JP2016536103A - 筋細胞パッチおよびその使用 - Google Patents
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- JP2016536103A JP2016536103A JP2016547972A JP2016547972A JP2016536103A JP 2016536103 A JP2016536103 A JP 2016536103A JP 2016547972 A JP2016547972 A JP 2016547972A JP 2016547972 A JP2016547972 A JP 2016547972A JP 2016536103 A JP2016536103 A JP 2016536103A
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Abstract
Description
本願は、参照によりその全体が本明細書に援用される、2013年10月9日出願の米国仮特許出願第61/888882号の優先権を主張する。
本発明は、VAによって与えられた助成金番号1−101−BX001406−01A1の下で政府支援によってなされたものである。
(a)線維芽細胞含を含む3次元足場(3DFCS)の表面上に未成熟収縮細胞を播種して、収縮構築物を生成することと、
(b)条線を形成する成熟収縮細胞への未成熟収縮細胞の分化を促進する条件下で収縮構築物を培養することと、
を含む方法を提供する。
・形態学的に小さい細胞サイズ;
・筋原繊維密度の減少;
・電気生理学的に抑えられ/減少した活動電位振幅;
・MYH7(ベータミオシン重鎖)、MYH6(アルファミオシン重鎖)、SCN5A、GJA1(コネキシン43)、HCN4(過分極活性化K+チャネル)、KCNJ2(内向き整流性カリウムイオンチャネル)、SERCA2a(サルコ/小胞体(sarcoendoplasmic reticulum)ATPアーゼ)、アルファアクチニン、心臓トロポニンI(cTnI)、心臓トロポニンT(cTnT)の遺伝子および/またはタンパク質の発現の減少。
・形態学的に小さい細胞サイズ;
・筋原繊維密度の減少;
・電気生理学的に抑えられ/減少した活動電位振幅;
・MYH7(ベータミオシン重鎖)、MYH6(アルファミオシン重鎖)、SCN5A、GJA1(コネキシン43)、HCN4(過分極活性化K+チャネル)、KCNJ2(内向き整流性カリウムイオンチャネル)、SERCA2a(サルコ/小胞体ATPアーゼ)、アルファアクチニン、心臓トロポニンI(cTnI)、心臓トロポニンT(cTnT)の遺伝子および/またはタンパク質の発現の減少。
クラスI:いかなる活動でも制約を経験しない;通常の活動からの症状はない。
クラスII:活動にわずかに軽い制約がある;患者は安静時または軽度の労作時に快適である。
クラスIII:いかなる活動でも顕著な制約がある;患者は安静時にのみ快適である。
クラスIV:いかなる身体活動も不快感をもたらし、安静時に症状が起こる。
(a)収縮構築物を生成するための線維芽細胞含を含む3次元足場(3DFCS)の表面上に未成熟収縮細胞を播種することと、
(b)条線を形成する成熟収縮細胞への未成熟収縮細胞の分化を促進する条件下で、収縮構築物を培養することと、
を含む方法を提供する。
パッチの製造
播種方法
簡単に説明すると、懸濁液中の細胞に遠心力を適用する。3次元線維芽細胞構築物(3DFC)の表面上に細胞を押しやる/強いると、細胞をランダムだが均一に分布できる。ベースの構築物(3DFC)が細胞の移植および配置のための支持体ならびに適切な要件を提供すると、収縮力が生じる。最終「生成物」は、線維芽細胞が埋め込まれ、収縮細胞集団、この調製ではiPSC由来の(「未成熟」)心筋細胞が播種された分解性メッシュである。
誘導性ヒト多能性幹細胞(hiPSC)の播種密度は、0.3×106細胞/cm2〜2.4×106細胞/cm2の範囲であり、1.2×106細胞/cm2が理想である。
心臓パッチ用の出発材料は、ヒト皮膚線維芽細胞が埋め込まれた合成ビクリルメッシュを含む3DFCである。線維芽細胞は血管新生を示し、したがって、心臓への移植後、播種されたiPSC由来の心筋細胞集団に栄養サポートを提供する。発明者らのデータは、細胞比(皮膚線維芽細胞に対するiPSC由来の心筋細胞)が3:20〜1.2:1の範囲であり、1.2:2が理想であることを示している。
1. Thai, H. M., Juneman, E., Lancaster, J., Hagerty, T., Do, R., Castellano, L., Kellar, R., Williams, S., Sethi, G., Schmelz, M., Gaballa, M., & Goldman, S. (2009). Implantation of a three-dimensional fibroblast matrix improves left ventricular function and blood flow after acute myocardial infarction. Cell Transplant., 18(3), 283-295. PMC2739416:PM19558777. doi:10.3727/096368909788535004
2. Lancaster, J., Juneman, E., Hagerty, T., Do, R., Hicks, M., Meltzer, K., Standley, P., Gaballa, M., Kellar, R., Goldman, S., & Thai, H. (2010). Viable fibroblast matrix patch induces angiogenesis and increases myocardial blood flow in heart failure after myocardial infarction. Tissue Eng.Part A., 16(10), 3065-3073. PM20486785. doi:10.1089/ten.TEA.2009.0589
3. Lancaster, J. J., Arnce, S. A., Johnson, N. M., Juneman, E. B., Thai, H. M., Kellar, R. S., Vitorin, J. E., Burt, J. M., Bahl, J. J., & Goldman, S. (2010). In vivo evaluation of a biologically active cardiomyocyte seeded scaffold to treat chronic heart failure. [abstract]. Paper presented at the Heart Failure Society of America: 14th Annual Scientific Meeting, San Diego,CA. , 16(8) S45. doi:10.1016/j.cardfail.2010.06.155
4. Lancaster, J. J., Arnce, S. A., Johnson, N. M., Juneman, E. B., Thai, H. M., Kellar, R. S., Vitorin, J. E., Burt, J. M., Gaballa, M. A., Bahl, J. J., & Goldman, S. Tissue engineered scaffold seeded with cardiomyocytes improves cardiac function in rats with chronic ischemic heart failure disease. (Journal of Heart and Lung Transplantation).
Claims (54)
- 収縮構築物を調製するための方法であって、
(a)線維芽細胞含を含む3次元足場(3DFCS)の表面上に未成熟収縮細胞を播種して、収縮構築物を生成することと、
(b)条線を形成する成熟収縮細胞への未成熟収縮細胞の分化を促進する条件下で前記収縮構築物を培養することと、
を含む方法。 - 前記未成熟収縮細胞が未成熟心筋細胞であり、前記成熟収縮細胞が成熟心筋細胞である、請求項1に記載の方法。
- 前記未成熟収縮細胞が未成熟平滑筋細胞であり、前記成熟収縮細胞が成熟平滑筋細胞である、請求項1に記載の方法。
- 前記未成熟収縮細胞が未成熟骨格筋細胞であり、前記成熟収縮細胞が成熟骨格筋細胞である、請求項1に記載の方法。
- 前記収縮構築物が約14〜240時間培養される、請求項1〜4のいずれか一項に記載の方法。
- 前記収縮構築物が48時間未満培養される、請求項1〜4のいずれか一項に記載の方法。
- 前記収縮構築物が約14〜36時間培養される、請求項1〜4のいずれか一項に記載の方法。
- 前記方法が、それを必要としている対象に前記収縮構築物を移植することをさらに含む、請求項1〜7のいずれか一項に記載の方法。
- 前記収縮構築物が細胞収縮および/またはパッチレベルの収縮の開始前に移植される、請求項8に記載の方法。
- 前記収縮構築物がパッチレベルの収縮の開始後に移植される、請求項9に記載の方法。
- 前記未成熟収縮細胞が未成熟心筋細胞であり、前記成熟収縮細胞が成熟心筋細胞であり、前記移植が、前記障害を治療するのに有効な量の前記構築物と、かかる障害に罹患している対象の心臓とを接触させることを含む、請求項8〜10のいずれか一項に記載の方法。
- 前記障害が、虚血誘発性心不全、慢性心不全(CHF)、心不全を伴わない虚血、心筋症、拡張型心筋症(DCM)、心停止、うっ血性心不全、安定狭心症、不安定狭心症、心筋梗塞、冠動脈疾患、心臓弁膜症、虚血性心疾患、駆出率の低下、心筋灌流の低下、不適応な心臓リモデリング、不適応な左心室リモデリング、左心室機能の低下、左心不全、右心不全、後方不全、前方不全、収縮機能障害、拡張機能障害、全身血管抵抗の増加または減少、低拍出性心不全、高拍出性心不全、労作時呼吸困難、安静時呼吸困難、起座呼吸、頻呼吸、発作性夜間呼吸困難、めまい、精神錯乱、安静時の四肢の冷え、運動不耐性、易疲労感、末梢浮腫、夜間頻尿、腹水、肝腫大、肺水腫、チアノーゼ、心尖拍動の側方移動、奔馬調律、心雑音、傍胸骨拍動、および胸水からなる群から選択される、請求項11に記載の方法。
- 前記障害がCHFを含む、請求項11に記載の方法。
- 前記障害が虚血誘発性心不全を含む、請求項11に記載の方法。
- 前記構築物を前記対象の心外膜に接着させる、請求項11〜14のいずれかに記載の方法。
- 前記構築物を前記対象の左心室に接着させる、請求項11〜15のいずれか一項に記載の方法。
- 前記方法が、前記構築物と目的の化合物とを接触させることと、前記構築物の1つまたは複数の特徴に対する前記化合物の効果を決定することと、をさらに含む、請求項1〜7のいずれか一項に記載の方法。
- 前記方法が、前記構築物と目的の化合物とを接触させる前に、前記構築物の収縮を促進させる条件下で前記構築物を培養することを含む、請求項17に記載の方法。
- 収縮変位、収縮率、収縮同期性、および収縮速度のうちの1つまたは複数に対する前記化合物の効果が決定される、請求項18に記載の方法。
- 線維芽細胞含を含む3次元足場(3DFCS)の表面に接着した収縮細胞またはその前駆体を含む構築物であって、該構築物は前記3DFCSの表面全体で自発的な同期収縮が可能であり、前記収縮細胞が、1.3×105細胞/cm2〜2.95×106細胞/cm2の密度で前記構築物の表面上に播種され、前記3DFCS上の線維芽細胞と共に約1:15〜約6:1の比で前記3DFCSの表面上に存在する構築物。
- 前記収縮細胞が、前駆収縮細胞および成熟収縮細胞の組み合わせを含む、請求項20に記載の構築物。
- 前記前駆収縮細胞および成熟収縮細胞が、約1:2〜約2:1の比で前記構築物表面上に存在する、請求項21に記載の構築物。
- 前記収縮細胞が、CD40および/またはHLAの発現を低減または排除するために操作される、請求項20〜22のいずれか一項に記載の方法。
- 前記収縮細胞が人工多能性幹細胞(iPSC)に由来する、請求項20〜23のいずれか一項に記載の構築物。
- 前記収縮細胞が未成熟心筋細胞を含む、請求項20〜24のいずれか一項に記載の構築物。
- 前記収縮細胞が成熟心筋細胞を含む、請求項20〜25のいずれか一項に記載の構築物。
- 前記未成熟心筋細胞および/または前記成熟心筋細胞が、1.3×105細胞/cm2〜2.7×106細胞/cm2の密度で前記構築物の表面上に播種され、前記収縮細胞が、前記3DFCS上の線維芽細胞と共に約1:7〜約3:1の比で前記3DFCSの表面上に存在する、請求項25〜26のいずれか一項に記載の構築物。
- 前記未成熟心筋細胞および/または前記成熟心筋細胞が、2.9×105細胞/cm2〜2.3×106細胞/cm2の総密度で前記構築物の表面上に播種される、請求項25〜26のいずれか一項に記載の構築物。
- 前記収縮細胞が平滑筋細胞を含む、請求項20〜24のいずれか一項に記載の構築物。
- 前記平滑筋細胞が、1.3×105細胞/cm2〜2.95×106細胞/cm2の密度で前記構築物の表面上に播種され、前記平滑筋細胞が、前記3DFCS上の線維芽細胞と共に約1:15〜約3.5:1の比で前記3DFCSの表面上に存在する、請求項29に記載の構築物。
- 前記平滑筋細胞が、1.0×105細胞/cm2〜1.2×106細胞/cm2の密度で前記構築物の表面上に播種され、前記平滑筋細胞が、前記3DFCS上の線維芽細胞と共に約1:1.7〜約1.5:1の比で前記3DFCSの表面上に存在する、請求項29に記載の構築物。
- 前記収縮細胞が骨格筋細胞を含む、請求項20〜24のいずれか一項に記載の構築物。
- 前記骨格筋細胞が、1.3×105細胞/cm2〜2.95×106細胞/cm2の密度で前記構築物の表面上に播種され、前記骨格筋細胞が、前記3DFCS上の線維芽細胞と共に約1:15〜約3.5:1の比で前記3DFCSの表面上に存在する、請求項32に記載の構築物。
- 前記骨格筋細胞が、1.0×105細胞/cm2〜1.2×106細胞/cm2の密度で前記構築物の表面上に播種され、前記骨格筋細胞が、前記3DFCS上の線維芽細胞と共に約1:1.7〜約1.5:1の比で前記3DFCSの表面上に存在する、請求項32に記載の構築物。
- 前記収縮細胞が前記構築物上に条線を形成する、請求項20〜34のいずれか一項に記載の構築物。
- 前記収縮細胞がヒト起源である、請求項20〜35のいずれか一項に記載の構築物。
- 血管前駆細胞をさらに含む、請求項20〜36のいずれか一項に記載の構築物。
- 収縮細胞の機能不全によって特徴付けられる障害を治療するための方法であって、収縮細胞系障害を有する患者と、前記障害を治療するのに有効な量で請求項20〜37のいずれか一項に記載の構築物とを接触させることを含む方法。
- 前記収縮細胞が、未成熟心筋細胞、成熟心筋細胞、またはそれらの組み合わせを含み、前記障害を治療するのに有効な量の前記構築物と、かかる障害に罹患している対象の心臓とを接触させることを含む、請求項38に記載の方法。
- 前記障害が、虚血誘発性心不全、慢性心不全(CHF)、心不全を伴わない虚血、心筋症、拡張型心筋症(DCM)、心停止、うっ血性心不全、安定狭心症、不安定狭心症、心筋梗塞、冠動脈疾患、心臓弁膜症、虚血性心疾患、駆出率の低下、心筋灌流の低下、不適応な心臓リモデリング、不適応な左心室リモデリング、左心室機能の低下、左心不全、右心不全、後方不全、前方不全、収縮機能障害、拡張機能障害、全身血管抵抗の増加または減少、低拍出性心不全、高拍出性心不全、労作時呼吸困難、安静時呼吸困難、起座呼吸、頻呼吸、発作性夜間呼吸困難、めまい、精神錯乱、安静時の四肢の冷え、運動不耐性、易疲労感、末梢浮腫、夜間頻尿、腹水、肝腫大、肺水腫、チアノーゼ、心尖拍動の側方移動、奔馬調律、心雑音、傍胸骨拍動、および胸水からなる群から選択される、請求項39に記載の方法。
- 前記障害がCHFを含む、請求項39に記載の方法。
- 前記障害が虚血誘発性心不全を含む、請求項39に記載の方法。
- 前記構築物を前記対象の心外膜に接着させる、請求項39〜42のいずれかに記載の方法。
- 前記構築物が前記心外膜との接触時に収縮しない、請求項43に記載の方法。
- 前記構築物が前記心外膜との接触時に収縮している、請求項44に記載の方法。
- 前記接触が前記対象の左心室に前記構築物を接触させることを含む、請求項38〜45のいずれか一項に記載の方法。
- チモシンβ−4(TB4)、aktマウス胸腺腫ウイルス癌遺伝子ホモログ(ΑΚΤ1)、間質細胞由来因子−1アルファ(SDF−1)、および肝細胞増殖因子(HGF)のうちの1つまたは複数と前記対象の心臓とを接触させることをさらに含む、請求項38〜46のいずれか一項に記載の方法。
- 前記治療が、左心室機能の改善、左心室拡張末期圧(EDP)の低下、心筋灌流の改善、心筋細胞による心臓壁の再構築、CHF対象における不適応な左心室リモデリングの逆進、左心室の受動的充満、能動的充満などの拡張機能の改善、心室腔コンプライアンス、ならびにE’(mm/秒)の増加、E/E’の減少、LV dP/dt(mmHg/秒)の増加およびTau(ミリ秒)の減少を含むが、これらに限定されない心不全パラメータのうちの1つまたは複数を含む、請求項38〜47のいずれか一項に記載の方法。
- 前記構築物上の前記心筋細胞を前記患者の生来の心筋に電気的に結合させる、請求項38〜48のいずれか一項に記載の方法。
- 前記収縮細胞が、未成熟骨格筋細胞、未成熟平滑筋細胞、成熟骨格筋細胞、成熟平滑筋細胞、またはそれらの組み合わせを含む、請求項38に記載の方法。
- 骨格筋組織および/もしくは平滑筋組織の増強、修復、または回復から恩恵をうけることができる全ての障害を治療するための方法であって、前記障害を治療するのに有効な量で請求項50に記載の前記構築物と前記障害を有する患者とを接触させることを含む方法。
- 薬物スクリーニングのための方法であって、目的の化合物と請求項20〜37のいずれか一項に記載の構築物とを接触させることと、前記構築物の1つまたは複数の特徴に対する前記化合物の効果を決定することと、を含む方法。
- 前記方法が、前記構築物と目的の化合物とを接触させる前に、前記構築物の収縮を促進する条件下で前記構築物を培養することを含む、請求項52に記載の方法。
- 収縮変位、収縮率、収縮同期性、および収縮速度のうちの1つまたは複数に対する前記化合物の効果が決定される、請求項53に記載の方法。
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