Oral tolerance is an immune regulatory system for foods. Eating foods gives healthy people nutrition. However, foods are immune exclusion material in patients of food allergy. We thought possibilities for immune intolerance for foods, failing acquisition of oral tolerance and breaking acquired tolerance. Then, we made murine models for the possibilities. First, we made the food allergy model and oral tolerance model for ovalbumin (OVA). Experimental oral tolerance was induced by previously oral treatment with OVA solution before the sensitization by intraperitoneal injection of OVA. In the oral tolerance model, elevation of OVA-specific IgE was suppressed completely and anaphylaxis was not induced. Next, as the model of failing acquisition of oral tolerance, we used the food additives into the OVA solution for tolerance. As results, intake of the OVA solution with food additives prevented acquiring oral tolerance and induced anaphylaxis for OVA. Recently, “dual-allergen exposure hypothesis” was suggested. The hypothesis proposed allergic sensitization to food could occur through cutaneous sensitization and that consumption of food protein induced oral tolerance. We attempted to override oral tolerance for the food by sensitization via skin. We found that epicutaneous sensitization and sensitization by intradermal injection of OVA could override acquired oral tolerance. As two common denominators for immune intolerance for foods, we confirmed the change of migration of dendritic cells and prevention of inducing regulatory T cells.

The prevalence of allergic diseases has been increasing, and sensitization to allergens such as cedar pollen and house dust mites has become a social issue. Allergic inflammation is primarily driven by type 2 inflammation, which is mediated by interleukin (IL)-4, IL-5, and IL-13 produced by Th2 cells and group 2 innate lymphoid cells (ILC2s). Recent studies have suggested that extracellular vesicle (EV) also plays critical roles in the pathogenesis of allergic diseases. EVs are lipid bilayer-enclosed particles containing proteins, mRNA, and microRNA (miRNA), which function as carriers of cytokines, antigens, and miRNAs, thereby activating Th2 cells and ILC2s and contributing to the progression of various inflammatory diseases. In contrast, we demonstrated that EVs contributed to the regression of allergic disease: EVs derived from the serum of allergen immunotherapy-treated mice exhibited suppression of ILC2 activation. Given their dual roles in both promoting and suppressing immune responses, EVs are emerging as promising targets and tools for novel treatment strategies. Understanding the immunomodulatory mechanisms mediated by EVs will be a crucial step toward developing safer and more effective therapies for allergic diseases. This review provides an overview of the role of EVs in allergic inflammation and highlights our recent findings on how allergen immunotherapy influences the properties and functions of EVs, thereby contributing to the regulation of immune responses and alleviation of allergic symptoms.

The prevalence of allergic diseases is increasing worldwide, with approximately one in two individuals in Japan affected by some form of allergic condition, making it a common disease. While most allergic diseases are multifactorial, involving a complex interplay between genetic predispositions and environmental factors, a subset of cases is attributed to monogenic disorders, which have been increasingly reported in recent years. This article focuses on JAK1 gain-of-function (GOF) variants, highlighting their clinical features, therapeutic potential, and the future prospects of research on monogenic disorders in allergic diseases. JAK1-GOF variants are characterized by early onset and severe atopic dermatitis that does not respond to conventional therapies. They are also frequently associated with other allergic diseases, such as food allergies and asthma, as well as autoimmune diseases and growth impairments. JAK inhibitors represent a promising therapeutic option for JAK1-GOF mutations, with previous reports suggesting their efficacy. Predicting drug efficacy through in vitro studies could enable the selection of tailored treatments for individual patients, potentially leading to significant clinical improvements. It is hypothesized that undiagnosed patients with such monogenic disorders may exist. Accurate diagnosis of these patients could facilitate effective treatments. Moreover, research on monogenic disorders has the potential to lead to the development of novel molecular-targeted therapies through the elucidation of disease pathophysiology, benefiting not only patients with rare genetic disorders but ultimately a broader population.

Allergic diseases have been considered multifactorial diseases. However, comprehensive genome sequencing, such as whole exome analysis, is revealing a group of diseases in which single genes are deeply involved in their pathogenesis. We identified a de novo missense variant of STAT6 [NM_003153:c.1255G>A,p.(Asp419Asn)] in a severely allergic patient with atopic dermatitis, hyper IgE, eosinophilic gastroenteritis, and food allergy by whole exome sequencing analysis. STAT6 is known as a transcription factor induced by IL-4 stimulation. Stimulation with IL-4 induces STAT6 phosphorylation via the JAK-STAT pathway and dimer formation. The STAT6 dimer quickly translocates into the nucleus and ultimately activates the expression of genes specific for TH2-type immune responses. Our experiments in vitro showed that nuclear translocation of mutant STAT6 (p.Asp419Asn) is enhanced compared to wild-type STAT6. In addition, even in the absence of IL-4 stimulation, we observed the translocation of mutant STAT6 in its unphosphorylated state, which activated gene expression. Mutant STAT6 knock-in mice elicited an abnormal TH2-dominant immune response in vivo, with findings similar to those observed in patients. Our findings suggest that mutant STAT6 is a gain-of-function variant. Currently, anti-IL-4Rα monoclonal antibodies, JAK inhibitors that block the JAK-STAT pathway, and non-specific anti-inflammatory drugs such as steroids are shown to be effective in treating this disease. The pathogenesis of immune dysregulation caused by gain-of-function variants of the STAT6 gene is being elucidated. Further efforts are required to elucidate the detailed mechanisms of this disease and it will hopefully lead to the development of more essential agents that specifically regulate STAT6 activity.

Hypoxic condition is formed in our body when the oxygen demand exceeds the supply. Hypoxic response is triggered under such condition to maintain homeostasis. However, it had been unclear for a long time how cells sense changes of surrounding oxygen environment and activate hypoxic response. Studies of molecular machinery responding to hypoxia largely progressed in the mid 90’s after the identification of Hypoxia-Inducible Factor, HIF. Then, the prolyl hydroxylase domain-containing protein (PHD)-HIF pathway was characterized as a central pathway for cells to monitor the decrease in oxygen concentration and maintain cellular function in hypoxia. PHD is recognized as one of the cellular oxygen sensors because it requires oxygen molecule for its enzymatic activity. Importantly, there is a large enzyme family named 2-oxoglutarate-dependent dioxygenase (2OGDD), which require O₂, Fe²⁺, 2-oxoglutarate as co-factors like PHD. In this review, we will overview how 2OGDDs operate, and what are their roles in pathological situation. We also discuss possible direction of how we can establish drugs to target 2OGDDs.

Aging serves as a risk factor for various age-associated disorders, such as cancer and type 2 diabetes. The study of aging is linked with metabolic research, due to the metabolic changes associated with aging. For example, chronic inflammation and the accumulation of DNA damages associated with aging lead to a decrease in NAD⁺ levels and mitochondrial dysfunction, resulting in cells becoming irreversibly cell cycle arrested, known as senescent cells. Senescent cells exhibit metabolic changes distinct from normal cells, along with distinct phenotypic characteristics, such as the senescence-associated secretory phenotypes (SASP), characterized by the excessive secretion of bioactive molecules such as inflammatory cytokines and chemokines. The accumulation of senescent cells has been observed in the pathology of age-related diseases, and their characteristics are thought to contribute to disease progression. Recent research has focused on the characteristics of senescent cells, such as their resistance to apoptosis, and aims to eliminate these cells from the body through pharmacological inhibition. Indeed, experimental evidence has demonstrated improvements in age-related phenotypes following the removal of senescent cells. Here, we review how age-related changes in cell metabolism induce cellular senescence, what are the metabolic characteristics of senescent cells, and how they affect the organism. Additionally, we also review our recent findings on the elimination of senescent cells by pharmacological inhibition of glutaminolysis rate-limiting enzyme GLS1, and outline the prospects for drug discovery targeting senescent cells.

NAD is an important metabolite that functions as a cofactor in various metabolic reactions, and its biosynthesis is known to be upregulated during malignant transformation. The NAD salvage, in which NAMPT is a rate-limiting enzyme, is a predominant pathway for NAD synthesis in most tissues including cancer. However, less is known about how cancer sensitivity against NAMPT inhibition (NAMPTi) is dictated. Here we report that lung and prostate neuroendocrine carcinomas (NECs) are extremely vulnerable to NAMPTi and that the therapeutic effect of NAMPTi is markedly enhanced by dietary restriction of the NAD precursor, niacin. We found that de novo NAD synthesis is inactivated during neuroendocrine differentiation of tumor cells, leading to a high dependence of NEC cells on NAD salvage. Further investigations in mouse transplantation models showed that lowering blood levels of nicotinic acid riboside (NAR), one of the non-classical niacin, dramatically increases the therapeutic effect of NAMPTi on NEC. Metabolic studies showed that dietary nicotinic acid is converted to NAR and then released into the circulation, and NAD synthesis using NAR substrates can compensate for the effects of NAMPTi in tumor cells. These findings reveal that niacin restriction with NAMPTi is synthetic lethal to NECs.

Aging is a physiological process caused by various genetic and environmental factors. Recently, it has been proposed that the disturbance of the nutritional-metabolic sensing pathway is one of the aging characteristics. In particular, nicotinamide adenine dinucleotide (NAD⁺) plays an important role in this pathway and is considered the regulator of aging. NAD⁺ regulates an energy metabolism as a co-factor and is also involved in various biological processes including transcription, stress responses, DNA repair, inflammatory responses as well as post-transcriptional modifications, as a substrate for sirtuins, poly ADP-ribose polymerase (PARP), and CD38. With age, DNA damage and chronic inflammation increase in organs, resulting in overconsumption of NAD⁺ via PARP and CD38. The reduced NAD⁺ levels decrease the activity of sirtuins and PARPs and impair energy metabolism, ultimately leading to aging and aging-related diseases. However, the precise metabolism of NAD⁺ in vivo and the mechanism of how NAD⁺ regulates aging remain elusive. Moreover, the clinical application of NAD⁺ supplementation therapy is still under development. In this review, we overview the NAD⁺ metabolism and its relation to aging. In addition, we describe the current issue and perspective of NAD⁺ supplementation therapy to promote a healthy lifespan.

Inspired by my experiences working in research at an overseas biotech venture, I founded GenAhead Bio Inc. in 2018. GenAhead Bio adopts a unique dual-business structure, providing contract services for generating genetically modified cells using highly efficient CRISPR/Cas9 genome editing technology for researchers, while simultaneously pursuing a nucleic acid drug business aiming to develop nucleic acid drugs such as antisense oligonucleotides and siRNAs. Based on the emerging delivery system called Antibody-Nucleic acid Conjugate, where an antibody is covalently linked to a nucleic acid as a targeting ligand, we are conducting drug developmental research by delivering nucleic acids to the organs where antibodies accumulate. Our ultimate goal is to apply this technology to genome editing for gene modification in specific cell types. In this review, we will introduce some case studies of genome editing, including single nucleotide substitutions, as well as the delivery of siRNA to the skeletal muscle using anti-transferrin receptor (CD71) antibody and its therapeutic effects on muscular diseases.

Danicopan (brand name: Voydeya^® tablets) is a new oral small molecule complement factor D inhibitor that was approved in Japan in January 2024 for paroxysmal nocturnal hemoglobinuria (PNH). PNH is a rare, chronic hematologic disorder caused by acquired mutations of hematopoietic stem cells in the PIGA gene. These mutations cause deficiencies in complement regulatory proteins CD55 and CD59 that may lead to uncontrolled terminal complement activation, intravascular hemolysis, thrombosis, and premature mortality. Complement C5 inhibitors (C5i; eculizumab and ravulizumab) are the current standard of care of PNH treatment, and control intravascular hemolysis (IVH) by inhibiting terminal complement pathway activation. However, extravascular hemolysis (EVH) with persistent symptoms, such as anemia, occurs in some C5i-treated patients with PNH. EVH is caused by the accumulation of proximal complement C3 fragment on the membrane of surviving PNH-type red blood cells. These cells subsequently undergo phagocytosis in the spleen or liver. Danicopan was developed to control EVH by targeting complement factor D involved in alternative pathway activation. Preclinical studies showed that danicopan selectively inhibits alternative complement pathway activation by reversibly binding to factor D and inhibiting its serine protease activity. A global phase III study (ALPHA study: ALXN2040-PNH-301 [NCT04469465]) investigated danicopan as add-on therapy to ravulizumab or eculizumab in patients with PNH and clinically significant EVH. Danicopan achieved statistically significant, clinically meaningful increases in hemoglobin levels, reduced transfusion, and reduced fatigue, while maintaining control of IVH. No new safety concerns were observed. Danicopan makes it possible to control EVH while controlling IVH with C5i.

The treatment of recurrent or metastatic cervical cancer has entered a new era, with immune checkpoint inhibitors now being used as first-line standard of care options. Meanwhile, there is a lack of second-line and subsequent treatment options that can adapt to this changing treatment landscape, highlighting the need for the development of new treatments with novel mechanisms of action. Tisotumab vedotin (recombinant) is an antibody-drug conjugate (ADC) consisting of tisotumab, an anti-human tissue factor (TF) monoclonal antibody (IgG1κ), the microtubule inhibitor monomethyl auristatin E (MMAE), and a valine-citrulline linker. When the linker is cleaved by a protease in a tumor cell, MMAE is released to induce cell cycle arrest and apoptosis via disruption of the microtubular network. In non-clinical studies, tisotumab vedotin demonstrated concentration-dependent cytotoxic and anti-tumor activities. Tisotumab vedotin also mediated antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) activities. In a global Phase III study of tisotumab vedotin as second- or third-line therapy in patients with recurrent or metastatic cervical cancer (Study SGNTV-003/innovaTV 301), the drug demonstrated higher efficacy than the investigator’s choice of chemotherapy. Although some eye-related adverse events occurred as unique toxicities, the safety profile of tisotumab vedotin was generally manageable. The results of analysis in the Japanese subpopulation of the SGNTV-003 (innovaTV 301) study were consistent with those of the overall population. Based on these results, tisotumab vedotin received regulatory approval in Japan in March 2025 for the indication of “advanced or recurrent cervical cancer that has progressed after cancer chemotherapy”.