JP2018516974A - 筋ジストロフィーキメラ細胞および筋ジストロフィーの処置方法 - Google Patents
筋ジストロフィーキメラ細胞および筋ジストロフィーの処置方法 Download PDFInfo
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Abstract
【選択図】なし
Description
本願は、2015年6月11日出願の米国仮特許出願シリアル番号62/174,122の優先権の利益を主張し、その内容をその全体について参照によって本願明細書に組み入れる。
筋ジストロフィー症(MD)は、動作を制御する骨格筋の進行性の虚弱および変質によって特徴づけられる30を超える遺伝子疾患の群である。MDのいくつかの形態は、幼少または幼年時に見られるが、その他は中年またはそれ以降まで現れない。障害は、筋肉虚弱(MDのいくつかの形態は、心筋に影響する)の分布および程度、発病年齢、進行速度、ならびに遺伝のパターンの見地から異なる。
患者における筋ジストロフィーを処置するためのMDCC組成物および方法が、今や開発された。MDCCラインは、筋芽細胞、間葉系幹細胞または間質細胞の第2集団と共に筋芽細胞の第1集団(自己または同種)の生体外融合によって作られる。MDCCの投与は、患者に筋原性および間葉系原細胞の同時送達を可能にする。したがって、本発明は、筋ジストロフィーを罹患した対象に由来する筋芽細胞および健康なドナーに由来する筋芽細胞;筋ジストロフィーを罹患した対象に由来する筋芽細胞および間葉系幹細胞;健康なドナーに由来する筋芽細胞および間葉系幹細胞;筋ジストロフィーを罹患した対象に由来する筋芽細胞および間質細胞;または健康なドナーに由来する筋芽細胞および間質細胞の融合によって調製されるMDCCを提供する。特定の態様において、本発明のMDCCは、筋ジストロフィーを処置するための方法における使用を見出す。
a)筋ジストロフィーを罹患している対象由来のヒト筋芽細胞および健康なドナー由来のヒト筋芽細胞;
b)筋ジストロフィーに罹患している対象由来のヒト筋芽細胞および健康なドナー由来のヒト間葉系幹細胞;
c)健康なドナー由来のヒト筋芽細胞および健康なドナー由来のヒト間葉系幹細胞;
d)筋ジストロフィーに罹患している対象由来のヒト筋芽細胞、および健康なドナー由来のヒト間質細胞;または
e)健康なドナー由来のヒト筋芽細胞、および健康なドナー由来のヒト間質細胞。
ポリエチレングリコール技術(図1)を用いて、2つの無関係なドナー由来の同種のヒト筋芽細胞およびMSCまたは筋芽細胞の生体外融合を行った。簡潔には、市販(Lonza, Inc.)のヒト筋芽細胞およびMSCを別々に6〜10日間培養した。次に、図1に示すように、PKH−26(赤色)またはPKH−67(緑色)追跡用色素のいずれかを用いて、細胞を蛍光標識した。PEGを用いて融合を行った。二重(PKH26およびPKH67)染色を表す細胞を、蛍光活性化細胞ソーティング(FACS; BD ASTERIOS)によって選択した。融合を確認するために、二重(PKH26およびPKH67)標識MDCCを、共焦点顕微鏡法およびフローサイトメトリーを用いて評価した(図2)。透過型電子顕微鏡を用いてMDCCの形態を評価した。MDCCは、2つの核、融合細胞膜および融合細胞質の存在によって確認された。
健康なsnjおよびmdx(ジストロフィン欠損)の一次筋芽細胞培養およびmdx MSC培養を確立し、生体内で増殖させた。3つのマウス筋芽細胞/MSCおよび筋芽細胞/筋芽細胞融合をポリエチレン−グリコール技術を用いて行った。筋原性分化能と同様に、ジストロフィン発現も融合前後で確認された。
Claims (13)
- (a)第1の筋芽細胞、および
(b)第2の筋芽細胞、間葉系幹細胞、または間質細胞
間の融合を含む筋ジストロフィーキメラ細胞(MDCC)であって、
第1の筋芽細胞、第2の筋芽細胞、間葉系幹細胞、または間質細胞の少なくとも1つが健康なドナーに由来する、
前記MDCC。 - 第1の筋芽細胞および第2の筋芽細胞が、異なるドナーに由来する、請求項1に記載のMDCC。
- 第1の筋芽細胞、第2の筋芽細胞、間葉系幹細胞、または間質細胞が、自己のものまたは同種である、請求項1に記載のMDCC。
- 健康なドナーが対象の父である、請求項1に記載のMDCC。
- 間葉系幹細胞が、骨髄または脂肪組織に由来する、請求項1に記載のMDCC。
- 前記MDCCが、1以上の免疫調節サイトカインおよび成長因子を分泌する、請求項1に記載のMDCC。
- 1以上の免疫調節サイトカインおよび成長因子が、インシュリン様成長因子1、肝細胞成長因子およびミオスタチンを含む、請求項6に記載のMDCC。
- a)筋ジストロフィーを罹患したヒト筋芽細胞および健康なドナーに由来するヒト筋芽細胞、
b)筋ジストロフィーを罹患したヒト筋芽細胞および健康なドナーに由来するヒト間葉系幹細胞、
c)健康なドナーに由来するヒト筋芽細胞および健康なドナーに由来するヒト間葉系幹細胞、
d)筋ジストロフィーに罹患した対象に由来するヒト筋芽細胞および健康なドナーに由来するヒト間質細胞、または
e)健康なドナーに由来するヒト筋芽細胞および健康なドナーに由来するヒト間質細胞
間の融合を含む、請求項1に記載のMDCC。 - 請求項1に記載のMDCCおよび薬学的に許容し得る担体を含む組成物。
- 処置を必要とする対象に請求項1に記載のMDCCの有効量を投与し、それによって対象の筋ジストロフィーを処置することを含む、筋ジストロフィーを処置する方法。
- 筋ジストロフィーがデュシェンヌ型筋ジストロフィーである、請求項10に記載の方法。
- 前記MDCCが、静脈注射、骨注射、または筋肉注射によって投与される、請求項10に記載の方法。
- a)融合剤、および
b)筋芽細胞、間葉系幹細胞、および間質細胞の群から選択される1以上のドナー細胞
を含む、筋ジストロフィーを処置するためのキット。
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