JP2019088310A - 瘻の治療における脂肪組織由来間質幹細胞の使用 - Google Patents
瘻の治療における脂肪組織由来間質幹細胞の使用 Download PDFInfo
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- JP2019088310A JP2019088310A JP2019018275A JP2019018275A JP2019088310A JP 2019088310 A JP2019088310 A JP 2019088310A JP 2019018275 A JP2019018275 A JP 2019018275A JP 2019018275 A JP2019018275 A JP 2019018275A JP 2019088310 A JP2019088310 A JP 2019088310A
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- adipose tissue
- stromal stem
- derived stromal
- fistula
- stem cells
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Abstract
Description
本願は、2005年2月25日出願の米国特許出願第11/065,461号の一部継続および2005年2月14日出願の米国特許出願第11/056,241号の一部継続であり、これらの出願の開示内容は、引用することによりそのまま本明細書の一部とされる。
一般に、瘻は、通常はつながっていない器官間または血管間に生じた異常な連結または通路である。瘻は体の様々な部分で発生し得る。例えば、瘻の種類は、瘻が生じる体の部位に由来し、肛門直腸瘻、すなわち肛門瘻または糞瘻(直腸または他の肛門直腸部位と皮膚表面との間)、動静脈瘻、すなわちA−V瘻(動脈と静脈との間)、胆道瘻(胆管と皮膚表面との間。多くの場合、これは胆嚢手術によって起こる)、頸瘻(子宮頸部の異常な開口)、頭蓋洞瘻(頭蓋内腔と副鼻腔との間)、腸腸瘻(enteroenteral fistula)(腸管の2つの部分の間)、腸皮瘻(腸管と皮膚表面との間。すなわち十二指腸または空腸または回腸に由来する)、腸腟瘻(腸管と膣との間)、胃瘻(胃と皮膚表面との間)、子宮腹腔瘻(子宮と腹膜腔との間)、外リンパ瘻(中耳と内耳の間にある膜間の裂け目)、肺動静脈瘻(肺の動脈と静脈との間。これにより血液の短絡が起こる)、直腸腟瘻(直腸と膣との間)、臍瘻(臍と消化管との間)、気管食道瘻(呼吸管と栄養管との間)、および膀胱腟瘻(膀胱と膣との間)が含まれる。瘻の原因としては、外傷、医療処置からくる合併症、および疾患が挙げられる。
様々な外科的処置が一般的に用いられるが、最も一般的には、瘻孔切開術、串線(排液用に瘻を開けておくために瘻の通路に通されるより糸)の留置、または直腸内フラップ手法(endorectal flap procedure)(糞便または他の物質がチャネルを再感染させないようにするために、健常組織を瘻の内側に引き寄せる)が用いられる。肛門直腸瘻の手術では、再発、再感染、および失禁などの副作用を避けられない。
この推定は、かなりの過小評価であるかもしれない。第一次外科的修復の成功率は88〜93%に及ぶが、試みるたびに低下する。そのため、かなりの割合の女性は、外科的に修復され得ない産科瘻を有している。
本明細書において、次の用語および表現は以下に記載する意味を有するものとする。特に断りのない限り、本明細書において用いられる総ての専門用語および科学用語は、当業者によって一般的に理解されるものと同じ意味を有する。
一つの態様では、本発明は、ある特定の特徴、例えば、特定の表現型を有する脂肪組織由来間質幹細胞含有組成物に関する。例えば、本発明の細胞組成物における脂肪組織由来間質幹細胞は、細胞表面マーカーの発現、サイズ、グルコース消費、乳酸生産、および細胞収率/生存力により特徴づけることができる。本発明のさらにもう一つの態様は、細胞成分として、特定の表現型を有する脂肪組織由来間質幹細胞、またはその後代の実質的に純粋な調製物を含む脂肪組織由来間質幹細胞含有組成物に関する。本発明の脂肪組織由来間質幹細胞含有組成物は、前駆細胞の実質的に純粋な集団を含むだけでなく、細胞培養成分、例えば、アミノ酸、金属、補酵素因子、ならびに他の間質細胞の小集団(例えば、それらの一部は本発明の細胞の後の分化によって生じる可能性がある)を含む培養培地も含み得る。さらに、他の非細胞成分には、特定の状況下、例えば、移植下、例えば、連続培養下での維持に適した、または生体材料もしくは医薬組成物としての使用に適した細胞成分を与えるものが含まれ得る。
好ましい実施態様では、前記チューブは、前記脂肪組織由来間質幹細胞含有組成物を被験体に所望の位置で導入することができる針、例えば、シリンジをさらに備えている。前記脂肪組織由来間質幹細胞含有組成物は様々な形態でかかる送達装置、例えば、シリンジに入れることができる。例えば、前記脂肪組織由来間質幹細胞含有組成物には、溶液に懸濁された、またはかかる送達装置に入れられる場合には支持マトリックスに埋め込まれた、脂肪組織由来間質幹細胞の組成物が含まれる。
前記溶液は、好ましくは無菌であり、そして容易に注射できる(easy syringability)程度に流体である。前記溶液は、製造および保存の条件下で安定し、そして、例えば、パラベン、クロロブタノール、フェノール、アスコルビン酸、チメロサールなどを用いて細菌および真菌などの微生物の混入作用から保護されることが好ましい。本発明の脂肪組織由来間質幹細胞組成物である溶液は、本明細書に記載の脂肪組織由来間質幹細胞を、薬学上許容される担体または希釈剤と、必要に応じて、上記に列挙した他の成分との中に組み込み、その後、濾過滅菌を行うことによって調製することができる。
保存的アミノ酸置換とは、類似側鎖を有する残基の互換性を指す。例えば、脂肪族側鎖を有するアミノ酸のグループは、グリシン、アラニン、バリン、ロイシン、およびイソロイシンであり;脂肪族ヒドロキシル側鎖を有するアミノ酸のグループはセリンおよびトレオニンであり;アミド含有側鎖を有するアミノ酸のグループはアスパラギンおよびグルタミンであり;芳香族側鎖を有するアミノ酸のグループは、フェニルアラニン、チロシン、およびトリプトファンであり;塩基性側鎖を有するアミノ酸のグループはリジン、アルギニン、およびヒスチジンであり;そして硫黄含有側鎖を有するアミノ酸のグループはシステインおよびメチオニンである。好ましい保存的アミノ酸の置換グループは:バリン−ロイシン−イソロイシン、フェニルアラニン−チロシン、リジン−アルギニン、アラニン−バリン、およびアスパラギン−グルタミンである。
脂肪組織由来間質幹細胞を含む上記脂肪組織由来間質幹細胞含有組成物を製造する方法も提供される。一つの実施態様では、該方法は、(a)被験体から脂肪組織を採取すること;(b)酵素消化により細胞懸濁液を得ること;(c)該細胞懸濁液を沈殿させ、該細胞を培養培地に再懸濁すること;(d)該細胞を少なくとも約10日間培養すること;および(g)該細胞を少なくとも2回の培養継代の間増殖させること:を含む。
目的の核酸としては、限定されるものではないが、修復する組織のタイプ、例えば、腸壁または膣壁に見られる細胞外マトリックス成分の生産を強化する遺伝子産物をコードするものが挙げられる。
本発明のもう一つの態様は、瘻および創傷の治療に脂肪組織由来間質幹細胞を用いるための新規方法に関する。好ましい実施態様では、前記脂肪組織由来間質幹細胞は、治療を受ける被験体の脂肪組織に由来するものとされる。他の好ましい実施態様では、前記脂肪組織由来間質幹細胞は、本明細書に記載の脂肪組織由来間質幹細胞含有組成物である。しかしながら、脂肪組織由来間質幹細胞の他の調製物も、本明細書に記載の方法、例えば、米国特許第6,777,231号および同第6,555,374号、ならびに2005年2月25日出願の米国特許出願第11/065,461号「Identification and Isolation of Multipotent Cells From Non-Osteochondral Mesenchymal Tissue」に記載されているものなどに用いてよい。
(i)少なくとも一つの瘻トラックを深く掻爬すること
(ii)該掻爬されたトラックの内部穴を縫合糸で閉鎖すること
(iii)該縫合閉鎖された内部穴に、例えば、本発明の脂肪組織由来間質幹細胞含有組成物において、少なくとも約10x106、少なくとも約20x106、少なくとも約30x106、または少なくとも約40x106の脂肪組織由来間質幹細胞を送達することを含む。
(iv)前記縫合閉鎖された内部穴に、例えば本発明の脂肪組織由来間質幹細胞含有組成物において、少なくとも約20x106の細胞、少なくとも約30x106、または少なくとも約40x106の脂肪組織由来間質幹細胞からなる2回目の投与量を送達すること
をさらに含み得る。
かかる情報を用いて、ヒトにおいて有用な用量をさらに正確に決定してもよい。血漿中のレベルは、例えば、高速液体クロマトグラフィーにより測定し得る。
他の実施態様では、本発明は、前記脂肪組織由来間質幹細胞含有組成物と、所望により、それらの使用説明書を含むキットに関する。本発明の医薬組成物および生体材料を含むキットもまた、本発明の範囲内である。キットの成分は、上述の方法を手動で実施するために、または部分的もしくは完全に自動で実施するためにパッケージングし得る。かかるキットは、例えば、療法、修復、生体材料の調製および他の用途なと広く利用し得る。
局所麻酔および全身鎮静を使って、脂肪吸引により脂肪組織を得た。小さな切開(直径0.5cm未満)を通して、先端に中空の短い太い針の付いたカニューレを皮下腔に挿入した。脂肪組織を機械的破砕するために、穏やかに吸引しながら、カニューレを脂肪組織、腹部壁コンパートメントを通して動かした。失血を最小限に抑えるために、食塩溶液と血管収縮薬のエピネフリンをその脂肪組織コンパートメントに注入した。このようにして、治療する各患者から生の脂肪吸引物80〜100mlを得た。
免疫蛍光染色により細胞を特徴づけるため、細胞を、24−ウェルプレートのガラスカバースリップ上の、10%FBSを添加したDMEMに低密度でプレーティングした。免疫組織化学研究では、細胞をPBSで洗浄し、アセトンで−20℃で10分間固定した。
a−アクチンの染色では、細胞をでRTで10分間固定した。4%ヤギ血清および0.1%Triton X−100を含有するPBSでブロックした後、細胞を、次の細胞マーカーに対する一次抗体(示した希釈度のもの)とともに4℃で一晩インキュベートした[(i)α−アクチン;Dako, Glostrup, Denmark;1/50;(ii)ビメンチン;Sigma, St. Louis, USA;1/200;(iii)CD90;CYMBUS, Biotechnology LTD, Chandlers Ford, Hants, UK;1/50;(iv)第VIII因子;Dako;1/100;(v)CD34;Chemicon, CA, USA;1/100;(vi)c−Kit;Chemicon;1/100;(vii)デスミン;Dako;1/100;(viii)サイトケラチン;Dako;1/100、および(ix)S−100;Dako;1/50]。次いで、細胞を適当なフルオレセインイソチオシアネート(FITC)を結合した、またはテトラメチルローダミンイソチオシアネートクロリド(TRITC)を結合した二次抗体(Sigma;1/50)とともにRTで45分間インキュベートした。我々は陰性対照については一次抗体を省略した。核を4’,6−ジアミジノ−2−フェニルインドール(DAPI)で対比染色した。その後、細胞をMobiglow (MoBiTec, Gottingen, Germany)に取り付け、落射蛍光顕微鏡 Eclipse TE300 (Nikon, Tokyo, Japan)を用いて観察した。我々は、いずれの場合にも、様々な領域の免疫陽性細胞の数を決定し、それらの数を染色された核の数と比較した。Spotlカメラ(Diagnostic Instruments Inc., Tampa, FL, USA)を通してランダムに選択した領域をコンピューター(MacIntosh G3; Apple Computer Ink., Cupertino, Ca, USA)にエキスポ
ートした。様々な抗体を用いた免疫染色の陽性対照として、ヒト大動脈平滑筋細胞、ヒト臍帯静脈内皮細胞(HUVEC)、およびヒト滑膜繊維芽細胞を用いた。
ビメンチンの発現は継代9代まで(継代9代を含む)同じレベルに維持された。しかしながら、他のマーカーのレベルは、時間とともに低下した。例えば、継代1代目のLPA由来細胞の17%に見られたa−アクチンは、継代7代目でもはや検出できなかった。内皮細胞のマーカーであるフォン・ウィルブランド因子(von Willebrandt factor)(第VIII因子)、およびCD34は、内皮細胞の表面でも見られ、継代1〜3代目にのみ検出された(それぞれ、7%および12%免疫陽性細胞)。一方、細胞増殖のマーカーであるc−Kit(CD117)の発現は、時間とともに高まり、継代4代以降99%免疫陽性細胞であった(図2)。初期におよそ80%のLPA由来細胞で発現された、繊維芽細胞マーカーであるCD90は、継代6代からは99%の細胞で見られた(図3)。神経外胚葉マーカーであるS100または外胚葉マーカーであるケラチンの発現は、どの時点においてもLPA由来細胞で観察されなかった。継代回数が増えるとともに観察されるマーカーの変化より、得られる細胞調製物の均一性が高まることが示される。
臨床用途では、上記で調製された細胞は3回以下の継代後に用い得る(図3)が、より高い均一性を有する細胞調製物を得るためには、上記のように、2回以上継代後に用いることが好ましい。臨床用の細胞培養物を37℃で3分間トリプシン処理した。FBSを加えたDMEMを添加することによりトリプシン処理を停止させ、この懸濁液を110xgで5分間遠心分離した。細胞をPBSで洗浄し、この懸濁液を再度150xgで5分間遠心分離した。細胞を、1〜2mlのリンガー乳酸溶液中3〜30x106細胞/ml間に再懸濁し、適切なシリンジに入れた。所望により、リンガー乳酸溶液にヒト血清アルブミン(HSA)を添加してよい。
我々は、クローン病の瘻の治療のための上記脂肪組織間質幹細胞組成物を用いた自己幹細胞移植の実現可能性および安全性を検証するように設計された第1相臨床試験を実施した。このプロトコールは2002年4月12日にthe Clinical Trial and Ethics Committee of La Paz Hospitalにより認可され、詳細なインフォームドコンセント用紙を作成して、患者により署名を受けた。The Ethics Committeeは、臨床試験の間の研究の進行に関する情報を耐えず提供し続けた。
患者は、次の試験対象患者基準に従って選択した:19歳以上であること;試験の少なくとも5年前にクローン病と診断を受けていること;医療処置に不応性であり、古典的な手術による処置に少なくとも2回失敗している1以上の複雑な、クローン病の瘻(腸皮瘻、括約筋上痔瘻、および/または直腸腟瘻)が存在していること;かつインフォームドコンセント用紙に署名があり参加に同意していること。試験除外基準は以下のとおりである:試験対象患者基準に満たないこと;精神障害者;極度のやせすぎ;局所麻酔薬に対するアレルギー;癌の診断前;およびエイズ。
接種を行った8つの瘻を週1回少なくとも8週間追跡調査した。6つの瘻では、第8週目の終わりに外部開口部が上皮で覆われており、このようなことから、これらの瘻は治癒したと見なされた(75%)。他の2つの瘻では、流出の減少を伴う外部開口部の不完全な閉鎖が起こっただけであった(治癒せず;25%)。いずれの患者においても追跡調査期間(少なくとも6ヶ月〜2年以内)の終わりに悪影響は認められなかった。
本研究には5名の患者が参加し、7種の脂肪吸引を実施した(図3)。患者番号003は、培養した脂肪吸引細胞にグラム陽性菌の混入が発見されたために、移植処置中に本試験から排除した。細菌はOerkovia xanthineolyticaと特定した。患者002の腸皮瘻は、急性敗血症を起こした新規エンテロベシキュラー瘻(enterovesicular fistula)の緊急腹部手術のために、本試験から排除した。開腹には移植部位の切除が必要であったため、この場合において、我々は最小8週間の追跡調査スケジュールを忠実に守ることができなかった。
これまでの報告において、我々は、医療処置に不応性であった再発性直腸腟瘻を有する若い女性についての細胞による治療の成功を記載した。それを受けて、我々は、不応性の、クローン病の瘻の治療のためのかかる自己脂肪組織間質幹細胞移植(オリジナルのプロトコールの改良を含む)の実現可能性および安全性を評価するため、さらに脂肪組織間質幹細胞のフィブリン糊との併用を検証するために本第1相臨床試験を設計した。
本発明の実施には、特に断りのない限り、細胞生物学、細胞培養、分子生物学、トランスジェニック生物学、微生物学、組換えDNA、および免疫学の従来の技術を使用し、それらの技術は当技術分野の技量の範囲内である。かかる技術は文献に十分に説明されている。例えば、Sambrook, Fritsch and ManiatisによるMolecular Cloning A Laboratory Manual, 2nd Ed., ed. (Cold Spring Harbor Laboratory Press: 1989);DNA Cloning, Volumes I and II (D. N. Glover ed., 1985);Oligonucleotide Synthesis (M. J. Gait ed., 1984);Mullis et al. 米国特許第4,683,195号;Nucleic Acid Hybridization(B. D. Hames & S. J. Higgins eds. 1984);Transcription And Translation (B. D. Hames & S. J. Higgins eds. 1984);Culture Of Animal Cells (R. I. Freshney, Alan R. Liss, Inc., 1987);Immobilized Cells And Enzymes (IRL Press, 1986);B. Perbal, A Practical Guide To Molecular Cloning (1984);the treatise, Methods In Enzymology (Academic Press, Inc., N.Y.);Gene Transfer Vectors For Mammalian Cells (J. H. Miller and M. P. Calos eds., 1987, Cold Spring Harbor Laboratory);Methods In Enzymology, VoIs. 154 and 155 (Wu et al. eds.), Immunochemical Methods In Cell And Molecular Biology (Mayer and
Walker, eds., Academic Press, London, 1987);Handbook Of Experimental Immunology, Volumes I-IV (D. M. Weir and C. C. Blackwell, eds., 1986);Manipulating the Mouse Embryo, (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N. Y., 1986)参照。
本発明は、特に、瘻を治療および予防するための方法および組成物を提供する。本発明の特定の実施態様を論じてきたが、上記の詳述は例示するものであり、限定するものではない。本発明の多くの変形形態は、当業者には本明細書を読み返すことにより明らかになる。添付の特許請求の範囲は、かかる総ての実施態様および変形形態を主張するものではなく、本発明の十分な範囲は、特許請求の範囲をそれらの十分な範囲の等価物とともに、そして上記の詳述をかかる変形形態とともに参照することにより決定されるべきである。
Claims (55)
- 脂肪組織由来間質幹細胞を含有する組成物であって、該組成物を構成する脂肪組織由来間質幹細胞の少なくとも約50%が、CD9、CD10、CD13、CD29、CD44、CD49A、CD51、CD54、CD55、CD58、CD59 CD90およびCD105マーカーを発現するものである、脂肪組織由来間質幹細胞含有組成物。
- 前記組成物を構成する脂肪組織由来間質幹細胞の少なくとも約85%が、CD9、CD10、CD13、CD29、CD44、CD49A、CD51、CD54、CD55、CD58、CD59 CD90およびCD105マーカーを発現するものである、請求項1に記載の脂肪組織由来間質幹細胞含有組成物。
- 前記組成物を構成する脂肪組織由来間質幹細胞の少なくとも約95%が、CD9、CD10、CD13、CD29、CD44、CD49A、CD51、CD54、CD55、CD58、CD59 CD90およびCD105マーカーを発現するものである、請求項2に記載の脂肪組織由来間質幹細胞含有組成物。
- 前記組成物を構成する脂肪組織由来間質幹細胞の少なくとも約99%が、CD9、CD10、CD13、CD29、CD44、CD49A、CD51、CD54、CD55、CD58、CD59 CD90およびCD105マーカーを発現するものである、請求項3に記載の脂肪組織由来間質幹細胞含有組成物。
- 前記組成物を構成する脂肪組織由来間質幹細胞の約5%未満が、CD34 CD11b、CD14、CD15、CD16、CD31、CD34、CD45、CD49f、CD102、CD104、CD106および/またはCD133マーカーを発現するものである、請求項4に記載の脂肪組織由来間質幹細胞含有組成物。
- リンゲル溶液およびHSAをさらに含んでなる、請求項1に記載の脂肪組織由来間質幹細胞含有組成物。
- 前記組成物を構成する脂肪組織由来間質幹細胞の濃度が少なくとも約10x106細胞/mLである、請求項6に記載の脂肪組織由来間質幹細胞含有組成物。
- 前記組成物を構成する脂肪組織由来間質幹細胞の濃度が少なくとも約20x106細胞/mLである、請求項7に記載の脂肪組織由来間質幹細胞含有組成物。
- 接着剤をさらに含んでなる、請求項1に記載の脂肪組織由来間質幹細胞含有組成物。
- 前記接着剤がフィブリン糊またはゲルである、請求項9に記載の脂肪組織由来間質幹細胞含有組成物。
- 請求項1に記載の脂肪組織由来間質幹細胞含有組成物を含んでなる、支持体。
- 縫合糸である、請求項11に記載の支持体。
- パッチである、請求項11に記載の支持体。
- 請求項1に記載の脂肪組織由来間質幹細胞含有組成物を製造する方法であって、
(a)被験体から脂肪組織を採取すること;(b)酵素消化により細胞懸濁液を得ること;(c)該細胞懸濁液を沈殿させ、脂肪組織由来間質幹細胞を培養培地に再懸濁すること;(d)該脂肪組織由来間質幹細胞を少なくとも約10日間培養すること;および(g)該脂肪組織由来間質幹細胞を少なくとも2回継代することを含んでなる、方法。 - 前記脂肪組織由来間質幹細胞が少なくとも約20日間培養される、請求項14に記載の方法。
- 前記脂肪組織由来間質幹細胞を少なくとも3回継代することを含んでなる、請求項14に記載の方法。
- 瘻修復用の接着剤を製造する方法であって、請求項1に記載の脂肪組織由来間質幹細胞含有組成物をフィブリンベースのポリマーに懸濁することを含んでなる、方法。
- 被験体における瘻を治療する方法であって、(a)内部穴を縫合糸で閉鎖すること、および(b)該縫合閉鎖された内部穴に少なくとも約10x106の脂肪組織由来間質幹細胞を送達することを含んでなる、方法。
- 前記脂肪組織由来間質幹細胞が請求項1に記載の脂肪組織由来間質幹細胞含有組成物である、請求項18に記載の方法。
- (d)少なくとも1つの瘻トラックを深く掻爬すること;(e)該瘻トラックに接着剤を充填することをさらに含んでなる、請求項18に記載の方法。
- (f)前記接着剤に少なくとも約10x106の脂肪組織由来間質幹細胞を送達することをさらに含んでなる、請求項20に記載の方法。
- 前記接着剤がフィブリン糊またはゲルである、請求項20に記載の方法。
- 前記接着剤が請求項1に記載の脂肪組織由来間質幹細胞含有組成物をさらに含むものである、請求項21に記載の方法。
- (c)少なくとも約20x106の脂肪組織由来間質幹細胞からなる2回目の投与量を送達することをさらに含んでなる、請求項18に記載の方法。
- 少なくとも約20x106の脂肪組織由来間質幹細胞を送達することを含んでなる、請求項18に記載の方法。
- (c)少なくとも約40x106の脂肪組織由来間質幹細胞からなる2回目の投与量を送達することをさらに含んでなる、請求項25に記載の方法。
- 前記脂肪組織由来間質幹細胞が前記被験体の脂肪組織に由来するものである、請求項18に記載の方法。
- 前記瘻が肛門直腸瘻、腸腸瘻、腸皮瘻、直腸腟瘻または膀胱腟瘻である、請求項18に記載の方法。
- 前記被験体に治療薬を投与することをさらに含んでなる、請求項18に記載の方法。
- 前記治療薬が前記縫合閉鎖された内部穴に局所投与される、請求項29に記載の方法。
- 前記治療薬が前記被験体に全身投与される、請求項30に記載の方法。
- 被験体における創傷を治療する方法であって、(a)創傷を縫合糸で閉鎖すること、および(b)該縫合閉鎖された創傷に少なくとも約10x106の脂肪組織由来間質幹細胞を送達することを含んでなる、方法。
- 前記脂肪組織由来間質幹細胞が請求項1に記載の細胞組成物である、請求項23に記載の方法。
- c−Kit、ビメンチンおよびCD90マーカーを発現し、CD34、第VIII因子、α−アクチン、デスミン、S−100およびケラチンマーカーを発現しない、脂肪組織由来間質幹細胞。
- CD9、CD10、CD13、CD29、CD44、CD49A、CD51、CD54、CD55、CD58、CD59 CD90およびCD105マーカーを発現し、CD34CD11b、CD14、CD15、CD16、CD31、CD34、CD45、CD49f、CD102、CD104、CD106および/またはCD133マーカーを発現しない、脂肪組織由来間質幹細胞。
- 被験体における瘻を治療するための医薬組成物の製造における、脂肪組織由来間質幹細胞の使用。
- 前記脂肪組織由来間質幹細胞が治療を受ける被験体の脂肪組織に由来するものである、請求項36に記載の使用。
- 前記脂肪組織由来間質幹細胞が、請求項1〜10、34または35のいずれか一項に記載の脂肪組織由来間質幹細胞含有組成物である、請求項36に記載の使用。
- 前記医薬組成物が少なくとも約10x106の脂肪組織由来間質幹細胞を含むものである、請求項36に記載の使用。
- 前記医薬組成物が、内部穴を縫合糸で閉鎖した後に、初回投与量として瘻孔の該閉鎖された内部穴に送達されるものである、請求項36に記載の使用。
- 前記医薬組成物が、瘻孔の内部穴を縫合糸で閉鎖した後に、初回投与量として該瘻孔の壁の1以上の部位に送達されるものである、請求項36に記載の使用。
- 前記医薬組成物が少なくとも約10x106の脂肪組織由来間質幹細胞を含むものである、請求項40または41に記載の使用。
- 前記医薬組成物の前記初回投与量の後に、2回目の投与量の前記医薬組成物が前記縫合閉鎖された内部穴または前記瘻孔の壁の1以上の部位に送達される、請求項40または41に記載の使用。
- 前記2回目の投与量の前記医薬組成物が少なくとも約20x106の脂肪組織由来間質幹細胞を含むものである、請求項43に記載の使用。
- 前記脂肪組織由来間質幹細胞が縫合糸に含まれる、請求項36に記載の使用。
- 前記脂肪組織由来間質幹細胞が、瘻トラックを充填するための材料に送達される、請求項36に記載の使用。
- 前記材料がフィブリンベースのポリマー、またはフィブリン糊もしくはゲルなどの接着剤である、請求項46に記載の使用。
- 前記瘻が、肛門直腸瘻、肛門瘻、糞瘻、動静脈瘻、胆道瘻、頸瘻、頭蓋洞瘻、腸腸瘻、腸皮瘻、腸腟瘻、胃瘻、子宮腹腔瘻、外リンパ瘻、肺動静脈瘻、直腸腟瘻、臍瘻、気管食道瘻、または膀胱腟瘻である、請求項36に記載の使用。
- 前記瘻が肛門直腸瘻、腸直腸瘻、腸皮瘻、直腸腟瘻または膀胱腟瘻である、請求項48に記載の使用。
- 前記医薬組成物が治療薬と組み合わせて治療を受けている被験体に投与されるものである、請求項36に記載の使用。
- 前記治療薬が、全身的に、または縫合部位に局所的に投与されるものである、請求項50に記載の使用。
- 前記医薬組成物が前記治療薬を含むものである、請求項51に記載の使用。
- 前記治療薬が前記脂肪組織由来間質幹細胞を含む前記医薬組成物とは別々に投与されるものである、請求項50に記載の使用。
- 前記治療薬が抗炎症薬、免疫抑制薬、生物学的製剤、抗生物質、または下痢止め薬である、請求項50に記載の使用。
- 被験体における瘻を治療する方法であって、
(i)少なくとも1つの瘻トラックを深く掻爬する工程、
(ii)該掻爬されたトラックの内部穴を縫合糸で閉鎖する工程、および
(iii)該縫合閉鎖された内部穴に少なくとも約10x106の脂肪組織由来間質幹細胞を送達する工程
を含んでなる、方法。
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