Exploring the Potential of Double-Stranded RNA Therapies
- Reference number
- ID24-0029
- Project leader
- Sarshad, Aishe
- Start and end dates
- 250101-291231
- Amount granted
- 3 250 000 SEK
- Administrative organization
- Göteborg University
- Research area
- Life Sciences
Summary
The Argonaute (AGO) proteins are directed by double-stranded RNAs (dsRNAs) to complementary sequences on target RNAs, leading to either target destabilization or target activation. While post-transcriptional gene regulation mediated by cytoplasmic dsRNA:AGO processes is well understood in humans, recent evidence of nuclear engagement by dsRNA:AGO has emerged, challenging our existing perspectives. Despite advancements, the function and mechanism of nuclear-targeting duplex RNAs remain poorly understood. Presently, only one saRNA-based therapeutic is undergoing clinical trials for gene activation, while six siRNAs have received FDA approval for mRNA silencing. However, nuclear directed siRNAs have not yet gained the attention from pharmaceutical companies. To maintain a position at the forefront of innovation, our research teams at Gothenburg University and AstraZeneca have joined forces to elucidate the basic mechanisms of nuclear-targeting duplex RNAs. In this project we will (1) determine the optimal chemistries of dsRNA for both RNAa and RNAi mechanisms in the nucleus. (2) Visualize nuclear dsRNA:AGO action. (3) Identify protein components of RNAa/RNAi effector complexes and (4) define the loading dynamics dsRNA onto AGO. Finally, we will (5) assess the slicing activity of AGO2 loaded with siRNA, (6) but the gene activation activity of AGO when loaded with saRNA.
Popular science description
Gene therapy is a promising medical approach that directly targets and modifies genes responsible for diseases. By introducing specific genetic materials into the patient's tissues, it can adjust gene activity—either turning it down, turning it up, or fixing it. There are different tools used in gene therapy: Small interfering RNA (siRNA) help to turn off genes. small activating RNA (saRNA) help to turn on or correct gene activity. Both types of small RNA work with Argonaute proteins to execute their functions. These small RNA molecules are introduced into cells as short double-stranded RNAs and use the cell's natural machinery to carry out their functions. However, our understanding of how these processes work inside the cell nucleus, especially in humans, is still limited. Recent research has shown that these siRNA and saRNA loaded protein complexes can also be present in the nucleus, suggesting they might play a role in gene regulation there too. This discovery has opened up new research areas to understand how saRNAs and siRNAs can both activate and silence genes within the nucleus under similar conditions. This project aims to uncover how saRNAs and siRNAs work differently to modulate gene expression, which could lead to more advanced gene therapy techniques.