Folia Pharmacologica Japonica最新文献

Distal myopathy with rimmed vacuoles (GNE myopathy) is an incurable disease that develops after the late teens, progresses slowly, and has no effective treatment. It is inherited in an autosomal recessive manner, and the number of patients in Japan is estimated to be around 400. The causative gene was revealed to be GNE, the rate-limiting enzyme in the sialic acid biosynthesis pathway, and non-clinical studies demonstrated the effectiveness of sialic acid. Tohoku University Hospital conducted an investigator-initiated phase I trial with aceneuraminic acid in 2010. After that, trials were conducted overseas, and a phase II trial using acenoiraminic acid sustained-release tablets confirmed that muscle strength in the upper limbs had recovered, and the drug progressed to a phase III trial. In Japan, a Phase II/III study was conducted at five domestic facilities using the same protocol as the overseas Phase III study, and efficacy and safety were confirmed. However, Phase III trials overseas failed to show efficacy and development was discontinued. An additional confirmation study was conducted in Japan, and as a result of confirming reproducibility, the product was approved for manufacturing and sales in March 2024, ahead of the rest of the world. This is a successful example of the development of a therapeutic drug for an ultra-orphan disease, which is said to be difficult to develop, and is expected to lead to early treatment for patients.

In the overall Japanese population, the prevalence of perennial allergic rhinitis (AR) increased from 18.7% to 24.5% from 1998 to 2019. For Japanese cedar pollen (JCP) induced AR, the prevalence in the same period increased from 16.2% to 38.8% in the general population and from 7.2% to 30.1% in children (5-9 years), indicating a serious problem especially in younger age groups. Allergy immunotherapy (AIT) is an AR treatment modality that induces immune tolerance to allergens by repeated allergen administration and is the only treatment form that reduces symptoms and medication use and provides sustained effect after treatment completion. In Japan, AIT is available primarily as sublingual immunotherapy (SLIT) tablets. Two tablets based on a freeze-dried formulation (a JCP SLIT-tablet, approved 2018, and a house dust mite (HDM) SLIT-tablet, approved 2015), and one tablet based on a compressed formulation (HDM, approved 2015) are available. For SLIT to be effective, the concentration of allergen when solubilized in saliva must be as high as possible for as long as possible within the recommended sublingual holding time (1-2 minutes), parameters that must be supported by the tablet formulation. The characteristics of the freeze-dried and compressed formulations were compared using the HDM SLIT-tablets. Freeze-dried tablets disintegrated immediately and displayed fast and complete HDM allergen release in solvent, while compressed tablets disintegrated more slowly and provided only incomplete allergen release. Freeze-dried SLIT-tablets are believed to provide full mucosal availability of the allergen content during the sublingual holding time, and a low medication burden.

Futibatinib (Lytgobi_® Tablets 4 ‍mg), a novel fibroblast growth factor receptor (FGFR) inhibitor developed by Taiho Pharmaceutical using the Cysteinomix Drug Discovery Platform, was approved in Japan in June 2023 for the treatment of patients with unresectable biliary tract cancer with FGFR2 fusion or rearrangement that had progressed after at least one prior chemotherapy. Futibatinib covalently binds to the cysteine residue in the FGFR kinase domain P-loop structure and is believed to exert antitumor activity by selectively and irreversibly inhibiting FGFR1-4. Many FGFR inhibitors under development are ATP-competitive; however, futibatinib is the first approved covalently-binding irreversible FGFR inhibitor. It inhibits cell proliferation by inhibiting FGFR phosphorylation and its downstream signaling pathways in cancer cell lines. Futibatinib showed inhibitory activity against a wider range of FGFR mutants than ATP-competitive, reversible FGFR inhibitors and inhibited cell proliferation without significantly deviating from the inhibitory effect on wild-type FGFR. Futibatinib showed antitumor efficacy in mice subcutaneously transplanted with human tumor cell lines driven by FGFR. The international phase 2 study (TAS-120-101) was conducted in patients with refractory intrahepatic cholangiocarcinoma with FGFR2 fusion or rearrangement. The overall response rate was 41.7%, showing consistent efficacy regardless of co-occurring genomic alterations. Although some typical FGFR inhibitor-related side effects were observed, they were manageable and futibatinib had a good safety profile. Futibatinib is an important drug for biliary tract cancer, which has limited treatment options; its development is underway for other types of cancer, and it is expected to benefit more patients.

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.

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.

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.