成果報告書詳細
管理番号20110000001415
タイトル*平成22年度中間年報 基礎研究から臨床研究への橋渡し促進技術開発/橋渡し促進技術開発/アルツハイマー病の根本治療を目指した新規治療法の研究開発(国立大学法人京都大学担当分)
公開日2012/12/26
報告書年度2010-2010
委託先名国立大学法人京都大学
プロジェクト番号P07022
部署名バイオテクノロジー・医療技術部
和文要約和文要約等以下本編抜粋:1. 研究開発の内容及び成果等 I-1: 老齢疾患モデルマウスを用いた抗体投与の有効性と安全性の検証 (京都大学医学研究科先端技術センター/腫瘍生物学講座) (1)齧歯類モデルを用いた特異抗体の有効性の検証 ヒトスウェーデン型突然変異を持つアミロイド前駆体タンパク質APP を過剰発現させたマウス「APP23」をモデルとして用い、有効性を検証します。APP23 は、14 ヶ月齢以降に神経細胞脱落が海馬に認められ、それに伴って学習障害が起きることからヒトの病態を良く反映していると考えられている。大規模な人工交配により約2000 個の凍結胚を用意し、それより214 匹のオスAPP23 マウスと213 匹のオス野生型マウスの産仔を得た。これらは、14 ヶ月齢に達する1 月より抗体の投与を行い、学習行動解析の後、病理解析並びに生化学的解析により神経細胞脱落とASPD の蓄積の関係を解析する予定である。予備的検討として、本実験には用いない11 ヶ月齢のメスマウスに抗ASPD 抗体を投与した結果から、抗ASPD 抗体の投与によって一般的な健康状態には影響がなく、活動性や不安様行動などの情動性も有意な差は認められていないため、抗体を投与することによる副作用は非常に小さいことが確認された。 今後、認知課題での影響を調べ、本実験での抗体投与量などを検討するための基礎データとする。
英文要約Title: Research aiming the development of new rational therapies for Alzheimer's disease.(FY2009-2010)FY2010 Annual Report
Currently, Alzheimer's disease (AD) causes about 60 % of dementia, which affects two million people in our country and thirty million more in worldwide, yet there exists no effective treatment so far. One of the problems with conventional treatment strategies is, although the patients’ brains contain various assemblies derived from amyloid β-protein (Aβ), that Aβ treatments to remove Aβ have been developed without clarifying which type of Aβ assemblies indeed serves as a toxin that causes neurodegeneration in AD brains. Unfortunately, results of most clinical trials of these therapies showed safety issues. In this situation, we consider that new treatments need to be developed based on a better understanding of the causative agent. We therefore isolated the toxic agents from the brains of AD patients, which we termed amylospheroids (ASPDs) (Noguchi et al. JBC 2009). ASPDs appear to acquire their strong neurotoxicity by forming unique toxic surfaces specific to them. We have succeeded to develop anti-ASPD antibodies that recognize the ASPD-specific tertiary structures and can neutralize the ASPD neurotoxicity. Here, we aim to develop an immunotherapy that targets the causative agent using an anti-ASPD antibody developed in our group. Since we have both antibody and antigen at hand, we also aim to develop an active immunotherapy using ASPDs themselves. Such therapies cannot be developed without identifying the neurotoxic assemblies that indeed exist in AD patient brains.
Following is our goal in this project;
(1) As for a passive immunotherapy using an anti-ASPD antibody, we will validate the concept using aged monkeys. After confirming effectiveness and safety of the antibody, we will start the exploratory clinical study with the approval of the Ethics Committee.
(2) As for an active immunotherapy using ASPDs, we will examine the effectiveness of vaccines using aged monkeys by monitoring PET changes as well as the cerebrospinal fluid AD markers.
(3) Based on the results obtained from the aged monkeys, we will determine a protocol for the exploratory clinical study, which shall be started with the approval of the Ethics Committee.
To reach the goals above, we have performed the following three projects: I. The validation of the concept targeting ASPDs using anti-ASPD antibodies, II. Developing ASPD vaccine therapy, III. Verification of safety and effectiveness of these therapies in exploratory clinical studies. As for the project I, we manufactured the drug substance and the test items were examined in non-clinical studies. As for the project II, we found administration of ASPD without adjuvant could produce antiserum against ASPDs. We newly developed both anti-ASPD and anti-anti-ASPD antibodies sandwich ELISA system. As for the project III, we determined the overall protocols of the exploratory clinical study and the future time schedule towards the Ethics Committee review. As noted above, our project has proceeded smoothly as planned this year.
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