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A revolution in targeted RNA delivery

The inability to deliver therapeutic RNA molecules to cell types beyond the liver is holding back the progress of RNA medicine, but Sixfold Bioscience has a solution. The company has engineered Mergo: a new platform that uses modified RNA molecules as vectors for delivering RNA therapeutics to an exact tissue or even a cell type (Fig. 1). The company’s ultimate goal is to develop a suite of solutions that allow short-RNA medicines to be delivered in a highly targeted way to any desired location.

“To deliver RNA to specific tissues and cell types throughout the body, it was obvious we couldn’t just make incremental alterations to what had failed previously. Sixfold had to engineer a new modality. We had to challenge the established convention,” said co-founder George Foot. He started the company in 2017 with fellow co-founder Anna Perdrix Rosell, after they completed their PhDs at the University of Cambridge and the Francis Crick Institute in London, respectively. The venture-backed startup—now with a team of over 20 chemists, biologists, and automation and machine-learning engineers—works in its London laboratories to foster seamless collaboration between disciplines.

Current approaches to delivering therapeutic RNAs are limited to lipid nanoparticles (LNPs) and ligands, such as lipids and peptides. The most successful method to date uses the N-acetylgalactosamine (GalNAc) ligand which, when conjugated to RNA moieties, allows cellular uptake, but only into liver hepatocytes. A few RNA medicines can be delivered locally—for example, to the eye or central nervous system (CNS)—but that leaves nearly 99% of the almost 500 cell types in the body still requiring a delivery system.

Solving the RNA-delivery problem

To overcome this challenge, Sixfold utilizes the way RNA is naturally delivered into cells. “We realized that nature has already solved the RNA-delivery problem,” said Perdrix Rosell. Non-coding RNAs such as microRNAs (miRNAs) are continually transferring messages from cell to cell via an ecosystem of delivery mechanisms. The Sixfold technology can access all of these different transport mechanisms, enabling delivery throughout the body.

“There is a widely held view that most of the RNA circulating naturally in our bodies is via exosomes or microvesicles, but the reality is over 99% of RNA is transported to cells via a diverse range of non-encapsulated mechanisms,” said Perdrix Rosell. The company is attempting to ‘hack’ these natural systems and design RNA tags that can bind to a myriad of different shuttles that provide access to different cell types. These RNA tags, which Sixfold calls ‘Mergos’, are attached to an RNA therapeutic so it can hitch-hike to its intended location (Fig. 1).

Diagram demonstrating how the Mergo platform works to deliver therapeutic RNAs to specific cell types

Fig. 1 | The Mergo platform. Sixfold is developing Mergo, an RNA-based tagging system, to deliver therapeutic RNAs to specific cell types by leveraging the body’s natural RNA-delivery pathways. HDL, high-density lipoprotein.

While the science of endogenous RNA delivery is still new, much of the design of Mergo tags is grounded in work from the RNA-therapeutics space. There is a substantial literature demonstrating that modifications to the sugar, base, and phosphate groups of RNA govern intracellular RNA–protein interactions, such as with the ribosome, DICER, and RNA-induced silencing complex (RISC) complex. Sixfold applied this to the extracellular space, hypothesizing that modifications are dictating the delivery mechanism and destination by altering how they interact with extracellular protein shuttles.

Efficient cellular delivery

To find the correct shuttles for a given cellular destination faster, Sixfold built a platform to cycle rapidly through this modification space. Using its high-resolution screening method, the company can test multiple Mergos in vivo at once, and track these tags to a single cell, allowing them to save animals, enable rapid design–build–test cycles, and dramatically lower the cost of data acquisition. This data-generation campaign has enabled Sixfold to apply the latest developments in machine learning and Bayesian optimization to the field of delivery, to efficiently determine which modifications influence delivery to various therapeutically relevant sites of interest.

Sixfold have already shown that Mergo can completely flip the normal delivery profile of RNA molecules. When injected systemically, its most advanced system can preferentially deliver RNA to the lung—rather than the liver—with higher activity than previously published ligand results, but at a quarter of the dose. In addition, Sixfold are able to tailor their delivery not only to a tissue type but also to a specific cell type, which has been demonstrated within lung and other tissues. With these capabilities, Sixfold intends to build the first RNA-delivery map of the entire body, providing options well beyond current delivery capabilities.

Sixfold’s immediate goal is to keep unlocking delivery mechanisms in new cell types with unmet need, such as the central nervous system. “We believe that Mergo is the enabling technology that will catalyze the shift from potential to reality for RNA medicines, solving one of the toughest challenges in biopharma today,” said Foot.


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