JP2022524927A - 創薬のためのヒトスフェロイドの使用方法 - Google Patents
創薬のためのヒトスフェロイドの使用方法 Download PDFInfo
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Abstract
Description
この出願は、2019年2月2日に出願された米国出願第62/800,430号の出願日の利益を主張し、その開示は参照により本明細書に組み込まれる。
定義
本発明を説明する際に、以下の用語は、以下に記載される定義に従って使用される。
一つの実施形態では、本開示は、ヒト誘導多能性幹細胞iPScを提供し、これは、その後、約50:50の比率でニューロンおよびアストロサイトを含むヒト皮質ニューロンに分化する。この比率は、特定の対象疾患に応じて、ニューロンまたはアストロサイトのいずれか1~99%のケースバイケースで調整することができる。3Dスフェロイドは、約50:50のニューロンとアストロサイトの比率+/-10%で構成されている。3次元スフェロイドを分化および形成する方法、ならびにFLIPR光学技術を用いた機能試験は、係属中の特許出願第62/532667号に記載されている。本発明の実施例では、レット症候群の原因となる遺伝子を保有することが知られている疾患モデル細胞株を使用する。
本開示は、自閉症スペクトラム障害またはレット症候群等の障害に関連する一つまたは複数の症状をヒトにおいて予防または軽減する、たとえば、抑制または治療するための方法を提供する。一部の実施形態では、疾患の神経学的または発達的症状を抑制または治療するための方法が提供される。
静脈内、筋肉内、局所または皮下経路等による、または薬物を身体または身体の特定の器官および組織に送達することを可能にする任意の他の投与経路による中枢神経系への髄腔内、脳室内または実質内送達等、任意選択で、無菌の水溶液または非水溶液、懸濁液、およびエマルジョンをさらに含む、投与、たとえば経鼻、非経口または経口投与に好適な、本明細書に記載の化合物の一つまたは複数を有する医薬組成物。組成物は、当技術分野で知られているように、補助剤または賦形剤をさらに含んでもよい。本明細書に記載の化合物の一つまたは複数を有する組成物は、一般に、個々の用量(単位用量)の形態で提示される。
一つの実施形態では、スフェロイドに対する一つまたは複数の化合物の効果を検出する方法が提供される。一つの実施形態では、この方法は、均一な直径のヒト細胞の一つまたは複数のスフェロイドと一つまたは複数の試験化合物とを接触させることを含み、ここでスフェロイドは、自閉症患者の細胞、レット症候群患者の細胞、またはレット症候群のモデル由来の細胞から得られる。一つまたは複数のスフェロイドに対する一つまたは複数の化合物の効果が、任意選択で対応する野生型細胞と比較して、検出され、たとえば、測定される。一つの実施形態では、一つまたは複数のスフェロイドは、マルチウェルプレートのウェル内にある。一つの実施形態では、各ウェルは一つのスフェロイドを有する。一つの実施形態では、ウェルは、カルシウムを検出するのに有用な蛍光分子とさらに接触され、経時的な蛍光の量または変化が、一つまたは複数のウェルで検出される。一つの実施形態では、蛍光の量または変化は、蛍光のピークの量、一つまたは複数のピークの振幅、一つまたは複数のピーク間のピーク間隔、一つまたは複数のピークの幅、またはそれらの任意の組み合わせを検出することである。一つの実施形態では、一つまたは複数のスフェロイドは、ニューロンを含む。一つの実施形態では、一つまたは複数のスフェロイドは、ニューロンおよびアストロサイトを含む。一つの実施形態では、一つまたは複数のスフェロイドは、心臓細胞、肝臓細胞、腎臓細胞、膵臓細胞、肺細胞、内皮細胞または上皮細胞を含む。一つの実施形態では、一つまたは複数のスフェロイドは、細胞またはオリゴデンドロサイトを含む。一つの実施形態では、一つまたは複数のスフェロイドは、周皮細胞および内皮細胞を含む。一つの実施形態では、一つまたは複数のスフェロイドは、内皮細胞、ミクログリア細胞、ニューロン、オリゴデンドロサイト、またはそれらの任意の組み合わせを含む。一つの実施形態では、細胞は、前駆細胞である。一つの実施形態では、前駆細胞は、ニューロン、アストロサイト、心臓細胞、肝細胞、腎臓細胞、膵臓細胞、肺細胞、内皮細胞、または上皮細胞の前駆細胞である。一つの実施形態では、一つまたは複数のスフェロイドは、約500~約600ミクロンの直径を有する。一つの実施形態では、一つまたは複数のスフェロイドは、約450~約500ミクロンの直径を有する。一つの実施形態では、一つまたは複数のスフェロイドは、一つまたは複数の試験化合物と接触する前に少なくとも6週間培養される。一つの実施形態では、蛍光分子はCalcium 3、Calcium 4、Calcium 5、Calcium 6、Fluo3、またはFluo4を含む。一つの実施形態では、方法は、ウェルを細胞膜非透過性クエンチャー(cell membrane impermeant quencher)と接触させることをさらに含む。一つの実施形態では、蛍光の変化量は、スフェロイドおよび蛍光分子を含むが、試験化合物を含まないウェル内の蛍光と比較される
Claims (27)
- スフェロイドに対する一つまたは複数の化合物の効果を検出する方法であって、
均一な直径のヒト細胞の一つまたは複数のスフェロイドを一つまたは複数の試験化合物との接触させる工程であって、ここで、前記スフェロイドは、自閉症患者の細胞、レット症候群患者の細胞、またはレット症候群のモデルに由来する細胞から得られる工程;および
一つまたは複数のスフェロイドに対する一つまたは複数の化合物の前記効果を検出する工程
を含む、方法。 - 前記一つまたは複数のスフェロイドは、マルチウェルプレートのウェル内にある、請求項1に記載の方法。
- 各ウェルが一つのスフェロイドを有する、請求項2に記載の方法。
- 前記ウェルは、カルシウムを検出するのに有用な蛍光分子とさらに接触され、経時的な蛍光の量または変化は、一つまたは複数のウェルで検出される、請求項2または3に記載の方法。
- 前記蛍光の量または変化は、蛍光のピークの量、一つまたは複数の前記ピークの振幅、一つまたは複数の前記ピーク間のピーク間隔、一つまたは複数のピークの幅、またはそれらの任意の組み合わせを検出する、請求項4に記載の方法。
- 前記一つまたは複数のスフェロイドはニューロンを含む、請求項1~5のいずれか一項に記載の方法。
- 前記一つまたは複数のスフェロイドはニューロンおよびアストロサイトを含む、請求項1~5のいずれか一項に記載の方法。
- 心臓細胞、肝臓細胞、腎臓細胞、膵臓細胞、肺細胞、内皮細胞または上皮細胞を含む一つまたは複数のスフェロイドを含む、請求項1~7のいずれか一項に記載の方法。
- 前記一つまたは複数のスフェロイドは、レット病(Rett disease)患者由来の細胞を含む、請求項1~8のいずれか一項に記載の方法。
- 前記一つまたは複数のスフェロイドは、ミクログリア細胞またはオリゴデンドロサイトを含む、請求項1~9のいずれか一項に記載の方法。
- 周皮細胞および内皮細胞を含む前記一つまたは複数のスフェロイドを含む、請求項1~10のいずれか一項に記載の方法。
- 前記一つまたは複数のスフェロイドは、内皮細胞、ミクログリア細胞、ニューロン、オリゴデンドロサイト、またはそれらの任意の組み合わせを含む、請求項1~11のいずれか一項に記載の方法。
- 前記細胞は前駆細胞である、請求項1~12のいずれか一項に記載の方法。
- 前記前駆細胞は、ニューロン、アストロサイト、心臓細胞、肝細胞、腎臓細胞、膵臓細胞、肺細胞、内皮細胞、または上皮細胞の前駆細胞である、請求項13に記載の方法。
- 前記一つまたは複数のスフェロイドは、約500~約600ミクロンの直径を有する、請求項1~14のいずれか一項に記載の方法。
- 前記一つまたは複数のスフェロイドは、約450~約500ミクロンの直径を有する、請求項1~14のいずれか一項に記載の方法。
- 前記一つまたは複数のスフェロイドが、前記一つまたは複数の試験化合物と接触する前に少なくとも4~6週間培養される、請求項1~16のいずれか一項に記載の方法。
- 蛍光分子がCalcium 3、Calcium 4、Calcium 5、Calcium 6、Fluo3、またはFluo4を含む、請求項3~17のいずれか一項に記載の方法。
- 前記ウェルを細胞膜非透過性クエンチャー(cell membrane impermeant quencher)と接触させることをさらに含む、請求項3~18のいずれか一項に記載の方法。
- 前記蛍光の変化量は、スフェロイドおよび前記蛍光分子を含むが、前記試験化合物を含まないウェル内の前記蛍光と比較される、請求項3~19のいずれか一項に記載の方法。
- ヒトにおけるレット症候群の一つまたは複数の症状を予防、抑制、または治療する方法であって、有効量の一つまたは複数の5-HT4受容体選択的アゴニスト、ザビシクロアルキルベンズイミダゾロン(zabicycloalkyl benzimidazolone)、GABA受容体アンタゴニスト、ベンゾジアゼピン、ベンゾジアゼピン受容体での競合的アンタゴニスト、アセタゾラミド、選択的ノルアドレナリン再取り込み阻害薬、抗ムスカリン薬、選択的セロトニン受容体アゴニスト、ゴナドトロピン放出ホルモンの放出を促進する化合物、選択的セロトニン再取り込み阻害薬、分岐鎖飽和脂肪酸アニオン、CYP2C9の阻害薬、グルクロニルトランスフェラーゼの阻害薬、ヒストンデアセチラーゼの阻害薬、エポキシドヒドロラーゼの阻害薬、ガンマアミノ酪酸(GABA)アゴニスト、非ステロイド性抗炎症薬(NSAID)、ビインドール、抗コリン作用薬、ドーパミンアンタゴニスト、アセチルコリンエステラーゼ阻害薬、抗ヒスタミン薬、ベンゾチアジアジン、グルタミン酸AMPA受容体の修飾薬、制吐薬、セロトニン逆作動薬、モノアミンオキシダーゼの阻害薬、またはアルカロイド、またはそれらの任意の組み合わせを含む組成物を前記患者に投与することを含む方法。
- 前記組成物は、アセタゾラミド、アトモキセチン(トモキセチン)、塩酸ベンズヘキソール、BIMU-8、エレトリプタン臭化水素酸塩(eletriptan HBr Salt)、イロペリドン、トラゾドン(ベネフィキャット[Beneficat])、バルプロ酸DPA、バクロフェン、塩酸ベンジダミン(benzydiamine hydrochloride)、ブロモインジルビン-3-オキシム、ビペリデン、シタロプラム、リンゴ酸クレボプリド、ドネペジル(bonepezil)、フルマゼニル、二塩化ヒドロキシジン(hydroxyzine dichloride)、IDRA-21、オンダンセトロン、パロキセチン、ピマバンセリン、メシル酸ピルリンドール、塩酸セレギリン、またはビンポセチン、またはそれらの任意の組み合わせを含む、請求項21に記載の方法。
- 前記組成物は、経口投与される、請求項21または22に記載の方法。
- 前記組成物は、徐放性製剤である、請求項21または22に記載の方法。
- 前記投与は、静脈内、動脈内、皮下、鼻腔内、髄腔内、脳室内、実質内、経網膜(trans-retinal)、筋肉内、経皮、または直腸内である、請求項21に記載の方法。
- 前記組成物は、徐放性製剤である、請求項25に記載の方法。
- 前記量は、成長遅延、正常な動きの喪失、協調の喪失、コミュニケーション能力の喪失、異常な手の動き、異常な眼球運動、呼吸障害、認知障害、発作(seizure)、脊柱側弯症、不規則な心拍、または睡眠障害を抑制、または治療する、請求項21~26のいずれか一項に記載の方法。
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