Oligo Safety Working Group Exaggerated Pharmacology Subcommittee Consensus Document

Kornbrust, Doug; Cavagnaro, Joy A.; Levin, Arthur A.; Foy, Jeffrey W.-D.; Pavco, Pamela A.; Gamba‐Vitalo, Christina; Guimond, Alain

doi:10.1089/nat.2012.0399

Cited by 39 publications

(34 citation statements)

References 5 publications

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“…This surrogate was also included in the 2-year rat carcinogenicity study. As discussed by Kornbrust et al [28], surrogate (analog) molecules and their human drug counterparts have different nucleotide sequences and, therefore, can potentially have different toxicity profiles. This was not the case for AD-59206, at doses that resulted in reductions in serum TTR in rodents that were similar to those observed in clinical studies.…”

Section: Discussionmentioning

confidence: 99%

Nonclinical Safety Profile of Revusiran, a 1st-Generation GalNAc-siRNA Conjugate for Treatment of Hereditary Transthyretin-Mediated Amyloidosis

Sutherland

Hettinger

Chan

et al. 2020

Nucleic Acid Therapeutics

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Revusiran is a 1st-generation short interfering RNA targeting transthyretin conjugated to an N-acetylgalactosamine ligand to facilitate delivery to hepatocytes via uptake by the asialoglycoprotein receptors. Revusiran, in development for the treatment of hereditary transthyretin-mediated amyloidosis, was discontinued after an imbalance in deaths in the ''ENDEAVOUR'' phase 3 clinical trial. Nonclinical safety assessments included safety pharmacology, acute and repeat-dose toxicity, genotoxicity, and carcinogenicity. There were no effects on cardiovascular or respiratory function in monkeys after single doses of up to 100 mg/kg. No neurological effects were noted in monkeys in repeat-dose studies up to 300 mg/kg. Revusiran was well tolerated in repeat-dose mouse (weekly doses) and rat and monkey (five daily doses followed by weekly doses) toxicity studies. The no observed adverse effect level (NOAEL) in rats was 30 mg/kg based on reversible microscopic changes in liver that were accompanied by correlating elevations in clinical chemistry at higher doses. Dose-limiting toxicity was absent in monkeys, and the NOAEL was 200 mg/kg. There was no evidence of genotoxicity in vitro or in vivo at limit doses or carcinogenicity in a 2-year study in rats at doses up to 100 mg/kg. Overall, these results demonstrate that revusiran had a favorable nonclinical safety profile.

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Section: Discussionmentioning

confidence: 99%

Nonclinical Safety Profile of Revusiran, a 1st-Generation GalNAc-siRNA Conjugate for Treatment of Hereditary Transthyretin-Mediated Amyloidosis

Sutherland

Hettinger

Chan

et al. 2020

Nucleic Acid Therapeutics

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“…These drugs will be instrumental to prove the principal efficacy of the siRNA technology and gather information about required dosing, target validation, achieved level of gene expression reduction and corresponding clinical effects. Furthermore, comprehensive drug safety assessments will have implications for the whole class of siRNA therapeutics [49,50]. For making full therapeutic use of the potency of the technology, it is essential to develop modalities for expansion of the target space to other organs, tissues, and tumors.…”

Section: Sirna Therapeutics -Efficient Reduction Of Liver Targetsmentioning

confidence: 99%

Going beyond the liver: Progress and challenges of targeted delivery of siRNA therapeutics

Lorenzer

Dirin

Winkler

et al. 2015

Journal of Controlled Release

246

204

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Therapeutic gene silencing promises significant progress in pharmacotherapy, including considerable expansion of the druggable target space and the possibility for treating orphan diseases. Technological hurdles have complicated the efficient use of therapeutic oligonucleotides, and siRNA agents suffer particularly from insufficient pharmacokinetic properties and poor cellular uptake. Intense development and evolution of delivery systems have resulted in efficient uptake predominantly in liver tissue, in which practically all nanoparticulate and liposomal delivery systems show the highest accumulation. The most efficacious strategies include liposomes and bioconjugations with N-acetylgalactosamine. Both are in early clinical evaluation stages for treatment of liver-associated diseases. Approaches for achieving knockdown in other tissues and tumors have been proven to be more complicated. Selective targeting to tumors may be enabled through careful modulation of physical properties, such as particle size, or by taking advantage of specific targeting ligands. Significant barriers stand between sufficient accumulation in other organs, including endothelial barriers, cellular membranes, and the endosome. The brain, which is shielded by the blood-brain barrier, is of particular interest to facilitate efficient oligonucleotide therapy of neurological diseases. Transcytosis of the blood-brain barrier through receptor-specific docking is investigated to increase accumulation in the central nervous system. In this review, the current clinical status of siRNA therapeutics is summarized, as well as innovative and promising preclinical concepts employing tissue- and tumor-targeted ligands. The requirements and the respective advantages and drawbacks of bioconjugates and ligand-decorated lipid or polymeric particles are discussed.

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“…Many host cells, both immune and nonimmune, have a variety of receptors that can sense nucleic acids and initiate an inflammatory response . Various strategies have been developed to decrease the immunological recognition of traditional TNAs, including backbone and 2′‐OMe modification of nucleotides, as well as the removal of 5′‐triphosphates . However, the applicability of these strategies to nano‐TNAs has never been fully investigated.…”

Section: Introductionmentioning

confidence: 99%

RNA Fibers as Optimized Nanoscaffolds for siRNA Coordination and Reduced Immunological Recognition

Rackley

Stewart

Salotti

et al. 2018

Adv Funct Materials

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RNA is a versatile biomaterial that can be used to engineer nanoassemblies for personalized treatment of various diseases. Despite promising advancements, the design of RNA nanoassemblies with minimal recognition by the immune system remains a major challenge. Here, an approach is reported to engineer RNA fibrous structures to operate as a customizable platform for efficient coordination of siRNAs and for maintaining low immunostimulation. Functional RNA fibers are studied in silico and their formation is confirmed by various experimental techniques and visualized by atomic force microscopy (AFM). It is demonstrated that the RNA fibers offer multiple advantages among which are: i) programmability and modular design that allow for simultaneous controlled delivery of multiple siRNAs and fluorophores, ii) reduced immunostimulation when compared to other programmable RNA nanoassemblies, and iii) simple production protocol for endotoxin-free fibers with the option of their cotranscriptional assembly. Furthermore, it is shown that functional RNA fibers can be efficiently delivered with various organic and inorganic carriers while retaining their structural integrity in cells. Specific gene silencing triggered by RNA fibers is assessed in human breast cancer and melanoma cell lines, with the confirmed ability of functional fibers to selectively target single nucleotide mutations.

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Oligo Safety Working Group Exaggerated Pharmacology Subcommittee Consensus Document

Cited by 39 publications

References 5 publications

Nonclinical Safety Profile of Revusiran, a 1st-Generation GalNAc-siRNA Conjugate for Treatment of Hereditary Transthyretin-Mediated Amyloidosis

Nonclinical Safety Profile of Revusiran, a 1st-Generation GalNAc-siRNA Conjugate for Treatment of Hereditary Transthyretin-Mediated Amyloidosis

Going beyond the liver: Progress and challenges of targeted delivery of siRNA therapeutics

RNA Fibers as Optimized Nanoscaffolds for siRNA Coordination and Reduced Immunological Recognition

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