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      Considerations of the Japanese Research Working Group for the ICH S6 & Related Issues Regarding Nonclinical Safety Assessments of Oligonucleotide Therapeutics: Comparison with Those of Biopharmaceuticals

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          Abstract

          This white paper summarizes the current consensus of the Japanese Research Working Group for the ICH S6 & Related Issues (WGS6) on strategies for the nonclinical safety assessment of oligonucleotide-based therapeutics (ONTs), specifically focused on the similarities and differences to biotechnology-derived pharmaceuticals (biopharmaceuticals). ONTs, like biopharmaceuticals, have high species and target specificities. However, ONTs have characteristic off-target effects that clearly differ from those of biopharmaceuticals. The product characteristics of ONTs necessitate specific considerations when planning nonclinical studies. Some ONTs have been approved for human use and many are currently undergoing nonclinical and/or clinical development. However, as ONTs are a rapidly evolving class of drugs, there is still much to learn to achieve optimal strategies for the development of ONTs. There are no formal specific guidelines, so safety assessments of ONTs are principally conducted by referring to published white papers and conventional guidelines for biopharmaceuticals and new chemical entities, and each ONT is assessed on a case-by-case basis. The WGS6 expects that this report will be useful in considering nonclinical safety assessments and developing appropriate guidelines specific for ONTs.

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          Expression profiling reveals off-target gene regulation by RNAi.

          RNA interference is thought to require near-identity between the small interfering RNA (siRNA) and its cognate mRNA. Here, we used gene expression profiling to characterize the specificity of gene silencing by siRNAs in cultured human cells. Transcript profiles revealed siRNA-specific rather than target-specific signatures, including direct silencing of nontargeted genes containing as few as eleven contiguous nucleotides of identity to the siRNA. These results demonstrate that siRNAs may cross-react with targets of limited sequence similarity.
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            Recognizing and avoiding siRNA off-target effects for target identification and therapeutic application.

            Small interfering RNAs (siRNAs) are widely used to study gene function owing to the ease with which they silence target genes, and there is considerable interest in their potential for therapeutic applications. In a remarkably short time since their discovery, siRNAs have entered human clinical trials in various disease areas. However, rapid acceptance of the use of siRNAs has been accompanied by recognition of several hurdles for the technology, including a lack of specificity. Off-target activity can complicate the interpretation of phenotypic effects in gene-silencing experiments and can potentially lead to unwanted toxicities. Here, we describe the types of off-target effects of siRNAs and methods to mitigate them, to help enable effective application of this exciting technology.
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              Antisense oligonucleotide therapies: the promise and the challenges from a toxicologic pathologist's perspective.

              Many antisense oligonucleotides (ASOs) from several classes of molecules are currently in drug development. Despite over 20 years of pharmaceutical research, few ASOs have been marketed due to problems with clinical efficacy or preclinical toxicologic challenges. However, a number of recent developments have renewed interest in this class including the registration of mipomersen, the advent of successful screening strategies to eliminate more toxic molecules, and new understanding of the risks of off-target nucleotide binding and mitigation of potential off-target effects. Recent advances in backbone chemistries, conjugation to other moieties, and new delivery systems have allowed better tissue penetration, enhanced intracellular targeting, and less frequent dosing, resulting in fewer toxicities. While these new developments provide invigorated interest in these platforms, a few lingering challenges and preclinical/clinical toxicity issues remain to be completely resolved, including: (1) proinflammatory effects (vasculitis/inflammatory infiltrates); (2) nephrotoxicity and hepatotoxicity unrelated to lysosomal accumulation; and (3) thrombocytopenia. Recent investigative work by several laboratories have helped elucidate mechanisms for these issues, allowing a better understanding of the clinical relevance and implications of particular toxicities. It is important for toxicologists, pathologists, and regulatory reviewers to be familiar with new developments in the ASO field and their implications, as a greater number of new types of antisense molecules undergo preclinical toxicity testing.
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                Author and article information

                Journal
                Nucleic Acid Ther
                Nucleic Acid Ther
                nat
                Nucleic Acid Therapeutics
                Mary Ann Liebert, Inc., publishers (140 Huguenot Street, 3rd FloorNew Rochelle, NY 10801USA )
                2159-3337
                2159-3345
                April 2021
                25 March 2021
                25 March 2021
                : 31
                : 2
                : 114-125
                Affiliations
                [ 1 ]National Institute of Health Sciences, Kawasaki, Japan.
                [ 2 ]Pharmaceuticals and Medical Devices Agency (PMDA), Chiyoda-ku, Japan.
                [ 3 ]The Japan Pharmaceutical Manufacturers Association (JPMA), Chuo-ku, Japan.
                [ 4 ]Open Circle Partners, Kobe, Japan.
                [ 5 ]Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan.
                [ 6 ]Clinical Research and Medical Innovation Center, Hokkaido University Hospital, Sapporo, Japan.
                [ 7 ]Faculty of Pharmacy, Osaka Ohtani University, Tondabayashi, Japan.
                Author notes

                All authors are members of the Japanese Research Working Group for the ICH S6 & Related Issues (WGS6) supported by the Japan Agency for Medical Research and Development (AMED).

                [*]Address correspondence to: Yoko Hirabayashi, MD, PhD, National Institute of Health Sciences, Kawasaki 210-9501, Japan yokohira@ 123456nihs.go.jp
                Article
                10.1089/nat.2020.0879
                10.1089/nat.2020.0879
                7997717
                33470890
                51ff8f6d-0a7f-48cc-952a-4b33d119863c
                © Yoko Hirabayashi et al. 2021; Published by Mary Ann Liebert, Inc.

                This Open Access article is distributed under the terms of the Creative Commons Attribution Noncommercial License [CC-BY-NC] ( http://creativecommons.org/licenses/by-nc/4.0/) which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and the source are cited.

                History
                : Received for publication August 27, 2020
                : accepted after revision December 11, 2020
                Page count
                Figures: 4, Tables: 4, References: 65, Pages: 12
                Categories
                Issues in Development

                ich s6,biopharmaceuticals,nonclinical safety assessments,international council for harmonisation of technical requirements for pharmaceuticals for human use (ich)

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