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From Bench to Bedside and Back: Improving the Safety of GalNAc-siRNA Conjugates Using GNA-Destabilized Seed-Pairing

ABSTRACT: From Bench to Bedside and Back: Improving the Safety of GalNAc-siRNA Conjugates Using GNA-Destabilized Seed-Pairing

PROVIDER: PRJNA767053 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR19503300.fastq.gz	Fastqsanger.gz
	SRR19503400.fastq.gz	Fastqsanger.gz
	SRR19503301.fastq.gz	Fastqsanger.gz
	SRR19503401.fastq.gz	Fastqsanger.gz
	SRR19503302.fastq.gz	Fastqsanger.gz

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From Bench to Bedside and Back: Improving the Safety of GalNAc-siRNA Conjugates Using GNA-Destabilized Seed-Pairing

Project description:Preclinical mechanistic studies have pointed towards RNAi-mediated off-target effects as a major driver of hepatotoxicity for GalNAc-siRNA conjugates. Here we demonstrate that a single glycol nucleic acid (GNA) modification can substantially reduce siRNA seed-mediated binding to off-target transcripts while maintaining on-target activity. In siRNAs with established off-target effects leading to hepatotoxicity, these Enhanced Stabilization Chemistry plus (ESC+) designs exhibit a substantially improved therapeutic window in rat. We utilized this strategy to improve the safety of ALN-HBV, which exhibited dose-dependent, transient, and asymptomatic alanine aminotransferase elevations in healthy volunteers.

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From bench to bedside: Improving the clinical safety of GalNAc-siRNA conjugates using seed-pairing destabilization.

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Overcoming GNA/RNA Base-Pairing Limitations Using Isonucleotides Improves the Pharmacodynamic Activity of ESC+ GalNAc-siRNAs

Project description:Overcoming GNA/RNA Base-Pairing Limitations Using Isonucleotides Improves the Pharmacodynamic Activity of ESC+ GalNAc-siRNAs

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Deconstruction of O-glycosylation â€“ Polypeptide GalNAc-T Isoforms Direct Distinct Subsets of the O-Glycoproteome

Project description:GalNAc-transferase (GalNAc-T) isoforms modify distinct subsets of the O-glycoproteome and GalNAc-type O-glycosylation is found on most proteins trafficking through the secretory pathway in metazoan cells. The O-glycoproteome is regulated by up to 20 polypeptide GalNAc-Ts and the contributions and biological functions of individual GalNAc-Ts are poorly understood. Here, we used a zinc-finger nuclease (ZFN)-directed knockout strategy to probe the contributions of the major GalNAc-Ts (GalNAc-T1 and T2) in liver cells, and explore how the GalNAc-T repertoire quantitatively affects the O-glycoproteome. We demonstrate that the majority of the O-glycoproteome is covered by redundancy, whereas distinct subsets of substrates are modified by non-redundant functions of GalNAc-T1 and T2. Differential transcriptomic analysis indicates that loss of function of a GalNAc-T induces specific transcriptional response. The non-redundant O-glycoproteome subsets for and the transcriptional responses for each isoform appeared to be related to different cellular processes, and for the GalNAc-T2 isoform supporting a role in lipid metabolism. The results demonstrate that GalNAc-Ts have non-redundant glycosylation functions, and that these may affect distinct cellular processes. The data provides a comprehensive resource for unique substrates for individual GalNAc-Ts. Our study provides a new view on the regulation of the O-glycoproteome, suggesting that the plurality of GalNAc-Ts arose to regulate distinct protein functions and cellular processes.

2015-09-30 | E-MTAB-3844 | biostudies-arrayexpress

Selection of well-tolerated GalNAc-conjugated siRNAs by screening for RNAi-mediated off-target effects in rodent toxicity studies

Project description:Small interfering RNAs (siRNAs) conjugated to a trivalent N-acetylgalactosamine (GalNAc) ligand are being evaluated in investigational clinical studies for a variety of indications. The typical development candidate selection process includes evaluation of the most active compounds for toxicity in rats at pharmacologically-exaggerated doses. The subset of GalNAc-siRNAs that show rat hepatotoxicity is not advanced to clinical development. Potential mechanisms of hepatotoxicity include toxicities associated with the intracellular accumulation of oligonucleotides and their metabolites, RNA interference (RNAi)-mediated hybridization-based off-target effects, and/or perturbation of endogenous RNAi pathways. Here we show that rodent hepatotoxicity observed at supratherapeutic exposures can be largely attributed to RNAi-mediated off-target effects, but not chemical modifications or the perturbation of RNAi pathways. Furthermore, these off-target effects can be mitigated by modulating seed-pairing using a thermally destabilizing chemical modification, which significantly improves the safety profile of a GalNAc-siRNA in rat and may minimize the occurrence of hepatotoxic siRNAs across species.

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Project description:This study aimed to investigate the hepatic transcriptomic effects of GalNAc-conjugated siRNA-mediated Rnf10 knockdown in vivo. Wild-type mice were maintained on a normal chow diet and treated with GalNAc-siNC or GalNAc-siRnf10 at the indicated time points. Liver tissues were collected at the end of the experiment and subjected to bulk RNA sequencing. Differential gene expression analysis was performed to identify genes and pathways altered by GalNAc-siRnf10 treatment. Seed match enrichment analysis was further used to evaluate potential off-target effects associated with the siRnf10 guide strand.

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Project description:Salmonella Typhi (STy), the causative agent of typhoid fever, preferentially infects the ileum, but the basis for this preference has remained unknown. We show that STy exploits MUC2-derived monosaccharides, such as GalNAc, to upregulate invasion and target the ileum—opposite to the response of closely related S. Typhimurium (STm), whose invasion is inhibited by MUC2. Three STy-specific extracellular residues of the outer-membrane protein OmpW (K141/T142/Q193) engage GalNAc, and a periplasmic relay through the short FepE_STy, RS12510, and TonB transmits this signal to activate the master invasion regulator HilD. Mice lacking MUC2 or gut microbiota lose STy ileal tropism, which is restored by oral GalNAc-containing monosaccharides. An OmpW triple-mutant STy strain establishes a murine oral STy infection model, identifying STy–MUC2 glycan interactions as one of the earliest steps of typhoid pathogenesis and a potential target for prevention.

2026-07-15 | GSE337718 | GEO

Transcription profiling by array to assess epidemic methicillin-resistant Staphylococcus aureus 16 phenotypes induced by PBD conjugates

Project description:Objectives Pyrrolobenzodiazepine (PBD) dimers, tethered through inert propyldioxy or pentyldioxy linkers, possess potent bactericidal activity against a range of Gram-positive bacteria by virtue of their capacity to cross-link duplex DNA in sequence-selective fashion. Here we attempt to improve the antibacterial activity and cytotoxicity profile of PBD-containing conjugates by extension of dimer linkers and replacement of one PBD unit with phenyl-substituted or benzo-fused heterocycles that facilitate non-covalent interactions with duplex DNA. Methods DNase I footprinting was used to identify high-affinity DNA binding sites. A staphylococcal gene microarray was used to assess epidemic methicillin-resistant Staphylococcus aureus 16 phenotypes induced by PBD conjugates. Molecular dynamics simulations were employed to investigate the accommodation of compounds within the DNA helix. Results Increasing the length of the linker in PBD dimers led to a progressive reduction in antibacterial activity, but not in their cytotoxic capacity. Complex patterns of DNA binding were noted for extended PBD dimers. Modelling of DNA strand cross-linking by PBD dimers indicated distortion of the helix. A majority (26 of 43) of PBD-biaryl conjugates possessed potent antibacterial activity with little or no helical distortion and a more favourable cytotoxicity profile. Bactericidal activity of PBD-biaryl conjugates was determined by inability to excise covalently bound drug molecules from bacterial duplex DNA. Conclusions PBD-biaryl conjugates have a superior antibacterial profile compared with PBD dimers such as ELB-21. We have identified six PBD-biaryl conjugates as potential drug development candidates. [Data is also available from http://bugs.sgul.ac.uk/E-BUGS-118]

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OmpW-mediated sensing of MUC2 GalNAc contributes to the ileal tropism of Salmonella Typhi [STy]

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