Foundation (Award No. 2120895). The contents of this article do not necessarily represent the views of these funding institutions.
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