Recent rapid progress in big data and breakthrough AI technologies have brought about significant changes in the medical field as well. Although biomedical literature databases contain so many articles that it is impossible to read them all, AI technology based on neural networks has dramatically advanced and is now able to efficiently process such vast amounts of literature information in a short time. Since drug discovery research requires up-to-date and extensive knowledge of various disciplines, it is necessary to proactively incorporate AI technology to seamlessly obtain the information needed. In this article, we introduce our effort to use the rapidly growing literature data and the latest AI technologies to drug discovery research. Conventional search engines take an enormous amount of time to identify and understand sentences describing the subject matter of interest in the retrieved articles. We developed and validated our new search tool that not only has a conventional keyword search function, but also enables conceptual search for disease mechanisms using sentences. We will also describe problems that we have identified through actual use of the tool. Finally, since literature data is expected to increase and efforts to determine how to efficiently analyze and obtain desired findings using AI will become even more active, we will discuss expectations for future technological advances and issues that need to be resolved.

To improve the decreased efficiency of drug discovery and development, drug repurposing (also called drug repositioning) has been expected, that it is a strategy for identifying new medical indications for approved, investigational or suspended drugs. Particularly, according to the rapid expansion of medical and life science data and the remarkable technological progress of AI technology in recent years, the approach of computational drug repurposing has been attracted as one of the applications in data-driven drug discovery. Computational drug repurposing is a method of systematical and strategical research for identifying novel indication candidates and prioritizing the indication candidates based on the various profiles of drugs, genes, and diseases. In this review article, the typical data science techniques for data-driven drug repurposing, 1. drug-target interaction prediction, 2. transcriptomics-based approach by using differentially gene expression profiles, 3. natural language processing and word embedding, and their current status were summarized. We have also introduced a use case of data-driven drug repurposing for the PPARγ/α agonist Netoglitazone that we actually analyzed. In addition, as an excellent successful case of data-driven drug repurposing in recent years, we have also discussed a repurposing case reported by BenevolentAI in 2020, that Baricitinib has been identified as a potential intervention for COVID-19, based on immunomodulatory treatment by its mechanism of action as a JAK1 and JAK2 inhibition.

TAR DNA-binding protein 43 (TDP-43) is an evolutionarily conserved RNA/DNA-binding protein that is nuclear-enriched in healthy cells, but deposited in the cytoplasm as aggregates in affected neurons in certain neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). We have previously developed an optogenetic TDP-43 variant (opTDP-43h) whose oligomerization status can be modulated via the CRY2olig tag, which self-assembles upon absorption of blue light. Illumination of zebrafish spinal motor neurons expressing opTDP-43h with a blue light triggers its cytoplasmic mislocalization, eventually leading to cytoplasmic deposition of opTDP-43h aggregates. Intriguingly, a light illumination-dependent transient opTDP-43 mislocalization can halt motor axon outgrowth, even in the absence of cytoplasmic deposition of opTDP-43 aggregates. These observations point toward an oligomerization-dependent, but aggregation-independent, cytotoxic effect of TDP-43 that might contribute to pathogenesis of ALS. In the present review, we would like to overview the zebrafish ALS model based on the optogenetic TDP-43, and then discuss about the potential mechanisms of TDP-43 cytotoxicity that trigger and/or promote motor neuron degeneration in ALS.

The production of amyloid β peptide (Aβ) is an important process relating to the pathogenesis of Alzheimer disease (AD). It is widely known that the sequential cleavage of amyloid precursor protein (APP) by β- and γ-secretases lead to the production of Aβ. However, the precise regulatory mechanism for Aβ production remains unclear. We have established a CRISPR-Cas9 based screening system to identify the novel regulators of Aβ production. Calcium and integrin-binding protein 1 (CIB1) was identified as a novel potential negative regulator of Aβ production. The knockdown and knockout of Cib1 significantly increased Aβ levels. In addition, immunoprecipitation showed that CIB1 interacts with the γ-secretase complex but did not alter its enzymatic activity. Moreover, Cib1 disruption specifically reduced the cell-surface localization of the γ-secretase complex. Finally, the single-cell RNA-seq analysis in the human brain demonstrated that early-stage AD patients have lower neuronal CIB1 mRNA levels compared to healthy controls. Taken together, we have shown that CIB1 controls the subcellular localization of γ-secretase, resulting in the regulation of Aβ production, suggesting the involvement of CIB1 in the development of AD pathogenesis.

Glial cells are non-neuronal cells that make up the central nervous system, including astrocytes, oligodendrocytes, microglia, and ependymal cells, which play an important role in brain homeostasis. However, activated microglia and reactive astrocytes cause neuroinflammation, which is closely related to neurodegeneration. Neuronal loss, gliosis, and accumulation of misfolded proteins are commonly observed in the brain of many neurodegenerative diseases at autopsy. Therefore, in vivo imaging of glial cell responses by positron emission tomography (PET) would be useful not only for understanding pathological processes, but also for differential diagnosis and evaluation of disease-modifying therapeutics targeting glial cells. The gold standard marker for reactive astrocytes is glial fibrillary acidic protein (GFAP), but no specific ligands are available. To date, there are two targets of reactive astrocytes that are under intense investigation: Monoamine oxidase-B (MAO-B) and imidazoline₂ binding site (I₂BS). PET radiopharmaceuticals for MAO-B and I₂BS have been developed and are under clinical investigation. In this chapter, we review the MAO-B and I₂BS as molecular targets for imaging reactive astrocytes and introduce the PET tracers and their clinical studies.

Repeat expansion diseases are caused by the aberrant repeat expansions within specific genes. RNAs derived from aberrant repeat sequences form non-canonical secondary structures, contributing to induce cell toxicity. In particular, RNA G-quadruplexes (G4RNAs) formed in guanine-rich repeat expanded RNAs trigger neurodegeneration. We have previously shown that the expanded CGG repeat-derived G4RNAs initiate aggregation of FMRpolyG, a neuropathogenic protein generated by repeat-associated non-AUG (RAN) translation in Fragile X-associated tremor/ataxia syndrome (FXTAS). In this review, we describe the neuropathological mechanism attributed to G4RNAs in guanine-rich repeat expansion diseases, including FXTAS.

Depression is a common mental disorder and mainly characterized by persistent sadness and a lack of interest or pleasure in previously rewarding or enjoyable activities. Despair is also a common symptom of depression, and the forced swim and tail suspension tests are widely used to measure this behavior in rodents, but the results from these tests can include the effects on stress resistance in addition to depressive-like states. Reduced motivation is an important marker of psychiatric disorders, including depression, and thus we have previously developed the female encounter test, a novel and simple procedure for assessing reward-seeking behavior in adult male mice. Importantly, female mice should be considered in the development of animal models of depression and assessment of mouse behaviors since the lifetime prevalence of a major depressive disorder in women is almost twice that in men, and around one in seven women can develop postpartum depression. In this review, we summarized our recent research on the male encounter test for assessing motivation in adult female mice and introduced new topics on animal models and therapeutic drugs for postpartum depression.

Chronic exposure to stress can lead to a variety of mental disorders such as depression. There are many treatment-resistant patients who do not respond adequately to the standard pharmacological treatments. Therefore, the development of novel therapeutic agents is highly expected. In rodents, socially defeated animals that were exposed to repeated physical aggression from other individuals are widely used in this field of research. The social defeat is considered as a stress that mimics human social stress. On the other hand, emotional stress, but not physical stress, is likely to contribute to the pathogenesis and etiology of depression in human. Therefore, there is a gap between the process of pathogenesis and the animal models, and this is one of the reasons why the development of new psychotropic drugs to treat depression has been difficult. Recently, a novel stress model has been introduced, in which mice are subjected to emotional stress without physical distress by witnessing social defeat scenes of their conspecifics. We have investigated the mechanisms by which emotional stress is transmitted by witnessing social defeat in mice, focusing on the insular cortex. In this article, we summarize and discuss the recent advancements in the neural basis of behavioral changes induced by emotional stress.

Post-traumatic stress disorder (PTSD) is often treated by (1) selective serotonin reuptake inhibitors (SSRIs), (2) exposure therapy, or a combination of the two. However, while all treatments have some efficacy, they are not fully effective. It is necessary to elucidate the causes of inadequate efficacy and to direct the development of effective treatments. First, regarding (1), pharmacological studies have indicated that the 5-HT_2C receptor is one of the receptor subtypes that interfere with the therapeutic effects of SSRIs. To compensate for nonselective effects in pharmacological manipulations, we replicated pharmacological results using mice deficient in the 5-HT_2C receptor gene. However, since either pharmacological blockade or gene knockout of the 5-HT_2C receptor could increase locomotor activity, the locomotor-enhancing effects make the interpretations of results difficult. Therefore, we used the conditioned lick suppression test to evaluate fear response using corrected values that consider the effects of differences in locomotor activity, thereby eliminating this possibility. Next, to address (2), we conducted fear conditioning by simultaneously presenting a composite of sound and environmental stimuli and then re-exposing the subjects to the sound and environmental stimuli separately. We found that the fear response to the sound stimuli quickly decreased, while the fear response to the environmental stimuli did not diminish even after repeated exposure. Thus, exposure therapy may exacerbate PTSD, depending on the method used. In this paper, we will introduce the above results and suggest directions for future PTSD research.

Because the early-life period is a critical window for the development and reorganization of neural circuits, the early life environment has a great impact on cognitive and emotional functions. It has been reported that a history of early life adversity such as child maltreatment and neglect increases the risk for psychiatric disorders with social and emotional problems. To develop treatments for these psychiatric disorders, it is important to understand the neural mechanisms of how early-life adversity causes social and emotional dysfunctions. In this article, we introduce our research that has revealed adolescent social isolation impairs social and stress-coping behaviors through subregion-dependent synaptic disruption in the orbitofrontal-amygdala circuit in mice.

Neurodegenerative disorders including Alzheimer’s disease (AD) and Parkinson’s disease (PD) are hard to treat once they have suffered. Therefore, the establishment of new prevention and treatment methods for neurodegenerative disorders is an urgent issue for Japan’s aging society, from the perspective of improving the quality of life of patients and medical staff involved in their care. Human induced pluripotent stem cells (hiPSCs) have contributed to the understanding of the pathology of neurodegenerative diseases, and to the development of new preventive and therapeutic strategies based on the understanding of human diseases. Furthermore, new cross-disciplinary scientific trends together with iPSC technology are emerging in the fields of life science, medical science, and information technology. The fusion of various research knowledges and technologies may provide new scientific progress for better understanding of molecular mechanisms of pathology and the onset of neurodegenerative diseases. Here we have developed new brain model with hiPSC technology for the understanding of pathology of AD and PD based on the induction of region-specific brain organoids and microglia using hiPSCs. These brain organoids technology enables us to provide simpler and reproducible analytical methods by combining with not only developmental biology and pharmacology but also transcriptome analysis and direct conversion. These technological advantages contribute to the creation of new research fields with human brain research to understand higher brain functions and pathophysiology of neurodegenerative diseases such as AD and PD.

Neurological diseases are often life threatening, with severely affecting an individual’s quality of life. However, the disease mechanisms are still less understood, mainly because of lacking good disease models. Over the past decades, researchers developed many models using cell lines or animals, but most of them did not faithfully recapitulate the disease phenotypes. In particular, it is almost impossible to create animal models for multifactorial diseases or sporadic cases of unknown etiology. In these circumstances, it has come to be expected that induced pluripotent stem cells (iPSCs) can revolutionize neurological disease research as they retain patient’s genetic information and provide an expandable source of disease-relevant neurons and glial cells. iPSC technologies are now widely used for disease modeling, and further for drug discovery and regenerative medicine. They are also enabling previously infeasible studies such as those uncovering how disease-associated single nucleotide polymorphism (SNP) and genetic variants increase the disease risk. This review describes a variety of iPSC technologies to produce various types of neurons and brain-like tissues (brain organoids) and summarize recent trends in iPSC technology-based neurological disease research. We also discuss the remaining challenges for understanding and overcoming brain disorders.

Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) have been widely used as materials for regenerative medicine and for modeling development and disease because of their pluripotency to differentiate into all cell types of the body. Recently, organoid research has attracted considerable attention as a constructive approach to reconstitute various tissues from ESCs or iPSCs in three-dimensional culture in vitro. Organoids can provide sophisticated in vitro models because of their ability to partially recapitulate different cell types of living tissues and their functions. However, given their complexity, conventional analyses of stem cell biology are insufficient for evaluating organoid performance, limiting basic research and clinical translation. In recent years, elucidating diverse and complex biological phenomena by integrating stem cell biology with other research fields has become feasible. In this review, we focus on brain organoids with some representative examples of interdisciplinary research using machine learning, genetic and viral engineering, and optical imaging, as well as findings obtained from such research. Furthermore, we will discuss the potential applications and future perspectives of interdisciplinary research in organoid biology.

The main function of the respiratory tract is gas exchange. Because dysfunction of gas exchange is lethal, a lot of people die of respiratory diseases every year. Many researchers are attempting to elucidate the pathophysiology of respiratory diseases and develop effective drugs using several in vitro respiratory models. Recently, respiratory organoids are widely used as human respiratory models. Respiratory organoids are self-organized three-dimensional tissue-like structures that are derived from pluripotent stem cells or tissue stem cells. Because respiratory organoids derived from a patient’s stem cells carry its genetic mutation, they are widely used to recapitulate respiratory genetic diseases. It has been reported that some respiratory genetic diseases, such as cystic fibrosis, primary ciliary dyskinesia, pulmonary alveolar proteinosis, or Hermansky-Pudlak syndrome, could be recapitulated using respiratory organoids. Moreover, because respiratory organoids possess innate immune response activity, they are also used as a model for respiratory infectious diseases. It has been reported that some respiratory diseases which are caused by the infection of pathogens, such as respiratory syncytial virus, seasonal influenza viruses, human parainfluenza virus, measles virus, enterovirus, or cryptosporidium spp., could be reproduced using respiratory organoids. This review introduces the current status and future prospects of respiratory organoids in respiratory disease research.

In the current drug development process, most safety pharmacological tests are animal experiments optimized for low molecular weight compounds. However, development trends have shifted to new modality drugs such as human specific mRNA, antisense oligonucleotides, and siRNA, etc., indicating that now the importance of the human predictability in safety pharmacology is more important than ever. In parallel with that, in vitro use of human cells, such as human iPS cell-derived tissue cells and chimeric mice with human hepatocytes, has been studied strenuously. In this review, we will discuss about IVIVE in safety pharmacology to improve human predictability in this trend of drug development.

The progress of computational toxicology (CompTox) in drug safety research is highly anticipated. CompTox provides toxicity screening methods for drug discovery in the early stages. CompTox also contributes to fostering the application of the principles of the 3Rs in toxicity testing by expanding non-animal test methods. The mechanism of toxicity is complex and varied, and drug discovery modalities are becoming more diverse. Consequently, the research is considered necessary to predict toxicity using not only chemical structures but experimental data as well. Additionally, various perspectives, such as interpretation of toxicity mechanisms and species differences, must be considered in risk assessment and management in drug safety research. Therefore, it is important to construct a comprehensive CompTox system that not only presents toxicity prediction results but also provides much information related to the relationship between drug candidate substances and living organisms. In this review paper, CompTox is positioned as a discipline of toxicology that applies computer-based technology, including AI (artificial intelligence). I also introduce toxicity prediction systems based on experimental data and an ontology system that supports the interpretation of toxicity prediction results as examples of research on constructing the foundation of a comprehensive CompTox system.

Andexanet alfa is a modified recombinant human factor Xa (FXa) that was designed to serve as a binding target for FXa inhibitors as decoy protein. It sequesters FXa inhibitors from binding to endogenous FXa, thereby reversing anticoagulant effect of FXa inhibitors. Andexanet alfa has been approved in March 2022 in Japan for patients with life-threatening or uncontrolled bleeding while on treatment with a FXa inhibitor, apixaban, rivaroxaban, or edoxaban tosilate hydrate. It is administered via two dosing regimens, based on the type of FXa inhibitor, dose, and time since the last dose. In nonclinical studies, andexanet alfa significantly inhibited bleeding induced by FXa inhibitors in animal bleeding models. In the development for Japanese patients, the following two clinical studies have been conducted to confirm the efficacy and safety. First, safety and the reversal effect of andexanet alfa on the FXa inhibitor-mediated anticoagulant activity in healthy adults were confirmed in the overseas phase 2 study including Japanese subjects. Next, the reversal effect of andexanet alfa on the anticoagulation activity and the hemostasis were demonstrated in patients with acute major bleeding while on FXa inhibitor treatment in the global phase 3b/4 study (ANNEXA-4 study). The subgroup analysis of Japanese population showed that the efficacy and safety results were consistent with those of overall population. Andexanet alfa is the first approved reversal agent for FXa inhibitors in Japan and is expected to contribute to the improvement of prognosis in patients with fatal and/or uncontrolled bleeding by timely reversing anticoagulant effect of FXa inhibitors.