JP5643200B2 - 筋萎縮性側索硬化症および関連する運動ニューロン疾患の診断、処置および予防のための、fus/tlsベースの化合物および方法 - Google Patents
筋萎縮性側索硬化症および関連する運動ニューロン疾患の診断、処置および予防のための、fus/tlsベースの化合物および方法 Download PDFInfo
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Description
本願は、2008年7月22日に出願された米国仮出願第61/135,689号の35U.S.C.119(e)に基づく利益を主張し、該仮出願は、本明細書においてその全体が参照として組み込まれる。
本発明は、国立神経疾患・脳卒中研究所(National Institute of Neurological Disorders and Stroke:NINDS)からの助成金第R01 NS050557-01号に基づく政府の支持によりなされた。政府は本発明において一定の権利を有する。
本発明は、運動ニューロン疾患、特に筋萎縮性側索硬化症の診断および処置に関する。
筋萎縮性側索硬化症(ALS)は、進行性の、致死性の神経変性障害である。その発症率は、0.6〜2.6/100,000であると報告されており(Roman, J Neurol Neurosurg Psychiatry. 1996. 61(2):131-7)、やや男性優位である。疾患の発症率のピークは60歳代においてであり(Nelson, Clin. Neurosci. 3, 327 (1995))、生存は典型的には2〜5年である。ALSは、機械的人工呼吸の不在下において、呼吸麻痺からの死を回避不能にもたらす。家族性の症例がALSの10%を占め、細胞質の銅−亜鉛スーパーオキシドジスムターゼ1(SOD1)における変異がこれらの家族性症例の20〜25%を占めることが示されている(Rosen, Nature 364, 362 (1993))。小胞結合膜タンパク質結合タンパク質(VAPB)における変異は、少数のブラジルの家族において古典的ALSまたは非定型運動ニューロン疾患のいずれかを引き起こすことが示されている。少数の遺伝子が、上位運動ニューロン優性ALS2(alsin)、若年性ALS(senataxin)および下位運動ニューロン疾患(lower motor neuropathy)(DCTN1)を含む、非定型運動ニューロン疾患に関連付けられている。若年性遺伝性ALS(この場合は劣性)の第2の形態は、染色体15qに関連付けられる(Hentati et al., Neurogenetics 2, 55 (1998))。しかし、家族性の古典的ALSの症例の大多数においては、原因遺伝子は未知である。染色体16および18への連鎖を有する高浸透率の古典的ALSの系統が報告されているが、一方で、染色体9への連鎖を有する前頭側頭型認知症を伴うかまたは伴わないALSを有する家系が報告されている。
本発明者らは、ヒトFUS/TLS遺伝子における変異が、ヒト筋萎縮性側索硬化症(ALS)および関連する運動ニューロン疾患に関連することを発見した。ここで、本発明者らは、優性な古典的ALSと見かけ上劣性で非定型のALSとの両方に関連する、染色体16上のFUS/TLS遺伝子における変異を報告する。したがって、本発明は、筋萎縮性側索硬化症および他の運動ニューロン疾患の診断および処置のための方法を提供する。方法は、FUS/TLS活性の変化および/またはFUS/TLSの物理的特性の変化の結果である家族性筋萎縮性側索硬化症および筋萎縮性側索硬化症ならびに他の運動ニューロン疾患を処置するために提供される。さらに、FUS/TLSの生化学的経路の変化により引き起こされる疾患のための治療が提供される。
なお別の側面において、本発明は、変異体FUS/TLSのタンパク質または核酸に選択的に結合する分子についてスクリーニングするための方法を提供し、該方法は、野生型および変異型FUS/TLSの核酸またはタンパク質を候補分子と接触させること、ならびに、候補分子の野生型および変異型FUS/TLSの核酸またはタンパク質への結合を測定することを含み、ここで、変異型FUS/TLSへの結合のレベルが野生型FUS/TLSへの結合のレベルよりも5倍大きいことが、変異型FUS/TLSに選択的に結合する分子の指標である。
ALSは、家族性、孤発性の定型または非定型の性質であってよい。
本発明のこれらのおよび他の側面、ならびにその多様な態様は、本発明の図面および詳細な説明を参照することによりより明らかとなるであろう。
本発明者らは、ヒトALS患者(優性および劣性遺伝する家族性ALSを含む)におけるFUS/TLS遺伝子における変異を同定した。この遺伝子配列中の変異の知識、およびFUS/TLS変異を保有する患者についての臨床情報を用いて、徴候性の個体および危険性がある個体においてALSを診断および予測することができる。さらに、ALSおよび運動ニューロンの生物学を研究するために、実験動物および培養細胞においてFUS/TLS遺伝子中に変異を導入することができる。かかる動物および細胞は、ALSおよび関連疾患を有するヒト患者における使用のために、治療的介入(薬物、siRNA、ならびに遺伝子およびタンパク質治療を含む)を開発して試験するために用いることができる。
配列番号1は遺伝子配列であり;
配列番号2はcDNA配列であり;
配列番号3はタンパク質コード配列であり;および
配列番号4は前記タンパク質のアミノ酸配列である。
一つの家系が、X連鎖する球脊髄性筋萎縮症およびFUS/TLS媒介性運動ニューロン疾患の両方を分離する場合がある。
用語「ハプロタイプ」とは、個体または試料中に存在する対立遺伝子の組み合わせを指す。
本発明は、以下の非限定的な例において、より詳細に説明される。
筋萎縮性側索硬化症(ALS)は、上位および下位運動ニューロンの致死性の変性障害である。ALSは、主に孤発性に発生するが、症例の10%は家族性であり、分離は典型的には常染色体優性であるが、遺伝様式が不明な多くの小さい家族クラスターが観察される。しかし、ほとんどの家族性の症例は、未だ同定されていない遺伝子に関与する。本発明者らは、常染色体優性ALSと関連するFUS/TLS遺伝子におけるいくつかの異なる変異、ならびに、希少な劣性の非致死性ALSバリアントと関連するユニークな変異を同定した。同族のタンパク質は広範に発現しており、核と細胞質との両方において見出される。FUS/TLSは、幾つかの細胞プロセス、特にmRNAのスプライシングおよび輸送に関与している。FUS/TLSの変異形態は、なおRNAに結合するが、in vitroで細胞の細胞質において凝集塊に蓄積する。患者の脳および脊髄は、同様に、細胞質のFUS/TLS貯留、ならびに核のユビキチン染色を示す。これらの結果は、ALSにおけるRNAのプロセッシングおよび/または輸送の役割を示唆する。
ヘテロ接合性欠損マッピング。TGENゲノミクスコアファシリティー(TGEN genomics core facility)において、DNA試料を増幅し、250k (Sty I) SNPマイクロアレイ(Affymetrix)にハイブリダイズさせた。遺伝子型データを、autoSNPaソフトウェアを用いて分析し、IBD(identical by descent)モジュールを用いて、20-SNP-runのカットオフを用いて、3個体全てのF577患者においてホモ接合性な領域を選択し、グラフに可視化した。
スクリーニングにより変異を確認した。さらに、pcDEST53プラスミド配列をその全体についてシークエンシングした。
染色体16への連鎖を有する常染色体優性の様式においてALSを分離する2つの大きな家系が、先に報告されている。これらの系統におけるハプロタイプ分析は、この遺伝子座についての40Mbの候補領域を示した。2つのさらなる家系は、この遺伝子座のテロメアのサブセットを含むより小さな領域への連鎖を示し、本発明者らが、この領域に努力の焦点を当てるよう導いた。徹底的なエクソンのシークエンシングによっても、対照においてもまた観察されない変異は明らかとならなかった。その後、さらなる個体の確認と、これらの2つの家系についてのデータの再分析により、染色体16への連鎖が除外された。
FUS/TLSは、脂肪肉腫における体細胞の染色体転座により作られる融合タンパク質のN末端の半分に寄与するものとして、もともとは記載された。その後、それがDNAの修復、RNAのプロセッシングおよび輸送において役割を有することが示された。FUS/TLSノックアウトマウスは、系統のバックグラウンドに依存して、周産期死亡またはオスの不妊のいずれかおよび放射線感受性を伴う多様な表現型を示す。ニューロンの機能不全はまだ記載されていないが、マウスのニューロン機能の長期的研究はなんら公開されていない。最近の報告は、非コードRNAがFUS/TLSタンパク質に結合し、それがCREB結合タンパク質(CBP)に結合して後者のヒストンアセチルトランスフェラーゼ活性を阻害し、転写の阻害をもたらすことを可能にすることを示す。GGUG含有ncRNAによるこのFUS/TLS結合の活性化は、FUS/TLSのN末端領域とC末端領域との結合を防止することにより作用すると考えられる。優性遺伝性ALS患者において見られるもののようなFUS/TLSのC末端領域におけるアルギニン残基の変異が、また、この自家結合を防止して構成的に活性な転写リプレッサーをもたらすと推測することは魅力的である。また、FUS/TLSは、ハンチントン病のモデルにおいて主要な核凝集物相互作用タンパク質であることが見出されている。凝集物中における貯留によるFUS/TLSの枯渇が、ポリグルタミン伸長媒介性疾患における神経細胞死に寄与し得、運動ニューロン疾患の劣性の症例におけるFUS/TLSの機能の喪失がこの病態を模倣し得ると推測することは魅力的である(注:。FUS/TLSの1つの結合パートナーであるCBPもまた、ポリグルタミン経路を含む)。
いくつかの発明の態様が本明細書において記載され説明される一方で、当業者は、本明細書において記載される1または2以上の機能を実施するため、および/または結果および/または利点を得るための、多様な他の手段および/または構造を容易に想起することができ、かかるバリエーションおよび/または改変の各々は、本明細書において記載される発明の態様の範囲内であるとみなされる。より一般的には、当業者は、本明細書において記載される全てのパラメーター、寸法、材料および配置が、例示的なものであることを意味しており、実際のパラメーター、寸法、材料および/または配置は、発明の技術が用いられる具体的な適用に依存するであろうことを理解する。当業者は、本明細書において記載される特定の発明の態様に対する多数の均等物を認識するか、または慣用的な実験のみを用いて確認することができる。したがって、前述の態様が例としてのみ提示されること、および、添付の請求の範囲およびその均等物の範囲において、発明の態様は、具体的に記載され請求されたもの以外の方法においても実施することができることが理解されるべきである。本開示の発明の態様は、本明細書において記載される各々の個々の特徴、システム、物品、材料、キットおよび/または方法に関する。さらに、かかる特徴、システム、物品、材料、キットおよび/または方法の2または3以上の任意の組み合わせは、相互に相反するものではなく、本開示の発明の範囲内に含まれる。
本明細書において開示される全ての参考文献、特許および特許出願は、各々が引用される主題に関して参考として組み込まれ、これは、一部の場合においては当該文書の全体を包含する。
不定冠詞「a」および「an」は、本明細書においておよび請求の範囲において用いられる場合、明確に逆に示されない限り、「少なくとも1つ」を意味すると理解されるべきである。
Claims (10)
- 対象において筋委縮性側索硬化症(ALS)の検出を補助する方法であって、
個体から得た試料において、FUS/TLSの核酸またはそのフラグメント中の1または2以上の遺伝子マーカーを検出すること、
を含み、
ここで、前記1または2以上の遺伝子マーカーは、配列番号3と比較して、C1551G、C1561G、G1542T、G1543T、C1561T、G1562A、A1564GまたはG1572Cからなる群より選択され、および
ここで、1または2以上のマーカーの存在は、前記個体がALSを有するか、またはALSについての遺伝的素因または易罹患性を有することを示す、
前記方法。 - 変異がFUS/TLSのエクソン15中にある、請求項1に記載の方法。
- 遺伝子マーカーの1または2以上が、FUS/TLSタンパク質中の(野生型と比較しての)アミノ酸変化をコードする、請求項1または2に記載の方法。
- アミノ酸変化が、H517Q、R521G、R514S、G515C、R521C、R521H、R522GまたはR524Sにおけるものである、請求項3に記載の方法。
- 8つ全てのマーカーを含むハプロタイプを検出することを含む、請求項1〜4のいずれか一項に記載の方法。
- 核酸が、DNA、ゲノムDNA、RNA、cDNA、hnRNAまたはmRNAである、請求項1〜5のいずれか一項に記載の方法。
- 1または2以上の遺伝子マーカーの検出が、シークエンシング、ハイブリダイゼーション、制限酵素断片分析、オリゴヌクレオチドライゲーションアッセイまたは対立遺伝子特異的PCRにより達成される、請求項1〜6のいずれか一項に記載の方法。
- 1または2以上の遺伝子マーカーが、変異体FUS/TLSタンパク質に選択的に結合する抗体またはその抗原結合フラグメントを用いて同定される、請求項1〜6のいずれか一項に記載の方法。
- FUS/TLSの核酸またはそのフラグメント中の1または2以上のマーカーであって、該マーカーが、配列番号3と比較して、C1551G、C1561G、G1542T、G1543T、C1561T、G1562A、A1564GまたはG1572Cからなる群より選択される1または2以上の前記マーカーを検出するためのプローブの少なくとも1つの組み合わせを含む、診断用キットおよび/または研究用キット。
- シークエンシングが、ゲノムDNAのエクソンシークエンシングである、請求項7に記載の方法。
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