JP6095893B2 - 傷害後の神経組織の再生および修復 - Google Patents
傷害後の神経組織の再生および修復 Download PDFInfo
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Description
本出願は、2008年12月19日出願の米国仮特許出願第61/139,305号の利益を主張するものであり、この内容は、参照により全体として本明細書に組み込まれる。
本発明は、神経傷害のための、細胞に基づく、または再生療法の分野に関する。具体的には、本発明は、細胞を用いた神経組織の再生または修復のための医薬組成物、キット、および方法を提供する。
様々な特許および他の文献が、この明細書全体にわたって言及される。これらの文献はそれぞれ、参照により全体として本明細書に組み込まれる。
本発明は、神経傷害のための細胞に基づく再生療法に適用可能な組成物、キット、および方法を提供する。具体的には、本発明は、分娩後組織由来細胞を用いて神経組織を再生または修復する医薬組成物、装置、および方法を特徴とする。
例示的な実施形態に関する、以下の詳細な説明では、その一部を形成する添付図面を参照する。これらの実施形態は、当業者が本発明を実施できるよう十分詳細に説明され、他の実施形態が利用され得ること、ならびに論理的、構造的、機械的、電気的、化学的変更が、本発明の趣旨または範囲を逸脱せずに行われ得ることが、理解される。本明細書に記載する実施形態を当業者が実施するのに必要でない詳細を省くため、説明では、当業者に既知の情報は省略され得る。したがって、以下の詳細な説明は、限定的な意味で理解されるべきではない。
ニューロン細胞死または不全(これは、脳血管不全、局所的もしくはびまん性脳外傷、びまん性脳損傷、および外傷性ニューロパチーを含む)に関連する状態を含む、神経傷害は、共通の特徴として、特定のまたは脆弱な神経細胞群の機能障害または損失を有する。この共通性により、脆弱なまたは損傷した神経組織の修復および再生のため、同様の治療アプローチが開発でき、そのうちの1つは、細胞に基づく療法である。本明細書に記載するその様々な実施形態では、本発明は、分娩後組織由来の前駆細胞および細胞集団を利用する、神経の修復および再生のための方法および医薬組成物を特徴とする。本発明は、任意の神経傷害に適用可能であるが、いくつかの傷害に特に適していると思われる。その傷害には、限定することなく、塞栓性閉塞および血栓性閉塞を含む脳虚血または梗塞、急性虚血後の再灌流、出生時低酸素−虚血性傷害、心停止、ならびに任意のタイプの頭蓋内出血(例えば硬膜外、硬膜下、くも膜下および脳内)、および頭蓋内および椎骨内病変(例えば挫傷、貫通、せん断、圧縮および断裂)、および揺さぶられ症候群を含む。
医薬品、成長因子、調節因子などの有効性および細胞毒性について広範な化合物をスクリーニングするために、UTCをin vitroで使用することができる。例えば、神経傷害の治療のため、UTCと共に処方されるか、または同時に投与されるべき候補化合物の有効性または毒性を評価するために、実質的に同種のUTC集団で、このようなスクリーニングを行ってもよい。あるいは、このようなスクリーニングは、新たな医薬品候補の有効性を評価する目的で、神経細胞もしくは神経前駆細胞へと分化するよう刺激されたUTCに対して行うことができる。この実施形態では、UTCは、in vitroで維持され、試験されるべき化合物に曝される。潜在的に細胞毒性の化合物の活性は、培養中の細胞を損傷するかまたは殺す能力により測定され得る。これは、生体染色技術により容易に評価することができる。成長または調節因子の効果は、それらの因子にさらされていない細胞と比較して、培養細胞の数または頑強性を分析することで評価できる。これは、型特異性の細胞抗原を定める抗体を利用する免疫細胞化学的技術の使用を含む、標準的な細胞学的および/または組織学的技術を用いて達成することができる。
実施例2〜10で述べるように、UTCは、体内に有効に移植され、ヒトにおける有効性を予測するために受け入れられた動物モデルに、失われた神経機能を供給することが分かっている。いったん体内の標的神経場所に移植されると、UTCはそれら自体が、1つまたは複数の神経の表現型に分化でき、あるいは、栄養的補助を神経前駆細胞および神経細胞にin situで供給でき、あるいは、それらの形で、ならびに他の形で、有益な効果をもたらすことができる。
ANG2(またはAng2):アンジオポエチン2
APC:抗原提示細胞
BDNF:脳由来神経栄養因子
bFGF:塩基性線維芽細胞成長因子
bid(BID):「bis in die」(1日に2回)
CK18:サイトケラチン18
CNS:中枢神経系
CXCリガンド3:ケモカインレセプターリガンド3
DMEM:ダルベッコ最小基本培地
DMEM:lg(またはDMEM:Lg、DMEM:LG):低グルコースのDMEM
EDTA:エチレンジアミン四酢酸
EGF(またはE):上皮成長因子
FACS:蛍光活性化細胞選別
FBS:ウシ胎仔血清
FGF(またはF):線維芽細胞成長因子
GCP−2:顆粒球走化性タンパク質−2
GFAP:グリア線維酸性タンパク質
HB−EGF:ヘパリン結合上皮成長因子
HCAEC:ヒト冠動脈内皮細胞
HGF:肝細胞成長因子
hMSC:ヒト間葉幹細胞
HNF−1α:肝細胞特異性転写因子1α
HUVEC:ヒト臍静脈内皮細胞
I309:ケモカインおよびCCR8レセプターのリガンド
IGF−1:インスリン様成長因子1
IL−6:インターロイキン−6
IL−8:インターロイキン8
K19:ケラチン19
K8:ケラチン8
KGF:ケラチノサイト成長因子
LIF:白血病抑制因子
MBP:ミエリン塩基性タンパク質
MCP−1:単球走化性タンパク質1
MDC:マクロファージ由来ケモカイン
MIP1α:マクロファージ炎症性タンパク質1α
MIPlβ:マクロファージ炎症性タンパク質1β
MMP:マトリックスメタロプロテアーゼ(MMP)
MSC:間葉幹細胞
NHDF:正常ヒト皮膚線維芽細胞
NPE:神経前駆細胞増殖培地
04:乏突起膠細胞もしくはグリア分化マーカー04
PBMC:末梢血単核細胞
PBS:リン酸緩衝生理食塩水
PDGFbb:血小板由来成長因子
PO:「per os」(経口)
PNS:末梢神経系
Rantes(もしくはRANTES):発現及び分泌され、活性時調節(regulated on activation)された、正常なT細胞
rhGDF−5:組み換えヒト成長および分化因子5
SC:皮下
SDF−1α:間質由来因子1α
SHH:ソニックヘッジホッグ
SOP:標準的な手術手順
TARC:胸腺および活性調節ケモカイン
TCP:組織培養プラスチック
TCPS:組織培養ポリスチレン
TGFβ2:形質転換成長因子β2
TGFβ−3:形質転換成長因子β−3
TIMP1:組織マトリックスメタロプロテイナーゼ抑制物質1
TPO:トロンボポエチン
TuJl:BIII Tubulin
VEGF:血管内皮成長因子
vWF:フォン・ヴィルブランド因子
αFP:α−フェトプロテイン
長期間にわたる細胞の神経の分化
臍由来細胞が長期間の神経系統細胞への分化を受ける能力が評価された。UTCは、実施例13〜15に記載するように単離および増殖された。
ラットにおける脳内出血(ICH)モデル
Seyfried,et al,J. Neurosurg,2006;104:313−318(2006)によって本質的には説明されるように、100μLの自家血液を注入することによって、300〜350gの体重のオスのWistarラットにおいて、ICHが誘導された。端的には、ラットは、キシラジン(10mg/kg)およびケタミン(80mg/kg)で麻酔された。いったん適切な麻酔が行われたら、ラットは、フィードバック調節された温水パッドを用いて、外科的手法中37℃に維持された。切開スコープ下で、2cm腹部皮膚切開部が、腹部および右大腿により形成されたしわにそって、作られた。内転筋の鈍的切開を使用して、右大腿動脈を可視化する。5〜10mmの動脈は、隣接する大腿静脈および伏在神経から注意深く動かされた。動脈は、遠位端で結紮され、近位部分は、4−0縫合糸で一時的に遮断された。PE50カテーテルが次に、小さな穿刺部を通して1〜2cm血管に挿入され、4−0縫合糸で所定の場所に固定される。次に、ラットは、定位固定フレーム(David Kopf Instruments,Tujunja,Ca.)上でうつぶせに置かれた。正中切開が、頭蓋冠に行われ、骨膜まで実行された。小さな骨膜エレベーターが使用され、頭蓋骨を露出した。いったんこれが達成されると、定位固定フレームの測定を使用して、頭蓋骨切除術が行われる部位をガイドした。ブレグマの最初の識別が行われ、次に、頭蓋骨切除術が、定位固定ドリル(外側から正中線3.5mm、前方からブレグマ0.5mm、正中線までの表面下、深さ5.5mm)を用いて行われる。大腿動脈から採取した0.3mLの自家血液が、定位固定フレームに取り付けられた26G1/2針を有する1mL(1cc)の注射器に入れられた。0.1mLの血液が次に、注入ポンプ(600−910/920,Harvard Appratus,Holliston,MA)で1分間に10μLの速度で、注入された。血液の逆流を防ぐため、骨ワックス片が使用されて、頭蓋骨切除部位を閉鎖し、血液を脳に維持する。皮膚は、4.0絹縫合糸を単純に通すことで、再び近づけられた。
脳室下帯の細胞増殖に対する、脳傷害後の細胞投与の影響
ブロモデオキシウリジン(BrdU)、チミジン類似体が、細胞周期のS期中に細胞のゲノムDNAに組み込まれ得る。脳室下帯(SVZ)内のBrdU陽性細胞は、細胞周期のS期にDNA合成を受ける前駆細胞だと考えられる。SVZ内のBrdU細胞数は、神経発生の指標として使用される。
脳の損傷エリアにおける血管新生に対する、脳傷害後の細胞投与の影響
病変周辺の境界の拡張および薄壁血管は、血管新生を示す(Li,Y,et al.,Neurology,2002;59:514−523)。28日後、組織学的評価のため、実施例3に詳述したように、動物は、再び麻酔され、屠殺され、脳が除去された。vWFに対するモノクローナル抗体(1:400,Dako,Carpinteria,Ca.)を使用した。
脳室下帯の神経発生に対する脳傷害後の細胞投与の影響
ダブルコルチン(DCX)は、神経発生のマーカーであり、これは、新たに形成される神経芽細胞に一時的に発現する(約2〜3週間)。28日後、組織学的評価のため、実施例3に詳述したように動物は、再び麻酔され、屠殺され、脳が除去された。ヤギ抗−DCX(1:200;Santa Cruz Biotechnology,Santa Cruz,Ca.)を使用した。
血腫の境界域のシナプス形成に対する脳傷害後の細胞投与の影響
シナプトフィジン、プレシナプス小胞タンパク質が、シナプス形成の指標として使用される(Ujike,H,et al,Ann N Y Acad ScL、2002;965:55−67)。28日後、組織学的評価のため、実施例3に詳述したように動物は再び麻酔され、屠殺され、脳が除去された。シナプトフィジン(1:40 mAb,Clone SY 38,Millipore,Billerica,MA)を使用した。
脳の損傷エリアのアポトーシスに対する脳傷害後の細胞投与の影響
28日後、組織学的評価のため、実施例3に詳述したように、動物は再び麻酔され、屠殺され、脳が除去された。終端デオキシヌクレオチド転移酵素(TdT)媒介dUTP−ビオチンニック末端標識(TUNEL)方法(ApopTag Kit;Oncor,Gaithersburg,MD)が使用されて、製造業者の仕様書に従って、in situのアポトーシスの検出を評価した。TUNEL方法は、DNAの3‘−OH末端に対するTdTの特異的結合、および後に続く、ポリデオキシヌクレオチドポリマー細胞の合成に基づく。端的には、脳切片の脱パラフィン処理、およびプロテイナーゼKを使用したタンパク質の消化、その後の、PBS中2%のH2O2による内因性ペルオキシダーゼ活性のクエンチの後、スライドは、平衡緩衝液に、その後、作用強度TdT酵素中に置かれ、続いて、作用強度停止/洗浄用緩衝液に置かれた。抗ジゴキシゲニンペルオキシダーゼを2滴スライドに加えた後、ペルオキシダーゼは、DABで検出された。陰性対照が、作用強度TdTの製剤中、TdT酵素に関して蒸留水を使用して行われた。TUNEL方法の標識標的は、DNA断片化により生成された新しい3’−OH DNA末端であり、これは、典型的には、暗褐色で丸いかまたは楕円の本体の、形態的に識別可能な核およびアポトーシス体に局在化する。
脳の損傷エリアの組織損失に対する、脳傷害後の細胞投与の影響
28日後、組織学的評価のため、実施例3に詳述したように、動物は、再び麻酔され、屠殺され、脳が除去された。大脳組織は、等しく離間した(2mm)7つの冠状ブロックに切り分けられ、その後、パラフィン切片化処理された。一連の隣接した6μm厚さの切片が、冠状面で各ブロックから切られ、ヘマトキシリンおよびエオシンで染色された。切片は、Global Laboratory Image分析システム(Data Translation,Mariborn,Ma.)により追跡された。出血の側の保存された線条体のエリアは、反対側のものから取り去られ、したがって、ICHに起因する組織損失の程度が判断され、処理動物と未処理動物が比較される。結果は、対照PBS群と比べて、ICH後24時間または72時間に3x106個のUTCで処理したものには、組織損失の著しい減少はなかったことを示した(図10Aおよび10Bを参照)。
脳傷害後の異なる時点における細胞投与の影響
実施例2〜8は、傷害後24時間および72時間におけるUTC投与の影響を示す。本研究では、治療濃度域が、7日目に遅延投与により広げられ、これにより、臨床的状況がよりよく模倣される(すなわち、細胞を7日目に投与することができれば、より多くの患者が、治療を受けることができる)。
1. 神経機能
機能試験の結果は、3x106個のUTCで7日目または3日目に処理されたラットは、mNSS試験、コーナーテスト、および円筒試験で著しい神経機能改善を表した(p<0.05)ことを示した。
BrdU陽性細胞の数は、対照PBS群と比較して、ICH後3または7日目に3x106個のUTCで処理されたラットの同側半球のSVZで著しく増加した(p<0.05)(図15A〜15Fを参照)。
組織修復を促進する脳傷害後の細胞投与の影響
UTCおよびMSCは、組織修復を促進する新しい方法を探すため、外傷性脳傷害のラットを処理するために試験された。UTCまたはMSCは、TBI後、若い成体のオスのラットを処理するため投与された。
両処理群(UTCまたはMSC処理のラット)と対照群との間で、mNSSに有意差があった。これは7日目に初めて目に見え、トライアル終了まで続いた(図22を参照)。2つの処理群には、差がなかった。
神経前駆細胞補助のための栄養因子
非接触依存(栄養)メカニズムを通じた、成体の神経幹細胞および前駆細胞の生存ならびに分化に対するUTCの影響を調べた。
(1)トランスウェル(成長培地中臍由来細胞、200μL)+神経前駆細胞(NPE+bFGF+EGF、1mL)
(2)トランスウェル(成体ヒト皮膚線維芽細胞[1F1853;Cambrex,Walkersville,MD]P12、成長培地中、200μL)+神経前駆細胞(NPE+bFGF+EGF、1mL)
(3)対照:神経前駆細胞単独(NPE+bFGF+EGF、1mL)
(4)対照:神経前駆細胞単独(NPEのみ、1mL)。
細胞の短期間の神経の分化
臍由来細胞が神経系統細胞に分化する能力を調べた。臍帯組織は、実施例12に示すように、単離され、増殖された。
細胞単離
臍帯が、National Disease Research Interchange(NDRI,Philadelphia,Pa.)から入手された。組織は、正常な配達に従って入手された。細胞単離プロトコルは、層流フードで無菌で行われた。血液および残骸を除去するため、臍帯が、100単位/mLのペニシリン、100mg/mLのストレプトマイシン、および0.025μg/mLのアンホテリシンB(Invitrogen Carlsbad,Ca.)の存在下で、リン酸緩衝生理食塩水(PBS; Invitrogen、Carlsbad、Ca.)で洗浄された。組織は次に、組織が細かな柔らかい塊(fine pulp)に刻まれるまで、50mLの培地(DMEM−低グルコースまたはDMEM−高グルコース;Invitrogen)の存在下で、150cm2組織培養プレートにおいて、機械的に解離された。切り刻まれた組織は、50mLの円錐チューブ(チューブ当たり約5gの組織)に移された。
細胞の成長特性
臍帯組織由来細胞の細胞増殖能力を、他の単離された幹細胞集団と比較した。老化までの細胞増殖のプロセスは、ヘイフリックの限界と呼ばれる(Hayflick、L、J. Am. Geriatr. Soc、1974;22(1):1−12;Hayflick、L、Gerontologist、1974;14(l):37−45)、1974)。
D‐バリン含有培地での細胞成長
通常のL−バリンアイソフォームの代わりにD−バリンを含有する培地を用いて、培養中の線維芽細胞様細胞の成長を選択的に抑制できることが報告されている(Hongpaisan J. Cell Biol Int.,2000;24:1−7;Sordillo LM,et al,Cell Biol Int Rep.,1988;12:355−64)。実験を行って、臍帯組織由来細胞が、D−バリンを含有する培地で成長できるかどうか判断した。
細胞の核型分析
細胞療法に使用される細胞株は、好ましくは、同種であり、汚染細胞型を含まない。細胞療法に使用されるヒト細胞は、正常な構造を有する、正常な数(46個)の染色体を有していなければならない。同種であり、分娩後組織由来でない細胞を含まない、臍帯組織由来細胞株を識別するため、細胞サンプルの核型を分析した。
細胞表面マーカーのフローサイトメトリー評価
フローサイトメトリーによる細胞表面タンパク質または「マーカー」の特徴づけを用いて、細胞株の同一性を判断することができる。発現の一貫性は、複数のドナーから、異なる処理および培養条件にさらされた細胞において、判断され得る。臍から単離された細胞株は、(フローサイトメトリーにより)特徴付けられ、これらの細胞株の同定のプロファイルを与えた。
オリゴヌクレオチドアレイによる細胞の分析
オリゴヌクレオチドアレイを使用して、臍由来細胞および胎盤由来細胞の遺伝子発現プロファイルを、線維芽細胞、ヒト間葉系幹細胞、およびヒト骨髄由来の別の細胞株と比較した。この分析により、分娩後由来細胞の特徴付けがもたらされ、これらの細胞に対する独自の分子マーカーが識別された。
臍帯組織由来細胞の細胞マーカー
臍帯由来の細胞の遺伝子発現プロファイルが、Affymetrix GENECHIPを用いて、他の供給源由来の細胞のものと比較された。6つの「シグネチャー(signature)」遺伝子が識別された、すなわち、酸化LDLレセプター1(oxidized LDL receptor 1)、インターロイキン−8(interleukin-8)(IL−8)、レニン(renin)、レティキュロン(reticulon)、ケモカインレセプターリガンド3(chemokine receptor ligand 3)(CXCリガンド3(CXC ligand 3))、および顆粒球走化性タンパク質2(granulocyte chemotactic protein 2)(GCP−2)である。これらの「シグネチャー」遺伝子は、臍由来細胞において比較的高いレベルで発現した。
細胞表現型の免疫組織化学的特徴付け
ヒト臍帯内で発見された細胞の表現型を、免疫組織化学的検査により分析した。
栄養因子の分泌
臍由来細胞からの、選択された栄養因子の分泌を測定した。検出のため選択された因子は以下を含んだ:(1)血管新生作用を有することが知られるもの、例えば、肝細胞成長因子(HGF)(Rosen et al.,Ciba Found. Symp.,1997;212:215−26)、単球走化性タンパク質1(MCP−1)(Salcedo et al.,Blood,2000;96:34−40)、インターロイキン−8(IL−8)(Li et al.,J. Immunol.,2003;170:3369−76)、ケラチノサイト成長因子(KGF)、塩基性線維芽細胞成長因子(bFGF)、血管内皮成長因子(VEGF)(Hughes et al.,Ann. Thorac. Surg.,2004;77:812−8)、マトリックスメタロプロテイナーゼ1(TIMP1)、アンジオポエチン2(ANG2)、血小板由来成長因子(PDGF−bb)、トロンボポエチン(TPO)、ヘパリン結合上皮成長因子(HB−EGF)、間質由来因子1α(SDF−1α);(2)神経栄養/神経保護活性を有することが知られるもの、例えば、脳由来神経栄養因子(BDNF)(Cheng et al.,Dev. Biol.,2003;258;319−33)、インターロイキン−6(IL−6)、顆粒球走化性タンパク質−2(GCP−2)、形質転換成長因子β2(TGFβ2);および、(3)ケモカイン活性を有することが知られるもの、例えばマクロファージ炎症性タンパク質1α(MIP1a)、マクロファージ炎症性タンパク質1β(MIP1b)、単球走化性因子−1(MCP−1)、Rantes(活性時に調節される、発現および分泌された正常なT細胞)、I309、胸腺および活性調節ケモカイン(TARC)、エオタキシン、マクロファージ由来ケモカイン(MDC)、およびIL−8。
In Vitro免疫学
免疫学的反応を予測しようとして、臍帯細胞株が、それらの免疫学的特徴についてin vitroで評価され、もしあれば、これらの細胞は、in vivo移植の際に引き出すであろう。臍帯細胞株は、HLA−DR、HLA−DP、HLA−DQ、CD80、CD86、およびB7−H2の発現についてフローサイトメトリーによりアッセイされた。これらのタンパク質は、抗原提示細胞(APC)により発現され、未処理のCD4+T細胞(Abbas & Lichtman, Cellular and Molecular Immunology, 5th Ed.(2003) Saunders, Philadelphia, p.171)の直接刺激のために必要である。細胞株はまた、HLA−G(Abbas & Lichtman, Cellular and Molecular Immunology, 5th Ed.(2003) Saunders, Philadelphia, p.171)、CD178(Coumans et.al., Journal of Immunology Methods, 1999;224:185−196)、およびPD−L2(Abbas & Lichtman, Cellular and Molecular Immunology, 5th Ed. (2003) Saunders, Philadelphia, p.171; Brown et. al., The Journal of Immunology, 2003;170:1257−1266)の発現について、フローサイトメトリーによって分析された。胎盤組織にある細胞によるこれらのタンパク質の発現は、子宮内での胎盤組織の免疫特権状態を媒介すると考えられる。どの程度まで臍帯組織由来細胞株がin vivoで免疫反応を引き出すかを予測するため、細胞株は、一方向混合リンパ球反応(MLR)で試験された。
テロメラーゼ活性のアッセイ
テロメラーゼは、染色体の完全性を保護し、また細胞の複製寿命を延ばすのに役立つ、テロメア繰り返し体を合成するよう機能する(Liu,K,et al.,PNAS,1999;96:5147−5152)。テロメラーゼは、2つの成分、テロメラーゼRNAテンプレート(hTER)、およびテロメラーゼ逆転写酵素(hTERT)のみからなる。テロメラーゼの調節は、hTERではなく、hTERTの転写により決定される。hTERT mRNAのリアルタイムポリメラーゼ連鎖反応(PCR)は、ゆえに、細胞のテロメラーゼ活性を決定する、認められた方法である。
リアルタイムPCR実験が行われ、ヒト臍帯組織由来細胞のテロメラーゼ産生が決定された。ヒト臍帯組織由来細胞が、実施例13〜15、および、米国特許第7,510,873号として特許となった米国特許出願第10/877,012号(‘012号出願)に記載される実施例に従って、準備された。概して、正常な運搬後にNational Disease Research Interchange(Philadelphia,Pa.)から入手された臍帯が洗浄され、血液および残骸を除去し、機械的に解離される。組織は次に、コラゲナーゼ、ディスパーゼおよびヒアルロニダーゼを含む消化酵素で、培養培地において37℃でインキュベートされる。ヒト臍帯組織由来細胞は、‘012号出願の実施例に記載された方法に従って培養された。間葉系幹細胞および正常な皮膚線維芽細胞(cc−2509 ロット# 9F0844)が、Cambrex,Walkersville,Md.から入手された。多能性ヒト精巣胎児性癌(テラトーマ)細胞株nTera−2細胞(NTERA− 2 cl.Dl)(Plaia et al, Stem Cells, 2006;24(3):531−546を参照)を、ATCC(Manassas,Va.)から購入し、‘012号出願に記載した方法に従って培養した。
RNAが、RNeasy(登録商標)kit(Qiagen,Valencia,Ca.)を用いて細胞から抽出された。RNAは、50μLのDEPC処理水で溶出され、−8O℃で保管された。RNAは、TaqMan(登録商標)逆転写試薬(Applied Biosystems,Foster City,Ca.)により、25℃で10分間、37℃で60分間、95℃で10分間、ランダムヘキサマーを用いて逆転写された。サンプルを−20℃で保管した。
PCRが、Applied Biosystems Assays−On−Demand(商標)(TaqMan(登録商標)遺伝子発現アッセイとしても知られる)を用いて、製造業者の仕様書(Applied Biosystems)に従って、cDNAサンプルに対して行われた。この市販のキットは、ヒト細胞のテロメラーゼのアッセイに広く使われる。端的には、hTERT(ヒトテロメラーゼ遺伝子)(Hs00162669)およびヒトGAPDH(内部対照)が、ABI prism 7000 SDSソフトウェア(Applied Biosystems)と共に7000配列検出システムを用いて、cDNAおよびTaqMan(登録商標)Universal PCRマスターミックスと混合された。熱サイクル条件は、最初は、50℃で2分、95℃で10分、その後、95℃で15秒および60℃で1分の40サイクルであった。PCRデータは、製造業者の仕様書に従って分析された。
(1) 神経傷害を有する患者を治療する方法において、
前記神経傷害を治療するのに有効な量の単離臍帯組織由来細胞を、前記患者に投与すること、
を含み、
前記臍帯組織由来細胞は、実質的に血液のないヒト臍帯組織由来であり、
前記細胞は、培養中に自己再生および増殖することができ、少なくとも神経の表現型の細胞に分化する能力を有し、
前記細胞は、CD117を発現しない、方法。
(2) 実施態様1に記載の方法において、
前記神経傷害は、脳虚血、急性虚血後の再灌流、出生時低酸素虚血性傷害、心停止、頭蓋内出血、頭蓋内病変、揺さぶられ症候群である、方法。
(3) 実施態様1に記載の方法において、
前記細胞は、前記神経傷害の治療を促進する遺伝子産物を産生するように、遺伝子操作される、方法。
(4) 実施態様1に記載の方法において、
前記細胞は、少なくとも1つの他の細胞型と共に投与される、方法。
(5) 実施態様4に記載の方法において、
前記他の細胞型は、星状細胞、乏突起膠細胞、ニューロン、神経前駆細胞、神経幹細胞、または他の多分化能もしくは多能性幹細胞である、方法。
前記細胞は、前記患者の中枢または末梢神経系の所定部位に投与される、方法。
(7) 実施態様1に記載の方法において、
前記臍帯組織由来細胞は、hTERTまたはテロメラーゼを発現しない、方法。
(8) 実施態様1に記載の方法において、
前記細胞は、注射または注入により投与される、方法。
(9) 患者の脳室下帯(SVZ)の再生能力を刺激する方法において、
神経発生、血管新生、またはシナプス形成を増大させるのに有効な量で、単離臍帯組織由来細胞を前記患者に投与すること、
を含み、
前記臍帯組織由来細胞は、実質的に血液のないヒト臍帯組織由来であり、
前記細胞は、培養中に自己再生および増殖することができ、少なくとも神経の表現型の細胞に分化する能力を有し、
前記細胞は、CD117を発現しない、方法。
(10) 実施態様9に記載の方法において、
前記細胞は、前記脳室下帯の前記再生能力を促進する遺伝子産物を産生するように、遺伝子操作される、方法。
前記細胞は、少なくとも1つの他の細胞型と共に投与される、方法。
(12) 実施態様11に記載の方法において、
前記他の細胞型は、星状細胞、乏突起膠細胞、ニューロン、神経前駆細胞、神経幹細胞、または他の多分化能もしくは多能性幹細胞である、方法。
(13) 実施態様9に記載の方法において、
前記細胞は、前記患者の中枢または末梢神経系の所定部位で投与される、方法。
(14) 実施態様9に記載の方法において、
前記細胞は、注射または注入により投与される、方法。
(15) 実施態様1に記載の方法において、
前記細胞は、成長にL−バリンを必要とし、少なくとも約5%の酸素中で成長することができる、方法。
前記細胞は、CD10、CD13、CD44、CD73、CD90、PDGFr−α、およびHLA−A、B、Cのうち1つまたは複数を発現する、方法。
(17) 実施態様1に記載の方法において、
前記細胞は、CD10、CD13、CD44、CD73、CD90、PDGFr−α、およびHLA−A、B、Cのそれぞれを発現する、方法。
(18) 実施態様1に記載の方法において、
前記細胞は、CD31、CD34、CD45、CD141、およびHLA−DR、DP、DQのうち1つまたは複数を発現しない、方法。
(19) 実施態様1に記載の方法において、
前記細胞は、CD31、CD34、CD45、CD141、およびHLA−DR、DP、DQのいずれも発現しない、方法。
(20) 実施態様9に記載の方法において、
前記細胞は、成長のためL−バリンを必要とし、少なくとも約5%の酸素中で成長することができる、方法。
前記細胞は、CD10、CD13、CD44、CD73、CD90、PDGFr−α、およびHLA−A、B、Cのうち1つまたは複数を発現する、方法。
(22) 実施態様1に記載の方法において、
前記細胞は、CD10、CD13、CD44、CD73、CD90、PDGFr−α、およびHLA−A、B、Cのそれぞれを発現する、方法。
(23) 実施態様1に記載の方法において、
前記細胞は、CD31、CD34、CD45、CD141、およびHLA−DR、DP、DQのうち1つまたは複数を発現しない、方法。
(24) 実施態様1に記載の方法において、
前記細胞は、CD31、CD34、CD45、CD141、およびHLA−DR、DP、DQのいずれも発現しない、方法。
(25) 神経傷害を有する患者を治療する医薬組成物において、
前記神経傷害を治療するのに有効な量の、医薬的に許容可能な担体、および単離臍帯組織由来細胞、
を含み、
前記臍帯組織由来細胞は、実質的に血液のないヒト臍帯組織由来であり、
前記細胞は、培養中に自己再生および増殖することができ、少なくとも神経の表現型の細胞に分化する能力を有し、
前記細胞は、CD117を発現しない、医薬組成物。
前記細胞は、CD10、CD13、CD44、CD73、CD90、PDGFr−α、およびHLA−A、B、Cのうち1つまたは複数を発現する、医薬組成物。
(27) 実施態様25に記載の医薬組成物において、
前記細胞は、CD10、CD13、CD44、CD73、CD90、PDGFr−α、およびHLA−A、B、Cのそれぞれを発現する、医薬組成物。
(28) 実施態様25に記載の医薬組成物において、
前記細胞は、CD31、CD34、CD45、CD141、およびHLA−DR、DP、DQのうち1つまたは複数を発現しない、医薬組成物。
(29) 実施態様25に記載の医薬組成物において、
前記細胞は、CD31、CD34、CD45、CD141、およびHLA−DR、DP、DQのいずれも発現しない、医薬組成物。
(30) 神経傷害を有する患者を治療するキットであって、医薬的に許容可能な担体、単離臍帯組織由来細胞集団、および前記患者を治療する方法において前記キットを使用するための説明書を含む、キットにおいて、
前記臍帯組織由来細胞は、実質的に血液のないヒト臍帯組織由来であり、
前記細胞は、培養中に自己再生および増殖することができ、少なくとも神経の表現型の細胞に分化する能力を有し、
前記細胞は、CD117を発現しない、キット。
少なくとも1つの他の細胞型の集団、
をさらに含む、キット。
(32) 実施態様30に記載のキットにおいて、
前記細胞は、CD10、CD13、CD44、CD73、CD90、PDGFr−α、およびHLA−A、B、Cのうち1つまたは複数を発現する、キット。
(33) 実施態様30に記載のキットにおいて、
前記細胞は、CD10、CD13、CD44、CD73、CD90、PDGFr−α、およびHLA−A、B、Cのそれぞれを発現する、キット。
(34) 実施態様30に記載のキットにおいて、
前記細胞は、CD31、CD34、CD45、CD141、およびHLA−DR、DP、DQのうち1つまたは複数を発現しない、キット。
(35) 実施態様30に記載のキットにおいて、
前記細胞は、CD31、CD34、CD45、CD141、およびHLA−DR、DP、DQのいずれも発現しない、キット。
Claims (15)
- 患者の頭蓋内出血を治療するための薬剤において、
臍帯組織由来細胞、
を含み、
前記臍帯組織由来細胞は、実質的に血液のないヒト臍帯組織由来であり、
前記細胞は、培養中に自己再生および増殖することができ、少なくとも神経の表現型の細胞に分化する能力を有し、
前記細胞は、CD117およびhTERTのいずれをも発現しないか、または、CD117およびテロメラーゼのいずれをも発現せず、
前記細胞は、塩基性線維芽細胞成長因子および上皮成長因子を加えた神経前駆細胞増殖培地で培養されたとき神経細胞のマーカーであるTUJ1の発現について陽性である細胞に分化するものであり、
前記薬剤は、前記出血後7日以内に静脈内投与されるべきものである、
薬剤。 - 請求項1に記載の薬剤において、
前記細胞は、前記頭蓋内出血の治療を促進する遺伝子産物を産生するように、遺伝子操作される、薬剤。 - 請求項1に記載の薬剤において、
前記細胞は、少なくとも1つの他の細胞型の細胞と共に投与される、薬剤。 - 請求項3に記載の薬剤において、
前記他の細胞型の細胞は、星状細胞、乏突起膠細胞、ニューロン、神経前駆細胞、神経幹細胞、または他の多分化能もしくは多能性幹細胞である、薬剤。 - 請求項1に記載の薬剤において、
前記細胞は、前記患者の中枢または末梢神経系の所定部位に投与される、薬剤。 - 請求項1に記載の薬剤において、
前記細胞は、注射または注入により投与される、薬剤。 - 請求項1に記載の薬剤において、
前記細胞は、CD10、CD13、CD44、CD73、CD90、PDGFr−α、およびHLA−A、B、Cのそれぞれを発現する、薬剤。 - 請求項1または7に記載の薬剤において、
前記細胞は、CD31、CD34、CD45、CD141、およびHLA−DR、DP、DQのいずれも発現しない、薬剤。 - 患者の頭蓋内出血を治療するための医薬組成物において、
頭蓋内出血を治療するのに有効な量の、医薬的に許容可能な担体、および単離臍帯組織由来細胞、
を含み、
前記臍帯組織由来細胞は、実質的に血液のないヒト臍帯組織由来であり、
前記細胞は、培養中に自己再生および増殖することができ、少なくとも神経の表現型の細胞に分化する能力を有し、
前記細胞は、CD117およびhTERTのいずれをも発現しないか、または、CD117およびテロメラーゼのいずれをも発現せず、
前記細胞は、塩基性線維芽細胞成長因子および上皮成長因子を加えた神経前駆細胞増殖培地で培養されたとき神経細胞のマーカーであるTUJ1の発現について陽性である細胞に分化するものであり、
前記医薬組成物は、前記出血後7日以内に静脈内投与されるべきものである、
医薬組成物。 - 請求項9に記載の医薬組成物において、
前記細胞は、CD10、CD13、CD44、CD73、CD90、PDGFr−α、およびHLA−A、B、Cのそれぞれを発現する、医薬組成物。 - 請求項9または10に記載の医薬組成物において、
前記細胞は、CD31、CD34、CD45、CD141、およびHLA−DR、DP、DQのいずれも発現しない、医薬組成物。 - 患者の頭蓋内出血を治療するためのキットであって、医薬的に許容可能な担体、単離臍帯組織由来細胞集団、および前記患者を治療するための方法において前記キットを使用するための説明書を含む、キットにおいて、
前記臍帯組織由来細胞は、実質的に血液のないヒト臍帯組織由来であり、少なくとも神経の表現型の細胞に分化し、
前記細胞は、CD117およびhTERTのいずれをも発現しないか、または、CD117およびテロメラーゼのいずれをも発現せず、
前記細胞は、塩基性線維芽細胞成長因子および上皮成長因子を加えた神経前駆細胞増殖培地で培養されたとき神経細胞のマーカーであるTUJ1の発現について陽性である細胞に分化するものであり、
前記細胞は、前記出血後7日以内に静脈内投与されるべきものである、
キット。 - 請求項12に記載のキットにおいて、
少なくとも1つの他の細胞型の細胞の集団、
をさらに含む、キット。 - 請求項12に記載のキットにおいて、
前記細胞は、CD10、CD13、CD44、CD73、CD90、PDGFr−α、およびHLA−A、B、Cのそれぞれを発現する、キット。 - 請求項12または14に記載のキットにおいて、
前記細胞は、CD31、CD34、CD45、CD141、およびHLA−DR、DP、DQのいずれも発現しない、キット。
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