JP2022501413A - 炎症性神経障害を処置するための組成物及び方法 - Google Patents
炎症性神経障害を処置するための組成物及び方法 Download PDFInfo
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Abstract
Description
本発明の開発中に実施された研究の一部では、国立衛生研究所助成金番号5R21NS091890−02及び1R01NS107523−01の下で米国政府の資金を利用した。米国政府は、本発明に特定の権利を有する。
局所脱ミエリン化を、いずれかの性別の8〜12週齢のC57Bl/6マウスの前索に、1%リゾレシチン(Sigma−Aldrich)を注射することによって誘発した。病変後(dpl)5日及び10日目に、4%(w/v)パラホルムアルデヒド(PFA;Sigma)を、マウスの心臓内に灌流させた。
10〜12週齢のC57BL/6雌マウス(Charles River)を7日間馴化させた後、実験的自己免疫性脳脊髄炎(EAE)を誘発させた。EAEを、EAEキット(Hooke Laboratories、カタログ番号:EK−2110)を使用して、Hooke Laboratoriesプロトコル(ワールドワイドウェブ上のhookelabs. com/protocols/eaeAI_C57BL6.html)に従って誘発させた。要約すると、完全フロイントアジュバント(CFA)中のMOG35−55のエマルションを2つの部位に皮下注射してマウスを免疫し(0日目)、続いて百日咳毒素(PTX)を最初に免疫付与の日(0日目)に、次に翌日(1日目)に再び、腹腔内投与した。2回のPTX投与のそれぞれに、およそ115ngのPTXを使用した。
1%リゾレシチンを注射することによって局所脱ミエリン化を誘発し、JPH203またはPBS対照に、5〜9dplで腹腔内を介して注射した。4%PFA(Sigma)を用いた心臓内灌流により、マウスを10dplで犠死させた。IHCを、先に記載したように実施した。クリオスタット(Leica CM1900)を使用して、厚さ12マイクロメートルの固定脊髄切片を切り取り、SuperFrostPlusスライド(VWR International)上に収集し、30分間乾燥させた後、−80℃で保存した。IHC用に、切片をブロッキング溶液(PBS中0.1%TritonTM X−100及び10%FBS)中で、室温(RT)にて1時間インキュベートした。一次抗体をブロッキング溶液で希釈し、4℃で一晩適用した。一次抗体の供給元及び希釈率は以下のとおりである:ウサギ抗Olig2(1:300;Millipore)、マウス抗CC1(1:200;Sigma)。蛍光色素コンジュゲート二次抗体はLife Technologiesから入手し、製造元の指示に従って使用した。
炎症及び再ミエリン化に対するSlc7a5阻害の効果を特徴決定するために、脱ミエリン化前(予防的アプローチ)対脱ミエリン化後(治療的アプローチ)のJPH203の全身投与を実施する。さらに、Slc7a5はオリゴデンドロサイト系統細胞では発現しないため、このアプローチでは、オリゴデンドロサイト系統細胞に影響を与えることなく、CNS病変のミクログリア/マクロファージを選択的に標的とすることにより、JPH203が再ミエリン化を促進するかどうかを判断することができる。予防的処置のために、JPH203(群1)またはビヒクル(群2)を、リゾレシチン誘発性脱ミエリン化の前に2日間連続して腹腔内注射によって野生型マウスに送達し、脱ミエリン化後、3日間連続して野生型マウスに送達し、その後10dplで犠死させる。治療的処置のために、JPH203(群3)またはビヒクル(群4)を、脱ミエリン化後5〜9dplで腹腔内注射によって送達し、10dplで犠死させる。10dplの時点を選択して、JPH203がオリゴデンドロサイトの分化を促進するかどうかを決定する。マウスはまた、病変の同定及び分析のためにニュートラルレッド(NR)注射を受け、その2時間後にマウスを犠死させる。
Claims (35)
- 対象の中枢神経系(CNS)における炎症の増強を特徴とする状態を処置する方法であって、そのような処置を必要とする対象に、前記CNSに存在する炎症性細胞におけるアミノ酸トランスポーターの阻害剤を投与することを含む、前記方法。
- 前記CNSにおける炎症の増強を特徴とする前記状態が、多発性硬化症(MS)、炎症性脱髄疾患、脳卒中、外傷性脳損傷(TBI)、ウイルス感染、脊髄損傷、視神経損傷、及び脳性麻痺、からなる群から選択される、請求項1に記載の方法。
- 前記CNSにおける炎症の増強を特徴とする前記状態が、炎症性脱ミエリン化疾患である、請求項1または2に記載の方法。
- 前記炎症性脱ミエリン化疾患が自己免疫性脳炎である、請求項3に記載の方法。
- 前記CNSに存在する前記炎症性細胞が、ミクログリア、マクロファージ、T細胞、B細胞、及び内皮細胞からなる群から選択される、請求項1〜4のいずれか1項に記載の方法。
- 前記CNSに存在する前記炎症性細胞がミクログリアである、請求項1〜5のいずれか1項に記載の方法。
- 阻害される前記アミノ酸トランスポーターが、大型アミノ酸トランスポーターの小サブユニット1(LAT1)である、請求項1〜6のいずれか1項に記載の方法。
- 前記アミノ酸トランスポーターの前記阻害剤が、JPH203またはその薬学的に許容される塩である、請求項1〜7のいずれか1項に記載の方法。
- 前記アミノ酸トランスポーターの前記阻害剤が全身投与される、請求項1〜8のいずれか1項に記載の方法。
- 全身投与の経路が、静脈内、経口、腹腔内、筋肉内、皮内、髄腔内、皮下及び経鼻からなる群から選択される、請求項9に記載の方法。
- 前記アミノ酸トランスポーターの前記阻害剤が前記CNSに局所投与される、請求項1〜8のいずれか1項に記載の方法。
- 前記対象が哺乳動物である、請求項1〜11のいずれか1項に記載の方法。
- アミノ酸トランスポーターの前記阻害剤の前記投与により、前記対象の前記CNS内におけるオリゴデンドロサイトの再ミエリン化オリゴデンドロサイトへの分化の増加がもたらされる、請求項1〜12のいずれか1項に記載の方法。
- アミノ酸トランスポーターの前記阻害剤の前記投与により、前記対象の前記CNSにおけるニューロンの再ミエリン化の増加がもたらされる、請求項1〜12のいずれか1項に記載の方法。
- アミノ酸トランスポーターの前記阻害剤の前記投与により、神経ジストロフィーの減少または神経変性の減少がもたらされる、請求項1〜12のいずれか1項に記載の方法。
- アミノ酸トランスポーターの前記阻害剤の前記投与により、前記対象の前記CNSにおける炎症の減少がもたらされる、請求項1〜12のいずれか1項に記載の方法。
- アミノ酸トランスポーターの前記阻害剤の前記投与により、前記CNSに存在する炎症性細胞におけるmTORシグナル伝達が選択的に阻害される、請求項1〜12のいずれか1項に記載の方法。
- アミノ酸トランスポーターの前記阻害剤が2回以上投与される、請求項1〜17のいずれか1項に記載の方法。
- 炎症誘発性細胞におけるアミノ酸トランスポーターの阻害剤、またはその薬学的に許容される塩を含む組成物であって、哺乳動物の中枢神経系(CNS)への投与用に処方される、前記組成物。
- 阻害される前記アミノ酸トランスポーターが、大型アミノ酸トランスポーターの小サブユニット1(LAT1)である、請求項19に記載の医薬組成物。
- 炎症誘発性細胞におけるアミノ酸トランスポーターの前記阻害剤が、JPH203またはその薬学的に許容される塩である、請求項19または20に記載の医薬組成物。
- 対象の中枢神経系(CNS)における炎症の増強の影響を前処置する方法であって、そのような処置を必要とする対象に、前記CNSに存在する炎症性細胞におけるアミノ酸トランスポーターの阻害剤を投与することを含む、前記方法。
- 前記対象が、アミノ酸トランスポーターの前記阻害剤の投与前に、前記CNSにおける炎症を誘発することが知られている損傷に罹患している、請求項22に記載の方法。
- 前記対象が、アミノ酸トランスポーターの前記阻害剤の投与前に、前記CNSにおける炎症のいかなる症状も呈していない、請求項23に記載の方法。
- 前記損傷が、がん治療後の放射線誘発損傷、脳卒中、外傷性脳損傷(TBI)、ウイルス感染、脊髄損傷、及び視神経損傷、からなる群から選択されるものである、請求項24に記載の方法。
- アミノ酸トランスポーターの前記阻害剤が、前記損傷から約48時間以内に前記対象に投与される、請求項25に記載の方法。
- アミノ酸トランスポーターの前記阻害剤が、前記損傷後1時間未満で前記対象に投与される、請求項26に記載の方法。
- アミノ酸トランスポーターの前記阻害剤が、前記対象に2回以上投与される、請求項22〜27のいずれか1項に記載の方法。
- アミノ酸トランスポーターの前記阻害剤が最初に前記対象に投与されたときに、前記対象が前記CNSにおけるニューロンの脱ミエリン化の症状を呈していない、請求項22〜28のいずれか1項に記載の方法。
- 阻害される前記アミノ酸トランスポーターが、大型アミノ酸トランスポーターの小サブユニット1(LAT1)である、請求項22〜29のいずれか1項に記載の方法。
- 前記アミノ酸トランスポーターの前記阻害剤が、JPH203またはその薬学的に許容される塩である、請求項22〜30のいずれか1項に記載の方法。
- 前記アミノ酸トランスポーターの前記阻害剤が全身投与される、請求項22〜31のいずれか1項に記載の方法。
- 全身投与の経路が、静脈内、経口、腹腔内、筋肉内、皮内、髄腔内、皮下及び経鼻からなる群から選択される、請求項32に記載の方法。
- 前記アミノ酸トランスポーターの前記阻害剤が前記CNSに局所投与される、請求項22〜31のいずれか1項に記載の方法。
- 前記対象が哺乳動物である、請求項22〜34のいずれか1項に記載の方法。
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PCT/US2019/054245 WO2020072608A1 (en) | 2018-10-02 | 2019-10-02 | Compositions and methods for treating inflammatory neurological disorders |
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