Annual Meeting of the Japanese Society of Toxicology
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Displaying 1-50 of 419 articles from this issue
Invited Lecture
  • Kohji NISHIDA
    Session ID: IL
    Published: 2021
    Released on J-STAGE: August 12, 2021
    CONFERENCE PROCEEDINGS FREE ACCESS

    In the conventional corneal transplantation, the shortage of donated eyes and rejection have been the main problems.

    To solve these problems, we have been developing corneal regenerative therapy using human iPS cells. Using human iPS cells, we have succeeded in developing the ocular organoid system (self-formed ectodermal autonomous multi-zone: named SEAM) that recapitulates the development of the entire eye (Nature 2016). We developed a technology for producing iPS cell-derived corneal epithelial cell sheets using this SEAM method and started first-in-human clinical research in 2019.

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Special Lecture
  • Kenneth L HASTINGS
    Session ID: SL1
    Published: 2021
    Released on J-STAGE: August 12, 2021
    CONFERENCE PROCEEDINGS FREE ACCESS

    A remarkable aspect of the otherwise terrible covid pandemic we are now experiencing is that medical technologies, both vaccine and therapeutic, had been in development that suddenly became front-line tools in public health efforts to control spread of disease and to treat victims of the infection. The messenger RNA-based vaccines have gone from experimental to game-changer in amazing time. Other therapeutics, such as monoclonal antibodies, have proven useful, although convalescent plasma remains an unproven treatment. Finally, there are drugs that have been developed and were abandoned for various reasons that are being re-examined for activity against coronaviruses. These issues will be discussed, including potential late-developing issues. When nonclinical data become available for products currently being distributed in the US under Emergency Use Authorization, these findings may be compared with clinical experience to assess the risk of expedited product development in the context of a global public health emergency.

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  • Masashi YANAGISAWA
    Session ID: SL2
    Published: 2021
    Released on J-STAGE: August 12, 2021
    CONFERENCE PROCEEDINGS FREE ACCESS

    Although sleep is a ubiquitous behavior in animal species with central nervous systems, the neurobiology of sleep remain mysterious. Our discovery of orexin, a hypothalamic neuropeptide involved in the maintenance of wakefulness, has helped reveal neural pathways in the regulation of sleep/wakefulness. Orexin receptor antagonists, which specifically block the endogenous waking system, have been approved as a new drug to treat insomnia. Also, since the sleep disorder narcolepsy-cataplexy is caused by orexin deficiency, orexin receptor agonists are expected to provide mechanistic therapy for narcolepsy; they will likely be also useful for treating excessive sleepiness due to other etiologies.

    Despite the fact that the executive neurocircuitry and neurochemistry for sleep/wake switching has been increasingly revealed in recent years, the mechanism for homeostatic regulation of sleep, as well as the neural substrate for "sleepiness" (sleep need), remains unknown. To crack open this black box, we have initiated a large-scale forward genetic screen of sleep/wake phenotype in mice based on true somnographic (EEG/EMG) measurements. We have so far screened >10,000 heterozygous ENU-mutagenized founders and established a number of pedigrees exhibiting heritable and specific sleep/wake abnormalities. By combining linkage analysis and the next-generation whole exome sequencing, we have molecularly identified and verified the causal mutations in several of these pedigrees. Biochemical and neurophysiological analyses of these mutations are underway. Indeed, through a systematic cross-comparison of the Sleepy mutants (with a gain-of-function change in a serine/threonine kinase pathway) and sleep-deprived mice, we have found that the cumulative phosphorylation state of a specific set of mostly synaptic proteins may be the molecular substrate of sleep need.

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  • Brett D HOLLINGSHEAD, Nasir KHAN, Maik SCHULER, Zaher RADI
    Session ID: SL3
    Published: 2021
    Released on J-STAGE: August 12, 2021
    CONFERENCE PROCEEDINGS FREE ACCESS

    Nonclinical development strategies for drugs intended to be administered clinically by the topical route are generally well defined and follow principles outlined in ICH guidelines. There are, however, some additional considerations for topical drug development compared to those administered via the oral route regarding both hazard identification and risk assessment approaches. For topical drug development, the minipig is the standard nonclinical non-rodent model that is more relevant to humans and used to characterize local skin effects because of the overall similarity to human skin anatomy and physiology, while the rodent species is utilized to understand systemic risks and has limited value for understanding local skin effects since rodent skin is anatomically and functionally dissimilar to humans. Risk assessment approaches to clearly define a threshold-based toxicity in skin can be complicated by the absence of validated tools to routinely and accurately model or measure drug concentrations at specific anatomic locations within the skin, and therefore reliance on species with comparable physiology, such as minipig, is required for extrapolations based on applied dose. Exploratory methods exist for measuring drug concentrations in deep dermis of skin but understanding bioavailable concentrations of topically applied drugs closer to the site of application in the viable epidermis, the stratum basale, are not validated. This presentation will discuss challenges associated with the conduct and interpretation of topical carcinogenicity studies in rodents. Emphasis will be on the characterization and positioning of potential risk for drugs that are aneugenic in vitro but not in vivo. The presentation will offer scenarios that involve compounds with existing comprehensive systemic nonclinical data packages including oral rodent carcinogenicity data for which conduct of additional topical carcinogenicity studies in rodents may not be warranted or scientifically justified, especially considering the 3Rs. In addition, exploratory experimental data from EpiDermTM in vitro micronucleus assay will be presented as a hazard identification tool of aneugens and how it compares to the physiologically relevant in vivo minipig model.

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Educational Lecture
  • Tsukasa SEYA, Misako MATSUMOTO
    Session ID: EL1
    Published: 2021
    Released on J-STAGE: August 12, 2021
    CONFERENCE PROCEEDINGS FREE ACCESS

    We have developed a new Toll-like receptor 3-specific adjuvant, named ARNAX, which specifically stimulates dendritic cells (DCs), and enables us to prime DCs safely without inflammation. Thus, administration of ARNAX with antigens in hosts guarantees antigen-specific CTL proliferation without cytokine toxicity. ARNAX consists of GpC DNA-cap and 120mer dsRNA, and targets TLR3 in DCs. We have established the strategy for a large-scale synthesis of ARNAX and defined its function for DC-priming without inflammation. Thus, immune-enhancing occurs independent of inflammation in hosts.

    In mouse tumor-implant models, immunotherapy with ARNAX and exogenous tumor antigen efficiently induces regression of various implant tumors and prolonged survival time. Even without identification of tumor antigen, combination therapy with ARNAX and PD-1/L1 Ab additively induces proliferation of tumor-specific CTLs and their infiltration into tumor tissues, leading to enhanced tumor regression and prolonged survival. Non-inflammatory tumor vaccine would be feasible using ARNAX.

    Adjuvants usually harbor cytokine toxicity, which is a great barrier against vaccine approval. There are a number of prophylactic vaccines against viral infectious diseases. Here we offer an ideal recipe of harmless adjuvant for vaccines against infectious diseases as well as cancers. We are obtaining non-clinical POC on ARNAX plus antigen in prophylactic vaccines against viral infections. We are planning toxicity and safety tests to make a protocol for the clinical test for POC in patients with cancer.

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  • Judith PRESCOTT
    Session ID: EL2-1
    Published: 2021
    Released on J-STAGE: August 12, 2021
    CONFERENCE PROCEEDINGS FREE ACCESS

    Proposed streamlined development approaches for vaccines for SDLT indications and non-oncology SDLT small molecule therapeutics will be presented. For therapeutics, this proposed approach would allow rapid initiation of patient trials and continued treatment beyond the conclusion of the early therapeutic studies regardless of availability of nonclinical safety data, as well as elimination or deferment of nonclinical studies that are not considered essential to supporting patient safety given the high unmet medical need. This approach would allow patients with SDLT conditions earlier and continued access to therapeutics and increase the speed of progression through development. For both therapeutics and vaccines, these approaches would enable an early understanding of potential efficacy and allow patients or participants, in conjunction with their physicians, to make more informed decisions regarding potential initiation and/or continuation of treatment in the context of benefit versus risk considerations. This may additionally increase the SDLT indication therapeutic pipeline, directly benefiting patients and reducing the economic and societal burden of SDLT conditions.

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  • Robert W. AMLER
    Session ID: EL2-2
    Published: 2021
    Released on J-STAGE: August 12, 2021
    CONFERENCE PROCEEDINGS FREE ACCESS
  • Takanori TAKEBE
    Session ID: EL3
    Published: 2021
    Released on J-STAGE: August 12, 2021
    CONFERENCE PROCEEDINGS FREE ACCESS

    Organoids are multicellular structures that can be derived from adult organs or pluripotent stem cells. Early versions of organoids range from simple epithelial structures to complex, disorganized tissues with large cellular diversity. The current challenge is to engineer cellular complexity into organoids in a controlled manner that results in organized assembly and acquisition of tissue function. These efforts have relied on studies of organ assembly during embryonic development and have resulted in development of organoids with multilayer tissue complexity and higher order functions. Coupled with patient-derived stem cells, my group studied the mechanisms of human hepatic organogenesis and pathogenesis that includes viral hepatitis, steatohepatitis, recently extended to drug induced liver injury (DILI), wherein organoid modelled the clinical phenotype and genotype are correlated. Here I will summarize the next generation of organoid-by-design, and discuss its promise and impact to elucidate personalized disease mechanisms and understand drug reactions underlying individual variations in humans.

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  • Sunao MANABE
    Session ID: EL4
    Published: 2021
    Released on J-STAGE: August 12, 2021
    CONFERENCE PROCEEDINGS FREE ACCESS

    Patient Centricity (PC) is a concept that relevant stakeholders should “always focus on Patients, take Patient focused action, and respect the Patient’s own judgment." PC activities in drug development include the preparation of protocol or other documents that incorporate Patient Voice, utilization of patient-reported outcomes, sharing of clinical trial results with patients, or in-house patient lectures. One of the role of toxicology in PC activities is to provide patient-sought safety information in an easy-to-understand manner. Involvement of toxicology in PC activities will be discussed.

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  • Stephanie Leuenroth QUINN
    Session ID: EL5-1
    Published: 2021
    Released on J-STAGE: August 12, 2021
    CONFERENCE PROCEEDINGS FREE ACCESS

    The Coronavirus Treatment Acceleration Program (CTAP) has been created by the US Food and Drug Administration during the COVID-19 public health emergency. Guidance documents have been created to facilitate the development of possible therapies and provide streamlined processes for feedback during this pandemic. It is recommended that sponsors seek initial advice under a Pre-Investigational New Drug (pre-IND) meeting request for investigational uses of unapproved drugs as well as for new indications of US FDA–approved drugs; therefore, the Center for Drug Evaluation and Research (CDER) has established a COVID-19 scientific triage team to ensure the completeness and sufficiency of the information provided by sponsors for expedited review by the Agency. Discussion of what constitutes a complete package for IND review, case studies, and related challenges will be presented from a nonclinical perspective.

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  • Stephanie Leuenroth QUINN
    Session ID: EL5-2
    Published: 2021
    Released on J-STAGE: August 12, 2021
    CONFERENCE PROCEEDINGS FREE ACCESS

    This talk will present the submission review process and will discuss the 30-day IND Integrated Assessment and the new review process of Integrated NDA/BLA Review within the Office of New Drugs (OND).

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  • Atsushi TAKEDA
    Session ID: EL6
    Published: 2021
    Released on J-STAGE: August 12, 2021
    CONFERENCE PROCEEDINGS FREE ACCESS

    Alzheimer’s disease (AD) and Parkinson’s disease (PD) are linked with age-related intracellular Zn2+ dysregulation induced by rapid influx of extracellular Zn2+. Zn-amyloid β1-42 (Zn-Aβ1-42) complexes formed in the extracellular fluid are synaptic activity-independently taken up into neurons, followed by rapid intracellular Zn2+ dysregulation. In PD, on the other hand, a unique mechanism of nigral dopaminergic degeneration, in which rapid intracellular Zn2+ dysregulation mediated with hydrogen peroxide causes PD in rats, which is induced by paraquart and 6-hydroxydopamine. I will talk about novel defense strategy against neurodegeneration via intracellular Zn2+ dysregulation.

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  • Tatsuhiko KODAMA
    Session ID: EL7
    Published: 2021
    Released on J-STAGE: August 12, 2021
    CONFERENCE PROCEEDINGS FREE ACCESS

    The new coronavirus mutates about 24 out of the 30,000 base sequences in one year. It is a relatively stable RNA virus. Viruses with new mutations are selected about every three months, and the number of infected people rises, then decrease due to self-destruction may happen, drawing a wave.

    As a mechanism to create this periodicity, selections are mediated by multi-scale of interactions such as molecular level, host immunity, social isolation and treatment, and zoonotic infections with animals. The pandemic is expected to end in the next few years.

    The problem is that with each wave, the number of carriers of a virus called basic clade, which has a relatively stable origin, increases at the epicenter, and mutant strains are produced from there. Of particular concern is the increase in vaccine-resistant viruses that reduce susceptibility and causes prolonged pandemic.

    I would like to consider a countermeasure to end the coronavirus pandemic from the view point of the mechanism generating periodicity.

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  • David R WOOLLEY
    Session ID: EL8
    Published: 2021
    Released on J-STAGE: August 12, 2021
    CONFERENCE PROCEEDINGS FREE ACCESS

    Computational or in silico toxicology is a broad and emerging field of toxicology. Quantitative Structural Activity Relationship ((Q)SAR) models are increasingly being used to identify hazards, assist in risk assessment, occupational banding assignments, early drug development and, ultimately, as a new test system for de novo evaluation of substances of interest. Acceptance of in silico is evident in the ICH M7 guidance on the assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals and, coupled with judicious use of read across and expert assessment these methods are increasingly used to supplement predictions from in vitro and in vivo test systems. This talk will aim to explore the basic background and history of computational toxicology, the advantages, and limitations of such tools, the current regulatory environment and acceptance of QSARs and potential future uses and applications.

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Symposium 1
  • Hideyuki NAKASHIMA, Kinichi NAKASHIMA
    Session ID: S1-1
    Published: 2021
    Released on J-STAGE: August 12, 2021
    CONFERENCE PROCEEDINGS FREE ACCESS

    Rett syndrome (RTT) is a neurodevelopmental disorder caused by methyl-CpG binding protein 2 (MECP2) mutations and accumulating evidence suggest that dysfunction of non-neuronal cells also participates in the RTT. We here report that the number of activated microglia is increased in the hippocampus of MeCP2 knock-out (KO) mice. This activation was suppressed in DNA recognizing Toll-like receptor 9 (TLR9) gene heterozygous MeCP2KO mice associated with attenuation of RTT phenotype observed in MeCP2KO mice. Thus, endogenous DNA may pertain to the RTT pathogenesis through microglial activation.

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  • Hiroyuki TAKEDA
    Session ID: S1-2
    Published: 2021
    Released on J-STAGE: August 12, 2021
    CONFERENCE PROCEEDINGS FREE ACCESS

    After fertilization, the epigenetic modification of a zygote undergoes drastic erasure and re-establishment to acquire totipotency and/or pluripotency. So far, detailed analyses of reprograming of histone modifications have been done mainly in mammals. In the present study, we quantitatively validated the epigenetic reprogramming of histone modifications in medaka embryos by conducting quantitative ChIP-seq (spike-in ChIP-seq), and found that all modifications are erased more or less after fertilization, but that H3K27ac, H3K27me3 and H3K9me3 largely or partially escape erasure.

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  • Kenichiro HATA
    Session ID: S1-3
    Published: 2021
    Released on J-STAGE: August 12, 2021
    CONFERENCE PROCEEDINGS FREE ACCESS

    The epigenome, a chemical modification of the genome, plays an important role in development, differentiation, and subsequent homeostasis, and is also known to change under the influence of the environment. Furthermore, the epigenome is also known to be affected by environmental changes. As a result, inappropriate changes in the epigenome may predispose to disease as well as genomic mutations. In addition, since the epigenome is stably transmitted over a long period of time, there is concern that an inappropriate environment during the fetal or neonatal period may lead to disease risk in adulthood. From this perspective, the DOHaD theory (Developmental Origins of Health and Disease) has been proposed, and intergenerational (from mother to fetus) or intragenerational (from parents or grandparents to germline) epigenetic changes are being studied using model organisms. In humans, on the other hand, the genome has been altered. On the other hand, in humans, epigenomic diversity exists as well as genomic diversity, and it is not easy to identify true epigenetic changes due to organ-specific differences and epigenetic clock (age in terms of epigenetic status). We collected and analyzed biological samples of infants exposed to various environments (e.g., maternal thinness or obesity during pregnancy, pregnancy complications, premature birth) to investigate the relationship between inappropriate environments and epigenetic changes in human fetal and neonatal life. In these cases, changes in DNA methylation were observed, but the changes were not necessarily concentrated in specific genetic regions, but occurred in random regions. In addition, by tracking preterm infants over time, it was possible to identify the epigenetic clock of preterm infants, but in some cases, the epigenetic clock was often not altered in regions involved in development and differentiation (the immature state left during preterm birth). Recently, some attempts to artificially change the epigenetic clock have been reported. I will give an overview of the environmental epigenetic changes observed in humans, including our data.

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  • Kenji TAKI
    Session ID: S1-4
    Published: 2021
    Released on J-STAGE: August 12, 2021
    CONFERENCE PROCEEDINGS FREE ACCESS

    For safety assessment of epigenetic drugs, indirect effects associated with changes in gene expression should be considered in addition to the direct effects of DNA methylation, demethylation and histone-modification. For example, the impact on the next generation and the long-term effects such as carcinogenicity would be pointed out.

    Following last year's presentation, this presentation will discuss the development of epigenetic drugs in some diseases other than anticancer drugs and introduce the issues that should be considered in future safety assessments of epigenetic drugs.

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  • Ryuichi ONO
    Session ID: S1-5
    Published: 2021
    Released on J-STAGE: August 12, 2021
    CONFERENCE PROCEEDINGS FREE ACCESS

    Recent findings reveal that there are exosomes, secreted from cells, are circulating in the blood.

    In this study, comprehensive sequencing of exosome-associated small RNAs for male C57BL/6J mice orally dosed with chemical substances and drugs were carried out. As a results, novel transcripts including novel miRNAs were identified as hepatotoxicity biomarkers. The liquid biopsy by using exosome-associated miRNA as biomarkers would accelerate a rapid safety evaluation of chemical substances and drugs.

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Symposium 2
  • Yasuhiro KAZUKI
    Session ID: S2-1
    Published: 2021
    Released on J-STAGE: August 12, 2021
    CONFERENCE PROCEEDINGS FREE ACCESS

    The development of vectors for expressing genes in mammalian cells and animals has not only been a tool for analyzing gene functions, but also has played an important role in industrial and medical applications. In the conventional transgenic technology, the DNA that can be introduced is usually limited to several hundred kb, and it has been impossible to introduce genes or gene clusters having a size exceeding 1 Mb. To solve these problems, we used chromosome engineering technology to develop human artificial chromosomes (HAC) and mouse artificial chromosomes (MAC) that can introduce large human genes, multiple human genes in a stable manner. In this presentation, we will introduce new drug discovery tools (fully human antibody-producing animal containing human Ig locus, mouse/rat expressing human drug metabolism, etc.) developed by HAC/MAC technology, and further introduce new combined technologies of DNA synthesis and HAC/MAC.

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  • Arata HONDA
    Session ID: S2-2
    Published: 2021
    Released on J-STAGE: August 12, 2021
    CONFERENCE PROCEEDINGS FREE ACCESS

    Jichi Medical University has been focusing on the use of laboratory pigs in medical research and education. One of these efforts was the establishment of the Center for Advanced Medical Technology Development. The Center was established in 2009 to support the development of advanced medical technology and surgical techniques and training using large animals, especially pigs. Recently, there has been a growing demand for the practical application of basic research, especially in medical research. Animal experiments are indispensable for the practical application of new medical technologies, and it is common to first obtain a proof-of-concept in mice and rats. However, this is not always sufficient, and in many cases, it is necessary to verify the efficacy and safety using larger animals. In particular, the Center is conducting research using laboratory pigs to translate the research results obtained in vitro and in mice to humans, as well as research on the practical application of these results. The research projects are open to the public from all over Japan. In this lecture, we will introduce the outline of our center and the medical research conducted using pigs.

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  • Chise TATENO
    Session ID: S2-3
    Published: 2021
    Released on J-STAGE: August 12, 2021
    CONFERENCE PROCEEDINGS FREE ACCESS

    We developed chimeric mice whose livers were repopulated with human hepatocytes (HHs) (PXB-mice). Recently, there have been advances in the development of oligonucleotide therapeutics and antibody drugs. Because the drug targets are human specific, PXB-mice would be useful in predicting the safety of these drugs in humans. Human hepatocytes propagate approximately 1000-fold in the body of PXB-mice, and approximately 200 million HHs (PXB-cells) can be obtained from a PXB-mouse. In this symposium, we demonstrate the use of PXB-mice or PXB-cells to predict liver toxicity in humans.

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  • Tomoya YAMADA
    Session ID: S2-4
    Published: 2021
    Released on J-STAGE: August 12, 2021
    CONFERENCE PROCEEDINGS FREE ACCESS

    Phenobarbital (PB) produced liver tumors in rodents. Epidemiological studies have found no causal links between PB and human liver tumors. The constitutive androstane receptor (CAR)-mediated mode of action (MOA) for PB-induced rodent liver tumor formation has been established, and increased hepatocyte proliferation represents an essential preneoplastic key event in carcinogenesis. We have demonstrated that PB stimulates proliferation in cultured rat hepatocytes but not in cultured human hepatocytes. However, in the genetically humanized CAR and pregnane X receptor (PXR) mouse (hCAR/hPXR mouse, down-stream genes are still mouse), PB increased hepatocyte proliferation and tumor production in vivo. In contrast to hCAR/hPXR mouse, chimeric mice with human hepatocytes (both receptor and down-stream genes are human) revealed that PB did not increase human hepatocyte proliferation in vivo. As PB increased rat hepatocyte proliferation in the chimeric mouse with rat hepatocytes, lack of proliferation of human hepatocytes in the chimeric mouse is not due to any functional problem in the chimeric mouse liver environment. Global gene expression analysis demonstrated that down-stream genes of CAR/PXR are similar between the hCAR/hPXR mouse and CD-1 mouse. The findings strongly support that the MOA for CAR activator-induced rodent liver tumor formation was considered to be qualitatively not plausible for humans, which is supported by the negative epidemiology. Based on our research, the chimeric mouse with human hepatocytes is reliable for human cancer risk assessment of test compounds.

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Symposium 3
  • Masayuki MISHIMA
    Session ID: S3-1
    Published: 2021
    Released on J-STAGE: August 12, 2021
    CONFERENCE PROCEEDINGS FREE ACCESS

    Ames test has long been the central position of genotoxicology assessment, which provided the traditional concept of classification of carcinogens into genotoxic and non-genotoxic ones. However, tumors generated by non-genotoxic carcinogens also have many mutations. Alterations of some factors involved in epigenetic repression increased mutations in some tumors. These alterations, non-DNA damage responses, cannot be detected by the standard test battery of genotoxicity assessment. Toxicologists need to update genotoxicity assessment. Here, I’ll discuss what we can do for next generation genotoxicology that may include QSAR and a view of genomic instability.

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  • Tetsuya SUZUKI
    Session ID: S3-2
    Published: 2021
    Released on J-STAGE: August 12, 2021
    CONFERENCE PROCEEDINGS FREE ACCESS

    DNA damages induce mutations, resulting in biological effects such as cancers. Organisms equip various defense systems against DNA damages. To understand the mechanisms of mutagenesis, we need to know the relationships between the defense systems and mutagenesis by the damages. Genetic modification is useful approach to know the roles of defense systems against mutagenesis by DNA damages.

    In this symposium, I will introduce application of genetically modified cells in molecular mechanism studies for mutation control with a focus on the results using DNA polymerase ζ gene-modified cells.

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  • Ryoko ARAKI, Yuko HOKI, Tomo SUGA, Misato SUNAYAMA, Kaori IMADOME ...
    Session ID: S3-3
    Published: 2021
    Released on J-STAGE: August 12, 2021
    CONFERENCE PROCEEDINGS FREE ACCESS

    There are great expectations for iPS cells as resources for regenerative medicine, and several clinical trials using iPSCs are already underway. However, some critical concerns still remain; genetic aberrations in iPS cells and their derivatives can cause immunogenicity and tumorigenicity. So far, we have focused on the genome instability, especially on point mutations, in reprogrammed pluripotent stem cells, iPSCs and ntESCs. Here we will discuss the genome reprogramming-associated genetic aberrations and the molecular mechanisms behind them, and we also report on an iPS cell system with a remarkable decrease in mutation frequency.

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  • Kei-ichi SUGIYAMA
    Session ID: S3-4
    Published: 2021
    Released on J-STAGE: August 12, 2021
    CONFERENCE PROCEEDINGS FREE ACCESS

    Epigenetic mechanisms play an important role in transcriptional regulation through modification of chromatin structure, and disruption of epigenetic processes can lead to cancer. DNA methylation is a major epigenetic mechanism that can affect FLO1-associated flocculation of yeast transformed with DNA methyltransferase genes. We named the method measuring flocculation and the gene promoter activity as FLO assay. This assay raises the possibility that the mycotoxin Ochratoxin A downregulated DNA methylation. Our results could allow us to discuss safety issues regarding genomic instability.

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  • Ayako FURUHAMA, Kei-ichi SUGIYAMA, Masamitsu HONMA
    Session ID: S3-5
    Published: 2021
    Released on J-STAGE: August 12, 2021
    CONFERENCE PROCEEDINGS FREE ACCESS

    The QSAR models for predicting Ames mutagenicity need the more predictive power to use the regulatory purposes. Previously, DGM/NIHS has conducted the first AMES/QSAR International Challenge Project to validate and improve QSAR tools for predicting Ames mutagenicity of chemicals. More than 10,000 Ames data which are collected under the Japanese Industrial Safety and Health Act were provided to the participants to improve their QSAR models for predicting Ames mutagenicity. Here, we presented the overview of the second project and the agenda for building Ames database.

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  • Shigeharu MUTO
    Session ID: S3-6
    Published: 2021
    Released on J-STAGE: August 12, 2021
    CONFERENCE PROCEEDINGS FREE ACCESS

    In drug discovery and development, structure-activity relationships (SAR) is sometimes used to avoid structures that are clearly predicted to be mutagenic in the early stages of discovery or to predict mutagenicity as part of the toxicity assessment of metabolites and impurities. For impurities in particular, the use of (Q)SARs has been recommended since the EMA guideline "Guideline on the Limits of Genotoxic Impurities" in 2006 and the FDA draft guidance " Genotoxic and Carcinogenic Impurities in Drug Substances and Products: Recommended Approaches" in 2008 were published, and this practice was globally harmonized following the implementation of the ICH M7 guideline in 2014.

    Commercial mutagenicity global (Q)SAR models based on big data are commonly used for mutagenicity prediction. New database construction and data sharing have been promoted to improve prediction accuracy, but there are compound groups such as "Aromatic amines" for which improvement of prediction accuracy is difficult. Aromatic amines are widely used as intermediates in the synthesis of drugs, but the metabolic hydrolysis of candidate compounds synthesized by linking carboxylic acid parts with amide bonds may result in the formation of Ames-positive aromatic amines as metabolites, which poses a challenge in drug development.

    We have developed a prediction model based on the nitrenium ion hypothesis, which is a well-known mechanism of aromatic amine mutagenicity induction. In the evaluation using our compounds, the prediction accuracy was better than that of commercial prediction models, and it was confirmed that the model is useful for selecting compounds in the early stage of drug discovery. We also would like to discuss the possibility of using this model to quantitatively support the substituent effects of aromatic amine mutagenicity in an expert review of mutagenicity prediction based on ICH M7 that has been qualitatively evaluated to date.

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Symposium 4
  • Li-Chi HSIEH, Ayano NODA, Nikko ADHITAMA, Yasuhiko KATO, Hajime W ...
    Session ID: S4-1
    Published: 2021
    Released on J-STAGE: August 12, 2021
    CONFERENCE PROCEEDINGS FREE ACCESS

    Daphnia magna has long been used to assess toxicity in environmental waters. However, there have been limited approaches to study the mechanisms how the chemicals affect Daphnia magna and cause adverse effect. In particular, it has been difficult to distinguish between general toxicity and endocrine disruption because changes in the molting interval, which is an indicator of the adverse effect of crustaceans, are not only observed in exposure to endocrine disrupting chemicals with activity such as molting hormone and juvenile hormone, but also in general toxic effects.

    To distiquish these adverse effects, we have developed a system to detect hormonal activities by the use of Daphnia manga. A reporter gene under the control of the molting hormone receptor or the juvenile hormone receptor was introduced into Daphnia genome by the genome editing technique. These genome-edited Daphnia magna not only responded to endogenous hormones, but also to chemical substances with hormone-like activity in environmental water and emitted fluorescence, indicating the possibility of using them for monitoring environmental water.

    It has been known that Daphnia magna exposed to juvenile hormone-like chemicals at a specific period produce males. In this study, we also found that the number of offspring was decreased when Daphnia is exposed to juvenile hormone-like chemicals. This finding suggests that the juvenile hormone regulates the population size, which is a new aspect of reproductive toxicity and may lead to the elucidation of the toxicological mechanism of hormone-like chemicals.

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  • Hiroyuki KOJIMA, Atsuhito KUBOTA, Masaru TERASAKI, Ryuta MUROMOTO, ...
    Session ID: S4-2
    Published: 2021
    Released on J-STAGE: August 12, 2021
    CONFERENCE PROCEEDINGS FREE ACCESS

    Benzotriazole UV stabilizers (BUVSs) are widely used as additives of various materials, including plastics, to prevent from UV-irradiation. In this study, we investigated the toxicological effects of BUVSs via the aryl hydrocarbon receptor (AhR). The cell-based transactivation assay and in silico analysis revealed that some BUVSs interact with AhR ligand binding domain and activate AhR. In addition, oral treatment of C57BL/6N mice with these compounds significantly increased the proportion of CD4+ Foxp3+ regulatory T cells (Tregs) in the spleen. These findings suggest that some BUVSs might induce Tregs through AhR activation and act as immunosuppressive modulators.

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  • Tsuyoshi NAKANISHI
    Session ID: S4-3
    Published: 2021
    Released on J-STAGE: August 12, 2021
    CONFERENCE PROCEEDINGS FREE ACCESS

    Although androgens are important factors for formation of sex-specific reproductive organs, etc, many environmental chemicals with potential androgen antagonism have been found in recent years. However, there are some problems with toxicity tests for androgen-dependent toxicity, since knowledge of endpoints dependent on androgen action is still insufficient. To solve the problem, we established transgenic mice that overproduce androgens from the fetal period and attempted to identify the endpoints for androgen-dependent toxicity. In my talk, I will introduce the androgen-dependent endpoints we have found and propose a novel testing method for androgen-dependent toxicity.

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  • Ryota SHIZU, Kouichi YOSHINARI
    Session ID: S4-4
    Published: 2021
    Released on J-STAGE: August 12, 2021
    CONFERENCE PROCEEDINGS FREE ACCESS

    Activation of the nuclear receptor constitutive androstane receptor (CAR) induces hepatocyte proliferation and liver carcinogenesis in rodents. However, its mechanisms are still unknown. Besides, it is well known that CAR-dependent hepatocyte proliferation and liver tumorigenesis are not observed in humans. We have been investigating the molecular mechanism and the species differences, and found an involvement of yes-associated protein (YAP), which is known as a liver cancer inducer, in the CAR-induced hepatocyte proliferation in rodents. In this presentation, I will introduce our recent progress on this topic by focusing on the interaction between CAR and YAP.

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Symposium 5
  • Ken J ISHII
    Session ID: S5-1
    Published: 2021
    Released on J-STAGE: August 12, 2021
    CONFERENCE PROCEEDINGS FREE ACCESS

    Preventive vaccines have been one of the most successful medical technologies since their invention through to the present day. The pathogens that cause infections in humans include parasites, protozoans (eukaryotic unicellular microorganisms), fungi (molds), bacteria, and viruses. The COVID-19 virus causing so many problems today is a member of the coronavirus family, which also includes the common cold, severe acute respiratory syndrome (SARS), and Middle East respiratory syndrome (MERS). The pandemic caused by this novel coronavirus has highlighted anew the importance and urgency of vaccine research.

    New types of vaccines are currently emerging, and vaccinations are being administered at a hitherto-unprecedented speed especially the ones made by mRNA and Adenovirus as new modalities of vaccine platform. In particular, nucleic acid such as DNA and RNA as vaccine platforms to create mock-up vaccines in advance would enable the optimal vaccine to be produced swiftly by introducing into them a modularized antigen tailored to the pathogen concerned. Potential issues in regulation of such new modality will be discussed.

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  • Yumiko NOMURA, Kiyohito NODA, Yuusuke OOHASHI, Mayumi SHIKANO
    Session ID: S5-2
    Published: 2021
    Released on J-STAGE: August 12, 2021
    CONFERENCE PROCEEDINGS FREE ACCESS

    Vaccines for the prevention of infectious diseases are characterized by the fact that they exert their efficacy through the induction of an immune response, and therefore, non-clinical study guidelines for ordinary drugs are not always applicable. In Japan, the concept was presented in 2010 by the "Guidelines for Non-clinical Studies of Vaccines for the Prevention of Infectious Diseases" (May 27, 2010), but the development environment for vaccines has changed in recent years, and the need for revision of guidelines was recognized.

    In a questionnaire survey of companies on difficulties in vaccine development, it was pointed out that the necessity of a systemic exposure toxicity study when adding a new route of administration and criteria for determining whether a safety pharmacology study is necessary in terms of non-clinical studies. To address these issues, we surveyed the status of developed products by review reports and compared domestic and overseas guidelines.

    With regard to the additional routes of administration, for the seven products that could be administered both intramuscularly and subcutaneously, repeated-dose toxicity studies were conducted for only one route of administration, while local irritation studies were conducted for both routes. The WHO guidelines also provided specific points to keep in mind when developing alternative routes, such as the effects of intranasal administration on the brain and nervous system.

    With regard to safety pharmacology studies, the domestic guidelines required that safety pharmacology endpoints could be assessed in advance by other toxicity studies, whereas the WHO guidelines stated that such studies should be conducted when there was concern about effects on physiological functions in other studies. Reflecting this difference, the rate of safety pharmacology studies was higher for vaccines developed only in Japan than for vaccines also developed overseas.

    Based on these results, we proposed that a systemic exposure toxicity study is not necessarily required for all routes of administration, and that safety pharmacology studies can be evaluated in other non-clinical safety studies. With regard to vaccines, it is important that new vaccines are introduced in Japan without delay. In order to prevent non-clinical trials from being redone due to differences in guidelines, we proposed revisions based on international consistency of requirements.

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  • Kazushige MAKI
    Session ID: S5-3
    Published: 2021
    Released on J-STAGE: August 12, 2021
    CONFERENCE PROCEEDINGS FREE ACCESS

    As a result of the pandemic of SARS-CoV-2 infectious disease (COVID-19), more than one hundred million people have been affected worldwide to date. To prevent its spread, COVID-19 vaccines are being developed using various modalities such as inactivated virus vaccines, mRNA vaccines and virus-based vector vaccines. The PMDA has taken several actions to facilitate vaccine development, and we recently revealed, “Principles for the Evaluation of Vaccines Against the Novel Coronavirus SARS-CoV-2” that presents our basic principles concerning the efficacy and safety evaluation of COVID-19 vaccines in Japan. This session will discuss our perspective on non-clinical assessment for the COVID-19 vaccine.

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  • Satoshi TSUNODA
    Session ID: S5-4
    Published: 2021
    Released on J-STAGE: August 12, 2021
    CONFERENCE PROCEEDINGS FREE ACCESS

    With the outbreak of SARS-CoV-2, there is a need for rapid IND and NDA for drugs against COVID-19. The development of the drugs needs to consider the administration to a wide range of COVID-19 patients in a short period of time and limited clinical trials. In addition, the weight of non-clinical safety studies is higher in the consideration of human safety compared to normal drug development, and it is necessary to be flexible in conducting studies. We will focus on the issues that PMDA considers particularly important in the development of therapeutic agents for COVID-19 from the viewpoint of non-clinical safety evaluation.

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Symposium 6
  • Myrtle DAVIS
    Session ID: S6-1
    Published: 2021
    Released on J-STAGE: August 12, 2021
    CONFERENCE PROCEEDINGS FREE ACCESS

    CRISPR is an acronym for Clustered Regularly Interspaced Short Palindromic Repeat that refers to the unique organization of short, partially palindromic repeated DNA sequences found in the genomes of bacteria and other microorganisms. Since that discovery, CRISPR-Cas9 is recognized as a powerful and flexible functional genomic screening approach that can be employed to provide mechanistic insight and advance or capabilities in toxicology. CRISPR is known for its role in gene editing and Toxicologists most often employ this technology to modulate gene expression in mechanistic investigations. When CRISPR is used as a modality to treat disease, the challenge for toxicologists in characterization of potential on-and off-target toxicities and informing human safety risks that may be caused by these unique treatments are significant. In this introductory segment, various methods and strategies that have evolved since the discovery of this special bacterial defense system will be discussed. The use of CRISPR for investigative work in toxicology, assay development and the challenges CRISPR-based therapies pose for toxicologists will also be reviewed. Last, an overview of some of the current challenges and potential for CRISPR in toxicology will be outlined to bridge to the main talks in the session.

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  • Jeff WILLY
    Session ID: S6-2
    Published: 2021
    Released on J-STAGE: August 12, 2021
    CONFERENCE PROCEEDINGS FREE ACCESS

    Drug Induced Liver Injury (DILI) is a major contributor to the overall clinical occurrence of acute liver failure (ALF), often leading to early termination of clinical trials, post-marketing drug withdrawals, and the need for liver transplantation, and compound-specific causality is not always clear. Despite a recent pivot toward utilization of in vitro tools for early safety assessment, nonclinical safety studies are still utilized to predict clinical liabilities for new drugs. However, recent advancements in genome editing coupled with network-based approaches in toxicogenomics allow new insight to explore relationships from molecular/cellular level to pathological changes occurring at the organ in preclinical studies. Here, we will focus on recent investigations utilizing an integrated systems biology toolkit consisting of CRISPR/Cas9 and toxicogenomics to reduce uncertainty for both adaptive and progressive changes in the liver during early safety assessment as well as implications for new therapeutics.

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  • Naoki YAMAMOTO, Noriko HIRAMATSU, Hiroshi SASAKI, Masashi KONDO, H ...
    Session ID: S6-3
    Published: 2021
    Released on J-STAGE: August 12, 2021
    CONFERENCE PROCEEDINGS FREE ACCESS

    In order to promote the development of alternative methods for systemic toxicity testing in the safety assessment of chemical substances, the Organization for Economic Co-operation and Development (OECD) has promoted the development of hazard expression pathways (AOP), and the AOP-based test method guidelines (TG) and the development of in silico was recommend. However, no AOP or TG has been developed in the reproductive / developmental toxicity test.

    Meanwhile, a description of alternative methods has been added to the test strategy of Step 5 (ICH S5 R3) of the International Council for Harmonization of Pharmaceutical Regulations (ICH). However, there is no description of a recommended test method as a new approach to properly predict malformation or embryo-Fetal Lethality (MEFL) in reproductive and developmental toxicity. Under the above circumstances, the development of alternative methods that can handle the safety evaluation of chemical substances as well as pharmaceuticals is urgently needed worldwide.

    In this presentation, based on the above situation, in order to search for genes that can detect adverse expression (AO) of MEFL, thalidomide, one of the representative test substances, was exposed to human iPS cells. The target gene was selected from changing candidate genes. Next, we created a human iPS reporter cell line into which a luciferase gene that can monitor changes in the expression of this gene was introduced. Using this cell line, we conducted exposure experiments on the positive substance sodium valproate (VPA), thalidomide and the negative substance D-mannitol in typical reproductive and developmental toxicity tests. This cell line was able to detect the effects of exposure to thalidomide and VPA.

    We are currently using this reporter cell line to conduct exposure experiments on the substances described in ICH S5 R3, and report efforts to establish alternative methods for animal experiments that can evaluate new reproductive and developmental toxicity.

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  • Yasuhiro KAZUKI
    Session ID: S6-4
    Published: 2021
    Released on J-STAGE: August 12, 2021
    CONFERENCE PROCEEDINGS FREE ACCESS

    The vectors for expressing genes in mammalian cells and animals has not only been a tool for analyzing gene functions, but also has played an important role in industrial and medical applications. In the conventional transgenic technology, the size of DNA that can be introduced into mammalian cells and animals is usually limited to several hundred kb, and to introduce genes or gene clusters having a size exceeding 1 Mb has been impossible. To solve these problems, we used chromosome engineering technology to develop human artificial chromosomes (HAC) and mouse artificial chromosomes (MAC) that can carry large human genes, multiple human genes in a stable manner. On the other hand, the endogenous gene or gene cluster that corresponds to the human GOI(s) being transferred needs to be disrupted to generate a fully humanized animal model. Cre/loxP-mediated deletion of large genomic regions in mouse ESCs has been used to generate gene cluster KO mice. However, this is labor intensive and time consuming because the targeting of two loxP sites and Cre/loxP-mediated chromosomal deletion via Cre expression must be performed in mouse ESCs. To overcome this limitation, genome editing technologies such as ZFN, TALEN, and CRISPR/Cas9 have been utilized to induce large genomic deletions and generate orthologous gene cluster KO animals. These technologies can also be used to further modify previously constructed HACs/MACs carrying human genomic regions. Therefore, the combination of chromosome transfer and genome editing technology is requisite for the efficient production of fully humanized animals. In this symposium, I will introduce new drug discovery tools developed by HAC/MAC and genome editing technology, and further introduce new combined technologies of DNA synthesis and HAC/MAC.

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Symposium 7
  • Mutsumi SUZUKI
    Session ID: S7-1
    Published: 2021
    Released on J-STAGE: August 12, 2021
    CONFERENCE PROCEEDINGS FREE ACCESS

    The development of biotechnology-derived pharmaceuticals (biopharmaceuticals) were initially developed in the early 1980s. It has been recognized that the selection of animal species is a crucial consideration in the safety assessment of biopharmaceuticals. Especially in the selection of animal species, monkeys are often used in non-clinical studies due to their cross-reactivity. However, simply crossing to the target molecule is not enough, and it is said that functional activity is important. I would like to discuss some points for nonclinical evaluation of biopharmaceuticals in monkeys.

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  • Mineo MATSUMOTO
    Session ID: S7-2
    Published: 2021
    Released on J-STAGE: August 12, 2021
    CONFERENCE PROCEEDINGS FREE ACCESS

    Here I present cases where results of toxicology studies using monkeys were efficiently used for labeling in some regulatory agencies as well as for establishing potential safety biomarkers. All of those examples of labeling are from immune check point inhibition and the resultant immune-related pregnancy risks. These include the cases of CTLA-4 inhibition that exhibits premature births and decreased birth weight (PMDA), PD-1 inhibition mAb that exhibits increased abortion and premature infant death (FDA), and PD-L1 inhibition that exhibits irregular menstrual cycle pattern (EMA), all of which have been observed in ePPND studies of cynomolgus monkeys. Since blockade of PD1/PDL1 (+CTLA-4) pathway may result in a decrease in the efficiency of Tregs and an increase in inflammatory Th17 cells leading to loss of tolerance at the feto maternal interface, the above finding are described as basis of clinical risks in respective labeling. In the course of monkey studies, etc, there are also recent research papers that have raised out Th17/Treg ratio, Th1/Th2 ratio, or NK cell activity in maternal peripheral blood as the potential predictive biomarkers for spontaneous abortion, preterm or preeclampsia. Thus, as far as drug-related immunological pregnancy risks, monkey studies appear to serve as a good translational model to clinical.

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  • Tatsuhiro ISHIDA
    Session ID: S7-3
    Published: 2021
    Released on J-STAGE: August 12, 2021
    CONFERENCE PROCEEDINGS FREE ACCESS

    Polyethylene glycol (PEG) is considered as non-toxic and non-immunogenic materials such as proteins, peptides and nanocarriers, and surface modification with them can improve their immunogenicity and pharmacokinetics. However, we have reported that PEGylated liposome (PEG-Lip) loses their long circulating properties when they are administered twice in same animal with certain interval (accelerated blood clearance (ABC) phenomenon). So far, such phenomenon has been observed in mice, rats, dogs, pigs and monkeys. Similar phenomenon has been reported in even patients who received PEGylated protein drugs. We elucidated that anti-PEG IgM, secreted in response to the first dose of PEG-Lip, is responsible for the rapid clearance of the second dose via initiation of complement activation. We further elucidated that such anti-PEG IgM production is caused in nude mice (no T-cells), while it was not caused in SCID mice (no B and T cells) and splenectomized mice (no spleen). Most recently, we reported contribution of phagocytic cells to induction of anti-PEG IgM in mice although the induction of anti-PEG IgM was mediated in a T-cell independent manner, which does not require antigen-presenting cells (APC). These suggest that spleen B cells produce the anti-PEG IgM in a T-cell independent manner with APC help.

    Of interest, an emerging body of evidence is emphasizing the existence of naturally occurring anti-PEG antibodies in normal individuals who have never received PEGylated therapeutics. Any PEGylated formulations might display unexpected pharmacokinetic behavior under such condition, resulting in less therapeutic efficacy or even cause undesirable side-effects. Therefore, a deep understanding of the prevalence and clinical implications of anti-PEG immunity is a prerequisite for the continual clinical application of PEGylated therapeutics.

    In this presentation, we do brief introduction about production of anti-PEG IgM and the ABC phenomenon in animals and patients. And, we try to focus on species difference in induction of anti-PEG IgM.

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  • Masayuki MISHIMA
    Session ID: S7-4
    Published: 2021
    Released on J-STAGE: August 12, 2021
    CONFERENCE PROCEEDINGS FREE ACCESS

    Monkey was very often recognized as a relevant animal species of non-clinical safety studies on antibody drugs. ICH S6 guideline gives monkey studies preference over those with surrogate antibodies to a human homologous target or transgenic animals. This may be a reasonable concept but not always correct. An antibody drug for human use is a surrogate antibody to monkeys because of differences in Fc function, pharmacokinetics and details of mode of action. Toxicologists would be interested in various predictable or unpredictable cases of human toxicity from monkey studies. Here, I’ll review how relevant monkey studies were and how we can use monkey studies in non-clinical safety assessment.

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  • Takehito ISOBE
    Session ID: S7-5
    Published: 2021
    Released on J-STAGE: August 12, 2021
    CONFERENCE PROCEEDINGS FREE ACCESS

    When planning animal experiments, we need to understand the harm of non-human primates (NHPs) which they suffer in captive environments in research facilities. In recent years, the awareness of animal welfare for NHPs is increasing at a global level. Given the current situation, we are working to improve the housing environment of NHPs. We have also conducted events that promote and develop the 3Rs and animal-welfare cultures within company. As the result, a new evaluation method was developed which realized the reduction of cynomolgus monkeys used in DMPK research. In this presentation, current challenges on NHPs animal welfare and our initiatives to improve it will be introduced.

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Symposium 8
  • Riki MATSUMOTO
    Session ID: S8-1
    Published: 2021
    Released on J-STAGE: August 12, 2021
    CONFERENCE PROCEEDINGS FREE ACCESS

    Convulsion occurs when the cortical neurons become hyperexcitable due to various reasons. It can happen as an acute symptomatic seizure, where the cortex becomes irritable due to acute brain insult such as encephalitis, stroke, electrolyte imbalance, hypoglycemia, or metabolic/toxic events. Convulsion can also occur as one form of the epileptic seizures. Epilepsy is defined as a brain disorder, where the cortical neurons acquire hyperexcitability and result in recurrent episodes of epileptic seizures. Seizure type (semiology) varies since the semiology depends on which part of the brain becomes hyperexcitable. Epileptic seizures can be generalized convulsion, convulsion of a part of the body or a non-convulsive seizure with impaired awareness. It is important to know that some drugs can decrease the seizure threshold to trigger convulsions or seizures. As a physician who sees epilepsy and convulsion in daily clinical practice, I will overview what is convulsion or seizure, and review the drug induced seizures by introducing our cases.

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  • Ikuro SUZUKI
    Session ID: S8-2
    Published: 2021
    Released on J-STAGE: August 12, 2021
    CONFERENCE PROCEEDINGS FREE ACCESS

    In this symposium, we will introduce the changes in electrical activities for seizure-positive compounds in cultured cells, brain organoids, brain slices, and in vivo brain, and the AI analysis methods for predicting seizure risk from waveforms. In addition, we will also introduce a method for predicting the mechanism of action from waveforms and a method for predicting the aura state of drug-induced seizures. I would like to discuss the interpretation and consistency of data obtained in vitro, ex vivo, in vivo.

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  • Motohiro SHIOTANI
    Session ID: S8-3
    Published: 2021
    Released on J-STAGE: August 12, 2021
    CONFERENCE PROCEEDINGS FREE ACCESS

    There are still many unmet medical needs for disorders of central nervous system (CNS). It’s well known that candidate compounds of new drugs for treatments of CNS disorders have potentials to induce convulsions in human due to their excessive pharmacological effects. Since convulsion is one of life-threatening adverse events in human, it’s essential to fully assess possible convulsion risks of drug candidate compounds before conducting clinical trials.

    These days, in vitro convulsion risk evaluation using human iPS cell-derived neurons assay is becoming popular; on the other hand, animal studies will be still necessary to evaluate 1. possible convulsions induced by metabolites, 2. plasma compound concentration at convulsions, and 3. some premonitory signs of convulsions. However, translation of convulsion risk from animals to humans is still a huge challenge because of species differences in susceptibility to drug-induced convulsions.

    To solve the issue, we compared convulsion susceptibilities and plasma concentrations at convulsion in mice, rats, and monkeys by using several reference compounds which induced convulsions in humans.

    In the symposium, I’ll show details of results in the animal studies and introduce an example of convulsion screening flow prior to clinical trials.

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  • Toshitaka YAMAKAWA, Koich FUJIWARA, Manabu KANO, Miho MIYAJIMA, Ta ...
    Session ID: S8-4
    Published: 2021
    Released on J-STAGE: August 12, 2021
    CONFERENCE PROCEEDINGS FREE ACCESS

    Heart rate variability (HRV) reflects autonomic nerve activity and provides beneficial information for both clinical and healthcare diagnoses. A telemetry system for the measurement of HRV has been developed with a low-cost manufacturing process and a low-power consumption design. All the components and functions for the measurement were implemented on a wearable telemeter that has a function for automated calibration of various ECG amplitudes among the subjects, and the obtained data is stored into a smartphone via a Bluetooth wireless transmission. The measurement accuracy and reliability of the system are reviewed in this talk, and the preliminary results of the application to the clinical and healthcare purposes: the prediction of epileptic seizures and drowsy driving are explained.

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