JP2005520521A - 統合失調症の診断および処置方法 - Google Patents
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Abstract
Description
1.発明の分野
本発明は、統合失調症と相互関係を示す遺伝子および統合失調症の診断および処置についての遺伝子の使用方法に関するものである。
統合失調症は、通常現実からの引きこもり、非論理的な思考パターン、妄想および幻覚を特徴とし、様々な程度で他の情緒的、行動的または知的障害を伴う深刻な精神障害である。Diagnostic and Statistical Manual of Mental Disorders、第4版、アメリカン・サイキアトリック・アソーシエーション、273−315(1994)(DSM−IV(登録商標))参照。しかしながら、そこに述べられている通り、一つの症状が統合失調症の特有症候というわけではない。診断は、職業的または社会的機能を十分に果たし得ない場合に伴う徴候および症状の布置(constellation)の認識を含む(同上)。若干の検出可能な生理学的変化が報告されており、たとえば神経病理学的および画像試験は、この病気に伴う解剖学的改変を描き出している。Arnold et al.、Acta Neuropathol.(Berl)92、217−231(1996);Harrison、Brain 122、593−624(1999)。ある種の細胞異常が観察されており、生化学的およびRNA解析は、若干の神経伝達物質経路およびシナプス前部成分における改変を立証している。同上;Benes、Brain Res.Rev.31、251−269(2000)。
一局面では、集団における統合失調症についてのスクリーニング方法であって、試料中におけるプロゲステロンにより誘導される脱落膜タンパク質(DEPP)をコードする遺伝子、アドレノメデュリン(adrenomedullin)をコードする遺伝子および低温ショックドメインタンパク質A(csdA)をコードする遺伝子から成る群から選択される一遺伝子の発現の規模を、集団の構成員において測定し、遺伝子発現の基準的規模と発現の規模を比較することを含み、遺伝子発現の増加が統合失調症の存在を示すものである方法が提供される。試料は、脳、脊髄、リンパ液、血液、尿または糞から採取され得る。好ましい実施態様において、試料は、前帯状回(anterior cingulated)から採取される。別の好ましい実施態様では、集団はヒトである。別の局面では、宿主における統合失調症の診断方法であって、試料中におけるプロゲステロンにより誘導される脱落膜タンパク質(DEPP)をコードする遺伝子、アドレノメデュリンをコードする遺伝子および低温ショックドメインタンパク質A(csdA)をコードする遺伝子から成る群から選択される一遺伝子の発現の規模を測定し、遺伝子発現の基準的規模と発現の規模を比較することを含み、遺伝子発現の増加が統合失調症の存在を示すものである方法が提供される。
図1は、プレプロアドレノメデュリンをコードする核酸配列を示す。
図2は、DEPPをコードする核酸配列を示す。
図3は、低温ショックドメインタンパク質A(csdA)をコードする核酸配列を示す。
本明細書は、3種の遺伝子、すなわちプロゲステロンにより誘導される脱落膜タンパク質(DEPP)をコードする遺伝子、アドレノメデュリンをコードする遺伝子および低温ショックドメインタンパク質A(csdA)をコードする遺伝子が罹患個体における統合失調症と関連しているという驚くべき発見に基いている。さらに詳しくは、これら3種の遺伝子は、通常患者と比して統合失調症患者の前帯状回ではアップレギュレーションされている。したがって、統合失調症の診断、スクリーニングおよび評価方法が本発明に従って提供される。たとえば、DEPP、csdAおよびアドレノメデュリン遺伝子の増加した発現レベルを測定する検定法が提供される。さらに、DEPP、csdAおよびアドレノメデュリンをコードする核酸分子は、診断用ハイブリダイゼーションプローブとして使用されるか、またはDEPP、csdAまたはアドレノメデュリン遺伝子突然変異、対立遺伝子変異およびDEPP、csdAまたはアドレノメデュリン遺伝子における調節欠損を同定するための診断的PCR分析用プライマーの設計に使用され得る。本明細書で使用されている「診断」の語は、一般的に個体に適用され、「スクリーニング」は一般的に集団または個体に適用され得るものとする。また、これらの語は両方とも、たとえば単離組織または単離細胞または培養で生長させた細胞を用いるインビトロ方法を包含する。本発明はまた、これらのタンパク質の利用可能な血漿レベルを減少させるのに使用され得るDEPP、csdAおよびアドレノメデュリン遺伝子産物に対する抗体、並びに遺伝子発現の阻害に使用され得るヌクレオチド配列(たとえば、アンチセンス、siRNAおよびリボザイム分子)、および遺伝子発現を低減化または促進するように設計された遺伝子または調節配列結合または置換構築物(たとえば、三重らせん形成部分または遺伝子を強力なプロモーター系の制御下に置く発現構築物)を包含する。
DNAマイクロアレイ解析
ヒト前帯状回試料を、10名の正常および10名の統合失調症死亡対象から得る(メリーランド・サイキアトリック・リサーチ・クリニック、バルチモア、メリーランド)。良質のRNAは、9正常(「N1」)および7統合失調症(「S1」)試料から得られる。
差次的調節遺伝子のリアルタイム定量的PCR確認
リアルタイム定量的PCR(Q−PCR)用プローブ対を、実施例1で同定された38の改変遺伝子用に設計する。アフィメトリックスは、チップ上のプローブが誘導される配列のファイルを提供する。このファイルから、これら38の改変遺伝子に対応する配列を得、プローブ対を調製する。良好なプライマー対がアフィメトリックス配列から得られない場合、さらに長い配列が、アフィメトリックス配列に対して良好なBLASTスコアを伴うRefSeqから得られ(Pruitt KD、Maglott DR Nucleic Acids Res 2001年1月1日、29(1):137−140;Introducing RefSeq and LocusLink:NCBIで管理されたヒトゲノムリソース、Pruitt KD、Katz KS、Sicotte H、Maglott DR Trends Genet.2000年1月;16(1):44−47参照)、プライマーはその配列から設計される。プローブ対の配列を表1に示す。
Claims (20)
- 集団における統合失調症についてのスクリーニング方法であって、試料中におけるプロゲステロンにより誘導される脱落膜タンパク質(DEPP)をコードする遺伝子、アドレノメデュリンをコードする遺伝子および低温ショックドメインタンパク質A(csdA)をコードする遺伝子から成る群から選択される少なくとも一遺伝子の、集団の構成員における発現の規模を測定し、遺伝子発現の基準的規模と発現の規模を比較することを含み、遺伝子発現の増加が統合失調症の存在を示すものである方法。
- 宿主における統合失調症の診断方法であって、試料中におけるプロゲステロンにより誘導される脱落膜タンパク質(DEPP)をコードする遺伝子、アドレノメデュリンをコードする遺伝子および低温ショックドメインタンパク質A(csdA)をコードする遺伝子から成る群から選択される少なくとも一遺伝子の発現の規模を測定し、遺伝子発現の基準的規模と発現の規模を比較することを含み、遺伝子発現の増加が統合失調症の存在を示すものである方法。
- 試料が、脳、脊髄、リンパ液、血液、尿または糞から採取される、請求項1または2記載の方法。
- 試料が前帯状回から採取されたものである、請求項3記載の方法。
- 試料が、ヒトから採取されたものである、請求項1、2、3または4記載の方法。
- プロゲステロンにより誘導される脱落膜タンパク質(DEPP)をコードする遺伝子、アドレノメデュリンをコードする遺伝子および低温ショックドメインタンパク質A(csdA)をコードする遺伝子から成る群から選択される少なくとも一遺伝子の発現を、アンチセンスオリゴヌクレオチドまたはsiRNAまたはリボザイムまたは核酸分子の発現低下量を宿主に投与することにより低下させることを含む方法。
- 統合失調症処置用医薬の製造を目的とするDEPP、csdAまたはアドレノメデュリン遺伝子の発現を特異的に阻害するアンチセンス分子またはsiRNAまたはリボザイムまたは三重らせん形成を促す核酸分子の使用。
- 患者においてDEPP、アドレノメデュリンおよびcsdAから成る群から選択される少なくとも一タンパク質の量を、タンパク質の正常活性を妨害するのに十分な抗DEPP、抗アドレノメデュリンおよび/または抗csdA抗体または機能的抗体フラグメントの有効量を投与することにより減少させることを含む統合失調症の処置方法。
- 統合失調症処置用医薬の製造を目的とするDEPPまたはcsdAまたはアドレノメデュリンのエピトープと特異的に結合する抗体の使用。
- 抗体または機能的抗体フラグメントが、全抗体、ヒト化抗体、キメラ抗体、Fabフラグメント、Fab'フラグメント、F(ab')2フラグメント、1本鎖Fvフラグメントおよび二重特異性抗体から成る群から選択される、請求項8記載の統合失調症の処置方法。
- 基準レベルより高いレベルでプロゲステロンにより誘導される脱落膜タンパク質(DEPP)をコードする遺伝子、アドレノメデュリンをコードする遺伝子および低温ショックドメインタンパク質A(csdA)をコードする遺伝子から成る群から選択される遺伝子の少なくとも一つを発現するヒト以外のトランスジェニック動物であって、統合失調症的行動を呈する動物。
- 遺伝子が基準レベルより高レベルで発現されるように遺伝子の調節配列に一つまたはそれ以上の改変を加えることにより遺伝子の発現が高められ、動物が統合失調症的行動を呈している、請求項11記載の動物。
- 遺伝子の発現が、遺伝子のコピー数増加により増強され、動物が統合失調症的行動を呈する、請求項11記載の動物。
- ヒト以外のトランスジェニック動物が哺乳類である、請求項11、12または13記載のヒト以外のトランスジェニック動物。
- 一またはそれ以上の改変が、遺伝子の天然プロモーターよりも高い発現率を有するプロモーターの置換を含む、請求項11、13または14記載のヒト以外のトランスジェニック動物。
- プロモーターが誘導性プロモーターである、請求項15記載のヒト以外のトランスジェニック動物。
- ゲノムが、プロゲステロンにより誘導される脱落膜タンパク質(DEPP)をコードする遺伝子、アドレノメデュリンをコードする遺伝子および低温ショックドメインタンパク質A(csdA)をコードする遺伝子から成る群から選択される1個またはそれ以上の遺伝子におけるホモ接合崩壊を含むヒト以外のトランスジェニックノックアウト動物であって、そのホモ接合崩壊により遺伝子の発現が阻止されており、ホモ接合崩壊の結果生じた、野生型動物と比べて1個またはそれ以上の遺伝子の発現レベルが減少しているトランスジェニックノックアウト動物。
- 統合失調症の症状を調節する治療薬についてのスクリーニング方法であって、請求項11〜16のいずれかに記載のヒト以外のトランスジェニック動物に候補化合物を投与し、統合失調症に伴う症状に対する化合物の効果を測定することを含む方法。
- 統合失調症の症状を調節する治療薬についてのスクリーニング方法であって、請求項17記載のヒト以外のトランスジェニック動物と候補化合物を合わせ、統合失調症に伴う症状に対する化合物の効果を測定することを含む方法。
- 統合失調症の処置に有用な化合物についてのスクリーニング方法であって、DEPP、アドレノメデュリンおよびcsdAから成る群から選択される遺伝子についての調節配列に検出可能なタンパク質を発現するリポーター遺伝子を機能し得るように結合することにより、リポーター構築物を製造し、リポーター構築物で細胞をトランスフェクションし、トランスフェクションされた細胞を試験化合物に曝露し、そして試験化合物に曝露後のリポーター遺伝子の発現レベルを、試験化合物に曝露する前の発現レベルと比較することを含み、曝露後の発現レベルの低下が統合失調症の処置に有用な化合物の指標となる方法。
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CA2242308A1 (en) * | 1997-12-08 | 1999-06-08 | Smithkline Beecham Laboratoires Pharmaceutiques | Novel compounds |
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AU2001241511A1 (en) * | 2000-02-28 | 2001-09-12 | Hyseq, Inc. | Novel nucleic acids and polypeptides |
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JP2009503524A (ja) * | 2005-08-01 | 2009-01-29 | ベー・エル・アー・ハー・エム・エス・アクティエンゲゼルシャフト | 神経変性疾患の診断のためのinvitro方法 |
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WO2003078658A3 (en) | 2004-02-19 |
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