GalNAc is a well-known delivery platform that delivers siRNAs (small interfering RNA) or ASOs (antisense oligonucleotides). The most successful route of administration is subcutaneous injection using a natural pathway. GalNAc is a natural ligand to the ASGPR receptor that brings the molecule of interest into hepatic cells, the method is celebrated for its high potency, long-duration, and patient-centric qualities. Jim Weterings, Senior Director & Head of Technology Development, at Sirnaomics explained that many companies are involved in optimising this GalNAc technology including Arrowhead, Alnyam, Dicerna, Silence, and Sirnaomics.
Weterings presented Sirnaomics’s proprietary GalNAc RNAi platform, GalAhead which includes mxRNA (miniaturized single targeting RNA triggers) and muRNA (multi-unit multi-targeting RNAi triggers). mxRHA is an siRNA molecule used to target a single disease. Weterings explained that conventional GalNAc siRNA includes a duplex antisense and sense strand. Whereas Sirnaomics’s design synthesises a single molecule that forms a duplex by itself and has a loop included.
Weterings commented: “Our single synthesis run on one synthesizer includes only 31 to 33 nucleotides, offering potential CMC advantages. So, for mxRNA the benefits are outstanding activity, relative ease of CMC, and its solid IP position.” Overall, Sirnaomics’s design reduces the number of synthesis and purification steps and lowers the risk of off-target effects. In in vitro hepatocyte models, mxRNA achieved robust knockdown of a selected target gene. In in vivo mouse studies, mxRNA molecules demonstrated potent and sustained activity, with certain variants maintaining over 90% target gene knockdown for up to six weeks following a single dose.
Regarding muRNA, the main goal is to target multiple positions in a disease pathway simultaneously. The model relies on a concept called “Sollbruchstelle” (weak spots) to design constructs that break apart and release RNAi triggers. The RNAi triggers must break to elicit their effect on the two different targets. The platform enables simultaneous suppression of multiple pathways as shown in studies targeting genes linked to hemochromatosis and hypertriglyceridemia.
Wetherings introduced an muRNA that targets TMPRSS6 and MAP4K4. In vitro studies in hepatocyte models demonstrated simultaneous knockdown of two targets with muRNA constructs. For example, a muRNA targeting TMPRSS6 and MAP4K4 achieved around 80% knockdown for both genes, demonstrating effective dual targeting. This was replicated in vivo, with strong reductions in gene expression observed in liver tissue in a mouse model.
The main advantages of this platform are its broad applicability, improved specificity, and synthesis efficiency. Sirnaomics’ pipeline includes multiple RNAi candidates targeting diseases like cardiovascular conditions, fibrosis, and metabolic disorders. The most advanced programs, such as those targeting APOC3, are on track to enter clinical trials soon.