Abstract
Nucleic acid therapeutics have revolutionized the treatment landscape by directly targeting DNA and RNA, allowing for the development of treatments for diseases that were previously challenging to address with small molecule drugs. Currently, siRNA and antisense oligonucleotides are the predominant forms of nucleic acid therapeutics. However, they are not without challenges, including off-target effects, stability within the biological environment, and efficient drug delivery. Our research group has developed a new approach using short nucleic acids, which we have named “Staple oligomers,” leading to the creation of RNAh （RNA hacking） technology. This innovative technology functions by inducing the formation of RNA G-quadruplex structures on specific mRNA sequences, thereby inhibiting the translation process. This mechanism of action ensures that RNAh technology only activates when it binds to the target sequence and induces the formation of the RNA G-quadruplex, thereby significantly reducing off-target effects compared to existing nucleic acid therapies. One of the most compelling features of RNAh technology is its precision in targeting mRNA. The ability to form G-quadruplex structures specifically at the desired site allows for highly selective inhibition of translation, minimizing unintended interactions with non-targeted mRNA sequences. In our study, we targeted TRPC6, a gene implicated in pulmonary arterial hypertension （PAH）, using the RNAh technology to demonstrate its efficacy in translation inhibition. TRPC6 was chosen due to its significant role in the pathology of PAH, making it an ideal candidate to illustrate the potential therapeutic benefits of RNAh technology. The results of our experiments showed that RNAh technology effectively inhibited the translation of TRPC6 mRNA, validating its potential as a powerful tool for gene-specific therapy. This research highlights the potential of RNAh technology to overcome some of the existing challenges faced by nucleic acid therapeutics. By offering a highly targeted approach with reduced off-target effects, RNAh represents a promising advancement in the development of more effective and safer therapeutic options for complex diseases. Future studies will focus on optimizing delivery methods and further evaluating the clinical applications of RNAh technology across various disease models.
