神経化学
臨床連携委員会企画シンポジウム
基礎研究、創薬開発から治験まで |
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| 7月8日（土） 16:00-18:00 Room A
3SY⑥-1
ALS: iPS細胞を用いた病態解析・創薬・治験・社会実装まで
ALS: From Pathophysiological Analysis, Drug Discovery, Clinical Trials, to Social Implementation Using iPS Cells.
岡野 栄之
慶應義塾大学 医学部 生理学
Hideyuki Okano
Dept. Physiol. Keio Univ. Sch. Med., Tokyo, Japan
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects upper motor neurons in the brain and lower motor spinal cord. We have performed iPSCs-based disease modeling, drug screening, and clinical trial for ALS. In our previous studies, we identified a new ALS drug candidate Ropinirole hydrochloride (ROPI), known as anti-Parkinson Disease drug with D2 Receptor (D2R) agonist activity, that most efficiently suppress ALS-related phenotypes (neurite retraction, mislocalization of FUS/TDP-43, stress granule formation and motor neuron deaths) in a dish. We found that ROPI potentially targets D2R-dependent and independent mechanisms of ALS pathology, including excitotoxicity, oxidative stress, mitochondrial dysfunction, and abnormal aggregation. In vitro results suggest ROPI is superior to existing anti-ALS drugs (riluzole and edaravone). Furthermore, of patients with sporadic ALS, 70% were ROPI-responder by in vitro assay. Our Phase 1/2a clinical trial using ROPI for ALS patients has found that ropinirole is safe and tolerable for patients with ALS. Reduced ALSFRS-R decline at 12 months and delayed disease progression by 27.9 weeks (p=0.008) at 12 months. These results indicate the feasibility of a subsequent large-scale trial, and we are preparing the Phase 3 trial of ROPI for ALS. | | 7月8日（土） 16:00-18:00 Room A
3SY⑥-2
福山型および糖鎖異常型筋ジストロフィーの基礎研究、創薬開発から治験まで
From basic research and drug development to clinical trials in Fukuyama muscular dystrophy and dystroglycanopathies
戸田 達史
東京大学 神経内科
Tatsushi Toda
Dept of Neurology, The University of Tokyo
Fukuyama muscular dystrophy (FCMD) and muscle-eye-brain (MEB) disease are similar disorders characterized by congenital muscular dystrophy, brain and eye anomalies. Hypoglycosylation of α-dystroglycan (α-DG) are common characteristics of these dystroglycanopathies. We identified the genes for FCMD (fukutin) and MEB (POMGnT1). FCMD results from ancestral insertion of a SVA retrotransposon. We show aberrant mRNA splicing induced by SVA exon-trapping. Antisense oligonucleotides (AONs) prevented pathogenic exon-trapping by SVA in patient cells and model mice, rescuing normal fukutin mRNA expression, protein production, O-glycosylation of α-DG and laminin binding by α-DG. We further optimized mix cocktails of AONs to one nucleic acid NS-035 and completed toxicity-safety-efficacy studies. We are now performing investigator-initiated clinical trials with the support of AMED. We identified the unknown glycan unit ribitol 5-phosphate (Rbo5P) that functions for the formation of the ligand-binding moiety of α-DG. We determined the enzyme activities of three major α-DGpathy-causing proteins to be involved in the synthesis of tandem Rbo5P. ISPD is CDP-Rbo synthase. Fukutin and fukutin-related protein are Rbo5P transferases that use CDP-Rbo. We further demonstrate that prodrug treatments (tetra-acetylated CDP-ribitol) can ameliorate muscular dystrophy caused by defects in ISPD. | | 7月8日（土） 16:00-18:00 Room A
3SY⑥-3
HAM研究の基礎から臨床まで
From Basic Research to Clinical Aspects of HAM Studies
山野 嘉久
聖マリアンナ医科大学 脳神経内科
Yoshihisa Yamano
Dept. of Neurology, St. Marianna University, Kawasaki, Japan
In HAM, chronic inflammatory lesions form and persist due to HTLV-1-infected T-cells infiltrating neural tissues and triggering an excessive immune response. Understanding these mechanisms is crucial for treatment.
Our focus is studying HAM pathogenesis, revealing HTLV-1 predominantly infects CCR4-positive cells. Infected cells transform into Th1-like cells, producing excessive IFN-γ and disrupting immune balance, leading to an exaggerated immune response. Additionally, Th1-like infected T-cells in spinal cord lesions induce CXCL10 overproduction from astrocytes, promoting migration of infected T-cells and inflammatory cells, playing a critical role in chronic inflammation and lesion formation/maintenance in HAM.
CXCL10's clinical significance is evident. Real-world data from the National HAM Patient Registry (HAM-net) classify HAM into three disease activities, using CXCL10 concentration in cerebrospinal fluid. Based on this evidence, the "HAM Treatment Guidelines" were created, implementing disease activity classification and stratified treatments, establishing a new treatment algorithm.
We compared infected cells in HAM, ATL, and AC using multi-omics analysis, characterizing genomic/epigenomic abnormalities and gene expression differences unique to each cell type. We aim to present insights gained from these analyses, including potential drug targets. | | | |
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