JP5433410B2 - 脳の損傷を診断するためのマーカーとしてのオルニチントランスカルバミラーゼ(otc)の使用 - Google Patents
脳の損傷を診断するためのマーカーとしてのオルニチントランスカルバミラーゼ(otc)の使用 Download PDFInfo
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- JP5433410B2 JP5433410B2 JP2009505996A JP2009505996A JP5433410B2 JP 5433410 B2 JP5433410 B2 JP 5433410B2 JP 2009505996 A JP2009505996 A JP 2009505996A JP 2009505996 A JP2009505996 A JP 2009505996A JP 5433410 B2 JP5433410 B2 JP 5433410B2
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- ornithine transcarbamylase
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Description
(i) 多数の遺伝子の発現は、ADの病因の間に修飾される(Blalockら, 2004; Brownら, 2002; Colangeloら, 2002; Liら, 2003; Loringら, 2001);
・ 第1の技術によると、髄液試料中のOTCの存在は、OTC活性を検出することにより決定される。OTC活性の量的測定により、OTCの定量も可能になる。OTC活性を検出するのに用い得るアッセイは、以下及び科学文献に記載される(Ishikawaら, 2003; Ohshitaら, 1976)。好ましい実施形態において、OTC活性は、上記の試料にカルバミルホスフェート及びオルニチンを添加した後に生成するシトルリンの生成を測定することにより検出される。有利には、OTCの基質であるカルバミルホスフェート及びオルニチンは、試料に過剰に加えられ、シトルリンの生成は、所定の時間の間測定される。シトルリンの生成は、比色アッセイにより、例えばOhshita, Takedaら(1976)に記載されるような、除蛋白を行わないジアセチルモノキシム-チオセミカルバジド反応を用いることにより測定できる。
特に、本発明は、個体からの生体試料中のオルニチントランスカルバミラーゼ(OTC)遺伝子の発現を制御する領域の遺伝子型を同定する工程を含む、個体が脳疾患を発病する危険性の増加をインビトロで予測するか、又は個体での脳疾患をインビトロで診断するための方法に関する。この方法は、神経変性性疾患、特にアルツハイマー病の危険性の増加の予測、又はそのインビトロでの診断に特に適切である。もちろん、本明細書に記載される新しい遺伝マーカーを、試験の統計的有意性を増加させるために、他のマーカー、例えばアポリポプロテインE遺伝子と組み合わせ得る。
図面の凡例
図1: 脳における尿素サイクルの酵素の発現。RT-PCR実験。トータルRNAを、トランスクリプトーム分析に用いた11名のADの症例(AD)及び9名の対照(T)の脳から抽出した。対照は、RNA試料の省略(T-)により行った; カルバモイルホスフェート合成酵素1 (CPS1)、オルニチントランスカルバミラーゼ(OTC)、アルギニノスクシネート合成酵素1 (ASS)、アルギニノスクシネートリアーゼ(ASL)。
図5: OTCにより触媒される反応の模式図。
図6: 対照(n=10)、MCI対象(n=14)、AD症例(n=16)及び非AD型認知症の症例(n=30)での50μlのCSF中で30分の間に測定されたOTCの活性に相当する、新しく生成されたシトルリンの定量。
図7: OTC基質の存在又は非存在下でのシトルリン測定。
図8: OTC活性の酵素的測定及び対照試験。
1.1. 材料及び方法
脳試料。脳は、1986〜2001年の間に英国のグレーターマンチェスター地域から入院した早発型及び晩発型の散発性ADの114人の患者(死亡時平均年齢 = 73.1±9.1歳;発症時平均年齢 = 65.9±10.3歳;男性51%)からの解剖から得た。全ての患者は、白人種の起源であった。病理的診断は、ADについてのCERAD神経病変基準(Neuropathological Criteria) (Mirraら, 1991)に従って行った。全ての患者は、死亡時にBraak段階5又は6であった。対照の脳は、ストラスブール市民ホスピス(フランス)で行われた日常的な解剖から得られた167名の脳の最初の組(initial set)から得た。採用は、認知症の症例を除くように設計した(患者の大多数が認知症を示す医療施設からの個体は採用せず、一般的な病院から採用した)。ほとんどの症例は、救急サービスにより死亡前48時間未満に入院し、その入院の前に家で生存していた。神経病変についての解剖に関連する症例は除いた。神経病変基準は、Braak段階を定義するように(Braak及びBraak, 1991)、又はCERAD神経病変基準に従って(Mirraら, 1991)当てはめた。ここでまた、全ての対照の対象は白人であった。
遺伝子発現のレベルを、12名の対照及び12名のAD患者の死後の脳組織からのトータルRNAにおいて評価した。今回の研究において、AD患者のそれぞれにおける脳発現プロファイルを、対照試料のプールと比較して、対象における個別の変動の影響を最小限にした。研究した2741遺伝子のうち、対照のプールに比較してAD患者の脳において、36が過剰発現され、70が過小発現されていた(選択の3倍, p<10-5)。興味のある異なる遺伝子座内でのこれらの遺伝子の分布を、表4に示す。
2.1. 材料及び方法
CSF試料:
CSFは、患者又は親類若しくは法的な保護者の告知されかつイニシャルで署名された同意とともに「Centre de Memoire du Service de Neurologie de l'Hopital Salengro, CHRU de Lille」サービスにより得た。酵素測定を行うために、200μlが必要であった。
簡単に、OTC活性は、過剰の基質の存在下で所定の時間の間に生成されるシトルリンの割合(rate)の決定により定量する(図5)。
OD値は、各ウェルに存在するシトルリンのナノモルでの量を決定するために、対応するシトルリン対照の範囲にあてはめた。それぞれの試料について、基質の非存在下で測定したシトルリンのナノモルでの量を、基質の存在下で測定したシトルリンのナノモル量から差し引き、得られた量は、30分間の間に試料中に存在するOTCにより生成されたシトルリンのレベルを表す。OTC対照範囲に対するこの値の繰越(carryforward)も、試料中に存在するOTC単位のレベルの決定を可能にすることに注目すべきである。しかし、OTC活性を、新しく生成されたシトルリンのナノモル/30分/50μl CSFで表すことを選択した。
図6に示す結果は、30分間にわたって測定されたOTCの活性に相当する新しく生成されたシトルリンの量が、対照と比較して、MCI、非AD又はAD型認知症を示す患者のうちで少なくとも平均で10倍高い(p<0.0001)ことを示す。
CSF中のOTC活性のレベルは、よって、わずかであっても他覚的な認知衰退及び認知症に進行する感受性の存在を検出するための有効なツールであろう。この測定は、よって、認知の変化及び認知症の非常に初期の診断の助けとして提案される。
Claims (19)
- 個体からの髄液試料中のオルニチントランスカルバミラーゼ(OTC)を検出する工程を含む、個体における脳の変性をインビトロで検出する方法。
- 前記脳の変性が、無症状のレベルで検出される請求項1に記載の方法。
- 対象者が神経変性性疾患を有する可能性をインビトロで評価するために利用される請求項1又は2に記載の方法。
- 対象者がアルツハイマー病を有する可能性をインビトロで評価するために利用される請求項1又は2に記載の方法。
- 対象者が非アルツハイマー型認知症を有する可能性をインビトロで評価するために利用される請求項1又は2に記載の方法。
- 前記個体が、軽度認知機能障害に罹患している請求項1又は2に記載の方法。
- 前記髄液試料中のオルニチントランスカルバミラーゼ(OTC)の検出が、OTC活性の検出により行われる請求項1〜6のいずれか1項に記載の方法。
- OTC活性が、カルバミルホスフェート及びオルニチンの前記試料への添加後に、シトルリンの生成を測定することにより検出されかつ定量される請求項7に記載の方法。
- OTC活性が、生成されたシトルリンの量の比色測定によりアッセイされる請求項7又は8に記載の方法。
- OTC活性が、オルニチントランスカルバミラーゼの逆反応に基づくアッセイにより測定される請求項7に記載の方法。
- 前記髄液試料中のオルニチントランスカルバミラーゼ(OTC)の検出が、OTCに指向されたモノクローナル又はポリクローナル抗体を用いるイムノアッセイにより行われる請求項1〜6のいずれか1項に記載の方法。
- 髄液中のオルニチントランスカルバミラーゼの存在が、脳の疾患を示す請求項1〜11のいずれか1項に記載の方法。
- 死亡した個体からの脳生検材料を、抗OTC抗体で標識する工程を含む、死亡した個体での脳の変性を検出する方法。
- 前記抗体が、ヒトOTCに特異的なポリペプチドに対して得られるモノクローナル又はポリクローナル抗体である請求項11又は13に記載の方法。
- 前記抗体が、ポリペプチドMKTAKVAASDWTFLHCLPRK (配列番号17)に対して得られるポリクローナル抗体である請求項14に記載の方法。
- 脳血管内皮細胞中のオルニチントランスカルバミラーゼの存在が、脳の変性を示す請求項13〜15のいずれか1項に記載の方法。
- 脳血管内皮細胞中のオルニチントランスカルバミラーゼの存在が、アルツハイマー病を示す請求項13〜16のいずれか1項に記載の方法。
- 対象者における脳の疾患のインビトロ診断のための、ヒトオルニチントランスカルバミラーゼに指向された抗体を含む組成物。
- 前記脳の疾患が、軽度認知機能障害、アルツハイマー病又は非アルツハイマー型認知症である請求項18に記載の組成物。
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ES2809171T3 (es) | 2008-01-18 | 2021-03-03 | Harvard College | Métodos para detectar distintivos de enfermedades o afecciones en fluidos corporales |
CN103124795A (zh) | 2010-07-23 | 2013-05-29 | 哈佛大学校长及研究员协会 | 利用吞噬细胞检测疾病或病症的方法 |
CA2806304A1 (en) | 2010-07-23 | 2012-01-26 | President And Fellows Of Harvard College | Methods of detecting prenatal or pregnancy-related diseases or conditions |
SG10201505723UA (en) | 2010-07-23 | 2015-09-29 | Harvard College | Methods for detecting signatures of disease or conditions in bodily fluids |
AU2011280997A1 (en) | 2010-07-23 | 2013-02-28 | President And Fellows Of Harvard College | Methods of detecting autoimmune or immune-related diseases or conditions |
JP2015522260A (ja) | 2012-06-15 | 2015-08-06 | ハリー スティリ, | 疾患または状態を検出する方法 |
US20150141260A1 (en) | 2012-06-15 | 2015-05-21 | Harry Stylli | Methods of detecting diseases or conditions using circulating diseased cells |
GB201212084D0 (en) | 2012-07-06 | 2012-08-22 | Randox Lab Ltd | Tropomyosin isoforms related to alzheimers disease and mild cognitive impairment |
EP2965086A4 (en) | 2013-03-09 | 2017-02-08 | Harry Stylli | Methods of detecting prostate cancer |
WO2014164366A1 (en) | 2013-03-09 | 2014-10-09 | Harry Stylli | Methods of detecting cancer |
EP3693742B1 (en) | 2014-09-11 | 2022-04-06 | Harry Stylli | Methods of detecting prostate cancer |
KR20230150497A (ko) | 2022-04-22 | 2023-10-31 | 사회복지법인 삼성생명공익재단 | 유럽-동아시아인 데이터 기반 알츠하이머병 치매의 발병 위험군 또는 조기 증상 발현 위험군, 기억상실형 경도인지장애의 발병 위험군 및/또는 아밀로이드β 침착에 대한 PET 양성 위험군을 예측하기 위한 정보를 제공하는 방법 |
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ES2449573T3 (es) | 2014-03-20 |
DK2013365T3 (en) | 2014-03-10 |
WO2007119179A2 (en) | 2007-10-25 |
CA2649462A1 (en) | 2007-10-25 |
US20090178152A1 (en) | 2009-07-09 |
KR101393204B1 (ko) | 2014-05-21 |
KR20090015065A (ko) | 2009-02-11 |
WO2007119179A3 (en) | 2008-03-06 |
AU2007237839A1 (en) | 2007-10-25 |
US8114624B2 (en) | 2012-02-14 |
EP2013365B1 (en) | 2013-12-04 |
EP1847615A1 (en) | 2007-10-24 |
EP2013365A2 (en) | 2009-01-14 |
AU2007237839B2 (en) | 2013-11-07 |
JP2009538122A (ja) | 2009-11-05 |
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