JP6184942B2 - 神経疾患を治療するまたは予防する方法 - Google Patents
神経疾患を治療するまたは予防する方法 Download PDFInfo
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Description
本出願は、2011年6月3に出願された、「神経疾患を治療するまたは予防する方法」と題された米国特許出願第61/493,073号からの優先権を主張する。その出願の内容全体は、ここに参照により組み込まれる。
配列表は、本出願とともに電子出願される。配列表の内容全体は、ここに参照により組み込まれる
配列番号1 GAPDHをコードする核酸を増幅するオリゴヌクレオチド
配列番号2 GAPDHをコードする核酸を増幅するオリゴヌクレオチド
配列番号3 SDF−1をコードする核酸を増幅するオリゴヌクレオチド
配列番号4 SDF−1をコードする核酸を増幅するオリゴヌクレオチド
配列番号5 IL−1βをコードする核酸を増幅するオリゴヌクレオチド
配列番号6 IL−1βをコードする核酸を増幅するオリゴヌクレオチド
配列番号7 FLT−1をコードする核酸を増幅するオリゴヌクレオチド
配列番号8 FLT−1をコードする核酸を増幅するオリゴヌクレオチド
配列番号9 TNF−αをコードする核酸を増幅するオリゴヌクレオチド
配列番号10 TNF−αをコードする核酸を増幅するオリゴヌクレオチド
配列番号11 KDRをコードする核酸を増幅するオリゴヌクレオチド
配列番号12 KDRをコードする核酸を増幅するオリゴヌクレオチド
配列番号13 RANKLをコードする核酸を増幅するオリゴヌクレオチド
配列番号14 RANKLをコードする核酸を増幅するオリゴヌクレオチド
配列番号15 レプチンをコードする核酸を増幅するオリゴヌクレオチド
配列番号16 レプチンをコードする核酸を増幅するオリゴヌクレオチド
配列番号17 CBFA−1をコードする核酸を増幅するオリゴヌクレオチド
配列番号18 CBFA−1をコードする核酸を増幅するオリゴヌクレオチド
配列番号19 PPARγ2をコードする核酸を増幅するオリゴヌクレオチド
配列番号20 PPARγ2をコードする核酸を増幅するオリゴヌクレオチド
配列番号21 OCNをコードする核酸を増幅するオリゴヌクレオチド
配列番号22 OCNをコードする核酸を増幅するオリゴヌクレオチド
配列番号23 MyoDをコードする核酸を増幅するオリゴヌクレオチド
配列番号24 MyoDをコードする核酸を増幅するオリゴヌクレオチド
配列番号25 SMMHCをコードする核酸を増幅するオリゴヌクレオチド
配列番号26 SMMHCをコードする核酸を増幅するオリゴヌクレオチド
配列番号27 GFAPをコードする核酸を増幅するオリゴヌクレオチド
配列番号28 GFAPをコードする核酸を増幅するオリゴヌクレオチド
配列番号29 ネスチンをコードする核酸を増幅するオリゴヌクレオチド
配列番号30 ネスチンをコードする核酸を増幅するオリゴヌクレオチド
配列番号31 SOX9をコードする核酸を増幅するオリゴヌクレオチド
配列番号32 SOX9をコードする核酸を増幅するオリゴヌクレオチド
配列番号33 X型コラーゲンをコードする核酸を増幅するオリゴヌクレオチド
配列番号34 X型コラーゲンをコードする核酸を増幅するオリゴヌクレオチド
配列番号35 アグリカンをコードする核酸を増幅するオリゴヌクレオチド
配列番号36 アグリカンをコードする核酸を増幅するオリゴヌクレオチド
本明細書を通じて、それ以外に具体的に述べられている場合または文脈がそれ以外に要求する場合を除いて、単一ステップへの参照、物質の組成物、ステップの群または物質の組成物の群は、1つおよび複数(すなわち一つまたは複数)のそれらのステップ、物質の組成物、ステップの群または物質の組成物の群を包含すると解されるものとする。
STRO−1+細胞は、骨髄、血液、歯髄細胞、脂肪組織、皮膚、脾臓、膵臓、脳、腎臓、肝臓、心臓、網膜、脳、毛包、腸、肺、リンパ節、胸腺、骨、靱帯、腱、骨格筋、真皮、および骨膜に見出される細胞であり、中胚葉および/または内胚葉および/または外胚葉等の生殖細胞系に分化することができる。
一例では、STRO−1+細胞および/またはその子孫細胞は、遺伝子改変されて、例えば、関心のタンパク質、例えば、治療および/または予防効能を提供するタンパク質、例えば、T細胞の活性化を予防する、または神経細胞の増殖および/もしくは分化ならびに/または髄鞘産生を誘導するポリペプチド、を発現および/または分泌する。例示的なT細胞拮抗剤には、例えば、Toda et al., Eur. J. Immunol., 30: 403-414, 2000.に記載されるペプチドが挙げられる。
細胞または可溶性因子の、炎症性神経学的状態の開始または進行を治療するまたは予防するまたは遅延させる能力を決定する方法は、当業者には明らかであろう。
(i)炎症性の神経学的状態を患う試験対象に細胞または可溶性因子を投与すること、および対象の免疫応答または神経機能/機能不全を評価すること;
(ii)(i)での対象の免疫応答または神経機能/機能不全を、細胞または可溶性因子を投与されなかった、炎症性の神経学的状態を患う対照である対象の、免疫応答または神経機能/機能不全と比較すること、
を含み、この場合に、対照である対象と比較して、試験対象における免疫応答または神経機能/機能不全の改善が、細胞または可溶性因子が炎症性の神経学的状態を治療するということを示していることは、当業者には明らかであろう。
本開示の一例では、STRO−1+細胞および/またはその子孫細胞は、組成物の形態で投与される。例えば、かかる組成物は薬剤的に許容できる担体および/または賦形剤を含む。
本開示の一例では、STRO−1*細胞由来の、および/もしくは子孫細胞由来の上清または可溶性因子は、例えば、適切な担体および/または賦形剤を含む組成物の形態で、投与される。例えば、担体または賦形剤は可溶性因子または上清の生物学的効果に悪影響を及ぼさない。
STRO−1+細胞由来の上清または可溶性因子、STRO−1+細胞またはその子孫は、他の有益な薬物または生化学的分子(増殖因子、栄養因子)とともに投与されてもよい。他の薬剤とともに投与されるとき、それらは、単一の薬剤的組成物で、または独立した薬剤的組成物で、同時にまたは連続して、他の薬剤とともに(他の薬剤の投与の前後に)投与されてもよい。同時投与されてもよい生理活性因子には、反アポトーシス剤(例えばEPO、EPOミメチボディ、TPO、IGF−IおよびIGF−II、HGF、カスパーゼ阻害剤);抗炎症薬(例えばp38MAPK阻害剤、TGFベータ阻害剤、スタチン、IL−6およびIL−1阻害剤、ぺミロラスト、トラニラスト、レミケード、シロリムスおよびNSAID(非ステロイド性の抗炎症薬物;例えば、テポキサリン、トルメン、スプロフェン);免疫抑制/免疫修飾剤(例えば、シクロスポリン、タクロニムスのようなカルシニューリン阻害剤;mTOR阻害剤(例えば、シロリムス、エベロリムス);抗増殖剤(例えばアザチオプリン、ミコフェノール酸モフェチル);コルチコステロイド(例えばプレドニゾン、ヒドロコルチゾン);コルチコステロイド(例えば、プレドニゾロン、ヒドロコルチゾン);モノクローナル抗IL−2Rアルファ受容体抗体(例えば、バシリキシマブ、ダクリズマブ)といった抗体、(例えば、抗胸腺細胞グロブリン(ATG);抗リンパ球グロブリン(ALG);モノクローナル抗T細胞抗体OKT3)といったポリクローナル抗T細胞抗体;反血栓形成剤(例えば、ヘパリン、ヘパリン誘導体、ウロキナーゼ、PPack(デキストロフェニルアラニン プロリン アルギニン クロロメチルケトン)、抗トロンビン化合物、血小板受容体拮抗薬、抗トロンビン抗体、抗血小板受容体抗体、アスピリン、ジピリダモール、プロタミン、ヒルジン、プロスタグランジン阻害剤および血小板阻害薬);および抗酸化剤(例えば、プロブコール、ビタミA、アスコルビン酸、トコフェノール、コエンザイムQ10、グルタチオン、L−システイン、N−アセチルシステイン)とともに局所麻酔薬、などが挙げられる。
本開示はまた、本明細書に記載のいずれかの例による方法において使用される医療デバイスを提供する。例えば、本開示は、本明細書に記載のいずれかの例による、STRO−1+細胞および/もしくはそれらの子孫細胞および/もしくはそれからの可溶性因子ならびに/または組成物を含む、注射器もしくはカテーテルまたは他の適切な送達デバイスを提供する。注射器またはカテーテルは、本明細書に記載のいずれかの例による方法における使用説明書と同梱されていてもよい。
STRO−1+細胞由来の上清もしくは可溶性因子、STRO−1+細胞またはその子孫は、外科的に移植、注射、送達(例えば、カテーテルまたは注射器を手段として)されてもよいし、あるいは、修復または増強を必要としている部位に直接的または間接的に投与されてもよい。
骨髄(BM)を、健康な正常成人の志願者(20〜35歳)から採取する。簡潔には、40mlのBMを、後腸骨稜から、リチウム−ヘパリン抗凝固剤含有チューブに吸引する。
STRO−3mAbを、STRO−1bright細胞を単離する単一試薬として用いることの可能性を確認する目的の実験を設計した。
第1の組の実験では、半定量的RT−PCR分析を適用して、蛍光標識細胞分取により単離したSTRO−1dullまたはSTRO−1bri集団により発現した、多様な系列関連遺伝子の遺伝子発現プロファイルを調べた(図2A)。第2の組の実験では、フローサイトメトリーおよび平均チャネル蛍光分析(mean channel fluorescence analysis)を適用して、蛍光標識細胞分取により単離したSTRO−1dullまたはSTRO−1bri集団により発現した、多様な系統関連タンパク質の表面タンパク質発現プロファイルを調べた。
以下の実験のために、C57Bl/6Jマウスにおける、髄鞘稀突起膠細胞糖タンパク質(MOG)誘導された実験的炎症性脳脊髄炎(EAE)を用いた。C57Bl/6Jマウスは、MS患者のものと同様な表現型症状(進行する性麻痺)だけでなく示すだけでなく、CNSに広範な炎症、脱髄および軸索の喪失/損傷を示す。使用された、EAE誘導の免疫化手順、臨床症状の評価およびMPC移植は以下のとおりである。
200μgの組み換えMOGをリン酸緩衝生理食塩水(PBS)中に溶解し、400μgの殺菌された結核菌H37Raを含む等容積の完全フロイントアジュバントと混合して、このMOGでマウスに免疫付与した。0.1mlのこの混合物を、25ゲージ(G)針を用いて、左右脇腹に皮下注入した(合計0.2ml/マウス)。また、0.30mlのPBS中350ngの不活性化した百日咳菌毒を、0日目と2日目に29G針を用いて尾静脈を通じ静注(i.v.)し、これによりマウスに免疫付与した。注入後に、穏やかな圧力をI.V.部位に30秒間かけて、i.v.部位からの出血の危険性を減少させた。
MPCを、本質的に実施例1に記載のとおりに単離した。疾患誘導の8、10、12日目に、容積200μlのPBS中、2×105または4x105個のMPCを、単回の静脈内(i.v.)注入として投与した(表5参照)。対照には、等容積のPBSのみをi.v.注入した。マウスを毎日監視し、以下に記載の尺度に従って、臨床的兆候を採点した。実験は、およそ36日間継続し、疾患の経過を監視した。実験の終了時に、脳、脊髄および視神経を切開し、ホルマリン中で固定した。
すべてのマウスを、実験全体について、神経機能障害の兆候について、毎日調査した。
神経機能障害の等級:
0−正常
1−尾の緊張喪失のみ
2−後肢1本または2本の軽度の脱力および異常な足取り
3−後肢の運動不能
4−後肢の運動不能および軽度の前肢脱力
5−死亡
対照C57Bl/6Jマウスは、MS患者のものと同様な表現型症状(進行性麻痺)を示すだけでなく、CNSに、広範な炎症、脱髄および軸索の喪失/損傷を示す。
表6:MPCを用いた治療後のマウスEAEモデルの臨床結果のまとめ
実施例3に記載の、MPC治療したマウスおよび対照を、病患誘導(MOG35−55免疫化)の36日後に選別した。脾臓細胞を、in vitroで培地のみで培養するか、またはMOG35−55を用いて再刺激し、そしてその後、[3H]チミジン取り込みを通じてT細胞増殖応答を測定した。MOGに特異的な増殖応答を、培地のみ(刺激せず)で培養した適合脾臓細胞と比較した。PMA/イオノマイシン中で培養した脾臓細胞は、T細胞増殖の非特異的(抗原依存性のない)刺激を決定する目的を果たした。
MPC免疫調節する性質を、増殖試験、混合リンパ球反応およびサイトカイン産生により、以下に記載のとおり試験する。
単核細胞を、健康なC57BL/6マウス、2D2トランスジェニックマウス、または本質的に実施例4に記載のとおりにMPCまたはビヒクルのみを用いて治療したMOG免疫付与マウスの脾臓から収集する。単個細胞懸濁液を、10%のFBS、2mMのL−グルタミン、100単位/mlのペニシリン、100μg/mlのストレプトマイシン(すべてインビトロジェン社から)、1mMのピルビン酸ナトリウム(シグマ社)および50μMのβ−メルカプトエタノール(シグマ社)を含む完全RPMI培地において調製する。赤血球細胞溶解の後、細胞を2回洗浄し、そしてその後、3とおりの96ウェル平底マイクロタイタープレート(Nunc社)中、ウェルあたり2.5×105個の細胞の濃度で、20μg/mlのMOG35−55(GLバイオケム社(GL Biochem))、800ng/mlのイオノマイシンおよび20pg/mlのホルボールミリステート酢酸(PMA)(ともにシグマ社)の存在下で播種するか、または\0μg/m\の抗CD3および^g/mlの抗CD8(ともBDから)を用いてプレコートしたウェル中へ播種する。細胞はその後、37°Cで5%CO2とともに72時間インキュベートし、^Ci/ウェル[3H]チミジンを、培養の最後18時間の間、加える。細胞をフィルターマット上に収集し、取り込まれた放射性核酸を、トップカウントハーベスター(Top Count Harvester)(パッカードバイオサイエンス(Packard Biosciences))上で計数する。MPCによるT細胞増殖の阻害に関連する実験のために、ウェルあたりの濃度が2.5〜0.002×104個の細胞の範囲にあるMPCを、脾臓細胞を加えるのに先立って播種する。
サイトカイン産生の分析に使用する上清は、20μg/mlのMOG35−55のみを用いて、または2×104個のMPC(MPC:脾臓細胞の比1:10)の存在のもとで刺激した、2D2トランスジェニックマウスからの2.5×106個の脾臓細胞との二日間の共培養から得られる。サイトカインの定量的分析をマウスTh1/Th2/Th17サイトメトリックビーズアレイ(CBA)キット(BD)を用い、基本的に製造元の説明書に従って実行し、BD FACSCanto IIフローサイトメーター上で分析(us)する。以下のサイトカイン:インターロイキン(IL)−2、IL−4、IL−6、IL−10、IL−17A、インターフェロン−γ(IFN−γ)および腫瘍壊死因子−a(TNF−a)を測定する。
Claims (34)
- 治療有効量の、多能性STRO−1+MPCが富化された細胞の集団を含む、炎症性神経疾患を治療するまたは予防するための薬剤。
- 炎症性神経疾患が、炎症性刺激に対するT細胞応答を伴うまたは原因とする、請求項1記載の薬剤。
- 集団が、多能性STRO−1brightMPCが富化された細胞である、請求項1または2に記載の薬剤。
- 炎症性神経疾患が、多発性硬化症、全身性エリテマトーデス、ギラン・バレー症候群、ランバート・イートン症候群、重症筋無力症、横断性脊髄炎、ロイコジストロフィー、および進行性多巣性白質脳症からなる群から選択される、請求項1〜3のいずれか一項に記載の薬剤。
- 疾患が、全身性エリテマトーデスである、請求項1〜4のいずれか一項に記載の薬剤。
- 疾患が、多発性硬化症である、請求項1〜4のいずれか一項に記載の薬剤。
- 疾患が、多発性硬化症の慢性進行型、または多発性硬化症の再発寛解型である、請求項6記載の薬剤。
- 多能性STRO−1+MPCが富化された集団が全身投与される、請求項1〜7のいずれか一項に記載の薬剤。
- 疾患が再発寛解疾患であって、多能性STRO−1+MPCが富化された集団が疾患再発期の間に投与され、疾患の再発を予防するまたは遅延させる、請求項7に記載の薬剤。
- 対象に、および/または疾患の病因部位に、制御性T(Treg)細胞の数を増加させるのに有効な量の、多能性STRO−1+MPCが富化された集団が投与される、請求項1〜9のいずれか一項に記載の薬剤。
- 多能性STRO−1+MPCが富化された集団が、kgあたり、2×106から8×106個の間の多能性STRO−1+MPCの量で投与される、請求項1〜10のいずれか一項に記載の薬剤。
- 多能性STRO−1+MPCが富化された集団が、kgあたり、3×106から6×106個の間の多能性STRO−1+MPCの量で投与される、請求項1〜11のいずれか一項に記載の薬剤。
- 多能性STRO−1+MPCが富化された集団が、低用量の、多能性STRO−1+MPCで投与される、請求項1〜12のいずれか一項に記載の薬剤。
- 低用量の、多能性STRO−1+MPCが、kgあたり、0.1×106と3×106個の間の多能性STRO−1+MPCを含む、請求項13記載の薬剤。
- 低用量の、多能性STRO−1+MPCが、kgあたり、約3×106個の多能性STRO−1+MPCを含む、請求項14記載の薬剤。
- 多能性STRO−1+MPCが富化された集団が、1週間毎に1回以下の頻度で投与される、請求項1〜15のいずれか一項に記載の薬剤。
- 多能性STRO−1+MPCが富化された集団が、4週間毎に1回以下の頻度で投与される、請求項1〜15のいずれか一項に記載の薬剤。
- 多能性STRO−1+MPCが富化された集団が、T細胞の刺激を遮断する分子を発現するように、遺伝子組み換えされている、請求項1〜17のいずれか一項に記載の薬剤。
- 多能性STRO−1+MPCが富化された集団が、T細胞の刺激を遮断する化合物と共に投与される、請求項1〜18のいずれか一項に記載の薬剤。
- 多能性STRO−1+MPCが富化された集団が、オートジェネイック(autogeneic)または同種異系である、請求項1〜19のいずれか一項に記載の薬剤。
- 多能性STRO−1+MPCが富化された集団が、投与に先だって、培養増殖されている、請求項1〜19のいずれか一項に記載の薬剤。
- 治療有効量の、多能性STRO−1+MPCが富化された細胞の集団を含む、対象において抗原に対する免疫応答を予防するための薬剤。
- 免疫応答が、T細胞介在性免疫応答である、請求項22記載の薬剤。
- T細胞介在性免疫応答が、T細胞増殖を含む、請求項23記載の薬剤。
- T細胞介在性免疫応答を、特異抗原に対して抑制する、およびT細胞介在性免疫応答を、他の抗原に対して抑制しない、請求項22〜24のいずれか一項に記載の薬剤。
- 対象が、前もって抗原に対する免疫応答を生じており、集団が、該抗原に対するさらなる免疫応答を抑制する、請求項22〜25のいずれか一項に記載の薬剤。
- 集団が、対象が抗原に対する免疫応答を生じた後に投与され、それにより、該抗原に対するさらなる免疫応答を予防する、請求項26記載の薬剤。
- 多能性STRO−1+MPCが富化された細胞の集団の投与後、少なくとも約24日の間、免疫応答を抑制する、請求項22〜27のいずれか一項に記載の薬剤。
- 多能性STRO−1+MPCが富化された細胞の集団を含む、対象において抗原に対する寛容性を誘導するための薬剤。
- 抗原または特異抗原は、それに対して炎症性応答が生じるものである、請求項22〜29のいずれか一項に記載の薬剤。
- 炎症性応答が、炎症性神経疾患の原因である、請求項30記載の薬剤。
- 多能性STRO−1+MPCが富化された細胞の集団が、炎症性神経疾患を治療するまたは予防する化合物とともに投与される、請求項1〜31のいずれか一項に記載の薬剤。
- 化合物が、酢酸グラチラマーおよび/またはβ−インターフェロンである、請求項32記載の薬剤。
- 炎症性神経疾患を治療するまたは予防する、および/または抗原に対する免疫応答を抑制する、および/または抗原に対する寛容性を誘導する薬剤の製造における、治療有効量の、多能性STRO−1+MPCが富化された細胞の集団の使用。
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IL229705A0 (en) | 2014-01-30 |
WO2012162754A1 (en) | 2012-12-06 |
AU2012262675A1 (en) | 2013-05-02 |
JP2014516974A (ja) | 2014-07-17 |
KR20140053940A (ko) | 2014-05-08 |
EP2714057A4 (en) | 2014-12-03 |
CA2837895A1 (en) | 2012-12-06 |
ES2763316T3 (es) | 2020-05-28 |
CN103841983B (zh) | 2018-11-02 |
US20190201448A1 (en) | 2019-07-04 |
AU2016216640A1 (en) | 2016-09-01 |
EP2714057B1 (en) | 2019-11-06 |
US20210169940A1 (en) | 2021-06-10 |
US10206951B2 (en) | 2019-02-19 |
CN103841983A (zh) | 2014-06-04 |
KR102002090B1 (ko) | 2019-07-19 |
EP2714057A1 (en) | 2014-04-09 |
SG195127A1 (en) | 2013-12-30 |
AU2012262675B2 (en) | 2016-05-19 |
CN109276706A (zh) | 2019-01-29 |
CA2837895C (en) | 2021-07-27 |
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