The primary cilium, an antenna-like structure of cell membrane, detects various signals and regulates cellular functions such as proliferation and differentiation. The impairment of primary cilium is associated with the etiologies of diseases including cancer, obesity, and congenital anomalies. In this review, novel functions of trichoplein, a suppressor of ciliogenesis, on the regulation of adipose progenitors and fibro-adipogenic progenitors are focused. Trichoplein-knockout mice show resistance to high-fat diet-induced obesity and accelerated regeneration after skeletal muscle injury. The primary cilia of adipose progenitors from trichoplein-knockout mice are elongated, leading to the inhibitions of the accumulation of lipid raft to the base of primary cilia and the phosphorylation of AKT. The primary cilia of fibro-adipogenic progenitors from trichoplein-knockout mice are also elongated, causing the increased expression of IL-13 through IL-33 receptor signaling. These mechanisms are involved in the resistance to diet-induced obesity and improved regeneration. These findings suggest that targeting the primary cilia of specific cells may be a novel therapeutic approach through modulating cellular functions.

Humans have a highly developed retina and obtain approximately 80% of their external information from vision. Photoreceptor cells, which are located in the outermost layer of the neuroretina and recognize light signals, are highly specialized sensory cilia that share structural and functional features with primary cilia. Genetic disorders of the retina or photoreceptor cells are termed inherited retinal diseases (IRDs) and are caused by variants in one of more than 280 genes identified to date. Among the genes responsible for IRDs, many are shared with those responsible for ciliopathies. In studies of inherited diseases, mouse models are commonly used due to their advantages in breeding, handling, and relative feasibility in creating pathological models. On the other hand, structural, functional, and genetic differences in the retina between mice and humans can be a barrier in IRD research. To overcome the limitations of mouse models, larger vertebrate models of IRDs can be a useful research subject. In particular, canines have retinas that are structurally and functionally similar and eyes that are anatomically comparable to those of humans. In addition, due to their unique veterinary clinical surveillance and genetic background, naturally occurring canine IRDs are more likely to be identified than in other large animals. To date, pathogenic mutations related to canine IRDs have been identified in more than 30 genes, contributing to the understanding of pathogeneses and to the development of new therapies. This review provides an overview of the roles of the canine IRD models in ciliopathy research.

Primary cilia are immotile cilia assembled from the centriole-derived basal body, and they protrude on the cell surface in almost all cell types during the cell cycle G₀ phase. Due to the diffusion barrier at the ciliary base, cilia harbor selective G protein-coupled receptors, growth factor receptors, and ion channels on their membrane. Thus, cilia act as sensory organelles, regulating the proliferation and differentiation of the cells and promoting the formation and maturation of various organs including bone, brain, and kidney. It has been unveiled that malformation and dysregulation of cilia cause organ dysplasia, so-called ciliopathy, thus research on primary cilia has become active during the past 20 years. Research on the roles of cilia in bone formation and its regulatory mechanisms have also progressed. It is widely recognized that cilia of preosteoblasts receive hedgehog and promote differentiation of the cells to osteoblasts, resulting in the formation of skulls and long bones. Recently, it has been shown that a membrane-associated protein 4.1G is important in ciliogenesis, hedgehog signaling, and osteoblast differentiation in neonatal bone formation. In this review, we would like to summarize the roles of primary cilia in bone formation and their regulatory mechanisms including the contribution of 4.1G.

A photoreceptor is a specialized neuron that is responsible for the conversion of light into an electrical signal. Photoreceptors are classified into rods and cones, and both photoreceptors possess light-sensing ciliary organelles called outer segments (OSs), anchored in the cells by a microtubule-based axoneme. The OS consists of a stack of disc membranes, which are abundant for the retinal phototransduction proteins such as rhodopsin. Recently, modern protein synchronization techniques using in vivo transfection in rodents revealed that rhodopsin transits through Rab11-positive recycling endosomes, preferentially entering the OS in the dark. Moreover, Peripherin-2 (PRPH2, also called retinal degeneration slow, RDS), a photoreceptor-specific tetraspanin protein essential for the morphogenesis of disc membranes, is delivered to the OS following complementary to that of rhodopsin. Various PRPH2 disease-causing mutations have been found in humans, and most of the mutations in the cytosolic C-terminus of PRPH2 are linked to cone-dominant macular dystrophies. It has been shown that the late endosome is the waystation that sorts newly synthesized PRPH2 into the cilium. The multiple C-terminal motifs of PRPH2 regulate its late endosome and ciliary targeting through ubiquitination and binding to an Endosomal Sorting Complexes Required for Transport (ESCRT) component, Hrs. These findings suggest that the late endosomes play an important role in the biosynthetic pathway of ciliary proteins and can be a new therapeutic target for the diseases caused by ciliary defects.

Typical monoamine-based antidepressants have significant limitations, including a time lag for therapeutic response and low efficacy (more than one-third of depressed patients fail to respond to multiple antidepressant medications and are considered treatment-resistant). Conversely, ketamine, an N-methyl-D-aspartate receptor antagonist, exhibits rapid and sustained antidepressant actions in patients with treatment-resistant depression. However, clinical use of ketamine is limited due to its serious side effects. Thus, there is a significant need to develop novel ketamine-like antidepressants with fewer side effects. We previously demonstrated that intracerebroventricular infusion of resolvins (RvD1, RvD2, RvE1, RvE2, and RvE3), specialized pro-resolving lipid mediators derived from docosahexaenoic and eicosapentaenoic acids, produce antidepressant-like effects in mouse models of depression. Among resolvins, RvE1 produces the most potent antidepressant-like effects likely via ChemR23 in several mouse models of depression. Local infusion of RvE1 into the medial prefrontal cortex (mPFC) or dorsal hippocampal dentate gyrus (DG) also produces antidepressant-like effects, suggesting that these brain regions are sites of action of RvE1. Additionally, intranasal (i.n.) administration of RvE1 produces antidepressant-like effects through mechanisms similar to ketamine: activity-dependent release of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF), and subsequent mechanistic target of rapamycin complex 1 (mTORC1) activation in the mPFC play a crucial role in the rapid and sustained antidepressant-like actions of i.n. RvE1. Moreover, the antidepressant-like effects of i.n. RvE1 require BDNF and VEGF release, but not mTORC1 activation, in the dorsal DG. These findings suggest that RvE1 can be a promising lead for a novel rapid-acting antidepressant.

Major Depressive Disorder (MDD) poses a significant global health burden, with 30–40% patients developing resistance to standard clinical antidepressants, such as selective serotonin reuptake inhibitors and tricyclic antidepressants. In 2016, Carhart-Harris and colleagues reported that psilocybin, the hallucinogenic compound derived from magic mushrooms, exhibits rapid and enduring antidepressant effects in patients with treatment-resistant depression. Subsequent clinical studies have found the therapeutic potential of psilocybin in MDD, depressive episode in bipolar disorder, anorexia, and drug addiction. In 2018 and 2019, the U.S. Food and Drug Administration designated psilocybin as a “breakthrough medicine” for treatment-resistant depression and MDD, respectively. Notably, the side effects of psilocybin are limited to transient and mild issues, such as headache and fatigue, suggesting its safety. In 2023, we published a review on the role of serotonin 5-HT_2A receptors in the antidepressant effects of serotonergic psychedelics (Nihon Yakurigaku Zasshi, Volume 158, Issue 3, Page 229–232). Here, we present our study alongside the latest clinical and preclinical research on the antidepressant effects of psilocybin and provide an overview of the potential and issues related to psilocybin therapy.

Major depressive disorder (MDD) is a psychiatric disorder that affects more than 300 million people worldwide and has a serious impact on society. Conventional antidepressants targeting monoamines in the brain based on the monoamine hypothesis are known to take a prolonged time to be effective or less effective in 30% of MDD patients. Hence, there is a need to develop antidepressants that are effective against treatment-resistant depression and have a new mechanism different from the monoamine hypothesis. An increasing number of research groups including us have been establishing that pituitary adenylate cyclase-activating polypeptide (PACAP) and one of its receptors, PAC1 receptor, are closely related to the etiology of stress-related diseases such as MDD. Therefore, it is strongly suggested that the PAC1 receptor is a promising target in the treatment of psychiatric disorders. We developed a novel, non-peptidic, small-molecule, high-affinity PAC1 receptor antagonists and conducted behavioral pharmacology experiments in mice to characterize a novel PAC1 receptor antagonist as a new option for MDD therapy. The results show that our novel PAC1 receptor antagonist has the potential to be a new antidepressant with a high safety profile. In this review, we would like to present the background of developing our novel PAC1 receptor antagonist and its effects on mouse models of acute stress.

Growing evidence has indicated that delta opioid receptor (DOP) agonists are potential psychotropic drugs such as for depression, anxiety, and PTSD. In rodent studies, we have also demonstrated that DOP agonists exhibit potent anxiolytic-like effects via the inhibition of the excitatory neuronal activity which projects to the amygdala from the prelimbic prefrontal cortex and facilitate extinction learning of contextual fear memory through PI3K-Akt signaling pathway in the infralimbic prefrontal cortex and MEK-ERK signaling pathway in the amygdala. In this article, we introduce the functional mechanisms underlying antidepressant-like effects and anti-stress effects of DOP agonists. Then, we employed a valid animal model of depression, chronic vicarious social defeat stress (cVSDS) mice, and investigated that the influence of DOP activation on pathopsychological factors in depression such as the adult hippocampal neurogenesis, hypothalamic-pituitary-adrenal (HPA) axis, and neuroinflammation. First, repeated administrations after the stress period to cVSDS mice with a selective DOP agonist, KNT-127, improved social interaction behaviors and reduced hyperactivation of the HPA axis without affecting hippocampal neurogenesis. Meanwhile, repeated KNT-127 administrations during the cVSDS period prevented the exacerbation of social interaction behaviors, dysregulation of the HPA axis, and excessive new-born neuronal cell death in the hippocampal dentate gyrus. Moreover, in both administration paradigms, KNT-127 suppressed microglial overactivation in the dentate gyrus of cVSDS mice. These results indicate that the underlying mechanism of DOP-induced antidepressant-like effects differ from those of conventional monoaminergic antidepressants. Furthermore, we propose that DOP agonists might have prophylactic effects as well as therapeutic effects on pathophysiological changes in depression.

The development of genetically-encoded fluorescent probes for the detection of intracellular calcium ions and various neurotransmitters has progressed significantly in recent years, and there is a growing need for techniques that rapidly and efficiently image these signals in the living brain for pharmacological studies of the central nervous system. In this article, we discuss one-photon fluorescence microscopy techniques used for brain activity imaging, particularly wide-field imaging and head-mounted miniaturized microscopy, and introduce their basic principles, recent advances, and applications in pharmacological research. Wide-field calcium imaging is suitable for mesoscopic observation of cortical activity during behavioral tasks in head-fixed awake mice, while head-mounted miniaturized microscopes can be attached to the animal’s head to image brain activity associated with naturalistic behaviors such as social behavior and sleep. One-photon microscopy allows for the development of a simple and cost-effective imaging system using an affordable excitation light source such as a light-emitting diode. Its excitation light illuminates the entire field of view simultaneously, making it easy to perform high-speed imaging using a high-sensitivity camera. In contrast, the short wavelength of the excitation light limits the field of observation to areas on or near the brain surface due to its strong light scattering. Moreover, the out-of-focus fluorescence makes it difficult to obtain images with a high signal-to-noise ratio and spatial resolution. The use of one-photon microscopy in brain activity imaging has been limited compared to two-photon microscopy, but its advantages have recently been revisited. Therefore, this technique is expected to become a useful method for pharmacologists to visualize the activity of the living brain.

Axcelead Drug Discovery Partners (Axcelead DDP) Inc is the first integrated drug discovery solution provider in Japan. Leveraging drug discovery platforms and knowledge inherited from Takeda Pharmaceutical Company, Ltd. alongside the latest science and technology, our experienced scientists with rich track records promote drug discovery research and contribute to co-creation of innovative drugs together with customers. In this article, we provide an overview landscape of the pharmaceutical industry and emerging trends in drug discovery research, and introduce Axcelead DDP’s services, its unique strengths, and the value (solutions) delivered to customers. Furthermore, we describe the current state of Japan’s bio-community and the roles and challenges for the development and enhancement of a true drug discovery ecosystem in Japan.

Pertuzumab and trastuzumab are anti-HER2 humanized monoclonal antibodies with different mechanisms of action. Their combination is expected to suppress intracellular HER2 signaling additively or synergistically. Their combination is widely recommended worldwide and has been established as a standard of care for HER2-positive breast cancer. However, improvement is required because of the prolonged time of intravenous infusion. Vorhyaluronidase alfa (rHuPH20) depolymerizes hyaluronan in the subcutaneous connective tissue. It’s reported to increase the permeability and absorption levels of drugs. PHESGO^® combination for subcutaneous injection MA/IN (PHESGO^®) is a fixed-dose combination of pertuzumab, trastuzumab, and rHuPH20. A confirmatory phase III study (FeDeriCa) was conducted following a dose-finding phase I study (BO30185). Patients with HER2-positive early breast cancer were randomly assigned to receive either intravenous infusion of pertuzumab and trastuzumab or subcutaneous injection of PHESGO^®, in combination with chemotherapy, to compare the pharmacokinetics (PK), efficacy and safety. A phase II study (PHranceSCa) was also conducted to assess patients’ preference and satisfaction. Based on these results, population PK analysis, and other data, PHESGO^® obtained marketing approval in Japan in September 2023 with indications for “HER2-positive breast cancer” and “advanced or recurrent HER2-positive colorectal cancer that has progressed following cancer chemotherapy and is not amenable to curative resection”. By reducing the administration time, PHESGO^® is expected to contribute to various needs of patients and improvement of their daily lives. Since drug preparation is not required, it can provide convenience to healthcare professionals, leading to stress reduction of medical resources as well.

Inclisiran sodium (Brand name: LEQVIO^® for s.c. injection syringe 300 ‍mg, hereinafter referred to as inclisiran), a small interfering ribonucleic acid (siRNA) product that targets the mRNA that encodes the proprotein convertase subtilisin/kexin type 9 (PCSK9) protein was approved on September 25, 2023 for the indication of “Familial hypercholesterolemia, hypercholesterolemia” in Japan. Inclisiran is conjugated on the sense strand with triantennary N-acetylgalactosamine to facilitate uptake by hepatocytes. In vitro and in vivo pharmacology studies demonstrated the lowering effects of PCSK9 and LDL-C in hepatocytes and cynomolgus monkeys. It was considered unlikely to cause clinically significant risks due to toxicities arising from complementary binding to non-target RNA sequences (hybridization-dependent off-target effects). Clinical trials conducted globally including Japan in patients with familial hypercholesterolemia and hypercholesterolemia who did not reach the LDL-C target showed that inclisiran sodium 300 ‍mg dosed at Day 1, Day 90 and then every 6 months demonstrated significant LDL-C reduction and the efficacy sustained long. The majority of patients achieved the guideline recommended LDL-C targets. Inclisiran sodium 300 ‍mg was well tolerated and there were no specific safety concerns. Therefore, inclisiran is expected to be a new therapeutic option for the patients with familial hypercholesterolemia and hypercholesterolemia.

Ensitrelvir fumaric acid (Xocova^® hereafter ensitrelvir) is a novel anti-SARS-CoV-2 drug for COVID-19. Hokkaido University and Shionogi & Co., Ltd. engaged in joint research targeting SARS-CoV-2 3C-like (3CL) protease at an early stage and started clinical trials in July 2021. In February 2022, an application was filed for manufacture and sales approval for the indication of “SARS-CoV-2 infection,”. Ensitrelvir recieved the first emergency regulatory approval from the Ministry of Health, Labour and Welfare (MHLW) in Japan in November 2022, and has obtained standard approval in March 2024. This emergency approval was based on the confirmed safety in a Phase 2/3 study (T1221) conducted in Japan and other Asian countries (Korea and Vietnam) in patients with mild/moderate COVID-19 and the presumed efficacy in Phase 3 Part (SCORPIO-SR), and the standard approval is based on efficacy from the Phase 3 part. In the Phase 3 part, ensitrelvir administered orally 375/125 ‍mg once daily for five days, in patients with irrespective of risk factors for severe complications and vaccination status, demonstrating a significant reduction vs placebo in the time to resolution of five typical Omicron-related symptoms (stuffy or runny nose, sore throat, cough, feeling hot or feverish, and low energy or tiredness), and also showed a significant reduction in viral RNA on day 4 relative to placebo (P < 0.001). In the Phase 2/3 study, there were no serious adverse events or deaths, indicating good tolerability and safety. We hope that ensitrelvir will contribute as a new treatment option for patients suffering from COVID-19 symptoms.