Based on the plan for Promotion of Medical Research and Development prescribed by the government of Japan, Japan Agency for Medical Research and Development (AMED) promotes integrated R&D in the field of medicine, from basic research to clinical trials, focusing on interrelated areas including regenerative medicine and oncology. In addition to ensuring that outcomes are linked through to practical application, it undertakes projects with aim of comprehensively and effectively establishing and maintaining an environment for this R&D. The project for psychiatric and neurological disorders accelerates endeavors aiming to overcome dementia, depression, and other brain disorders. Our goal is to establish innovative strategies for diagnosis, prevention, and treatment of brain disorders through the strong promotion of research on neural circuits and brain functions related to pathophysiology of brain.
Pathological and molecular genetic analyses have revealed that amyloid-β peptide and tau protein are involved in the pathogenesis of Alzheimer disease (AD). Moreover, identification of cerebrospinal biomarker, advances in brain imaging and results of observational cohort studies indicate that AD is a chronic disease with abnormal protein metabolism in the brain. Current approaches targeting pathogenic molecules for AD have been developed as preventive medicine. In addition, abnormal protein aggregation is now recognized as a common pathological feature of neurodegenerative diseases that cause dementia. Thus, cellular pathologies in the brain along with the deposition of aggregated protein are highlighted as novel therapeutic key targets in the drug development.
We are developing an efficient blood-brain barrier(BBB)-crossing drug delivery system utilizing a physiological glucose transport pathway via glucose transporter-1(GLUT1). Several drug carriers targeting GLUT1 by incorporating glucose as the ligand have been tried, but none of them was transported into the brain at a high level upon intravenous administration. Thus, we adopted an original biological strategy of glycemic control. We constructed a self-assembled supramolecular micellar nanoparticle, having a property as a drug carrier, decorated with glucose ligands on the surface. Intravenously injected glucose-decorated nanoparticle accumulated highly in the brains of mice in response to an increase of glycemic concentration after a prior fasting condition. We observed the transport of glucose-decorated nanoparticle from cerebral blood vessels into brain parenchyma in real time, and identified the delivery of glucose-decorated nanoparticle into neurons and microglia. The BBB-crossing delivery is considered to occur along with the phenomenon of intracellular recycling of GLUT1 in the brain microvascular endothelial cells. Our novel BBB-crossing technology introducing glycemic control as an animal-side conditioning is expected to become a powerful tool for delivering high molecular drugs such as oligonucleotide and monoclonal antibody drugs, to achieve effective disease modifying therapy in the brain.
The occurrence of dementia, such as during Alzheimer’s disease, has grown with increasing average age in human society. We currently have very limited options in terms of medicines that symptomatically delay the development of dementia in early stages without curing the disease. In the past few decades, while several pharmaceutical companies have taken up the challenge of developing such medicines, candidate drugs have typically failed to show the expected therapeutic effects in humans, presumably because of their low efficiency of distribution to the brain. We have recently developed the strategy to effectively deliver the new candidate peptide drugs, such as insulin and GLP-1 receptor agonist (Exendin-4), for treatment of dementia via intranasal administration. Nasal administration is currently considered an ideal route for delivering drugs to the central nervous system by bypassing the blood-brain barrier. We demonstrated that nasal coadministration of peptide drugs with CPPs can accelerate their nose-to-brain transport and improve or prevent the cognitive dysfunction in the senescence-accelerated mouse. Thus, our study suggests that nose-to-brain delivery of insulin and exendin-4 via coadministration with CPP shows promise for the treatment of cognitive dysfunction in dementia.
In Japan, a rare disease is defined as a condition that affects less than 50,000. Of those diseases, lysosomal storage diseases, a group of inherited metabolic diseases, are well known, characterized by abnormal accumulation of various toxic substrates in cells as a result of enzyme deficiencies. There are more than 50 disorders altogether in this group, and they may affect different parts of the body, including the liver, spleen, heart, skeleton, brain, and central nervous system. Hunter syndrome（MPS II） is a lysosomal storage disorder resulting from a lack of a specific enzyme that breaks down mucopolysaccharides, and over 70 percent of the patients show progressive central nervous system(CNS) manifestations. Although enzyme replacement therapy(ERT) is effective on systemic symptoms, current ERT product cannot address CNS manifestations because the therapeutic enzyme does not cross the blood-brain barrier. To overcome this problem, we successfully developed JR-141, a novel ERT product for treatment of MPS II using our proprietary antibody-based drug delivery system called “J-Brain Cargo®” for delivering enzymes of interests across the blood-brain barrier. In this paper, we present the data from the Phase I/II clinical trials with JR-141 as well as the brain distribution and efficacy data for JR-141 in mice and monkeys.
One of the main obstacles for the drug development for central nervous system disease is the strong tight junction-seals in the blood-brain barrier (BBB). Claudin-5 (CLDN-5) is the essential protein for tight junction in the BBB, which restricts the influx of small molecules up to 1 kDa. Many researchers have attempted to develop methodologies to selectively inhibit the CLDN-5 dependent tight junction and open the BBB. Recently, our group successfully developed anti-CLDN-5 monoclonal antibodies that inhibit the barrier function of CLDN-5. In this review, we introduce the characteristics of our anti-CLDN-5 monoclonal antibodies, and discuss potential of tight junction modulators for treating central nervous system diseases.
So far, drug contribution has been low for the treatment of diseases in the central nervous system (CNS). This is partly because drug delivery system(DDS)which can migrate across the blood-brain barrier has not been successfully developed, and it has been difficult to develop new drugs for CNS diseases. Although some developing drugs have progressed to phase II or III in clinical trials, they are not always successful. However, some of the approved drugs for the CNS diseases have been effective when directly administered by highly invasive methods into the CNS, such as the medullary cavity. In this paper, we describe the expectation for the latest DDS technology from the viewpoint of the Pharmaceuticals and Medical Devices Agency, based on the background that there are needs to improve the situation.
The orally disintegrating tablets REMITCH® OD TABLETS 2.5µg composing Nalfurafine hydrochloride was launched. The composition rate of the active ingredient is extremely low and the Nalfurafine is unstable for temperature, humidity and light. To overcome these difficulties, the original film coating technology for OD tablets “RADIFIL®” was developed and applied to “REMITCH® OD TABLETS 2.5µg”. The key technology of RADIFIL® and the bioequivalence study between REMITCH® CAPSULES 2.5μg and REMITCH® OD TABLETS 2.5µg was summarized in this report.