Alzheimer disease (AD) is characterized by major pathological features in the brain, such as plaques composed of amyloid β protein (Aβ) and neurofibrillary tangles of tau protein. Genetic studies, biochemical data, and animal models suggest that Aβ is a key species in the pathogenesis of AD (amyloid hypothesis). Aβ molecules aggregate to form oligomers, protofibrils, and mature fibrils. We especially focused on soluble Aβ oligomers, which are unstable and difficult to characterize. Using photoinduced chemical crosslinking, we successfully extracted low molecular weight Aβ oligomers, dimers, trimers, and tetramers in a stable state. Compared with monomers, dimers, trimers, and tetramers not only have an increased proportion of β–sheet structure, but also have increased cytotoxicity to neurons. In addition, we have shown that high molecular weight oligomers such as Aβ protofibrils can cause increased oxidative stress to damage cell membranes, leading to reduced membrane fluidity, depolarization, and impaired synaptic plasticity, exerting neuro and synaptic toxicities. These studies suggest that soluble Aβ oligomers are more toxic to neurons and may be the main target for disease–modifying therapy of AD.

Due to its instability and structural heterogeneity, Aβ misfolding and aggregation is a very complex process, leading to various aggregates with different structures and morphologies. We applied high–speed atomic force microscopy (HS–AFM) to investigate its dynamic and structural changes. We found that Aβ42 aggregation not only forms in a stepwise manner, but also has unidirectional advantages. Subsequent studies revealed that mature Aβ fibrils can have linear, helical, hybrid, and other types, which can be interchangeable depending on the surrounding electrolyte. Moreover, we recently used to HS–AFM to reveal that the anti–Aβ monoclonal antibody lecanemab binds to and surrounds protofibrils with high affinity, resulting in the reduction of neurotoxicity.

Neurological and muscular diseases are often difficult to treat, particularly those caused by genetic abnormalities. However, the advent of new therapeutic modalities, such as antisense oligonucleotide drugs and gene therapies, has significantly expanded treatment possibilities. In general, clinical trials for neurological diseases are time–consuming, with a median development period of 87.1 months, longer than other therapeutic areas. A significant issue discussed is the “drug loss” problem, where medications approved overseas remain undeveloped in Japan. This issue, exacerbated by the rise of bioventures in foreign markets, creates disparities in drug availability between Japan and other countries. The need for international cooperation and the evolution of clinical trial methodologies to address these challenges should be discussed, with a focus on improving Japan's drug development capability. Key strategies include promoting collaboration between academia and industry, utilizing real–world data, and fostering international clinical trial networks.

Most medical research is mainly clinical research conducted to gain knowledge that contributes to promoting the public's health, patients' recovery from diseases, or improving the quality of life through understanding the causes of diseases. The establishment of full–fledged ethical guidelines for clinical research was concentrated after 2000. However, the ethical guidelines are not legally binding, nor is administrative guidance for failing to comply. Under such circumstances, the need for a legal system was considered, and the “Clinical Trials Act” was enacted and issued after thorough consideration of the scope of the legal regulations and the content of specific regulations and measures, and came into effect in April 2018.

With the enactment of the Clinical Trials Act, clinical research in Japan now includes clinical trials conducted under the “Act on Securing Quality, Efficacy and Safety of Products Including Pharmaceuticals and Medical Devices”, clinical trials conducted under the “Clinical Trials Act”, and other clinical researches conducted under the “Ethical Guidelines for Medical and Health Research Involving Human Subjects”. In this manuscript, after mentioning the Declaration of Helsinki, on which these laws and regulations are based, the laws and regulations that must be complied with in the above three types of clinical research are summarized.

Good Clinical Practice (GCP) is a set of standards to ensure clinical trials' scientific and ethical conduct. GCP was first introduced in Japan in 1989, but initially, it was not legally binding and caused many problems. Subsequently, in 1996, international standardization efforts led to the formulation of ICH–GCP, which was also introduced into Japanese regulations. This movement strengthened the rules governing the conduct of clinical trials. ICH–GCP became an essential guideline for improving the quality of clinical trials in Japan and around the world. However, the existing GCP could not adequately respond to the drastically changing clinical development environment for pharmaceuticals, and revising the GCP began in 2013. ICH–E6 (R2) introduced new concepts regarding quality management and monitoring. Furthermore, in 2017, ICH published a new proposal called “GCP Renovation” to address the diversification of clinical trial designs and data sources. Based on this proposal, ICH developed ICH–E8 (R1) and ICH–E6 (R3), introducing a new approach to quality management in clinical trials. In particular, the concept of Quality by Design (QbD) was emphasized, and efforts to improve quality from the planning stage of clinical trials are essential. Quality management in clinical trials is expected to improve trial efficiency and reliability by introducing risk–based approaches (RBA) and QbD. The entire process ensures that clinical trial deliverables meet expected standards. Clinical Researchers should set different quality standards for each trial and conduct ongoing quality control to meet those standards.

The development of treatments for ALS has been active in recent years, and including pre–clinical trials, there are around 50 clinical trials being conducted worldwide, the most of any neuromuscular disease. In Europe and North America, there is a problem with the large number of clinical trials that ALS patients can participate in, and this has become a new issue in ALS clinical trials called “pipeline pressure”. An attempt to overcome this “pipeline pressure” is being developed by the NEALS (Northwest ALS consortium) in North America. Based on the current situation of ALS clinical trials in Japan, we will introduce the platform trials by NEALS, as well as initiatives for rare cancers and neuroimmunological diseases (CIDP, NMOSD) in Japan, and finally outline the prospects for ALS clinical trials. To avoid the drug loss in ALS in Japan, the key is to consider the establishment of a genetic testing system, the formulation of clinical trial guidelines, and the introduction of adaptive trials that optimize the clinical trial process.

The elucidation of rare disease pathogenesis and the development of novel therapeutics have traditionally progressed at a slow pace. To overcome this, establishing a comprehensive platform that facilitates drug discovery and the creation of patient registries for rare diseases is urgently needed. Such a platform should not only accelerate drug development but also enhance the understanding of disease mechanisms through clinical epidemiological studies and genomic and multi–omics analyses. Additionally, fostering collaborations between academia and industry is essential for translating research into therapeutic breakthroughs more rapidly.

The Rare Disease Data Registry of Japan (RADDAR–J) serves as a critical repository of information, encompassing nearly half of the 341 designated intractable diseases. Its publicly accessible database provides detailed catalogs of registries and biorepositories managed by rare disease research groups, thereby fostering cooperation between academia and industry.

In recent years, patient registries have increasingly been used across various stages of pharmaceutical development, including post–marketing surveillance, cohort studies on disease progression, and patient recruitment for clinical trials. This paper provides a comprehensive overview of the activities conducted under the Rare Disease Platform and explores emerging trends in the application of real–world data (RWD) and real–world evidence (RWE) in the study and treatment of rare diseases.

Research and development for diseases in the field of neurology have dramatically advanced over the past two decades. This owes to the identification of disease causes through advances in genome research, the development of imaging and body fluid biomarkers, the enhancement of academia–led research such as physician–led clinical trials and registries, and the development of new modalities of therapeutic agents such as nucleic acid medicine and antibody therapy. In particular, genomics and biomarkers are undergoing extremely rapid technological innovation and are expected to be further utilized for diagnosis and prognosis prediction of diseases, and for stratification in clinical trials. Biotechnologies such as cell therapy, genome editing, and CAR–T, as well as bioengineering technologies such as robotics and brain–computer interfaces, are also being applied to neurological diseases. Further innovations are expected to emerge in the future, such as the integration of different modalities and the combination of pharmaceuticals and medical devices. The Japanese Society of Neurological Therapeutics established the Drug Discovery Working Group in 2020 with the aim of stimulating the development of treatments for neurological diseases, and in 2022, this working group became the Drug Discovery Promotion Committee, which has been promoting projects including the support for clinical trial execution, initiation of a consultation service for clinical research, and holding symposium. This article introduces the activities of the Drug Discovery Promotion Committee and explains the current status and prospects of drug discovery in the field of neurology, which is the background of the committee's activities.

【目的】球脊髄性筋萎縮症（spinal and bulbar muscular atrophy：SBMA）の歩行障害に対して，hybrid assistive limb^®医療用下肢タイプ（HAL）を用いた治療（HAL治療）が保険適応となっているが，SBMA単独での有効性評価は十分とは言えない．SBMAに対するHAL治療の効果について後方視的に検討した．

【方法】HAL治療を実施したSBMA患者13名．HAL初回クール（1回40分，9回のHAL治療で1クール）実施前後の2分間歩行距離（2MD），6m歩行時間，Timed Up & Go test（TUG），creatine kinase（CK）を比較した．

【結果】治療の前後で2MD，6m歩行時間，TUGは有意に改善した（それぞれ，p=0.003，p<0.001，p=0.002）．CKに有意な差は認められなかった（p=0.425）．

【結論】HAL治療がSBMAの歩行障害に対して有用である可能性が示唆された．