TOP ＞ Symposium

Symposium 28 Parkinson's disease: Translational from clinic to research シンポジウム28 日本神経化学会臨床連携委員会企画シンポジウム パーキンソン病：臨床から研究へのトランスレーショナル SY28-1 Novel anti α-Synuclein therapy using antisense oligonucleotide containing Amido-bridged nucleic acid AmNA修飾アンチセンス核酸を用いた新規αシヌクレイン治療 Mochizuki Hideki（望月 秀樹） Dept.of neurology, Osaka Univ Parkinson’s disease (PD) is a neurodegenerative disease caused by loss of dopaminergic neurons in the substantia nigra. One of the characteristic pathological features of PD is the cytoplasmic accumulation of alpha-synuclein (SNCA) protein. The identification of SNCA gene multiplication in familial PD and the pathological SNCA protein accumulation along the disease progression in sporadic PD, suggest that increased levels of SNCA protein might be a significant risk of PD. Hence, reducing expression levels of SNCA might delay onset or modify course of the disease. The aim of our study is to establish a novel therapy for PD by using antisense oligonucleotide (ASO) targeting SNCA. To knock down levels of SNCA mRNA efficiently, we designed and synthesized amido-bridged nucleic acids (AmNA)-modified ASO with improved stability and cellular uptake in vivo. We evaluated the potency of AmNA-ASO targeting SNCA in HEK cells. We injected AmNA-ASO into intraventricular space of mice and measured expression levels of SNCA gene and protein in the brain of SNCA transgenic mice. We also performed behavioral tests of the mice. AmNA-ASO significantly downregulates SNCA at both mRNA and protein levels in vitro and in vivo. Notably, AmNA-ASO can be efficiently delivered into mouse brain by intracerebroventricular injection without the aid of additional chemicals. Administration of AmNA-ASO ameliorates neurological defects in the PD model mice expressing human wild-type SNCA. We have established AmNA-ASO targeting SNCA efficiently. Our study suggests that treatment using AmNA-ASO is a promising therapeutic strategy for SNCA-associated pathology in PD. SY28-2 Translational from clinical research: from the point of view of neuropathology 臨床から研究へのトランスレーショナル：神経病理の立場から Saito Yuko（齊藤 祐子） Dept. of Neuropath., NCNP It has been 10 years since we started brain bank activities based on our living consent system at our facility. Today, it covers mental / neurological disorders / control group, but initially it was a process of treating the subject as "Parkinson's disease", registrants of Parkinson's disease and related diseases, and therefore until now the number of pathological autopsies is very large Usually, as for Parkinson's disease patient, most doctors are unlikely to have doubts about diagnosis, in addition, most of the death facilities can’t perform pathologic anatomy, so that in clinical practice there is little opportunity to get pathological diagnosis and research consent. However, on the patient side, there are many people who have volunteers' desire to help research for overcoming long-standing diseases. That's why common disease, autopsy and registration in brain bank are necessary, and demand from researchers is also high. Bridging the needs of those volunteers and researchers is nothing but our activity. Indeed, I have the opportunity to learn from precious cases. For example, autopsy cases of rare cases, such as cases that were thought to be Parkinson's disease but were different diseases, the cases where young deaths resulted in pathological autopsy and the cases that were scrutinized at the prodromal PD time and died earlier, etc. Now such important cases are accumulating. Although it is still in the case reporting stage, it is expected to increase the important samples of brain bank registrations in the future. We believe that the path to drug discovery will be opened through examination in many cases. SY28-3 Biomarker for Lewy body diseases レビー小体病のバイオマーカー Ono Kenjiro（小野 賢二郎） Dept. of Neurol., Showa Univ. Sch. of Med. Although α-synuclein protein (αS) aggregates from a monomer to assemblies such as oligomer, protofibril and mature fibril, the early intermediate aggregate, that is, oligomer has been considered to be most critical species in the pathogenesis of Lewy body diseases, that is, Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). While it was reported that αS concentration in cerebrospinal fluid (CSF) was decreased significantly in the patients with PD and DLB, there were reports that αS oligomer concentration was elevated in CSF and blood of PD patients. Recently, it was reported that alterations in blood total and exosomal αS concentrations are likely associated with PD progression, especially in the aspect of cognitive impairment, at early stages of the disease. In addition, it was reported that lower cerebrospinal β-amyloid (Aβ)(1-40) and Aβ(1-42) levels were also associated with cognitive decline in PD. Further combination studies with CSF and blood would lead to establishment of the candidates such as αS and Aβ as biomarkers for Lewy body diseases. SY28-4 Stem cell-based therapy for Parkinson's disease パーキンソン病に対する幹細胞治療 Takahashi Jun（高橋 淳） Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan 中枢神経系は再生能力が乏しく、失われた神経機能の回復は非常に困難である。しかしES細胞、iPS細胞を含む幹細胞に関する研究が進み、神経疾患治療において薬物や機器とは違う新たな治療戦略が加わろうとしている。近年iPS細胞を用いた神経再生医療が現実味を帯びており、パーキンソン病はその対象疾患のひとつと考えられている。我々は臨床応用に向けて、マウスフィーダー細胞を使わずラミニンフラグメントを用いて大量の神経誘導を行う技術を開発した。また、コリンというfloor plateの特異的表面マーカーを用いて、ドパミン神経前駆細胞のみを選別するセルソーティング技術の開発を行った。これにより、ドパミン神経細胞の純度が高まり不必要な増殖性細胞（未分化iPS細胞や初期神経幹細胞など）を取り除くことができ、有効かつ安全なドパミン神経前駆細胞を安定して作製することが可能になった。さらにこの方法で作製したヒトiPS細胞由来ドパミン神経前駆細胞をカニクイザルのパーキンソン病モデルに移植し、その有効性と安全性を確認した。細胞移植を受けたカニクイザルは自動運動の量が増加し、パーキンソン病症状の改善がみられた。またPET解析では移植細胞が脳内でドパミンを合成していることが確認された。さらに最大2年間の経過観察で腫瘍形成はみられず、脳切片の組織学的解析でも悪性化所見は認められなかった。我々はこれらの結果に基づいて治験を行うべく準備を進めており、本講演ではこれらのiPS細胞を用いた再生医療開発研究の現状についてパーキンソン病を中心に紹介し、臨床応用に向けた課題や展望について述べる。