Antisense oligonucleotides and small interfering RNAs—two types of synthetic genetic molecules—can silence disease-causing genes, but they rely on the body’s own protein machinery to cut their targets, which limits which sequences they can attack and where they can work. This project tackles a fundamental bottleneck in nucleic acid therapeutics. Current gene-silencing tools like ASOs and siRNAs must be recognised by specific proteins (RNAse H or RISC) to function. That chemical requirement restricts their design, delivery, and effectiveness. The researchers aim to bypass this limitation entirely by attaching synthetic “molecular scissors” directly to nucleic acids, enabling them to cut RNA without any protein help. In a parallel approach, they will test whether small synthetic tags can recruit an alternative RNA-degrading protein instead. If successful, this would expand the chemical toolkit for gene silencing beyond what current protein-dependent systems allow. The work is fundamental science—it does not promise an immediate therapy. But similar fundamental advances in nucleic acid chemistry have already led to approved drugs for spinal muscular atrophy and hereditary transthyretin amyloidosis. A broader arsenal of RNA-cutting tools could eventually enable treatments for diseases where current oligonucleotide therapies fail due to delivery or toxicity constraints.
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Advances in nucleic acid therapeutics have caused a paradigm change in drug design, shifting the focus from drugging proteins to targeting nucleic acids. With a better knowledge of RNA biology and improvements in nucleic acid chemistry, RNA modulation has become more viable. Antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) are amongst the most promising tools for gene silencing. These are now being developed into therapeutics for a broad range of diseases, including metabolic diseases, cancers, neurology, and ophthalmology. ASOs and siRNAs also provide powerful tools for studying genome regulation and mechanisms of disease. Developments in nucleic acid chemistry have culminated in the recent approval of ASOs and siRNAs in the clinic; however, challenges associated with biodistribution, delivery, cell uptake, and toxicity, limit their efficacy and broader adoption. Whilst further improvements are needed, the chemical evolution of ASOs and siRNAs is inherently limited due to their requirement to be recognised by their cognate proteins (RNAse H or RISC respectively). Our overarching aim is to develop tools to convert promising emergent nucleic acids that are not compatible with these proteins into potent RNA cutting tools and gene silencing agents. We will investigate attaching synthetic "molecular scissors" to nucleic acids so that they cut target RNA independent of proteins. In a complementary approach, we will determine whether it is possible to recruit an alternative RNA degrading protein by attaching small synthetic tags. If successful, we will expand the arsenal of oligonucleotide-based approaches for RNA manipulation and provide powerful alternatives for gene silencing.
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