JP5236488B2 - 新規な神経栄養因子タンパク質およびその用途 - Google Patents
新規な神経栄養因子タンパク質およびその用途 Download PDFInfo
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Description
本発明は、新規な神経栄養因子タンパク質であるMANF2とそれをコードする遺伝子配列を開示する。この分子は、MANF2依存性の病態の治療、予防および/または診断において有用な、多岐にわたる治療法や診断法の開発に有用となる。更に本発明の分子は、一次ニューロンおよび中枢ニューロンのエフェクターとしても有用である。
国立医学図書館(National Library of Medicine)(NLM)のwwwサーバー内の国立バイオテクノロジー情報センター(National Center for Biotechnology Information)(NCBI)でBlastサーチ(Altschul et al. "Gapped BLAST(R) and PSI-BLAST: a new generation of protein database search programs(Gapped BLAST(R)とPSI-BLAST:新世代のタンパク質データベースサーチプログラム)", Nucleic Acids Res. 25 (1997): 3389-3402を参照)を行うことで、我々はMANF1と高い配列類似性を示す、いくつかのヒトとマウスのEST(expressed sequence tag)cDNAを同定した。しかし、明らかにMANF1ホモログである全長オープンリーディングフレームを含有するヒトESTはなく、その多くは挿入、欠失およびMANF1と全く相同性を示さない長さの異なる5’末端を有していた。
ヒト由来ではない組み換え細胞によってMANF2を製造した場合、得られたMANF2はヒト由来のタンパク質やポリペプチドを全く含まない。しかし、MANF2として実質的に均質な調製物を得るためには、製造したMANF2を組み換え細胞のタンパク質やポリペプチドから精製する必要がある。精製を行うには、まず、培地または細胞溶解物を遠心分離することで、そこから粒状の細胞片を取り除くことができる。次いで、適切な精製方法の例として以下に挙げる方法で、異物である可溶性のタンパク質やポリペプチドからMANF2を精製することができる。このような方法としては、イオン交換カラムによる分取、エタノール沈殿法、逆相HPLC、シリカ充填カラムを用いたクロマトグラフィー、クロマトフォーカシング(chromatofocusing)、イムノアフィニティ法、エピトープタグ結合樹脂を用いる方法、SDS−PAGE、硫安沈殿法、Sephadex G-75などを用いたゲル濾過、およびIgGなどの異物を取り除くためのプロテインAセファロースカラムを用いる方法が挙げられる。
MANF2核酸は、本発明で例示する組み換え技術によるMANF2ポリペプチドの調製に有用であり、このようにして得られるMANF2ポリペプチドは、後述する多様な用途を有する抗MANF2抗体の製造に用いることができる。
MANF2またはMANF1の活性に関連する疾患や障害、またはMANF2/MANF1の反応性に益を得る疾患や障害の治療において、MANF2タンパク質およびMANF2遺伝子は、哺乳動物(特にヒト)に投与することを目的としたex vivoまたはin vivoにおける治療用途を有すると考えられる(WO 01/19851参照)。特にMANF2が適した疾患は、神経障害、好ましくは中枢神経系障害、パーキンソン氏病またはアルツハイマー病である。
本発明のMANF2核酸分子、MANF2ポリペプチドおよび抗MANF2抗体(活性化合物)ならびにそれらの誘導体、断片、類似体およびホモログは、医薬組成物に組み込むことができる。
本発明はまた、生物学的試料中のMANF2またはそのアレル変異を検出するために用いる診断用のまたは予後判定用のキットに関する。このキットは、上述したMANF2依存性病態を診断するための手段、あるいはMANF2の変異または機能不全が介在する病態に関する個体の疾病素質を評価するための手段を提供する。このキットは、生物学的試料中のMANF2ポリペプチドまたはMANF2核酸(例えばmRNA)を検出することができる標識化合物を含んでいてもよい。キットはまた、MANF2遺伝子またはそのアレル変異の少なくとも一部分に特異的にハイブリダイズすることができる核酸プライマーまたはプローブを含んでいてもよい。キットは適当な容器に入れることができ、該キットを使用するための説明書を含むことが好ましい。
本発明の更に別の態様においては、MANF2やMANF2類似体を、MANF2に結合する受容体のアフィニティー精製に用いることができる。MANF2は、精製のための好ましいリガンドである。簡単に言えば、この技術は以下の工程を包含する。(a)精製すべきMANF2受容体が、支持体に固定化したMANF2上に選択的に吸着される条件下で、該MANF2受容体の原料を固定化したMANF2に接触させ、(b)固定化したMANF2とその支持体を洗浄して、吸着されていない物質を取り除き、そして(c)固定化したMANF2に吸着しているMANF2受容体分子を溶出バッファーで溶出して、MANF2受容体分子を得る。アフィニティー精製の特に好ましい態様においては、MANF2は不活性で多孔性のマトリックスまたは樹脂(例えば、臭化シアンと反応させたアガロース)に共有結合している。ここで特に好ましいのは、プロテインAカラムに固定化したMANF2イムノアドヘシンである。次に、MANF2受容体を含む溶液を、クロマトグラフィー材料に流す。MANF2受容体はカラムに吸着し、溶出条件(例えば、pHまたはイオン強度)を変えることによってMANF2受容体を溶出させる。
MANF2をコードする核酸、好ましくはヒト以外の生物種(例えばマウスやラット)のMANF2タンパク質をコードする核酸は、トランスジェニック動物または「ノックアウト」動物の作製に用いることができ、作製した動物は、治療に有用な試薬の開発やスクリーニングに役立てることができる。トランスジェニック動物(マウスなど)とは、トランスジーンを含有する細胞を有する動物であり、そのトランスジーンは、出生前段階、例えば胚の段階で該動物またはその祖先に導入したものである。トランスジーンは、トランスジェニック動物の発生の出発点となる細胞のゲノムに組み込まれるDNAである。1つの態様においては、確立された技術を用いてMANF2をコードするヒトおよび/またはマウスのcDNA、あるいはその適当な配列を、MANF2をコードするゲノムDNAのクローニングに用い、得られたゲノム配列を、MANF2をコードするDNAを発現する細胞を有するトランスジェニック動物の作製に用いることができる。トランスジェニック動物(特にマウスなど)の作製法は当業界では既に一般的なものとなっており、例えば米国特許第4,736,866号および米国特許第4,870,009号に開示されている。典型的には、組織特異的エンハンサーを用いたMANF2トランスジーンの導入のために特定の細胞を標的とすることにより、所望の治療効果の実現につながると考えられる。胚発生期に生殖細胞系列にMANF2をコードするトランスジーンが導入されており、トランスジーンの複製物を内包するトランスジェニック動物は、MANF2をコードするDNAの発現増加の与える効果を調べるために用いることができる。このような動物は、例えばMANF2関連疾患からの保護を与えると考えられる試薬のための実験動物として使用することができる。本発明のこのような態様に基づけば、試薬で動物を処置することによって、疾患の発病率がトランスジーンを有する未処置の動物の発病率と比べて低下することは、疾患に対するの治療的介入の可能性を意味する。
また、MANF2の非ヒトホモログは、MANF2「ノックアウト」動物(即ち、内因性MANF2遺伝子と動物の胚細胞に導入した改変ゲノムMANF2 DNAとの相同組み換えの結果、MANF2をコードする遺伝子が欠陥を有するかまたは改変されている動物)の作製に用いることもできる。例えば、マウスのMANF2 cDNAを用い、確立された手法でゲノムMANF2 DNAをクローニングすることが可能である。ゲノムMANF2 DNAの一部を欠損させたり、他の遺伝子(例えば組み込みをモニターするのに使うことのできる選択的マーカーをコードする遺伝子)などで置換したりすることが可能である。典型的には、ベクターには数キロベースの非改変隣接DNA配列が(5’末端と3’末端の両方に)含まれている(相同組み換えベクターに関する記載については、Thomas and Capecchi, Cell 51:503 (1987)等を参照)。ベクターを胚性幹細胞系に(エレクトロポレーション法などで)導入し、導入したDNAが内因性DNAと相同組み換えした細胞を選択する(例えば、Li et al., Cell 69:915 (1992)を参照)。続いて、選択した細胞を(マウスなどの)動物の胚盤胞に注入し、凝集キメラ(aggregation chimera)を形成する(Bradley, "Teratocarcinomas and Embryonic Stem Cells: A Practical Approach (奇形癌と胚性幹細胞:実践的アプローチ)", E. J. Robertson編 (IRL, Oxford, 1987), pp. 113-152等を参照)。その後、偽妊娠した適切な代理母動物にキメラ胚を移植し、「ノックアウト」動物が生まれるようにキメラ胚を出産日まで育てる。胚細胞に相同組み換えDNAを有する子孫は標準的な手法で同定することができ、また、全細胞が相同組み換えDNAを有する動物を交配するために用いることができる。ノックアウト動物は、ヒトの神経学的な障害や欠陥を模倣する能力によって特徴付けることができる。
本明細書中ではある特定の態様を詳細に開示しているが、これはあくまで説明を目的として実例を挙げたにすぎず、添付の請求項に定義する本発明の請求の範囲を限定するものではない。特に、本発明者らは、請求項で定義した本発明の精神および範囲を逸脱することなく、本発明に多様な置き換え、変更および修飾をなし得ることを意図している。出発物質とする核酸、目的のクローン、ライブラリーの種類などの選択は、本明細書に開示する態様についての知識を有する当業者には慣例的な事項であると考える。本発明の他の態様、効果および改良に関しては、添付の請求の範囲内に含まれるものとする。
実施例
我々は、RT−PCR法によって、マウス脳細胞(プライマーとしてm-MANF2-ATGとm-MANF2-STOP-delを使用)およびヒト脳細胞(プライマーとしてh-MANF2-ATGとh-MANF2-STOP-delを使用)からマウスとヒトの全長cDNAをクローニングすることができた。マウス全RNAはRNA抽出キット(Ambion製)を用いて単離し、ヒトRNAはClontechから入手した。種々の組織から得た、オリゴ(dT)(Promega製)でプライミングした全RNA(5μg)またはポリ(A)+RNA(1μg)をテンプレートとして用い、逆転写酵素(SuperscriptII、Invitrogen製)で一本目のcDNA鎖を合成した。
m-MANF2-ATG
ACC ATG CGG TGC ATC AGT CCA ACT GC (配列番号5)
m-MANF2-int-as
CTC ATG GGA CGA GTG ACT TCT CC (配列番号6)
m-MANF2-STOP
GTC AGA GCT CCG TTT GGG GGT ATA TC (配列番号7)
m-MANF2-STOP-del
GAG CTC CGT TTG GGG GTA TAT C (配列番号8)
h-MANF2-ATG
ACC ATG TGG TGC GCG AGC CCA GTT GC (配列番号9)
h-MANF2-int-as
GCA CAC TCA TTG GGC GAG TGA CTT C (配列番号10)
h-MANF2-stop
GAT CAG AGC TCT GTT TTG GGG TGT GTC (配列番号11)
h-MANF2-stop-del
GAG CTC TGT TTT GGG GTG TGT C (配列番号12)
COS−7細胞を、10%ウシ胎児血清(Gibco製)を含有するダルベッコの変性イーグル培地(DMEM)で培養した。Fugene 6(Roche製)のトランスフェクションプロトコルを用いて、細胞にヒトまたはマウスのMANF2全長cDNAを含有するpcDNA3.1(Invitrogen製)発現ベクターをトランスフェクトした。12時間後に培地を除去し、無血清のDMEMで置換した。48時間後に細胞を回収し、細胞からタンパク質抽出物を調製した。分泌タンパク質(培地)は濃縮した。タンパク質抽出物をポリアクリルアミドゲルで展開し、V5抗体(Invitrogen製)を用いたウエスタンブロットで分析した。
RNAプローブを合成する前に、pCRIIベクター内のマウスMANF2の全長cDNAを線状化した。一本鎖RNAプローブを、50μCiの[35S]−UTPとT3ポリメラーゼまたはT7ポリメラーゼを使用して、in vitroで転写した。DNA分解酵素で消化した後、プローブを沈殿させ、50% ホルムアミドを含む10mM DTT溶液に再懸濁した。マウス脳の矢状断切片および冠状断切片をクリオスタットで切り出し、埋設用スライドに移した。切片を乾燥し、4% パラホルムアルデヒドで固定し、50% ホルムアミド、0.3M NaCl、10mM トリス、10mM NaPO4(pH6.8)、5mM EDTA、1×デンハルト溶液、10% 硫酸デキストラン、10mM DTT、1mg/ml tRNAおよび特異的なプローブを含むバッファー中でハイブリダイズさせた。ハイブリダイゼーションは50℃で一晩行った。洗浄は、50% ホルムアミドを含む2×SSC中、37℃で行い、続いて、RNA分解酵素による消化を実施した。スライドをX線フィルムに暴露するか、またはKodak NTB-2エマルジョンに浸し、14〜30日後に現像した。
プローブ
pCRII-TOPO TAベクター(Invitrogen製)にクローニングした全長MANF2 cDNAを用いて、アンチセンスcRNAプローブおよび対照センスcRNAプローブを作製した。適切な酵素でプラスミドを線状化し、35S標識UTP(Amersham製)およびSP6またはT7転写システム(Promega製)を用いたin vitroの転写法で、35S標識プローブを作製した。取り込まれなかったヌクレオチドをSephadex G-50(NICKカラム、Pharmacia Biotech製)を用いたゲル濾過で除去した。プローブをエタノール沈殿し、ハイブリダイゼーションバッファー(60% 脱イオンホルムアミド(FA)、0.3M NaCl、20mM トリス−HCl(pH8.0)、5mM EDTA、10% 硫酸デキストラン、1×デンハルト溶液、100mM ジチオスレイトール、0.5mg/ml 酵母tRNA)に終濃度が32,000〜36,000cpm/μlとなるように溶解した。
出生後NMRIマウスの脳(P1、P5、P10と成体)をドライアイス上のTissue-Tekにマウントし、−70℃で保存した。凍結組織から冠状断切片をクリオスタットで切り出した。マウス胚(E11、E12、E15)と成体マウス精巣を4%パラホルムアルデヒド(PFA)中、4℃で一晩固定し、エタノールの希釈系列で脱水し、トルエンで清浄化し、パラフィンに包埋した。矢状断切片を切り出した後、シリル化処理済のスライドガラスに接着した。
凍結切片(融解し、風乾したもの)を、4% PFAを使用して室温で15分間固定し、PBSですすいだ。次に、プロテネーズK(1μg/ml、Sigma製)で処理し、すすいだ後、4% PFAで再固定した。切片をPBSですすいだ後、50% FAを含む2×SSCで10分間インキュベートし、水ですすぎ、アセチル化してから、50% FAを含む2×SSCに10分間浸漬した。52℃、1.5〜2時間の条件下で切片とハイブリダイゼーションバッファーのプレハイブリダイゼーションを行い、52℃でプローブ(120〜150μl)とのハイブリダイゼーションを一晩行った。
推定シグナル配列なしのヒトMANF2 cDNAを、N末端ミツバチメリチン分泌シグナルとC末端V5−6×Hisタグの読み枠を合わせながら、pMIB/V5-His発現ベクター(InsectSelect system、Invitrogen製)にクローニングした。抗生物性の抗真菌薬(Gibco製)を含むSF−900 II培地(Gibco製)で培養したSf9細胞を6穴プレート(9×105細胞/ウエル)に植え付け、細胞が付着したら、6μlのCellfectin試薬(Invitrogen製)を用いて2μgのプラスミドをトランスフェクトした。28℃で48時間後には、細胞を1:5にわけ、一晩付着させた後、ブラストシチジンS(50μg/ml、Invitrogen製)を添加した。ポリクローナルな細胞株(Sf9−hMANF2)を形成するために、耐性コロニーをコンフルエントになるまで培養した。安定な細胞を、l0μg/mlブラストシチジンで維持した。組み換えMANF2の培養液への分泌は、マウスモノクローナル抗V5抗体(1:5000、Invitrogen製)によるウエスタンブロッティングで確認した。
タンパク質の産生のために、Sf9−hMANF2懸濁培養細胞(250ml容)を対数増殖期終了まで4〜6日間培養した。細胞を1200rpmでl0分の遠心分離で除去し、MANF2を1Lの清浄化培地から4℃で精製した。
Hisタグを付したタンパク質の結合条件を調節するために、培地をPBSで希釈(1:2)し、終濃度が5mMとなるようにイミダゾール(Sigma製)を添加した。Chelating Sepharose Fast Flow(Pharmacia Biotech製)に0.1M NiCl2をチャージし、洗浄後、1ゲル等量のPBSに再懸濁した。50mlの培地につき、1mlのNi−セファローススラリーを添加し、サンプルのエンド−オーバー−エンド回転を4℃で1時間継続した。ゲルを500×gで2分の遠心分離で析出させ、0.5M KClと5mMイミダゾールを含むPBSで4回洗浄した。ゲル容量と等量の0.5Mイミダゾールを含むPBS(pH7.4)を用いてタンパク質を溶出した。溶出液をまとめ、YM-10 Centriconフィルター装置(Millipore製)で終容量が50〜100μlになるように濃縮した。一部を15%ゲルによるSDS−PAGEで流し、クーマシー染色で可視化した。
COS−7細胞を3枚の9cmシャーレに植え付け、Fugene 6試薬(Roche製)を用いて10μgのhMANF2-pcDNA3.1をトランスフェクトした。24時間後に培地を無血清DMEMで交換し、細胞を更に48時間インキュベートした。培養液(24ml)を回収し、組み換えMANF2を精製工程1と同様に精製した(上記参照)。
培養ドーパミンニューロン
ドーパミンニューロンの調製には、E14ラットまたはE13マウスの中脳底板を解剖した。組織を0.5% トリプシンを含むHBSSを用いて、37℃で20分間消化した。トリプシン活性は、胎児ウシ血清(FCS)の添加でブロックした。DnaseI(1mg/ml)を添加し、シリコン処理済のガラスピペットでサンプルを粉砕した。細胞を完全培地(10% HC−3、0.6% グルコース(Sigma製)と1×Glutamax I(Gibco製)を含むDMEM−F12)で2回洗浄し、カバーガラス当たり150.000細胞となるように、ポリ−L−オルニチン/ラミニンでコートしたカバーガラスに細胞を植えつけた。次の日にはタンパク質因子を添加し、細胞を6日間培養した。4%PFAを含むPBSを用いて培養細胞を室温で10分間固定し、PBSで3回洗浄し、氷冷アセトンを用いて−20℃で15分の固定後処理を行い、洗浄した。固定した培養細胞を10% HSを含むPBSを用いて室温で1時間ブロッキングし、ヒツジ抗チロシンヒドロキシラーゼ(TH)抗体(1:200、Chemicon International製)による処理を4℃で一晩行った。培養細胞をPBSで3回洗浄し、二次抗体であるCy3抗ヒツジ抗体(1:500)による処理を室温で45分間行った。培養細胞を洗浄し、マウント用メジウムでマウントした。
DRGニューロンの調製には、1% トリプシンを含むHBSSを用いて、E16マウスの組織を37℃で45分消化した。組織を培養ドーパミンニューロンと同様に処理し、単離した細胞を完全培地(SATO添加Ham’s F14培地)に植えつけた。細胞はタンパク質因子有りまたは無しの条件で6日間培養し、細胞数を計測した。
全てのラットに定位マイクロインフュージョンを2回施した。具体的には、1回目には、ベヒクル(4μl)、MANF2(10μg)またはGDNF(10μg)のいずれかを注入し、6時間後にはそれぞれの動物に6−OHDA(8μg)を左尾状核の同じ部位に投与した。前頂と硬膜に対する左線条体における座標は、PaxinosとWatsonのアトラス(Paxinos and Watson, 1997, The rat brain in stereotaxic coordinates (ラット脳の定位座標), Academic press, San Diego)によるとA/P +1.0、L/M +2.7、D/V −4だった。この研究は、以下のグループからなるものである: 線条体 PBS+6−OHDA、線条体 GDNF+6−OHDA、および線条体 MANF2+6−OHDA。
損傷から2週間後と4週間後に行動試験を実施した。D−アンフェタミン(フィンランド国、ヘルシンキ、University Pharmacy製)投与(2.5mg/kgを腹腔注射)の30分前には、ラットを試験チャンバーに慣らしておいた。完全な(360°の)同側性回転および反対側性回転の数を2時間にわたり記録した。損傷に対する累計同側性回転数は右回転の数から左回転の数を引くことで算出した。
損傷から4週間後には、過剰量のペントバルビトールナトリウム(90mg/kgを腹腔注射)(フィンランド国、Orion Pharma製)でラットを麻酔し、リン酸緩衝化生理食塩水(PBS)、続いて4% パラホルムアルデヒドを含む0.1M リン酸ナトリウムバッファー(pH7.4)による心臓内還流を行った。脳を取り出し、4時間の固定後処理を行い、20% ショ糖含有リン酸ナトリウムバッファー中、4℃で保存した。40μm厚の連続した環状断凍結切片をスライド式ミクロトームで切り出した。6セットの切片を凍結保護溶液(0.5M PB、30% グリセリンと30% エチレングリコール)に回収し、免疫組織学的処理を行うまで−20℃で保存した。浮動性切片をTH−免疫組織学のために処理した。PBSで3回すすいだ後、3% H2O2/10% メタノール/PBS中で内因性ペロキシダーゼ活性の抑制処理を5分間行った。PBSで3回すすいだ後、切片を正常ウマ血清(NHS)/0.3% Triton X-100 を含むPBSとプレインキュベートすることで非特異的な染色をブロックした。その後、切片1:2000に希釈したビオチン化マウス−抗TH抗体(カリフォルニア州、テメクラ、Chemicon製)と共に室温で一晩インキュベートした。続いて、1:200に希釈したビオチン化ウマ抗マウス抗体(BA2001、Vector製)とのインキュベーション、およびElite ABC Vectastainキット(Vector Laboratories製)を用いたアビジン−ビオチンペルオキシダーゼ複合体とのインキュベーションを行った。DABを発色団として使用し、反応を可視化した。
SN細胞数
光学フラクショネーター(Optical fractionator)法を解像原理と公平な計測規則(West et al.,1991, Anat. Rec. 231, 482-497、Mouton et al. 2002, Brain Res. 956, 30-35)と組み合わせて使用する、公平なステレオロジーによる細胞計数法で、黒質緻密部(SNpc)のTH陽性細胞数を計測した。SNpcの全体を、Olympus BX51顕微鏡に装着したStereo Investigator(ドイツ国、MicroBrightField製)のプラットフォーム上で解析した。容量解析のために、それぞれの動物について、内側の尾状核(MTN)が存在する(A/P軸は−5.3)SNpcの中央部から3つの切片を選択した。光学フラクショネーターによる推定は、個別の脳サンプルに関する計数誤差がx%未満となるように最適化した。それぞれの参照空間は低倍率(4×)で輪郭をとり、細胞は高倍率(60×、油浸)の対物レンズを用いて計数した。
オスのウイスターラットでは、線条体への1回のMANF2注射(10μg)が黒質線条体路におけるドーパミン作動性神経の6−ヒドロキシドーパミン(6−OHDA、8μg)誘導変性を防止した。麻酔下でラットに2回の定位マイクロインフュージョンを施した。具体的には、1回目には、ベヒクル(PBS、4μl、対照群)またはMANF2(10μg、処置群)を投与し、6時間後にはそれぞれの動物に6−OHDA(8μg)を左尾状核の同じ部位に投与した。前頂と硬膜に対する左線条体における座標は、PaxinosとWatsonのアトラス(Paxinos and Watson, 1997, The rat brain in stereotaxic coordinates (ラット脳の定位座標), Academic press, San Diego)によるとA/P +1.0、L/M +2.7、D/V −4だった。
年齢と関連のある神経変性障害であるパーキンソン氏病では、黒質のドーパミン作動性ニューロンが徐々に失われてゆく。神経栄養因子は変性脳疾患の処置における顕著な治療可能性を有している。ニューロンの変性を遅らせるか逆行させる、あるいは神経の損傷を回復させる神経栄養因子は、創薬の潜在的な標的分子である。グリア細胞株誘導神経栄養因子(GDNF)は、ドーパミン作動性ニューロンの、これまでに報告されている最も強力な標的誘導性栄養因子である(Lin et al., 1993, Science 260, 1130-2)。ヒトパーキンソン氏病患者の被殻へのGDNFの送達は、臨床上の改善をもたらした(Gill et al., 2003, Nat. Med. 9, 589-95)が、Amgenからのより最近のデータは、副作用の深刻な危険性を示している。この結果は、神経変性疾患の処置のための新規神経栄養因子の探索が有効であることを保証している。
配列番号6: オリゴヌクレオチドプライマー
配列番号7: オリゴヌクレオチドプライマー
配列番号8: オリゴヌクレオチドプライマー
配列番号9: オリゴヌクレオチドプライマー
配列番号10: オリゴヌクレオチドプライマー
配列番号11: オリゴヌクレオチドプライマー
配列番号12: オリゴヌクレオチドプライマー
Claims (2)
- 配列番号2のアミノ酸配列を含むMANF2タンパク質の機能的断片を包含し、該機能的断片は、シグナルペプチドを欠失したMANF2ポリペプチドであり、該シグナルペプチドの開列部位は、配列番号2のアミノ酸配列の26位のアミノ酸と27位のアミノ酸の間に存在することを特徴とする、ドーパミン作動性ニューロン障害の治療用の医薬化合物。
- 該ドーパミン作動性ニューロン障害がパーキンソン氏病であることを特徴とする、請求項1に記載のドーパミン作動性ニューロン障害の治療用の医薬化合物。
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WO2002079246A2 (en) * | 2001-03-30 | 2002-10-10 | Geneprot, Inc. | Human arginine-rich protein-related compositions |
GB0113657D0 (en) | 2001-06-05 | 2001-07-25 | Geneprot Inc | Improved native chemical ligation with three or more components |
US20060195915A1 (en) * | 2002-08-30 | 2006-08-31 | Licentia Ltd. | Novel neurotrophic factor protein and uses thereof |
US7452969B2 (en) * | 2002-08-30 | 2008-11-18 | Licentia Ltd | Neurotrophic factor protein and uses thereof |
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2005
- 2005-12-14 EP EP20050817611 patent/EP1969003B8/en active Active
- 2005-12-14 CA CA 2633468 patent/CA2633468C/en active Active
- 2005-12-14 DE DE200560023550 patent/DE602005023550D1/de active Active
- 2005-12-14 PL PL05817611T patent/PL1969003T3/pl unknown
- 2005-12-14 AT AT05817611T patent/ATE480559T1/de not_active IP Right Cessation
- 2005-12-14 WO PCT/FI2005/050461 patent/WO2007068784A1/en active Application Filing
- 2005-12-14 JP JP2008545024A patent/JP5236488B2/ja not_active Expired - Fee Related
- 2005-12-14 ES ES05817611T patent/ES2352205T3/es active Active
- 2005-12-14 DK DK05817611T patent/DK1969003T3/da active
- 2005-12-14 AU AU2005339101A patent/AU2005339101B2/en not_active Ceased
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2006
- 2006-12-14 US US12/086,397 patent/US20100285045A1/en not_active Abandoned
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2008
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2011
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Also Published As
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WO2007068803A1 (en) | 2007-06-21 |
WO2007068784A1 (en) | 2007-06-21 |
PL1969003T3 (pl) | 2011-05-31 |
AU2005339101B2 (en) | 2013-01-10 |
US9127082B2 (en) | 2015-09-08 |
EP1960426B1 (en) | 2014-04-02 |
US20080269154A1 (en) | 2008-10-30 |
CA2633468A1 (en) | 2007-06-21 |
ES2352205T3 (es) | 2011-02-16 |
EP1960426A1 (en) | 2008-08-27 |
ATE480559T1 (de) | 2010-09-15 |
EP1969003B1 (en) | 2010-09-08 |
EP1969003A1 (en) | 2008-09-17 |
EP1969003A4 (en) | 2009-03-25 |
EP1969003B8 (en) | 2010-11-10 |
US20110251132A1 (en) | 2011-10-13 |
US8980821B2 (en) | 2015-03-17 |
US20190153052A1 (en) | 2019-05-23 |
US20100285045A1 (en) | 2010-11-11 |
JP2009519028A (ja) | 2009-05-14 |
CA2633468C (en) | 2014-02-18 |
DK1969003T3 (da) | 2010-12-13 |
AU2005339101A1 (en) | 2007-06-21 |
DE602005023550D1 (de) | 2010-10-21 |
EP1960426A4 (en) | 2009-07-08 |
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