JP6920062B2 - 子宮内膜病変における幹細胞治療 - Google Patents
子宮内膜病変における幹細胞治療 Download PDFInfo
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Description
本出願は、2014年6月17日に出願された米国仮特許出願第62/013,121の35U.S.C§119(e)の下での利益を主張し、当該出願の内容全体が、ここで参考として援用される。
本発明は、一般に、子宮内膜再生を誘導し、アッシャーマン症候群および子宮内膜萎縮のような子宮内膜病変を処置するための自己由来CD133+骨髄幹細胞(BMDSC)の使用に関する。
生殖可能年齢の女性において、子宮内膜のうちの2層は、区別され得る:(i)子宮腔に隣接する機能的層、および(ii)子宮筋層に隣接しかつ上記機能的層の下にある基底層。上記機能的な層は、以前の月経周期の第1の部分の間の、月経の終了の後に構築される。増殖は、エストロゲンによって誘導され(月経周期の卵胞期)、この層における後の変化は、黄体に由来するプロゲステロンによって生じる(黄体期)。それは、胚の着床および成長に最適な環境を提供するように適応される。この層は、月経の間に完全に脱落する。対照的に、上記基底層は、上記月経周期の間のいかなるときにも脱落しない。各月経周期における全身性の卵巣ステロイド変化の下でのヒト子宮内膜の再生は、その主要な機能のためのこの器官の準備(すなわち、着床しつつある胚盤胞を迎え入れる(host)ための子宮内膜の着床ウインドウを発生させ、妊娠が起こることを可能にする)に必須である。従って、各月経周期に伴う子宮内膜機能的層の全ての細胞区画の補充は、正常な生殖機能に必須である。
本開示は、少なくとも部分的に、自己由来CD133+骨髄由来幹細胞(BMDSC)が自己由来の機能的子宮内膜の新規生成をもたらす血管形成を再生し得るという発見に関する。よって、本開示の局面は、子宮内膜再生を誘導するための方法を提供する。いくつかの実施形態において、上記方法は、自己由来CD133+骨髄由来幹細胞(BMDSC)の有効量を、子宮内膜再生が必要な被験体の子宮動脈へと投与して、子宮内膜再生を誘導することを包含する。
本発明は、例えば、以下の項目を提供する。
(項目1)
子宮内膜再生を誘導するための方法であって、該方法は、
自己由来CD133 + 骨髄由来幹細胞(BMDSC)の有効量を、子宮内膜再生が必要な被験体の子宮動脈へと投与して、子宮内膜再生を誘導すること
を包含する、方法。
(項目2)
前記被験体は、アッシャーマン症候群もしくは子宮内膜萎縮を有することが既知である、項目1に記載の方法。
(項目3)
前記被験体は、ホルモン処置に抵抗性である子宮内膜萎縮を有する、項目2に記載の方法。
(項目4)
前記被験体は、1回もしくはこれより多く、胚着床に以前失敗したことがある、項目1〜3のいずれか1項に記載の方法。
(項目5)
前記自己由来CD133 + BMDSCは、
前記被験体に、該被験体の骨髄から末梢血へとBMDSCを動員するための薬剤を投与すること;および
CD133 + BMDSCを該被験体の末梢血から単離すること、
によって調製される、項目1〜4のいずれか1項に記載の方法。
(項目6)
BMDSCを動員するための前記薬剤は、顆粒球コロニー刺激因子(G−CSF)である、項目1〜5のいずれか1項に記載の方法。
(項目7)
前記自己由来CD133 + BMDSCは、抗CD133抗体を使用するアフェレーシスによって前記被験体の末梢循環から単離される、項目5〜6のいずれか1項に記載の方法。
(項目8)
前記CD133 + BMDSCは、カテーテルを介して前記子宮動脈へと投与される、項目1〜8のいずれか1項に記載の方法。
(項目9)
前記CD133 + BMDSCは、前記被験体の子宮螺旋細動脈へと投与される、項目1〜8のいずれか1項に記載の方法。
(項目10)
子宮内膜再生を誘導するための方法であって、該方法は、
自己由来CD133 + 骨髄由来幹細胞(BMDSC)を、子宮内膜再生が必要な被験体から単離すること;および
該単離されたCD133 + BMDSCの有効量を、該被験体の子宮動脈へと投与して、子宮内膜再生を誘導すること
を包含する方法。
(項目11)
顆粒球コロニー刺激因子(G−CSF)は、前記自己由来BMDSCを単離する前に前記被験体へと投与される、項目10に記載の方法。
(項目12)
前記自己由来CD133 + BMDSCは、抗CD133抗体を使用するアフェレーシスによって前記被験体の末梢循環から単離される、項目10〜11のいずれか1項に記載の方法。
(項目13)
前記CD133 + BMDSCは、カテーテルを介して前記子宮動脈へと投与される、項目10〜12のいずれか1項に記載の方法。
(項目14)
前記CD133 + BMDSCは、前記被験体の子宮螺旋細動脈へと投与される、項目10〜13のいずれか1項に記載の方法。
(項目15)
前記被験体は、アッシャーマン症候群もしくは子宮内膜萎縮を有することが既知である、項目10〜14のいずれか1項に記載の方法。
(項目16)
前記被験体は、ホルモン処置に抵抗性である子宮内膜萎縮を有する、項目15に記載の方法。
(項目17)
前記被験体は、1回もしくはこれより多く、胚着床に以前失敗したことがある、項目10〜16のいずれか1項に記載の方法。
本発明は、少なくとも部分的に、自己由来幹細胞治療を使用して子宮内膜再生を誘導する新たな治療アプローチの発見に基づく。特に、本出願は、自己由来CD133+骨髄由来幹細胞(BMDSC)が自己由来機能的子宮内膜の新規生成をもたらす血管形成を再生し得るという知見に基づく。BMDSCは、種々の子宮内膜細胞区画(間質、腺上皮、および内腔上皮)における非造血細胞の供給源であることが公知であったものの、BMDSCの亜集団(複数可)が子宮内膜の修復を促進することは公知ではなかった。本出願は、子宮内膜再生を誘導し、アッシャーマン症候群および子宮内膜萎縮のような子宮内膜変性と関連する病変を処置するために安全かつ有効な細胞ベースの治療を提供する。
・上記CD133+BMSC幹細胞処置後の月経の再開;
・子宮内膜厚の増大;(子宮内膜厚は、子宮内膜腔の底において子宮筋層の上限から下限までの長さとして測定される)。例えば、上記増大は、子宮底において長軸方向の膣超音波によって測定される、ホルモン補充療法(HRT)でこれまで得られた最大厚の50%の増大であり得る(4〜6mmのvgr);
・新規子宮内膜形成の子宮鏡検査によるおよび組織学的な証拠;ならびに/または
・これら患者における胚配置(embryo placement)後の生児出生率(live−birth rate)、妊娠および着床率に関する再構築された子宮内膜の機能性。
(材料および方法)
(デザイン)
以下は、Hospital Clinico de Valencia(Spain)のIRBによって承認され、Spanish Ministry of Healthによって資金援助(Ref EC 11−299)された、難治性ASを有する16名の患者における実験的な非対照研究である。BMDSC動員を、顆粒球−CSF(G−CSF)(4日間の間に5mg/kg/12時間 sc)を使用して行った。7日後に、末梢血アフェレーシスとCD133+細胞の単離を、行った。次いで、自己由来CD133+細胞を、非侵襲性放射線医学介入によって、2.5 Fマイクロカテーテルを使用して子宮動脈を介して、螺旋細動脈へと送達した。子宮内膜腔状態を、幹細胞介入の前、ならびに該介入の3ヶ月後、6ヶ月後および9ヶ月後に、子宮鏡検査、膣超音波、および組織学を介して評価した。
(患者および方法)
(包含基準)
(排除基準)
(方法論)
(1.骨髄幹細胞(BMSC)動員)
・上記患者に、上記手順について情報を与え、上記動員の少なくとも24時間前に同意書を与えた。
・相当する医学的評価を、関連する補完的触診(exploration)とともに行い、BMSC再収集に責任のある医師が確認した。
・関連する血清学的試験結果(HIV、HBcAg、HBsAg、HCV、梅毒)を利用可能になった。
・静脈を評価して上記手順に彼らが適切であることを決定した。
次いで、末梢血へのBMSC動員を、G−CSF(5mcg/kg sc 12時間ごと)によって4日間誘導した。
(2.BMSC再収集)
(3.動脈内カテーテル法による子宮螺旋細動脈へのCD133+細胞移植)
(応答基準)
・月経転帰。月経は、上記CD133+BMSC処置の後に再開しなければならない。
・子宮内膜厚の増大。これまでHRTで得られた最大厚のうちの最小50%が、子宮底において縦軸方向の(longitudinal axis)膣超音波によって測定された(4〜6mmのvgr)。
・形成される新規子宮内膜の子宮鏡検査によるおよび組織学の証拠。
・これら患者における胚移植(embryo replacement)後の生児出生率、妊娠および着床率に関する上記再構築された子宮内膜の機能性。
(結果)
(実施例2)
(研究参加者)
(BMDSC動員および単離)
(BMDSCの送達)
(追跡)
(子宮内膜免疫組織化学)
(統計分析)
(結果)
(考察)
Claims (8)
- アッシャーマン症候群または子宮内膜萎縮の処置を必要とする被験体におけるアッシャーマン症候群または子宮内膜萎縮の処置において使用するための、単離された自己由来CD133+骨髄由来幹細胞(BMDSC)を含む組成物であって、前記組成物が前記被験体の子宮動脈へと投与されることを特徴とし、前記被験体がホルモン処置に抵抗性である子宮内膜委縮を有する、組成物。
- 前記被験体が1回またはこれより多く、胚着床に以前失敗したことがある、請求項1に記載の使用のための組成物。
- 前記単離された自己由来CD133+BMDSCは、前記被験体の骨髄から末梢血へとBMDSCを動員するための薬剤を前記被験体に投与した後に前記被験体の末梢血から単離される、請求項1または2に記載の使用のための組成物。
- BMDSCを動員するための前記薬剤が顆粒球コロニー刺激因子(G−CSF)である、請求項3に記載の使用のための組成物。
- 前記組成物がカテーテルを介して子宮動脈へと投与されることを特徴とする、請求項1〜4のいずれか一項に記載の使用のための組成物。
- 前記組成物が前記被験体の子宮螺旋細動脈へと投与されることを特徴とする、請求項1〜5のいずれか一項に記載の使用のための組成物。
- 前記自己由来CD133+BMDSCはアフェレーシスによって、前記被験体の前記末梢血から単離され、前記アフェレーシスは抗CD133抗体を使用して行われる、請求項3〜6のいずれか一項に記載の使用のための組成物。
- 前記組成物が少なくとも4500万個のCD133+BMDSCを含む、請求項1〜7のいずれか一項に記載の使用のための組成物。
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