JP7177404B2 - 新規ジストニア治療用薬学的組成物 - Google Patents
新規ジストニア治療用薬学的組成物 Download PDFInfo
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- JP7177404B2 JP7177404B2 JP2020529253A JP2020529253A JP7177404B2 JP 7177404 B2 JP7177404 B2 JP 7177404B2 JP 2020529253 A JP2020529253 A JP 2020529253A JP 2020529253 A JP2020529253 A JP 2020529253A JP 7177404 B2 JP7177404 B2 JP 7177404B2
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Description
本明細書で使われる用語「ジストニア」、「筋異常緊張」または「筋緊張異常症」は、本人の意志と無関係に持続的に非正常な姿勢を取るか、またはひねる筋肉運動を誘発する不随意的な異常運動現象を特徴とする神経学的疾患であって、家族性またはストレス性ジストニアが存在すると知られている。特に、ストレス性ジストニアは、特別に遺伝的素因がない場合にも、公演や発表などを前にして激しいストレスによって誘発される場合がある。
本発明の一観点によれば、セロトニン受容体5-HT2A阻害剤を有効成分として含む筋緊張異常症治療用または筋緊張によって発生する疼痛緩和用薬学的組成物が提供される。
7~8週齢のCACNA1Atot/totマウス(Fletcher,Cell,87(4):607-617,1996,The Jackson Laboratory,Stock No:000544)を韓国科学技術院(Korea Advanced Institute of Science and Technology、KAIST)の実験動物運営委員会規定(プロトコル番号KA2014-05)によってマウスを飼育及び扱った。マウスは、水と飼料とに自在に接近可能な状態に保持され、明暗周期は、12時間であった。行動試験は、ウイルス発現製作をした日から4週後に実行した。前記CACNA1Atot/totマウスは、P/Q型カルシウムチャネルであるCav2.1の反復地域II S5-S6に存在するプロリン(proline)がロイシン(leucine)残基で置換されてニューロンでのP/Q型チャネル活性が減少した形質転換マウスである。従来の研究によれば、P/Q型チャネル活性の減少からL型カルシウムチャネルであるCav1.2の発現が増加すると報告されており(Fletcher,Cell,87(4):607-617,1996)、前記不安定マウスを新たな環境に置く場合、10分程度経過後、筋異常緊張の現象が表われると報告されている(Alvina,K.,& Khodakhah,K.,Neurosci.,30(21):7258-7268,2010)。
ジストニア症状の程度とニューロン内のカルシウム濃度との相関関係を分析するために、光遺伝学(optogenetic)モデル動物を製造した。具体的に、偏光保持単一モード光繊維を通じた測光システムのために、AAV2/9-CAG-FLEX-GCaMP6m(Izadmehr et al.,cell,164:617-631,2016)及びAAV2/9-CMV-Cre(Gompf et al.,Front.Behav.Neurosci.9:152,2015)ウイルスベクターを定位的(stereotaxic)手術を通じて、前記CACNA1Atot/totマウスの右側室頂核(fastigial nucleus)にそれぞれ0.25μlずつ一方的に微小注入した。前記ウイルス注入は、実験4週前に行われた。引き続き、ステンレススチール製の耐熱導管内に挿入された光繊維を注射部位真上に移植した。蛍光測定は、TCSPC基盤の光測定システム(Becker & Hickel,Germany)を使用した。
5-HT1A選択的拮抗剤であるWay100135、5-HT2A選択的拮抗剤であるMDL100907(ボリナンセリン)及び5-TH3選択的拮抗剤であるオンダンセトロンは、いずれもSigma Aldrich社から購入し、生理食塩水に溶解させて、12時間明/暗周期の調節された環境に置かれた前記実施例2から製造された雄性不安定マウスに静脈注射した。以前に報告されたように、前記Way100135(10mg/kg、Loscher et al.,Eur.J.Pharmacol.,255(1-3):235-238,1994)、MDL100907(1mg/kg、Barr et al.,Neuropsychopharmacol.,29(2):221-228,2004)またはオンダンセトロン(1mg/kg、Minville et al.,Br.J.Anaesth.,106(1):112-118,2010)を前記不安定マウスにそれぞれ投与し、対照群の記録のために、前記不安定マウスに同一体積の生理食塩水を静脈注射した。行動テストは、薬物治療30分後に行い、居所で30分間順化させた実験動物を開放状ボックス(open field box)に移動させて、30分間放置してストレス環境に露出させた後、筋異常緊張症状を測定した。前記筋緊張異常症状及びその重症度は、5点尺度の筋異常緊張指数として算定したが、0=正常行動、1=非正常な運動行動、筋緊張異常姿勢ない、2=軽微な運動障害、妨害された時の筋緊張異常-類似姿勢、3=中等度障害、頻繁な自発的筋緊張異常姿勢、4=重症障害、持続的な筋緊張異常姿勢と決めて採点した。
EMG記録のために、電極(A-Mシステム,USA)を手術で伸筋及び前脛骨筋にそれぞれ挿入した。前記電極は、テプロンがコーティングされた互いに付着されたステンレス鋼線の多重鎖を用いて作られた。右側下肢と首の後ろの毛を切った後、背中側首部位の皮膚に小さな切開部位を形成した。4セットの記録電極は、首切開部位から筋肉まで皮膚の下に連結された。筋電図(EMG)電線は、皮膚の下に配線されて、頭蓋骨に固定されたコネクタに連結された。前記電線の露出された末端の低いインピーダンスは、相対的に長い距離を通過した電気信号の捕捉を許容する(Pearson et al.,J.Neurosci.Methods,148(1):36-42,2005)。電極からEMG信号を10kHzでサンプリングし、MiniDigi 1A(Axon Instrument,USA)でデジタル化した。原信号(raw trace)は、Clampfit 9.2(Axon Instrument,USA)を使用して分析した。相互相関(cross correlation)を計算するために、NeuroExplorer(Ver.4,Nex Technologies,USA)の基準を利用した。前記相互相関は、0msで高い筋異常症状指数を示す時、ジストニア症状が激しいことを示す。前記相互相関は、2ヶ所の筋肉(TA及びGS)で一定時間の筋電図が重なる程度を示すものであって、2ヶ所の筋肉での同時に筋異常緊張症状が出るかを判断する尺度である。これは、筋肉部位間の筋収縮タイミングに対する尺度であって、分析方法は、互いにタイミングが類似しているほど時間(ms)のX軸0ms部分で高い値を示すようになる。すなわち、相互間の信号が0ms(同じ時間に収縮する時)である時、出るY軸値である相互相関値(Cross Corr.)が大きなほど2つの筋肉が同時に収縮する筋異常緊張症状がさらに激しいことを表わす。Y軸の単位であるAUは、対照群を1に置いて見た時の相対的な相互相関値であって、任意的単位(arbitrary unit)である。
本発明者らは、前記結果から、5-HT2Aが小脳でカルシウム信号伝達に密接な関連性があるという点に着眼して、不安定マウスモデルの小脳でのカルシウムイオン濃度を測定することにより、筋異常緊張症状を確認し、治療薬物の治療効果を検証できるか否かを調査した。小脳でのカルシウム信号伝達の変化は、GCaMP6というカルシウムセンサータンパク質をコードする遺伝子をジストニアモデルの小脳に局所的に形質導入させた後、カルシウムイオンと結合したGCaMP6タンパク質の蛍光の強度を測定することで可能である。既存の薬物の場合には、全般的な緩和程度を通じて治療効果を類推し、一方、本発明で使用した方法は、薬物による効果をさらに効率的に、そして、リアルタイムで実験動物を通じて定量化することができる。本発明者らは、前記実施例2から製造された局所的形質導入不安定マウスでジストニア症状と神経組織内でのカルシウムイオン濃度との相関関係を分析するために、リアルタイム蛍光分析を行った。具体的に、偏光保持単一モード光繊維を通じて脳組織を刺激するために、20MHzの周波数を有する488nmの波長のパルスレーザを照射した(図4の(A)左側)。前記パルスレーザ照射後、509nmの波長の放射形光をTCSPC基盤の光測定システム(Becker & Hickl,Germany)を使用して測定した。該測定された蛍光に基づいて蛍光変化率(ΔF/F)を計算した。前記ΔF/Fは、100×(F-Fmean)/Fmeanによって計算され、ここでは、Fmeanは、全体獲得切片での蛍光強度の平均値を意味する(Cui et al.,Nature,494(7436):238-242,2013;Matthews et al.,Bone,84:69-77,2016)。GCaMP6m蛍光は、マウスがケージ内の開放状ボックスにある時、30分間記録された。
前記実施例2で製造し、ストレス環境に露出させた不安定マウスを麻酔させた後、最初にはPBSに溶解されたヘパリンナトリウム塩で再灌流した後、PBSに溶解された4%ホルムアルデヒドで再灌流した。脳を摘出した後、摘出された脳を4%ホルムアルデヒド溶液で一晩中固定した。固定後、脳を振動式薄片機(vibrating microtome、Leica,Germany)上で40μmの厚さで薄片化した。脳に対する映像は、LSM780共焦点顕微鏡(Zeiss,Germany)を用いて収得し、ZEN2009光編集ソフトウェア(Zeiss,Germany)で分析した。
本発明は、遺伝的または環境的要因によって発生するジストニア症状はもとより、うつ病治療剤の副作用を発生するジストニア症状を効果的に緩和させる医薬の製造に使われる。
本発明は以下の態様を含む。
<1> セロトニン受容体5-HT 2A 阻害剤を有効成分として含む筋緊張異常症治療用または筋緊張によって発生する疼痛緩和用薬学的組成物。
<2> 前記筋緊張は、ジストニア、脳性麻痺、筋緊張性異栄養症または球脊髄性筋萎縮症によって発生する、<1>に記載の組成物。
<3> 前記5-HT 2A 阻害剤は、5-HT 2A 拮抗剤または5-HT 2A 逆作用剤である、<1>に記載の組成物。
<4> 前記5-HT 2A 拮抗剤は、前記5-HT 2A に特異的に結合する拮抗抗体または前記拮抗抗体の機能性断片、クロザピン、オランザピン、クエチアピン、リスペリドン、ジプラシドン、アリピプラゾール、アセナピン、アミトリプチリン、クロミプラミン、アミトリプチリン、クロミプラミン、シプロヘプタジン、エプリバンセリン、エトペリドン、ハロペリドール、ヒドロキシジン、イロペリドン、ケタンセリン、メチセルジド、ミアンセリン、ミルタザピン、ネファゾドン、ピマバンセリン、ピゾチフェン、リタンセリン、トラゾドン、またはヨヒンビンである、<3>に記載の組成物。
<5> 前記5-HT 2A 拮抗剤は、他の類型のセロトニン受容体には作用を行わない5-HT 2A 選択的拮抗剤または5-HT 2A/2C 二重拮抗剤である、<3>に記載の組成物。
<6> 前記5-HT 2A 選択的拮抗剤は、エプリバンセリン、2-アルキル-4-アリール-テトラヒドロ-ピリミド-アゼピン、AMDA(9-アミノメチル-9,10-ジヒドロアントラセン)、ヒドロキシジン、ピゾチフェン、5-メトキシ-N-(4-ブロモベンジル)トリプタミン(5-MeO-NBpBrT)、グレマンセリン、ニアプラジン、ピマバンセリン、ボリナンセリン、またはLY-367265である、<5>に記載の組成物。
<7> 5-HT 2A/2C 二重拮抗剤は、リタンセリン、ケタンセリン、シプロヘプタジン、AC-90179、トラゾドンまたはエトペリドンである、<5>に記載の組成物。
<8> 前記機能性断片は、Fab、Fab’、F(ab’) 2 、scFv、diabody、tribody、sdAb、V H H、nanobody、monobody、可変性リンパ球受容体(VLR)、Affilin、Affimer、Affitin、Avimer、DARPin、Fynomer、またはAffibodyである、<4>に記載の組成物。
<9> 前記5-HT 2A 逆作用剤は、AC-90179、ピマバンセリン、ネロタンセリン、ボリナンセリンまたはエプリバンセリンである、<3>に記載の組成物。
<10> 前記筋緊張は、過度なストレス、選択的セロトニン再吸収抑制剤の投与またはセロトニン回路の非正常な活性化によるセロトニンの非正常な増加によって起因する、<1>に記載の組成物。
<11> 前記選択的セロトニン再吸収抑制剤は、シタロプラム、ダポキセチン、エスシタロプラム、フルボキサミン、パロキセチン、フルオキセチン、セルトラリン、ジメリジン、またはボルチオキセチンである、<10>に記載の組成物。
<12> 被検化合物または天然物をセロトニン受容体5-HT 2A の機能を阻害するか否かを観察する段階と、
前記5-HT 2A を阻害すると確認された被検化合物または天然物を選別する段階と、
を含む筋緊張による疾患治療または筋緊張によって発生する疼痛緩和候補物質のスクリーニング方法。
<13> 5-HT 2A を阻害することを確認された被検化合物または天然物が、5-HT 2A を除いたセロトニン受容体の機能を阻害するか否かを確認する段階と、
前記5-HT 2A を除いたセロトニン受容体の機能を阻害しない被検化合物または天然物を選別する段階と、
をさらに含む、<12>に記載の方法。
<14> セロトニン受容体5-HT 2A の機能を阻害するか否かは、試験管内、生体内または仮想環境内での多様な分析方法を通じて行われる、<12>に記載の方法。
<15> 前記試験管内の方法は、前記セロトニン受容体5-HT 2A 、そのリガンド(例えば、セロトニン)及び被検化合物または天然物を反応させ、前記セロトニン5-HT 2A 及びそのリガンドの結合を阻害した被検化合物または天然物を選別する工程を通じて行われる、<14>に記載の方法。
<16> 前記試験管内の方法は、セロトニン受容体5-HT 2A が発現される細胞に前記被検化合物または天然物を処理した後、5-HT 2A の下位段階に存在する信号分子の濃度または活性を分析する段階と、
前記5-HT 2A の下位段階に存在する信号分子の活性を抑制した被検化合物または天然物を選別する段階と、
を含む、<4>に記載の方法。
<17> 前記信号分子は、イノシトールトリスリン酸(IP 3 )、ジアシルグリセロール(DAG)、アラキドン酸(AA)、2-アラキドノイルグリセロール(2-AG)、Ca 2+ またはPKCである、<14>に記載のジストニア治療候補物質のスクリーニング方法。
<18> 前記生体内の方法は、P/Q型カルシウムチャネルに突然変異が誘発された不安定動物をストレス条件に放置するストレス誘発段階と、
ストレスが誘発された不安定動物に被検化合物または天然物を投与する段階と、
前記ストレスが誘発された不安定動物の筋異常緊張指数を有意に減少させた被検化合物または天然物を選別する段階と、
を含む、<14>に記載の方法。
<19> 前記生体内の方法は、前記ストレスが誘発された不安定動物の小脳にカルシウムセンサータンパク質をコードする遺伝子を局所的に形質導入する段階と、
前記カルシウムセンサータンパク質をコードする遺伝子が小脳に局所的に形質導入された不安定動物をストレス条件に放置するストレス誘発段階と、
前記ストレスが誘発された不安定動物に被検化合物または天然物を投与する段階と、
前記ストレスが誘発された不安定動物の小脳でのカルシウムと結合したカルシウムセンサータンパク質の量を測定する段階と、
カルシウムと結合したカルシウムセンサータンパク質の量を有意に下げた被検化合物または天然物を選別する段階と、
を含む、<14>に記載の方法。
<20> 前記カルシウムセンサータンパク質は、yellow camelon(YC)、Inverse-Pericam、Camgroo、TN-L15、SynapCamまたはGCaMPである、<19>に記載の方法。
<21> 前記GCaMPは、GCaMP1、GCamP2、GCaMP3、GCaMP4、GCaMP5またはGCaMP6である、<20>に記載の方法。
<22> 筋緊張異常症治療用または筋緊張によって発生する疼痛緩和用薬学的組成物の製造において、セロトニン受容体5-HT 2A 阻害剤の用途。
Claims (1)
- ピマバンセリンを有効成分として含む、ストレス誘導筋緊張異常症(dystonia)治療用またはストレス誘導筋緊張によって発生する疼痛緩和用の経口投与用薬学的組成物。
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