神経化学
企画シンポジウム
プロテイノパチーの疾患修飾療法への展望 |
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| 7月6日（木） 9:00-11:00 Room A
1SY①-1
アルツハイマー病の疾患修飾療法
Disease-modifying therapies for Alzheimer's disease
小野 賢二郎
金沢大学医薬保健研究域 脳神経内科学
Kenjiro Ono
Dept. of Neurol., Kanazawa Univ.
Alzheimer's disease (AD) is currently treated with acetylcholinesterase inhibitors and NMDA receptor antagonists. These drugs are limited to symptomatic therapy, and the symptoms will eventually progress. Therefore, there is an urgent need to develop a disease-modifying therapy (DMT) that suppresses the pathological change itself. Pathological features of AD include senile plaques composed of amyloid β protein (Aβ), neurofibrillary tangles composed of tau protein (tau), and neuronal cell death. In AD pathogenesis, the process in which Aβabnormally aggregates prior to tau and damages neurons is considered to play an important role (amyloid hypothesis). Although fibrils were previously thought to be neurotoxic, the toxicity of early and intermediate aggregates such as oligomers and protofibrils is recently emphasized (oligomer hypothesis). Based on these hypotheses, various DMTs have been developed centering on anti-Aβ antibodies. Unfortunately, many have failed, but some promising DMTs remain. In June 2021, the US Food and Drug Administration (FDA) conditionally approved aducanumab as the world's first DMT for AD. Although approval was postponed in Japan at the end of the same year, lecanemab, an anti-protofibril antibody, was also approved by the FDA in January 2023, and the development of DMTs for AD, mainly anti-Aβ antibodies, is progressing steadily. | | 7月6日（木） 9:00-11:00 Room A
1SY①-2
筋萎縮性側索硬化症の疾患修飾療法
Disease-modifying therapies for amyotrophic lateral sclerosis
狩野 修, 渋川 茉莉, 蝦名 潤哉, 花城 里依, 長澤 潤平, 柳橋 優, 平山 剛久
東邦大学医学部内科学講座神経内科学分野
Osamu Kano, Shibukawa Mari, Junya Ebina, Sayori Hanashiro, Junpei Nagasawa, Masaru Yanagihashi, Takehisa Hirayama
Dept. of Neurology, Toho Univ. Tokyo, Japan
Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease characterized by the degeneration of upper and lower motor neurons. Homeostasis of motor neuron depends on local translation through controlled regulation of axonal mRNA localization, transport, and stability. Cytoplasmic aggregation of TDP-43 is a pathological hallmark of ALS and frontotemporal dementia, however, what drives its nuclear clearance have not been determined. TDP-43-positive inclusions are detected in most of all ALS cases, and nearly half of Frontotemporal lobar degeneration (FTLD) cases. Hence, ALS and FTLD are recognized as forming continuum of broad neurodegenerative diseases, and TDP-43 is recognized as playing an important role in the pathogenesis of ALS. The pathogenic mechanism is unknown and various pathways have been proposed but can be divided into loss of function associated with the loss of TDP-43 from the nucleus, and gain of toxicity associated with the formation of cytoplasmic aggregates. Riluzole and Edaravone are the only ALS drugs currently available in Japan, but their efficacy is limited. In recent years, molecular therapy approaches have gained traction in ALS. These come in modalities that offer the ability to selectively silence, upregulate, edit, or introduce a gene or transcript to correct the underlying cause of disease. | | 7月6日（木） 9:00-11:00 Room A
1SY①-3
タウオパチーの疾患修飾療法
Disease-modifying therapies for tauopathies
村松 大輝, 小野 賢二郎
金沢大学 脳神経内科
Daiki Muramatsu, Kenjiro Ono
Department of Neurology, Kanazawa University, Kanazawa, Japan
Tauopathies are neurodegenerative diseases characterized by the abnormal deposition of tau protein in the brain. These include Alzheimer’s disease, progressive supranuclear palsy, corticobasal degeneration, frontotemporal lobar degeneration, argyrophilic grain disease, and chronic traumatic encephalopathy. Many aspects of the pathological mechanism of tauopathies remain unknown, and there are currently no disease-modifying therapies (DMT) available to treat tauopathies. Abnormal phosphorylation, oligomerization, and fibrillization of tau are closely involved in the pathogenesis of tauopathies. Many therapeutic agents have been developed to inhibit these tau aggregation processes. DMT for tauopathies currently in development include tau aggregation inhibitors, immunotherapy, kinase inhibitors, and microtubule stabilizers. These therapeutic agents have been shown to reduce tau lesions and improve cognitive impairment in animal models. Many clinical trials have been conducted for Alzheimer’s disease, progressive supranuclear palsy, and frontotemporal lobar degeneration; however, most of these trials failed to show significant improvements in patients. Although no DMT are yet available, many new agents are still in clinical trials to find effective DMT for tauopathies. | | 7月6日（木） 9:00-11:00 Room A
1SY①-4
パーキンソン病の疾患修飾療法
Disease-modifying therapy for Parkinson's disease
望月 秀樹
大阪大学大学院医学系研究科神経内科学
Hideki Mochizuki
Department of Neurology, Osaka University Graduate School of Medicine
Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive movement disability accompanied by non-motor symptoms. The neuropathology hallmark of PD is the loss of dopaminergic neurons predominantly in the substantia nigra pars compacta and the presence of intracellular inclusions termed Lewy bodies, which are mainly composed of α-synuclein (αSyn). Detailed staging based on the distribution and progression pattern of αSyn pathology in the postmortem brains of PD patients revealed a correlation with the clinical phenotypes but not invariably. Cumulative evidence from cell and animal studies has implied that αSyn propagation contributes to the anatomical spread of αSyn pathology in the brain. I review our studies on the structural analysis of αSyn and LBs, the cell-to-cell propagation of αSyn as well as αSyn fibril polymorphisms, which underlie the phenotypic differences in synucleinopathies. Reduction of αSyn production may provide a disease-modifying therapy for synucleinopathies. I also introduce our disease-modifying therapeutic approach for PD. | |
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