TWI492707B - 治療心臟疾病之藥品配方 - Google Patents
治療心臟疾病之藥品配方 Download PDFInfo
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- TWI492707B TWI492707B TW099116052A TW99116052A TWI492707B TW I492707 B TWI492707 B TW I492707B TW 099116052 A TW099116052 A TW 099116052A TW 99116052 A TW99116052 A TW 99116052A TW I492707 B TWI492707 B TW I492707B
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Description
本發明係相關於心臟疾病或心臟異常前兆的療法：將藥品配方注入需要心臟組織再生的患者。尤其是，本發明提出了一種至少包含將生成心臟組織的細胞(cells committed to the generation of heart tissue)以及至少一種藥理上可接受的賦形劑(excipient)所製成的藥品配方，以及可以保持細胞存活並讓醫療人員運送到世界各地給予接受者的包裝方法，其中所述的細胞是依照國際認可的製藥標準所製成的。
細胞再生療法(Regenerative cell therapies)的重要性對於需要組織重建的器官特別顯著，例如：當恢復受損器官的型態和功能需要恢復，或是當生理修復機制喪失之時。心臟是終端分化的器官，大量喪失心肌細胞(cardiomyocyte)，如心臟病發作，會造成不可逆的傷害，並因此需要被修復。此外，心臟疾病在世界各地都是領先的死亡原因。針對心臟修復的細胞療法是因此是一項最重要的挑戰。
現有之臨床經驗皆係基於應用未經改變之成人幹細胞上。第一代生物製劑是應用天然人類幹細胞(naive adult stem cells)，因其被認為係易於獲得的細胞型(cytotype)。已被證明的是，有一些病患在被投予天 然人類幹細胞後能夠獲得改善。對人類心臟移植天然人類細胞之習知技術，在Abdel-Latif A.等人的「’Adult bone marrow-derived cells for cardiac repair：a systematic review and meta-analysis’,Arch Intern Med.(2007)167：989-997」原文中及在其引用之參考文獻中都有被特別描述到。為了有更好的臨床效果，第二代幹細胞療法的觀念被提出，其包含了在注入患者之前，先引導原生幹細胞發展成為心臟組織(guiding naive stem cells towards the generation of heart tissue prior to delivery to the patient)。
關於心臟再生這個領域的基礎研究的幾個重要里程碑在若干文獻中，以及下文中被揭示：Behfar等人，在「’Derivation of a cardiopoietic population from human mesenchymal stem yields progeny’,Nature Clin.Pract.,Cardiovasc.Med.(2006)3：S78-S82」以及Behfar等人，在「’Cardiopoietic programming of embryonic cells for tumor-free repairs’,J.Exp.Med.(2007)204：405-420」，以及由馬友醫學教育研究基金會(Mayo Foundation for Medical Education and Research)的Terzic A.和Behfar A.所獲有的專利WO 2006/015127、US 2008/0019944和WO 2009/151907等。
上述的作者、申請者和發明者發現：當天然人類幹細胞(naive adult stem cells,mESCs)被培養在各種心原細胞生成因子(cardiogenic factors)組成之溶液，即所謂之「雞尾酒藥劑配方(cocktail)」中時，mESCs細胞會開始分化成可以產生心臟組織的細胞。如在WO2006/0151275中所述，當由mESCs演變成的心原細胞(cardiopoietic cells)被送到梗塞的老鼠心臟時，可以達成心臟修復的效果。因此，這清楚的說明了mESCs演變成的心原細胞對於心臟細胞的再生是有幫助的。然而，和ESCs相關的腫瘤發生(tumourigenic)
風險也使這個發現應用在治療時有了安全的顧慮。此外，這些實驗都是在實驗室中的老鼠身上進行，且心原細胞從組織培養中被取出後，係立刻被使用的。
成人幹細胞的療法被認為是沒有腫瘤發生的風險的。Behfar等人，在「’Derivation of a cardiopoietic population from human mesenchymal stem yields progeny’,Nature Clinical Practice,Cardiovascular Medicine(2006)3：S78-S82」中描述了一種沒有腫瘤發生風險的幹細胞來源。在「US 2008/0019944」中，從間質幹細胞(mesenchymal stem cells)獲取的心原細胞(cardiopoietic cells)的技術被揭示出來。
這些作者也提到，使用含有心原細胞生成因子(cardiogenic factors)的雞尾酒藥劑配方可以使間質幹細胞(mesenchymal stem cells)分化成心原細胞(cardiopoietic cells)，見WO 2009/151907。
關於人類心臟細胞移植的先前技術被描述在Abdel-Latif A.等人，「’Adult bone marrow-derived cells for cardiac repair：a systematic review and meta-analysis’,Arch Intern Med.(2007)167：989-997」中，以及該文之引用文獻中。另外一篇Behfar等人在，「’Guided stem cell cardiopoietic：Discovery and translation’,J.Mol.and Cell.Cardiology(2008)45：523-529」中，也討論了使用心原細胞來進行心臟再生。
將實驗室的技術應用在臨床上往往是製藥工業的一大挑戰。在這個案例中，其挑戰特別不易被克服，因為，直到運送並注入一個不在實驗室附近的患者身上之前，可以生成心臟組織的細胞的所有生物特徵都必須要完全地被保持。
本發明解決了這個問題，就在於揭示出一個可以用工業生產的方法來產製一種藥品配方(a pharmaceutical composition)，其包含將生成心臟組織的細胞(containing cells committed to the generation of heart tissue)以及至少一種賦形劑(excipient)，其係依照國際認可的製藥標準所製成，以及一種細胞的保存及包裝的方法來提供不同用途，並保持可生成心臟組織的細胞的各種特性，並且使其維持存活，且方便運送人員處理並運送到世界各地以及施予給接受者(delivery into the recipient)。
定義：在這份文件的架構中，除非有另外提及，否則下列引號內的術語均定義如後。
名詞「BMMSC」是指骨髓間質幹細胞(bone marrow mesenchymal stem cells)。名詞「hBMMSC」代表人類來源的骨髓間質幹細胞(BMMSCof human origin)。
名詞「心原細胞」(Cardiopoietic cells)是指一種中間型的細胞表現型(an intermediate cell phenotype)，其將生成心臟組織但還沒完全分化完成(comrnitted to the generation of heart tissue but not yet fully differentiated)。其特徵為：轉錄因子Nkx2.5和MEF2C的細胞核轉位以及沒有肌漿蛋白(sarcomeric proteins)(Behfar等人，「’Derivation of a cardiopoietic population from human mesenchymal stem yields progeny’,Nature Clin.Pract.,Cardiovasc.Med.(2006)3：S78-S82」)。心原細胞保有分裂的能力(Cardiopoietic cells retain a proliferative capacity)。心原細胞也可以由幹細胞取得，包含，譬如說，人類成人間質幹細胞(mesenchymal stem cells)、
人類胚胎幹細胞(不損害胚胎的方式取得)、類胚胎幹細胞(embryonic-like stem cells)、可誘發性多能幹細胞(inducible pluripotent stem cells)或其他相應來源。
名詞「有促進具發展為心肌之潛能細胞之生成之混合雞尾酒藥劑配方」(cardiogenic cocktail)或名詞「雞尾酒藥劑配方」(cocktail)是指包含至少兩種可促進具發展為心肌之潛能細胞(心原細胞)，生成之物質(cardiogenicsubtstance)之組合。
名詞「可促使心原細胞生成之物質」(cardiogenic subtstance)是指和細胞接觸，並可以促進細胞分化成心臟細胞的物質。
名詞「聚集」(Confluence)表示在特定空間細胞數量已經達到極限。在這個條件下細胞間的接觸會限制細胞生長。
名詞「有效劑量」(effective amount)是指可達到預期的療效，生理反應或效果的足夠藥品配方之劑量。所謂療效或效果包含心臟組織的修復、維持、再生、增強以及心臟功能的改善。不良的效果，即副作用，有時會和預期的療效一同顯現，因此潛在利益和潛在風險的平衡是決定什麼是合適「有效劑量」的因素。這個劑量可能隨著不同個體而有差異，取決於個體年齡，身體狀況，基因或基因表現(epigenetic)異同，和藥物給予方式。因此，訂出一個精準的「有效劑量」是不可能的。然而，適合特定個體的「有效劑量」可以在給予藥品配方時或給予前由一個本產業中之一般技術人員來決定，例如，給予不會產生副作用的最高藥品配方劑量。
名詞「賦形劑」(Excipient)是指一種不活化的物質，可作為藥品中活性物質的攜帶者。在很多情況下，「活性」(active)物質可能
無法容易的被給予人體以及被人體吸收。在這些情況下，這些物質可以溶解或混和在賦形劑之中。除了在單一劑量中使用之外，賦形劑也可以被用在生產過程，它可以幫助處理有疑慮的活性物質。根據給予的方法、藥劑的形式，會使用不同的賦形劑。為了使活性物質變得更穩定，加入賦形劑可以確保活性物質保持其「活性」，而且，重要的是，可以確保活性物質穩定地存在足夠長的時間，這樣產品的儲存時間(shelf-life)使其相對於其他產品更有競爭力。
名詞「分裂能力」(proliferative capacity)是指，在本發明的框架下，細胞增加的數量。
名詞「生存力」(viability)是指在本發明的框架下，細胞不吸收錐藍(trypan blue)染劑，用來表示細胞膜的完好(integrity)。
名詞「個體」(subject)、「接受者」(recipient)和「患者」(patient)，除非有註明並非如此，否則在文中均代表有心臟疾病或心臟功能異常需要以本發明所提出的藥品配方治療的人或其他哺乳類動物。個體亦包含有罹患該心臟疾病或心臟功能異常風險的人或動物。
在本專利說明書中，單數型的一個、這個(a，an，the)可同時代表其指明個體的複數，除非有明白的說明並非如此時才是例外。因此，例如：「一個幹細胞」可代表單一個細胞，也可代表兩個或多個細胞；「一種物質」或「一種反應物質」可以代表一種物質或反應物質，也可以代表兩種或多種物質或反應物質；「這個發明」，「一個發明」可以代表這個發明的一個或多個方面，以此類推。
除非另有指明，否則在這個發明中提及的所有的技術或科學
專有名詞均代表其先前廣泛被本產業中之一般技術人士所習知接受的意義。儘管和此述相似或相同的多種方法和材料可以用來實施或測試本發明，以下記述一些適當的方法和材料。
在以下的詳細敘述中，許多細節是為了對本專利申請之範圍提供完整的瞭解。然而，對於在本產業中這些技術人員而言，專利申請內容仍可以在沒有這些細節下被實施。此外，廣泛被瞭解的方法、流程、組成等等，並未被詳加敘述以免模糊本專利申請的焦點。
本發明係相關於藥品配方(a pharmaceutical composition)，其至少包含可以生長為心臟組織的細胞和至少一種藥理上可接受的賦形劑(excipient)。可以產生心臟組織的細胞最好是根據國際認可的製藥標準製成的。所謂藥理上可接受的賦形劑是一種保存液。例如，賦形劑是由可以進行-196℃至0℃間的冷凍保存以及可在0℃至+40℃間保存的保存液中選出來的。例如，保存液是一種包含離子、酸鹼緩衝劑、不通透物質、膠體、代謝物、二甲基亞碸(dimethylsulfoxide,DMSO)、甘油(glycerol)、蔗糖、血清白蛋白(serum albumin)、海藻糖(trehalose)或其各種組合的保存液。例如，離子可以由含有鈉離子、鉀離子、鈣離子、鎂離子、氯離子等物質的不同組成取得。例如，酸鹼緩衝劑可以由含有磷酸根(H2PO4 -)、碳酸根(HCO3 -)、HEPES(4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid)等物質的不同組成取得。例如，不通透物質可由含有乳糖酸(lactobionate)、蔗糖、甘露醇(mannitol)、葡萄糖等物質的不同組成取得。例如，膠體可以是Dextran-40。例如，代謝物可以由含有腺苷(adenosine)、麩氨基硫(glutathione)等物質的不同組成取得。例如，至少一種藥理上可接受的賦形劑會進一步
包含至少一種以下物質：生長激素、細胞激素(cytokines)、和器官發生(organogenesis)相關的蛋白質、藥品、血小板溶解物(platelet lysate)、血清、同位素(用來在體內(in viivo)追蹤細胞)、稀釋劑、潤滑劑、基質(matrix)或支架(scaffold)物質及其各種組合。
有利的是，可以產生心臟組織的細胞可以是幹細胞或是從幹細胞衍生而來。有利的是，幹細胞可選自：成人幹細胞、胚胎(embryonic)幹細胞、誘發性多能幹細胞(induced pluripotent stem cells,IPS)、骨髓分離成人誘導性多品系細胞(Marrow-Isolated Adult Multilineage Inducible cells(MIAMI))、心臟常駐幹細胞(resident cardiac stern cells)、植物極(vegetal)幹細胞，或其各種組合。有利的是，幹細胞是從合適組織中取得的間質幹細胞，這些組織包含骨髓、脂肪組織、臍帶血、羊水(amniotic fluid)、月經液(menstrual fluid)、血液等。有利的是，用來生成心臟組織的細胞是哺乳動物細胞。有利的是，哺乳動物細胞是選自人、貓、狗、豬、馬、小鼠(mice)、大鼠(rats)、倉鼠(hamsters)或其他種哺乳動物。有利的是，這些細胞是自體細胞(autologous cells)、同源細胞(allogeneic cells)、非同源細胞(xenogenic cells)或其組合。
有利的是，用來生成心臟組織的細胞是心原細胞(cardiopoietic cells)。有利的是，心原細胞可以由幹細胞而來：例如類成人間質幹細胞(human adult mesenchymal stem cells)、人類胚胎幹細胞(不傷害人類胚胎下取得)、類胚胎幹細胞(embryonic-like stem cells)、心臟常駐幹細胞(resident cardiac stem cells)、誘發性多能幹細胞(induced pluripotent stem cells)或其他相應來源分化而成。
有利的是，這個的藥品配方沒有可偵測到的非心原細胞，包含但不僅止於，心肌細胞(cardiomyocytes)、血球原細胞(hematopoietic cells)、內皮前驅細胞(endothelial progenitor cells)、脂肪母細胞(adipoblasts)、脂肪細胞(adipocytes)、軟骨母細胞(chondroblasts)、軟骨細胞(chondrocytes)、骨母細胞(osteoblasts)、骨細胞(osteocytes)、神經母細胞(neuroblasts)以及神經元細胞(neurocytes)。有利的是，所有非心原細胞佔所有細胞的比率可在0-50%之間，但最好是在0-15%之間。此外，任何一種非心原細胞佔所有細胞的比例可在0-50%之間，但最好是在0-15%之間。
本發明也是相關於一種藥品配方，其可以用來治療缺血性心臟病(ischemic cardiomyopathy)、急性心肌梗塞(acute myocardial infarction)、慢性心肌梗塞(chronic myocardial infarction)、非缺血性心臟衰竭(heart failure of non-ischemic origin)、缺血性心臟衰竭(heart failure of ischemic origin)或其組合。
本發明係也相關一種和前述的藥品配方有關之的生產方法，其包含以下步驟：- 取得有生成心臟組織能力的細胞；- 在可以讓細胞生成心臟組織的條件下培養前述細胞；- 採集前述培養的細胞；- 將前述細胞加入至少一種藥理上可接受的賦形劑。
有利的是，開始生成心臟組織的細胞可以和至少一種包含以下所述的可促使心原細胞生成之物質(cardiogenic substance)接觸：例如，可促使心原細胞生成之物質可以選自：TGF-β 1、TGF-β 2、TNF-α、BMP 1、
BMP 2、BMP 4、BMP 6、FGF-2、FGF-4、FGF-5、FGF-12、FGF-13、FGF-15、FGF-20、白血病抑制因子(leukemia inhibitory factor,LIF)、VEGF-A、VEGF-C、類胰島素生長因子(insulin-like growth factor 1,IGF-1)、介白素6(interleukin 6,IL-6)、促進素A(Activin A)、α凝血酶(α thrombin)、視網膜酸(retinoic acid)、心營養素1(cardiotrophin 1)、心生素C(cardiogenol C)等或其任何的組合。
有利的是，本發明的生產程序(the process)是依照國際認可的製藥標準，其包含在過程中各個步驟取樣以進行品質管理。最有利的是，本發明的生產程序是依照國際認可的製藥標準，其包含在細胞培養的最後一個步驟取樣以進行活性物質的品質管理(performing quality control of the active substance)。
有利的是，品質管理的標準包含以下測試的至少一個或其組合：細胞身份測試(identity test)、均質測試(homogeneity test)、純度測試(purity test)。有利的是，當進行心臟新生的細胞是心原細胞時，認證所述的心原細胞必須滿足以下條件：觀察到至少一種以下基因或其同源基因(homologus)的表現度(expression level)之增加：Nkx2.5、Tbx5、MEF2C、GATA4、GATA6、Mesp1、FOG1、FOG2、Flk1。有利的是，在這個情況下，基因表現度增加指的是在qPCR檢測上有相對於對照組至少兩倍的增加。有利的是，當開始生成心臟組織的細胞是心原細胞時，要認證其為心原細胞必須滿足以下條件：觀察到至少一種以下多肽(polypeptide)或其同源(homologus)產物相對於對照組的含量增加：Nkx2.5、Tbx5、MEF2C、GATA4、GATA6、Mesp1、FOG1、FOG2、Flk1；此外，Nkx2.5，Tbx5兩者
或其一會進一步轉移到心原細胞的細胞核內。有利的是，這個認證之成立可以由至少一種使用下列抗體或其同源抗體的免疫標記法(immuno-labelling)觀察到：anti-Nkx2.5、anti-Tbx5、anti-MEF2C、anti-GATA4、anti-GATA6、anti-Mesp1、anti-FOG1、anti-FOG2、anti-Flk1。有利的是，其和已知心原細胞樣本的均質度(homogeneity)高於50%即滿足均質度(homogeneity)認證。有利的是，其和已知心原細胞樣本的均質度(homogeneity)必須高於50%，最好是高於85%。有利的是，如果收成的細胞含有間質幹細胞，以下表面標記物(surface marker)的抗體的免疫標記法(immuno-labelling)會呈現陽性：CD105、CD90、CD133、CD105、CD166、CD29和CD44。且CD14、CD34和CD45等表面標記物(surface marker)的抗體的免疫標記法會呈現陰性。有利的是，當CD34、FABP4、骨鈣素(Osteocalcin)、巢蛋白(Nestin)及MYH7基因或其同源基因(homologues)的表現量增加大於對照組兩倍時，即不符合純度標準。有利的是，基因表現度增加指的是以qPCR檢測認定。有利的是，對照組細胞是非心原細胞。有利的是，對照組細胞係被培養在不含可促使心原細胞生成之物質中。有利的是，細胞培養的條件包含使用生物反應器(bioreactor)，而該生物反應器為至少可以將前述細胞固定至、或將其包覆到顆粒或基質上，且又可以將細胞培養液灌澆到該顆粒或基質上者。
這個發明也和將有效劑量的藥品配方注入體內的心臟疾病或心臟異常前兆的治療方法有關。有利的是，這個被注入者可能有心血管系統功能不全。有利的是，這個被注入者可能受缺血心肌病變(ischemiccardiomyopathy)、心肌梗塞(myocardial infarction)、缺血性心臟
衰竭(heart failure of ischemic origin)或非缺血心臟衰竭(heart failure of non-ischemic origin)所苦。
有利的是，這個藥品配方最好是經由以下方式注入患者：心肌內注射(intramyocardially)、心包膜內注射(intra-cardiac)、冠狀內注射(intra-coronary)、肌肉內注射(intra-muscular)、皮下注射(sub-cutaneous)、腹腔注射(intra-peritoneal)、子宮內注射(in utero)、腸胃外注射(parenteral)或系統性注射(systemic)。有利的是，這個藥品配方最好是用一個導管、針具或其組合進行心肌內注射。
開始生成心臟組織的細胞可以和至少一種以下所述的可促使心原細胞生成之物質的基質接觸：TGF-β 1、TGF-β 2、TNF-α、BMP-1、BMP-2、BMP-4、BMP-6、FGF-2、FGF-4、FGF-5、FGF-12、FGF-13、FGF-15、FGF-20、白血病抑制因子(leukemia inhibitory factor,LIF)、VEGF-A、VEGF-C、類胰島素生長因子(insulin-like growth factor 1,IGF-1)、介白素6(interleukin 6,IL-6)、促進素A(Activin A)、α凝血酶(α thrombin)、視網膜酸(retinoic acid)、心營養素1(cardiotrophin 1)、心生素C(cardiogenol C)，或前述物質之任何組合。
有許多種不同的可促使心原細胞生成之物質混合成之雞尾酒藥劑配方可以被使用。以下之清單決非限制性者。例如，可以使用包含TGF β-1、BMP4、α-凝血酶(α-thrombin)的雞尾酒藥劑配方，或是包含心營養素(Cardiotrophin)和IL 6的雞尾酒藥劑配方，或是包含心生素C(Cardiogenol C)和視網膜酸(retinoic acid)的雞尾酒藥劑配方。另一種雞尾酒藥劑配方可包含TGF β-1、BMP4、α凝血酶(α thrombin)、心營養素
(Cardiotrophin)和心生素C(Cardiogenol C)。又另一種雞尾酒藥劑配方可包含至少一種以下所述物質：FGF 2、IGF-1、促進素A(Activin-A)、TNF α、FGF-4、LIF、VEGF-A或其組合。它們也可以包含FGF 2、IGF-1和促進素A(Activin-A)。其他合適的雞尾酒藥劑配方也可以至少包含促進素A(Activin-A)、FGF-2、IL 6、IGF-1和視網膜酸(retinoic acid)。其他合適的雞尾酒藥劑配方也可以缺少TNF α、FGF-4、LIF和VEGF-A之中的一個或多個。
當其中一種以下所述的物質出現在雞尾酒藥劑配方中時，它的濃度可為以下所述：TGF β-1：每毫升1-5ng、BMP4：每毫升1-10ng、心營養素(cardiotrophin)：每毫升0.5-5ng、α-凝血酶(α-thrombin)：每毫升0.5-5單位、心生素C(cardiogenol C)：50-500nM、FGF2：每毫升1-10ng、IGF-1：每毫升10-100ng、促進素A(Activin-A)：每毫升1-50ng、TNF α：每毫升1-50ng、FGF-4：每毫升1-20ng、IL 6：每毫升10-100ng、LIF：每毫升1-10單位、VEGF-A：每毫升1-50ng、視網膜酸(retinoic acid)：每毫升0.1-1.0μM。
一種特別的雞尾酒藥劑配方至少包含新合成(recombinant)TGF β-1(2.5ng/ml)、BMP4(5ng/ml)、心營養素(Cardiotrophin)(1ng/ml)、心生素(CardiogenolC，100nM)等物質的混和。特別合適的雞尾酒藥劑配方至少包含前述混合物而且又再添加了α-凝血酶(α thrombin)(1U/ml)、FGF-2(10ng/ml)、IGF-1(50ng/ml)和促進素A(Activin-A)(5ng/ml)等或其組合。
另一種的雞尾酒藥劑配方的例子至少包含新合成(recombinant)的TGF β 1(2.5ng/ml)、BMP4(5ng/ml)、促進素A(Activin-A)
(5ng/ml)、FGF-2(10ng/ml)、IL 6(100ng/ml)、2a因子(Factor IIa)(h α-thrombin,1U/ml)、IGF-1(50ng/ml)以及視網膜酸(retinoic acid)(1μM)等物質的混和。
雞尾酒藥劑配方可以存在包含下列物質的溶液中：小牛血清(foetal calf serum)、人類血清、血小板溶解物等或其混和。
這個發明也和一個給予此藥品配方的醫療用套組(kit)有關，其包含了一個裝有所述藥品配方的容器。有利的是，該容器是生物適應(biocompatible)的容器，它可以讓細胞存活並運送到世界各地，且方便被醫療人員處理，以及將細胞投予接受者(recipient)。有利的是，該容器是密封的。有利的是，該容器是可以和賦形劑相容並能適應儲存條件的。有利的是，該容器是玻璃容器。有利的是，該容器有一個密封的隔膜蓋(piercable septum cap)。有利的是，該隔膜蓋為可以配合一個藥瓶接頭(adapter)使用，後者包含一個螺旋閥(luer activated valve)以供抽取該容器內之液體者。這個隔膜蓋為可以用針具插入以行抽取者。藥品配方係存放於該密封容器之內而適合被冷凍保存(cryopreservation)者。例如，這種存放在密封的容器內的藥品組合的存放時間至少是72小時。有利的是，該組件也包含至少一個導管。有利的是，該導管也包含至少一個針具。
圖一A部份表示了比較基準值和治療後六個月的左心室終舒張容積(LV End Diastolic Volume,LVEDV)在實驗組與對照組之比較；圖一B是左心室終收縮容積(LV End Systolic Volume,LVESV)的基準值和治療後六個月的值，在實驗組與對照組之比較；圖一C是左心室排血分量(LV Ejection Fraction,LVEF)的基準值和治療後六個月的值，在實驗組與對照組
之比較，數據都是在基準值(baseline)和治療六個月後測量得來，受試者隨機的分配至對照組(樣本數=8)和治療組(樣本數=9)。結果被校正至基準值。
開始生產：人類骨髓樣本(Human bone marrow sample)是由病人的髂棘(iliac crest)處取得，在確定符合品質要求下限後，放入175-cm2的培養瓶以純化骨髓間質幹細胞(BMMSCs)，並且培養在37度攝氏，5%二氧化碳的培養箱中。品質要求的下限為：血清學(serology)檢測陰性(至少包含愛滋病毒1/2(HIV1/2)、梅毒(syphilis)、B型肝炎(HBV)、C型肝炎(HCV))、控制收集處和製造處間骨髓運送溫度、總容量，記錄是否有凝血塊及其大小，以及沒有被細菌污染。24小時後，骨髓和細胞殘渣被小心的從培養瓶中移除。附著在培養瓶上的骨髓間質幹細胞被磷酸鹽緩衝劑(phosphate buffer saline,PBS)沖洗後，加入培養液繼續培養，此後每四到六天換一次培養液直到P0代為止。
P0-從細胞聚落擴張到一層細胞：初始代(initial passage,P0)細胞有分散的聚落使其有空間可以擴張成單一的細胞層。細胞以1：1的比例種在175-cm2的培養瓶上使其可以在六天中擴張並形成單一細胞層。以細胞聚集(Confluence)的程度決定下一次繼代(the next passage)的時間。如果骨髓間質幹細胞沒有形成可被觀察到的聚落就直接形成單一細胞層，那麼這個步驟可以跳過。這個程序會被繼續實施，並被記錄為P0之後加一個附屬字母，直到細胞數量超過50x106個為止。一些參數例如種下時的細胞密度和聚集促成的細胞代(confluence-triggered passages)需要定義下來。一個細胞
代所獲取的細胞數量(the number of cells obtained at a passage)決定了細胞種入的容器大小，以達到最佳化的產量且避免接觸抑制。P0代細胞培養過程中的品管檢測包含細胞數量和存活百分比。
P1-心臟發生雞尾酒藥劑配方的開始處理：細胞在培養液及心臟發生雞尾酒藥劑配方中培養五天。例如，可以使用在WO2006/015127，PCT/US08/64895及Behfar等人，在「’Derivation of a cardiopoietic population from human mesenchymal stem yields progeny’,Nature Clinical Practice,Cardiovascular Medicine,March 2006 vol.3 supplement 1,pages S78-S82」中所提及的心臟發生雞尾酒藥劑配方。
P2-心臟發生雞尾酒藥劑配方的結束處理：將培養液中的心臟發生雞尾酒藥劑配方丟棄。這時培養液中包含心原細胞。將這些細胞繼續作繼代及種在新的容器內(The culture is passaged and seeded in new containers)，換新培養液使其可以再依需求增加增長的次數。
P3-繁殖及採集：以下的細胞代被編為P3並附帶一個字母。細胞在達到理想的聚集度後被繼代，不斷重複此過程直到細胞數量達到600x106至1200x106個。細胞在此時被採集。這個步驟包含最後一次蛋白酶切除(trypsinization)，之後將其沖洗並離心濃縮。這個沖洗是在一種細胞保存液進行。這裡使用的保存液和一般器官或生物組織的保存液相似，皆為液狀且冰冷的保存液，例如BioLifeSolutions(Bothell,Wash)生產的HypoThermosol-FRS®。
濃縮後的細胞會移到生物適用(biocompatible)的容器內(在此是第一型，Ph.Eur.的玻璃瓶)並加入保存液達到總體積為10毫升且細胞
濃度在每毫升60x106至120x106個細胞之間。生產藥品配方的過程到此結束。
藥品配方釋出的標準包含了：細胞身份(cellular identity)、均質度(homogeneity)、純度(purity)以及確認生產過程沒有外來污染(無菌、沒有內毒素(endotoxin)、生產過程中沒有加入肌漿(mycoplasm))。
另外值得一提的是，在不偏好這個發明的前提，推測可能有利用可促使心原細胞生成之物質之外的其他的方法生產心原細胞。
在這個實施例裡，保存液是BioLifeSolutions(Bothell，Wash)生產的HypoThermosol-ERS®。HypoThermosol-FRS®中含有離子：100mM的鈉離子、42.5mM的鉀離子、0.05mM的鈣離子、5mM的鎂離子、17.1mM的氯離子；酸鹼緩衝劑：10mM的磷酸根(H2PO4 -)離子、5mM的碳酸根(HCO3 -,)離子、25mM的HEPES；避免細胞膨脹的不通透物質：100mM的乳糖酸、20mM的蔗糖、20mM的甘露醇；膠體：6%的Dextran-40和細胞代謝物：5mM的葡萄糖、2mM的腺苷(adenosine)、3mM的麩氨基硫(glutathione)。
根據本發明，其中保存該藥品配方也可以使用二甲基亞碸(dimethylsulfoxide,DMSO)來作冷凍保存(cryopreservation)。其優點是，若在溫控良好的情形下又以乾冰運送，可以提供更長的儲存時間(shelf-life)至一週或大於一週。
根據這個發明的實施例，其中以HypoThermosol-ERS為賦形劑，包裝好的藥品配方可以存放至少72小時。尤其難得的一項事實是，總共1200x106個細胞的體積是8毫升，而適合心肌內注射的最大體積大約是10毫升。這代表HypoThermosol-FRS的量，相對於細胞的體積是很少的，只有幾毫升而已。
令人驚訝的事實是，這麼少量的HypoThermosol-FRS就足夠讓藥品配方的儲存時間達到關鍵的72小時。這提供了足夠的時間來確定所有的釋出條件已經達到，以及將藥品配方運送到世界各地並注入接受者體內。
藥品配方的釋出條件-身份(identity)：心原細胞有以下特徵：Nkx2.5、MEF2C和GATA-4等心臟分化早期的標記物表現陽性以及其細胞核轉位(如適用)。藥品配方裡的心原細胞之確實身份為，需可見MEF2C及/或Tbx5的表現量在即時量化反轉錄聚合酶連鎖反應(real-time quantitative RT-PCR,qPCR)的測量下相對於對照組至少兩倍增加，並且在儲存期間中維持該表現量。
在此有利的實施例中，由以下的表格1，表格2，表格3可知早期心臟分化標記物的表現及其細胞核轉位可以在藥品配方保存在最終的容器內維持14天之久，且這些細胞的活性(viability)和增殖力(proliferation)可以維持至少五天。這表示本發明所揭示的這個生產程序的特殊優越性，這些細胞在置於可促使心原細胞生成之物質中，可以並維持其身份(identity)，而維持適用於其所設定之用途。
此外，可由表格4和表格5中看出，這個藥品配方不僅限於單一種指定的細胞濃度產量(cell concentration yield)。在不同的細胞濃度下維持此述藥品配方細胞活性和增殖力正是本發明中這個藥品配方最優異的特性。
表4：細胞濃度對存活率(percent viability)的影響
有(*)註記，在第一批，第二天，每毫升80百萬個細胞的實驗數值被認定是一個實驗錯誤
藥品配方的釋出條件-均質度(Homogeneity)：為了測定在這個有利的實施例中的藥品配方中含有多少百分比的心原細胞，在部分的細胞中使用了針對MEF2C和CD105的抗體的雙重免疫標記法(dual-immuno-labelling)，接著用DAPI來染色細胞核。其目的是要測量心原細胞(細胞核被MEF2C染色)和間質幹細胞(CD105-陽性)佔所有被DAPI染色的細胞核總數的百分比。分析從病人取得的心原細胞，經過qPCR身份認證(MEF2C：2.8±0.6倍增加，Tbx5：2.2±0.6倍增加)後，証實有96±2%的
細胞是心原細胞。此外100%的細胞是CD105-陽性。而且CD34的表現量(血球源幹細胞和內皮先驅細胞的標記，詳見「純度(Purity)」段落中記述)沒有增加，代表的是100%的細胞都是間質幹細胞或源自間質幹細胞。
藥品配方的釋出條件-純度(Purity)：在依據本發明的這個有利的實施例中有，進行純度的測試會來確保藥品配方中沒有心原細胞或骨髓間質幹細胞(BMMSCs)之外的細胞種類之存在。qPCR檢測被選來做純度測試(The purity test)。發展qPCR來做純度測試的方式包含：找出合適的標記物，設計專門的引子(primer)和探子(probe)，分析增加曲線(amplification curves)和融化高峰(melting peaks)，找出可在市場取得的的RNAs陽性對照組。在藥品配方中若沒有表現CD34的細胞，則可以排除血球原細胞之表現型(hematopoietic phenotype)和內皮前驅細胞表現型(endothelial phenotype)，這兩種細胞常出現在骨髓中。在藥品配方中的細胞沒有量測出表現FABP4的細胞、表現Sox9的細胞、表現骨鈣素(osteocalcin)的細胞、表現巢蛋白(nestin)的細胞，則可以依序排除脂肪母細胞(adipoblasts)、軟骨母細胞(chondroblasts)、骨母細胞(steoblasts)或神經母細胞(oneuroblasts)。在藥品配方中的細胞沒有出現表現MYH7的細胞，則可以排除成熟心肌細胞(cardiomyocytes)。
這裡敘述的一個本發明的有利的實施例中，曾將有效數目為1200x106的細胞，以心肌內注射(injected endocardially)的方式注入缺血造成的心臟衰竭病人，注射方式是用特製的導管注射在不活化(non-viable)的心肌邊緣區。其結果為獲得了良好之反應。
根據這個發明，包含心原細胞的藥品配方的可行性
(feasibility)、安全性(safety)和療效(efficacy)是用一種前瞻性(prospective)、隨機的(randomized)、開放的(open)、平行雙軌多中心臨床試驗(sequential parallel two-armed,multi-centre clinical trial)來作評定的。
若干患有因缺血性心肌病變而次發慢性心臟衰竭的患者(Subjects presenting with chronic heart failure secondary to ischemic cardiomyopathy)被隨機的指定到對照組或治療組。對照組獲得最佳的標準照護。治療組則是除最佳的標準照護之外，又接受了包含心原細胞的藥品配方。
包含心原細胞的藥品配方用心室內注射(endoventricularly)的方式，用MyoStar®注射導管(Biologics Delivery Systems,California,USA)注入梗塞區域的邊緣(in the border zone of the infracted area)。在一次注射程序中，最多1.2 x 109個細胞被注入約二十處圍繞梗塞區域的位置。
針對在參加試驗的17個受試者中(9個治療組，8個對照組)，在基準值(baseline)和治療後六個月進行了二維心臟超音波(Two-dimensional echocardiographic)來評量左心室(LV)功能。心臟功能是認定的方式是比較基準值和治療後六個月的左心室終舒張容積(LV End Diastolic Volume,LVEDV)、左心室終收縮容積(LV End Systolic Volume,LVESV)、和左心室排血分量(LV Ejection Fraction,LVEF)。在治療組中，這三種重要的指標表現了一個傾向藥品組合有正向療效的趨勢(圖1)。熟悉此技術的醫師可以認同這個結果指出對於療效和預後(prognostic)的重要影響。
其他實施例：本發明的描述以及詳細說明，皆係為闡述發明但絕非限制由專利申請範圍所定義的發明範圍。其他的觀點、優勢以及修
改都應涵蓋在下列的申請範圍之範疇內。
尤其是，這裡所述的藥品配方，包含其儲存條件和儲存時間只是使用自體(autologous)骨髓間質幹細胞(bone marrow mesenchymal stem cells,BMMSCs)的一個有利的實施例，也就是說，一個從個體中取出的骨髓間質幹細胞所製成的藥品配方會被使用在同樣的個體內。這個發明的範圍不止侷限在自體的骨髓間質幹細胞，也包括了使用其他種的幹細胞，不論其來源為何。可以被用來生成心臟組織的細胞(也就是本段落以下所用的「來源細胞(original cells)」)，它可以是同源(allogenic)或非同源(xenogenic)。來源細胞也可以從新鮮骨髓以外的方法取得。來源細胞可以是在不傷及人類胚胎下取得的胚胎幹細胞。來源細胞可以是類胚胎幹細胞(embryonic-like stem cells)，例如的誘導性多能幹細胞(Induced Pluripotent Stem(IPS)cells)，其可以用包含轉植(transfection)，細胞重設(cellular reprogramming)等其他方法取得沒有外來基因(exogenous)的誘導性多能幹細胞。來源細胞也可以是骨髓分離成人誘導性多品系細胞(Marrow-Isolated Adult Multilineage Inducible cells(MIAMI))。常駐心臟幹細胞(Resident cardiac stem cells)…。這個發明並不侷限在特定的配方組成、生產方法、生物材料或反應物、劑量療法和此類可能會變化的東西。
在另一個的實施例中，此藥品配方可包含額外的成分，例如可促使心原細胞生成之物質、生長激素、如纖維母細胞生長因子(fibroblast growth factors)、胎盤生長因子(placental growth factor)、血管內皮生長因子(vascular endothelial growth factor)、細胞激素(cytokines)和器官發生信號有關的蛋白質、分子結構、體外(ex vivo)改良的非心原細胞、藥品、血小
板溶解物(platelet lysate)、支架材料如膠原帶白(collagen)、板蛋白(laminin)或其他細胞外基質(extracellular matrix)蛋白。
本發明的描述以及詳細說明，皆係為闡述發明但絕非限制由專利申請範圍所定義的發明範圍。
Claims (28)
- 一種藥品配方，其包含將生成心臟組織的幹細胞，其中該些幹細胞顯示：i.相對於參考值可觀察到MEF2C的表現量增加及視情況至少一種選自由以下者所組成之群組的其他基因的表現量增加：Nkx2.5，Tbx5，GATA4，GATA6，Mesp1，FOG1，FOG2，Flk1；及/或ii.相對於參考品可觀察到至少一種選自由以下者所組成之群組之多肽種類之存在：Nkx2.5，Tbx5，GATA4，GATA6，Mesp1，FOG1，FOG2，Flk1；以及Nkx2.5及MEF2C之一或多者核轉位(nuclear translocation)至細胞核；及至少一種藥理上可接受的賦形劑(excipient)，其中該至少一種藥理上可接受的賦形劑為一種保存液(preservation solution)，其包含二甲基亞碸(dimethylsulfoxide,DMSO)，離子、酸鹼緩衝劑(pH buffers)、不通透物質(impermeants)、膠體(colloid)、及代謝物(metabolites)，且條件是該幹細胞非為人類胚胎幹細胞。
- 依據申請專利範圍第1項所述之藥品配方，其中觀察到的表現量之增加，指的是在qPCR檢測上有相對於參考值至少兩倍。
- 依據申請專利範圍第1項所述之藥品配方，其中該保存液是選自包含可以在-196℃和0℃之間的溫度冷凍保存(cryopreservation)的保存液和可以在0℃和+40℃之間的溫度 保存的保存液之群組。
- 依據申請專利範圍第1項所述之藥品配方，其中該保存液係為一種可包含甘油(glycerol)、蔗糖、血清白蛋白(serum albumin)、海藻糖(trehalose)或以上物質之任何組合之保存液。
- 依據申請專利範圍第1項所述之藥品配方，其中所稱之離子是選自由以下者所組成之群組：Na+、K+、Ca2+、Mg2+、Cl-及前述離子之組合。
- 依據申請專利範圍第1項所述之藥品配方，其中所稱之酸鹼緩衝劑(pH buffers)係選自由以下者所組成之群組：H2PO4 -、HCO3 -、HEPES(4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid)及其混合物。
- 依據申請專利範圍第1項所述之藥品配方，其中所稱之不通透物質(impermeants)係選自由以下者所組成之群組：乳糖酸(lactobionate)、蔗糖、甘露醇(mannitol)、葡萄糖及其組合。
- 依據申請專利範圍第1項中所述之藥品配方，其中所稱之膠體(colloid)為Dextran-40者。
- 依據申請專利範圍第1項中所述之藥品配方，其中所稱之代謝物(metabolites)係選自由以下者所組成之群組：腺苷(adenosine)、麩氨基硫(glutathione)及其組合。
- 依據申請專利範圍第1項所述之藥品配方，其中該至少一種之藥理上可接受的賦形劑(excipient)包含至少一種選自由以下者所組成之群組的組分：生長因子(growth factors)、細胞激素(cytokine)、器官發生信號相關的蛋白質(proteins involved in organogenesis signalling)、藥品(pharmaceuticals)、血小板溶 解物(platelet lysate)、血清、同位素(isotopes)，用來追蹤體內細胞的工具(means for tracing cells in vivo)、稀釋劑(diluents)、潤滑劑(lubricants)、基質(matrix)或支架(scaffold)材料以及其組合。
- 依據申請專利範圍第1項所述之藥品配方，其中該將生成心臟組織的幹細胞是源自幹細胞，其條件是，該幹細胞非為人類胚胎幹細胞。
- 依據申請專利範圍第11項中所述之藥品配方，其中該幹細胞是成人幹細胞。
- 依據申請專利範圍第12項中所述之藥品配方，其中該成人幹細胞係選自由以下者所組成之群組：間質幹細胞(mesenchymal stem cells)、誘發性多能幹細胞(induced pluripotent stem cells,IPS)、骨髓分離成人誘導性多品系細胞(Marrow-Isolated Adult Multilineage Inducible cells,MIAMI)、心臟常駐幹細胞(resident cardiac stem cells)、植物極(vegetal)幹細胞，或其任何組合。
- 依據申請專利範圍第1項所述之藥品配方，其中該將生成心臟組織的幹細胞是哺乳動物細胞，其條件是，該哺乳動物細胞非為人類胚胎幹細胞。
- 依據申請專利範圍第1項所述之藥品配方，其中該將生成心臟組織的幹細胞是心原細胞(cardiopoietic cells)，其可自以下者得到：人類成人間質幹細胞(human adult mesenchymal stem cells)，類胚胎幹細胞(embryonic-like stem cells)，可誘發性多能幹細胞(inducible pluripotent stem cells)，心臟常駐幹細胞(cardiac resident stem cell)或任何其他合適的來源或其組合。
- 依據申請專利範圍第1項所述之藥品配方，其中所有細胞總數的0至50%係為非心原細胞。
- 依據申請專利範圍第1項所述之藥品配方，其中所有細胞總數的0至15%係為非心原細胞。
- 依據申請專利範圍第16或17項所述之藥品配方，其中該非心原細胞係選自包含以下者之群組：心肌細胞(cardiomyocytes)，血球原細胞，(hematopoietic cells)，內皮前驅細胞(endothelial progenitor cells)，脂肪母細胞(adipoblasts)，脂肪細胞(adipocytes)，軟骨母細胞(chondroblasts)，軟骨細胞(chondrocytes)，骨母細胞(osteoblasts)，骨細胞(osteocytes)，神經母細胞(neuroblasts)以及神經元細胞(neurocytes)。
- 依據申請專利範圍第1項所述之藥品配方，其係使用於治療缺血性心肌病變，急性心肌梗塞，慢性心肌梗塞，非缺血性心臟衰竭，缺血性心臟衰竭，先天性心肌病，或以上病的組合。
- 一種依據申請專利範圍第1項所述之藥品配方之生產程序，其包含以下步驟：- 取得可得到將生成心臟組織之幹細胞的細胞；- 在可以獲得將生成心臟組織之幹細胞的條件下培養前述細胞；- 採集前述將生成心臟組織的幹細胞；- 將至少一種藥理上可接受的賦形劑加入前述將生成心臟組織的幹細胞中。
- 依據申請專利範圍第20項所述之程序，其中將所稱之可得到將生成心臟組織之幹細胞的細胞與心原配方(cardiogenic composition)接觸，該心原配方由選自由以下者所組成的群組之促使心原細胞生成之物質(cardiogenic substance)之一或多者構成：促進素A(Activin A)，α-凝血酶(α-thrombin)，血管生成素(angiopoietin)，骨型態生成蛋白(Bone morphogenetic proteins,BMP)，心營養素1(cardiotrophin 1)，心生素C(cardiogenol C)，表皮生長因子(Epidermal growth factor,EGF)，紅血球生成素(Erythropoietin，EPO)，纖維母細胞生長因子(Fibroblast growth factors,FGF)，顆粒球群眾刺激因子(Granulocyte-colony stimulating factor,G-CSF)，顆粒球-巨噬細胞群眾刺激因子(Granulocyte-macrophage colony stimulating factor,GM-CSF)，生長分化因子-9(Growth differentiation factor-9,GDF-9)，肝細胞生長因子(Hepatocyte growth factor,HGF)，類胰島素生長因子(insulin-like growth factor,IGF)，肌定蛋白(Myostatin,GDF-8)，神經營養素(Neurotrophins)，血小板源性生長因子(Platelet-derived growth factor,PDGF)，血小板生成素(Thrombopoietin,TPO)，轉型生長因子α(Transforming growth factor α,TGF-α)，轉型生長因子β(Transforming growth factors β,TGF-β)，血管內皮生長因子(Vascular endothelial growth factor,VEGF)，TNF-α，白血病抑制因子(leukemia inhibitory factor,LIF)，介白素6(interleukin 6,IL-6)，視網膜酸(retinoic acid)，基質細胞源性因子-1(stromal cell-derived factor-1,SDF-1)，腦源性神經營養因子(brain-derived neurotrophic factor,BDNF)，類骨素(Periostin)，血管收縮素II(Angiotensin II)，Flt3配體(Flt3 Ligand)，膠源性神經營養因子(Glial-Derived Neurotrophic Factor)，類胰島素生長因子黏結蛋白-3(Insulin-Like Growth Factor Binding Protein-3)，類胰島素生長因子黏結蛋白-5(Insulin-Like Growth Factor Binding Protein-5)，介白素-3(Interleukin-3)，介白素-8(Interleukin-8)，中激素(Midkine)，黃體酮(Progesterone)，腐胺(Putrescine)，幹細胞因子(Stem Cell Factor)，TGF-alpha，Wnt1，Wnt3a，Wnt5a，半胱胺醯天冬胺酸特異性蛋白酶-4(caspase-4)，化學趨素配體1(chemokine ligand 1)，化學趨素配體2(chemokine ligand 2)，化學趨素配體5(chemokine ligand 5)，化學趨素配體7(chemokine ligand 7)，化學趨素配體11(chemokine ligand 11)，化學趨素配體20(chemokine ligand 20)，肝球蛋白(haptoglobin)，凝集素(lectin)，膽固醇25-羥化酶(cholesterol 25-hydroxylase)，神經突觸素-8(syntaxin-8)，神經突觸素-11(syntaxin-11)，血漿銅藍蛋白(ceruloplasmin)，補體組分1(complement component 1)，補體組分3(complement component 3)，整合蛋白(integrin)alpha 6，溶體酸性脂肪酶1(lysosomal acid lipase 1)，β-2微小球蛋白(β-2microglobulin)，泛素(ubiquitin)，巨噬細胞移動抑制因子(macrophage migration inhibitory factor)，絲切蛋白(cofilin)，親環素A(cyclophillin A)，FKBP12，NDPK，肌動蛋白聚合蛋白1(profilin 1)，半胱氨酸蛋白酶抑制劑C(cystatin C)，鈣週期蛋白(calcyclin)，斯鈣素相關蛋白-1(stanniocalcin-1)，PGE-2，mpCCL2，IDO，iNOS，HLA-G5，M-CSF，PIGF，MCP-1，細胞外基質分子(extracellular matrix molecules)，CCL2(MCP-1)，CCL3(MIP-1 α)，CCL4(MIP-1 β)， CCL5(RANTES)，CCL7(MCP-3)，CCL20(MIP-3 α)，CCL26(eotaxin-3)，CX3CL1(fractalkine)，CXCL5(ENA-78)，CXCL11(i-TAC)，CXCL1(GRO α)，CXCL2(GRO β)，CXCL8(IL-8)，CCL10(IP-10)及其組合。
- 依據申請專利範圍第21項中所述之程序，其中該心原配方係被稀釋於包含選自由以下者所組成之群組的化合物之培養基中：小牛血清(foetal calf serum)，人類血清，血小板溶解物(platelet lysate)，血小板源性生長因子，和它們的混合物和選自如下的化合物：第1群組，其由以下者組成：TGF β-1，BMP-4，α-凝血酶(α-thrombin)，選自由以下者所組成之群組的化合物，心營養素1(Cardiotrophin 1)和IL 6，以及選自由以下者所組成之群組的化合物，心生素C(Cardiogenol C)和視網膜酸(retinoic acid)；第2群組，其由以下者組成：TGF β-1，BMP-4，α-凝血酶(α-thrombin)，心營養素1(Cardiotrophin 1)，IL-6，視網膜酸(retinoic acid)和心生素C(Cardiogenol C)；第3群組，其由以下者組成：促進素-A(Activin-A)，FGF-2，IL-6，IGF-1和視網膜酸(retinoic acid)；及第4群組，其由以下者組成：TGF-β 1，TGF-β 2，TNF-α，BMP-1，BMP-2，BMP-4，BMP-6，FGF-2，FGF-4，FGF-5，FGF-12，FGF-13，FGF-15，FGF-20，白血病抑制因子(leukaemia inhibitory factor)，VEGF-A，VEGF-C，類胰島素生長因子1(insulin like growth factor 1)，介白素-6(interleukin 6，IL-6)，促進素-A(Activin-A)，α-凝血酶(α-thrombin)，視網膜酸(retinoic acid)，心營養素1(Cardiotrophin 1)，心生素C(Cardiogenol C)及其組合。
- 依據申請專利範圍第20項所述之程序，其中當將生成心臟組織的幹細胞是心原細胞時，該心原細胞之識別對應於至少一種由以下者所組成之群組中的基因之觀察到的表現量(expression level)增加：Nkx2.5，Tbx5，MEF2C，GATA4，GATA6，Mesp1，FOG1，FOG2，Flk1。
- 依據申請專利範圍第23項所述之程序，其中所謂基因表現增加是指相對於參考值以qPCR方法測定至少為兩倍。
- 依據申請專利範圍第20項所述之程序，其中當將生成心臟組織的幹細胞是心原細胞時，該心原細胞之識別被認為要滿足以下條件：相對於參考值觀察到至少一個選自由以下者所組成之群組的多肽(polypeptide)種類的存在：Nkx2.5，Tbx5，MEF2C，GATA4，GATA6，Mesp1，FOG1，FOG2，Flk1；以及Nkx2.5與MEF2C兩者或其一會進一步轉位到心原細胞的細胞核內。
- 依據申請專利範圍第20項至第25項中任何一項所述之程序，其中均質度(homogeneity)的標準為一個樣品中至少有50%為心原細胞。
- 依據申請專利範圍第20項至第25項中任何一項所述之程序，其中均質度(homogeneity)的標準為一個樣品中至少有85%為心原細胞。
- 一種用來投予如申請專利範圍第1項所述之藥品配方的套組，其包含裝有該藥品配方的容器。
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| US20080276643A1 (en) * | 2005-09-12 | 2008-11-13 | Adam Heroux | Thermally Insulated Transport Container For Cell-Based Products and Related Methods |
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| US6921633B2 (en) * | 2002-11-18 | 2005-07-26 | Biolife Solutions Incorporated | Methods and compositions for the preservation of cells, tissues or organs in the vitreous state |
| KR100674783B1 (ko) * | 2003-12-09 | 2007-01-25 | (주)안트로젠 | 세포 이식을 위한 세포의 생산 방법 |
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| US9782439B2 (en) * | 2005-01-27 | 2017-10-10 | Japan Health Sciences Foundation | Cell sheet containing mesenchymal stem cells |
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| EP2126052B1 (en) | 2007-01-09 | 2014-12-10 | Lead Pharma Cel Models IP B.V. | Provision of new cardiomyocyte progenitor cells and cardiomyocytes derived therefrom |
| EP2131868A4 (en) * | 2007-03-07 | 2011-04-13 | Mayo Foundation | HEART-SPECIFIC STORAGE CELLS |
| KR20080103637A (ko) * | 2007-05-25 | 2008-11-28 | 주식회사 알앤엘바이오 | 지방유래 줄기세포를 함유하는 사지말단부 허혈성 질환의세포치료용 조성물 |
| FR2917381B1 (fr) | 2007-06-15 | 2009-10-16 | Ceva Sante Animale Sa | Conditionnement plastique multicouche pour la conservation d'une composition pharmaceutique |
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| KR101689415B1 (ko) | 2016-12-23 |
| WO2010133686A8 (en) | 2012-03-08 |
| JP6029468B2 (ja) | 2016-11-24 |
| IL216399A0 (en) | 2012-01-31 |
| SG175880A1 (en) | 2011-12-29 |
| CA2762584A1 (en) | 2010-11-25 |
| US20160279168A1 (en) | 2016-09-29 |
| HK1163500A1 (zh) | 2012-09-14 |
| MX2011012183A (es) | 2012-03-06 |
| US9446076B2 (en) | 2016-09-20 |
| KR20120046107A (ko) | 2012-05-09 |
| WO2010133686A1 (en) | 2010-11-25 |
| RU2595801C2 (ru) | 2016-08-27 |
| ES2541212T3 (es) | 2015-07-16 |
| AU2010251151A1 (en) | 2011-11-24 |
| NZ623454A (en) | 2015-12-24 |
| CN102438636A (zh) | 2012-05-02 |
| BRPI1012116A2 (pt) | 2016-03-15 |
| CN107028980A (zh) | 2017-08-11 |
| NZ596162A (en) | 2014-06-27 |
| US20120128638A1 (en) | 2012-05-24 |
| US10086016B2 (en) | 2018-10-02 |
| JP2012527432A (ja) | 2012-11-08 |
| RU2011145370A (ru) | 2013-06-27 |
| TW201108935A (en) | 2011-03-16 |
| AU2010251151B2 (en) | 2015-08-20 |
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