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Immune Reactions in the Delivery of RNA Interference-Based Therapeutics: Mechanisms and Opportunities
Published in Raj Bawa, János Szebeni, Thomas J. Webster, Gerald F. Audette, Immune Aspects of Biopharmaceuticals and Nanomedicines, 2019
Kaushik Thanki, Emily Falkenberg, Monique Gangloff, Camilla Foged
Chemical modification can also be harnessed to address immunostimulation, which is another key hurdle to RNAi therapy (Fig. 14.3, right). The innate immune system is activated when siRNA molecules are recognized by toll-like receptors (TLRs), e.g., TLR3, TLR7 and TLR8. The 2′-O-Me, 2′-F and phosphorothioate modifications discussed above are multifunctional in nature, because they also impede TLR recognition. Incorporation of as few as two 2′-O-Me nucleotides is sufficient to abrogate TLR recognition of an entire siRNA molecule [18]. Mechanistically, 2′ methyl groups act as competitive inhibitors of TLR7 thereby protecting them in trans [15]. Other modifications, which prevent immunostimulation in naturally occurring RNA molecules, can be incorporated in synthetic siRNAs to achieve a similar effect. These include incorporation of pseudouridine and N6-methylated-adenosine (Fig. 14.3), respectively, inhibiting binding to TLR7 and TLR3. Incorporation of N6-methyladenosine specifically evades immune stimulation by destabilizing the duplex structure, recognized by TLR3. However, pseudouridine and N6-methylated-adenosine modifications are utilized to a limited extent due to the success of other modifications, in particular 2′-O-Me [19]. Finally, 2′-deoxynucleotides (Fig. 14.3) have recently been reported to impede immune recognition, particularly dU and dT bases [20]. Unlike other modifications, this modification is exceptionally versatile with the possibility for incorporation in the entire passenger strand and the 5' end of the guide strand without affecting RNAi potency [21].
The roadmap towards cure of chronic hepatitis B virus infection
Published in Journal of the Royal Society of New Zealand, 2022
TLR-8 is a transmembrane receptor counsellor located in the endosomal membrane of a subset of immune cells and recognises single-stranded RNA. TLR-8 activates innate and adaptive effector cells. GS-9688 is the first oral TLR8 agonist. Once-weekly dosing of oral GS-9688 induced dose-dependent increase in serum interferon-gamma (IFN-γ), interleukin-12 (IL-12) and interleukin-1 receptor antagonist (IL-1RA) in cynomolgus monkeys and Functional Cure in the woodchucks (Daffis et al. 2017). In phase II studies, weekly dosing of GS-9688 for 24 weeks in patients with chronic HBV induced dose-dependent cytokine and PD responses, as well as shifts in peripheral immune cell subsets. Profound HBsAg suppression and isolated HBeAg and HBsAg loss were observed in isolated patients (Gane, Zhao, et al. 2019). Ongoing studies are now evaluating TLR-8 agonists in combination with other novel therapies.