CN109929806B - 一种表达glp1和fgf21的干细胞及其用途 - Google Patents
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Abstract
本发明涉及细胞治疗领域。具体而言,本发明涉及一种经修饰的间充质干细胞及其培养上清,以及包含此类细胞或其培养上清的药物组合物。本发明还涉及所述经修饰的间充质干细胞及其培养上清,用于在受试者(例如,人)中治疗代谢病症的用途,以及在制备用于在受试者(例如,人)中治疗代谢病症的药物中的用途。本发明还涉及一种治疗代谢病症的方法,其包括向有此需要的受试者施用本发明的经修饰的间充质干细胞或其培养上清或药物组合物的步骤。
Description
技术领域
本发明涉及细胞治疗领域。具体而言,本发明涉及一种经修饰的间充质干细胞及其培养上清,以及包含此类细胞或其培养上清的药物组合物。本发明还涉及所述经修饰的间充质干细胞及其培养上清,用于在受试者(例如,人)中治疗代谢病症的用途,以及在制备用于在受试者(例如,人)中治疗代谢病症的药物中的用途。本发明还涉及一种治疗代谢病症的方法,其包括向有此需要的受试者施用本发明的经修饰的间充质干细胞或其培养上清或药物组合物的步骤。
背景技术
糖尿病等代谢病症与参与代谢调控的一些内源性分子密切相关。已发现的此类内源性分子主要有三类:一是激素类,包括胰岛素、胰高血 糖素、GLP1、糖皮质激素等;二是具有激素样功能的细胞生长因子类,包括FGF19、FGF21和FGF23等;三是参与代谢调控或细胞信号转导的酶类,包括SPK1、PI3K、HSL等。
内源性的激素、细胞因子或酶类的分泌不足、活性降低或功能缺陷 与代谢病的发生密切相关,如胰岛素抵抗和相对分泌不足是导致糖尿病 的核心原因。因此,这些糖脂代谢平衡调控的关键分子也是治疗糖尿病 等代谢综合征药物开发的重点对象,其中胰岛素和胰高血糖素样的多肽 1(GLP1)已成为目前最主要的糖尿病治疗药物。
目前,针对GLP1开发的降糖药物主要是抑制GLP1降解的DPP4抑制剂和GLP1类似物,将GLP1与人抗体Fc融合后的GLP1-Fc半衰期长,耐受性良好。纤维母细胞生长因子(FGF)是一类重要的组织生长因子,包括22个家族成员。FGF19/21/23是FGF家族的一类成员,它们具有激素样的作用,在糖脂代谢调控中发挥中重要作用。其中,FGF21主要由肝脏合成,通过内分泌途径作用于脂肪组织,调控糖脂的代谢。作为一种糖脂代谢调控分子,FGF21已经被作为药物开发,用于代谢病的治疗。GLP1-Fc和FGF21在临床应用中患者均需面临长期用药、终身用药、联合用药降糖降脂等问题,而且这些药物只能起到治疗病症的效果,均无法从根源上改善疾病的诱因。
总之,鉴于目前可获得的降糖降脂药物都受限于一些缺陷,寻找一种全新的、可靠的、从根本上治疗代谢病症的方法迫在眉睫。
发明内容
本申请的发明人经过大量实验和反复摸索,出人意料地发现,经FGF21和GLP-1基因修饰的间充质干细胞具备显著提高的降低血糖、血脂等生物学活性。基于这一发现,本发明人开发了新的用于代谢病症 的经修饰细胞以及基于该细胞的代谢病症治疗方法。
经修饰的间充质干细胞
因此,在一个方面,本发明提供了一种经修饰的间充质干细胞,其表达:(1)第一蛋白,其选自:FGF21或其变体,或包含所述FGF21或其变体的第一融合蛋白;和,(2)第二蛋白,其选自:GLP-1或其变 体,或包含所述GLP-1或其变体的第二融合蛋白。
在某些优选的实施方案中,所述FGF21的变体与其所源自的序列 相比,具有一个或多个氨基酸的替换、插入或删除,或者具有至少 80%,85%,90%,95%,96%,97%,98%,或99%的序列同一性, 并且保留了FGF21活性。
在本发明中,所述“FGF21活性”是指天然存在的FGF21的一种或 多种生理作用,其是本领域技术人员熟知的,包括但不限于,诱导不依 赖胰岛素的葡萄糖摄入,降低血浆葡萄糖、果糖胺、甘油三酯、胰岛 素、高血糖素水平,减少LDL胆固醇和增加HDL胆固醇,增强胰岛素 敏感性等,其详细教导可参见,例如DostálováI等人.Physiol Res.2009; 58(1):1-7;Kharitonenkov A等人.J Clin Invest.2005Jun;115(6):1627-3 5.
在某些优选的实施方案中,所述GLP-1的变体与其所源自的序列 相比,具有一个或多个氨基酸的替换、插入或删除,或者具有至少 80%,85%,90%,95%,96%,97%,98%,或99%的序列同一性, 并且保留了GLP-1活性。
在本发明中,所述“GLP-1活性”是指天然存在的GLP-1的一种或 多种生理作用,其是本领域技术人员已知的,包括但不限于,对胰岛素 分泌的葡萄糖依赖性刺激、对高血糖素分泌的阻抑、胰岛素(原)生物合 成的刺激、食物摄取减少、胃排空减速等,其详细教导可参见例如Nau ck MA等人.Exp Clin Endocrinol Diabetes.1997;105(4):187-95.。
在某些优选的实施方案中,所述FGF21具有如SEQ ID NO:1所示 的氨基酸序列。
在某些优选的实施方案中,所述GLP-1具有如SEQ ID NO:4所示 的氨基酸序列。
在某些优选的实施方案中,所述经修饰的间充质干细胞表达:(1) 第一蛋白,其选自:SEQ ID NO:2所示的氨基酸序列,或包含SEQ ID NO:2所示的氨基酸序列的第一融合蛋白;和,(2)第二蛋白,其选自: SEQ ID NO:5所示的氨基酸序列,或包含SEQ ID NO:5所示的氨基酸 序列的第二融合蛋白。
在某些优选的实施方案中,所述经修饰的间充质干细胞能够分泌所 述第一蛋白和第二蛋白。
在某些优选的实施方案中,所述第一融合蛋白还包含第一额外多 肽。在某些优选的实施方案中,所述第一额外多肽能够延长所述第一融 合蛋白在体内的半衰期。
在某些优选的实施方案中,所述第一额外多肽选自免疫球蛋白Fc 结构域(例如,人免疫球蛋白Fc结构域,例如人IgG的Fc结构域)、 血清白蛋白(例如,人血清白蛋白(HSA))、白蛋白结合多肽(例如, HSA结合多肽)、转铁蛋白,及前述任一项的功能性片段。
在某些优选的实施方案中,所述第一额外多肽为人免疫球蛋白Fc 结构域,例如人IgG的Fc结构域,例如人IgG1、IgG2、IgG3或IgG4 的Fc结构域。在某些示例性实施方案中,所述第一额外多肽具有如 SEQ ID NO:7所示的氨基酸序列。
在某些优选的实施方案中,所述第一额外多肽任选地通过接头与所 述FGF21或其变体融合。在某些优选的实施方案中,所述第一额外多 肽任选地通过接头与所述FGF21或其变体的N端或C端融合。在某些 优选的实施方案中,所述接头为富含Gly和Ser的组合的肽接头,例如 由重复的GGGGS氨基酸序列组成的序列。在某些示例性实施方案中, 所述接头为GGGGSGGGGSGGGGS(SEQ ID NO:9)。
在某些优选的实施方案中,所述第二融合蛋白还包含第二额外多 肽。在某些优选的实施方案中,所述第二额外多肽能够延长所述第二融 合蛋白在体内的半衰期。
在某些优选的实施方案中,所述第二额外多肽选自免疫球蛋白Fc 结构域(例如,人免疫球蛋白Fc结构域,例如人IgG的Fc结构域)、 血清白蛋白(例如,人血清白蛋白(HSA))、白蛋白结合多肽(例如, HSA结合多肽)、转铁蛋白,及前述任一项的功能性片段。
在某些优选的实施方案中,所述第二额外多肽为人免疫球蛋白Fc 结构域,例如人IgG的Fc结构域,例如人IgG1、IgG2、IgG3或IgG4 的Fc结构域。在某些示例性实施方案中,所述第二额外多肽具有如 SEQ ID NO:7所示的氨基酸序列。
在某些优选的实施方案中,所述第二额外多肽任选地通过接头与所 述GLP-1或其变体融合。在某些优选的实施方案中,所述第二额外多 肽任选地通过接头与所述GLP-1或其变体的N端或C端融合。在某些 优选的实施方案中,所述接头为富含Gly和Ser的组合的肽接头,例如 由重复的GGGGS氨基酸序列组成的序列。在某些示例性实施方案中, 所述接头为GGGGSGGGGSGGGGS(SEQ ID NO:9)。
在某些示例性实施方案中,所述经修饰的间充质干细胞表达:(1) 第一蛋白,其选自:SEQ ID NO:2所示的氨基酸序列,或包含SEQ ID NO:2所示的氨基酸序列的第一融合蛋白;和,(2)第二蛋白,其选自: SEQ ID NO:5所示的氨基酸序列,或包含SEQ ID NO:5所示的氨基酸 序列的第二融合蛋白。
在某些示例性实施方案中,所述经修饰的间充质干细胞表达:如 SEQ ID NO:2所示的氨基酸序列;和如SEQ ID NO:10所示的氨基酸 序列。
在某些优选的实施方案中,所述经修饰的间充质干细胞包含:
(1)第一外源核酸,其包含编码所述第一蛋白的核苷酸序列;和
(2)第二外源核酸,其包含编码所述第二蛋白的核苷酸序列。
在某些优选的实施方案中,所述第一外源核酸和/或第二外源核酸 可操作地连接至启动子(例如,组成型启动子、组织特异性启动子或诱 导型启动子)。
在某些优选的实施方案中,所述第一外源核酸和/或第二外源核酸 连接有编码信号肽的核苷酸序列。在某些示例性实施方案中,所述第二 外源核酸的5’端连接有编码信号肽(例如,如SEQ ID NO:22所示的信 号肽)的核苷酸序列。
在某些优选的实施方案中,所述第一外源核酸与第二外源核酸可以 通过编码自我切割肽的序列连接。在某些示例性实施方案中,所述编码 自我切割肽的序列连接至所述第一外源核酸的3’端,并且连接至所述第 二外源核酸的5’端。
在某些优选的实施方案中,所述第一外源核酸和/或第二外源核酸 整合于所述间充质干细胞的基因组中。
在某些优选的实施方案中,所述第一外源核酸和/或第二外源核酸 独立于所述间充质干细胞的基因组。在此类实施方案中,所述经修饰的 间充质干细胞包含表达载体,并且所述第一外源核酸和第二外源核酸包 含于同一或不同的表达载体中。
在某示例性实施方案中,所述表达载体包含所述第一外源核酸和所 述第二外源核酸。在此类实施方案中,所述第一外源核酸与第二外源核 酸可以通过编码自我切割肽的序列连接。在某些示例性实施方案中,所 述编码自我切割肽的序列连接至所述第一外源核酸的3’端,并且连接至 所述第二外源核酸的5’端。
在本发明中,适宜的自我切割肽是本领域技术人员已知的,其实例 包括但不限于,源自口疮病毒属或心病毒属的2A肽,例如源自口蹄疫 病毒(FMDV)、马鼻炎A病毒(ERAV)、Thoseaasigna病毒(TaV)或猪捷 申病毒(PTV-1)的2A肽。
在某些优选的实施方案中,所述第一外源核酸与第二外源核酸通过 编码2A肽的序列连接。在某些示例性实施方案中,所述编码2A肽的 序列连接至所述第一外源核酸的3’端,并且连接至所述第二外源核酸的 5’端。在某些优选的实施方案中,所述2A肽为源自Thoseaasigna病毒 (TaV)的2A肽。在某些示例性实施方案中,所述2A肽具有如SEQ ID NO:12所示的氨基酸序列。在某些示例性实施方案中,所述编码2A肽 的序列具有如SEQ ID NO:13所示的核苷酸序列。
在本发明中,可以通过本领域中公知的方法和技术对间充质干细胞 进行遗传修饰,例如物理、化学或生物学方法,或其组合。例如,所述 生物学方法包括使用病毒载体,例如慢病毒、逆转录病毒、痘病毒、单 纯疱疹病毒I、腺病毒和腺伴随病毒等等。例如,所述化学手段包括胶 体分散系统,诸如大分子复合物、纳米胶囊、微球、珠等;基于脂质的 系统,包括水包油乳剂、胶束、混合胶束或脂质体等。例如,所述物理 方法包括磷酸钙沉淀、脂质转染法、粒子轰击、微注射、电穿孔等等。
在某些优选的实施方案中,本发明的经修饰的间充质干细胞通过将 所述第一外源核酸和第二外源核酸导入间充质干细胞而获得。
在某些优选的实施方案中,所述经修饰的间充质干细胞通过以下步 骤获得:
(1)提供包含第一外源核酸和第二外源核酸的表达载体;
(2)将步骤(1)所述的表达载体转染至间充质干细胞。
在某些优选的实施方案中,在步骤(2)中,将所述表达载体稳定转染 至所述间充质干细胞。在某些优选的实施方案中,在步骤(1)中,所述表 达载体为病毒载体,例如慢病毒载体。在某些优选的实施方案中,所述 表达载体包含SEQ ID NO:15所示的核苷酸序列。
在某些优选的实施方案中,所述间充质干细胞来源于脂肪组织、脐 带、骨髓或脐血。在某些示例性实施方案中,所述间充质干细胞来源于 脂肪组织。
本发明的经修饰的间充质干细胞可以作为药物组合物被配制和施 用。这样的药物组合物可以是医学领域已知的任何形式,优选为注射剂 (包括注射液、冻干粉剂)。在某些优选的实施方案中,该药物组合物 包含药学上可接受的无菌等渗水性或非水性溶液(例如,平衡盐溶液或 生理盐水)、分散液、悬浮液或乳液。关于该药物组合物的配制的一般 原则可参考由G.Morstyn和W.Sheridan编著的《细胞疗法:干细胞移 植,基因疗法和细胞免疫疗法(Cell Therapy:Stem Cell Transplantation,Gene Therapy,and CellularImmunotherapy)》,剑桥 大学出版社,1996;和《造血干细胞疗法(Hematopoietic StemCell Therapy)》,E.D.Ball,J.Lister&P.Law,Churchill Livingstone,2000。
在某些优选的实施方案中,本发明的经修饰的间充质干细胞用于在 受试者中治疗代谢病症,或者用于制备在受试者中治疗代谢病症的药 物。
在某些优选的实施方案中,所述代谢病症选自肥胖、I型和II型糖 尿病、血脂异常(例如,高脂血症)、非酒精性脂肪肝病(NAFLD)、非 酒精性脂肪性肝炎(NASH)、胰岛素耐受、高胰岛素血症、葡萄糖不耐 受、高血糖、代谢综合征、动脉粥样硬化、冠心病、高血压和其他的代 谢病症,及这些疾病的继发性并发症(例如,糖尿病并发症,如视网膜 病、神经病、肾病以及延缓的创伤愈合)。
在某些优选的实施方案中,所述受试者为哺乳动物,例如人。
培养物及培养上清
在另一个方面,本发明提供了一种培养物,其包含本发明的经修饰 的间充质干细胞,以及培养基。
在本发明中,可用于干细胞培养的培养基是本领域技术人员已知 的,其非限制性实例包括,α-MEM培养基、DMEM培养基、IMDM 培养基、Ham's F12培养基、RPMI1640培养基,以及上述任一项组合 形成的混合培养基(例如,IMDM与HamF12等量混合而成的 IMDM/HamF12培养基)。上述培养基任选地进一步包含补充物质,例 如血清(例如,胎牛血清、人血清、羊血清等)、血清替代物(例如, Knockout serum replacement(KSR)等)、牛血清白蛋白(BSA)、抗生 素、维生素、矿物质。
在某些示例性实施方案中,所述培养基为含有或不含有血清的α- MEM培养基。
本发明的培养物可以作为药物组合物被配制和施用。这样的药物组 合物可以是医学领域已知的任何形式,优选为注射剂(包括注射液、冻 干粉剂)。在某些优选的实施方案中,该药物组合物包含药学上可接受 的无菌等渗水性或非水性溶液(例如,平衡盐溶液或生理盐水)、分散 液、悬浮液或乳液。关于该药物组合物的配制的一般原则可参考由G.Morstyn和W.Sheridan编著的《细胞疗法:干细胞移植,基因疗法和 细胞免疫疗法(CellTherapy:Stem Cell Transplantation,Gene Therapy, and Cellular Immunotherapy)》,剑桥大学出版社,1996;和《造血干 细胞疗法(Hematopoietic Stem Cell Therapy)》,E.D.Ball,J.Lister& P.Law,Churchill Livingstone,2000。
在某些优选的实施方案中,如本文所述的培养物用于在受试者中治 疗代谢病症,或者用于制备在受试者中治疗代谢病症的药物。
在某些优选的实施方案中,所述代谢病症选自肥胖、I型和II型糖 尿病、血脂异常(例如,高脂血症)、非酒精性脂肪肝病(NAFLD)、非 酒精性脂肪性肝炎(NASH)、胰岛素耐受、高胰岛素血症、葡萄糖不耐 受、高血糖、代谢综合征、动脉粥样硬化、冠心病、高血压和其他的代 谢病症,及这些疾病的继发性并发症(例如,糖尿病并发症,如视网膜 病、神经病、肾病以及延缓的创伤愈合)。
在某些优选的实施方案中,所述受试者为哺乳动物,例如人。
在另一个方面,本发明提供了一种培养上清,其为本发明的培养物 的上清液。
在某些优选的实施方案中,所述培养上清不含所述经修饰的间充质 干细胞。
在某些优选的实施方案中,所述培养上清不含血清。
在某些优选的实施方案中,所述培养上清包含基础培养基、或在基 础培养基中添加有一种或多种补充物质(例如血清)的培养液。所述基 础培养基任选地进一步包含一种或多种补充物质(例如血清)。在某些 示例性实施方案中,所述培养上清包含含有或不含有血清的α-MEM培 养基。
本发明的培养上清可以作为药物组合物被配制和施用。这样的药物 组合物可以是医学领域已知的任何形式,例如片剂、丸剂、混悬剂、乳 剂、溶液、凝胶剂、胶囊剂、粉剂、颗粒剂、酏剂、锭剂、栓剂、注射 剂(包括注射液、冻干粉剂)等形式。
在某些优选的实施方案中,如本文所述的培养上清用于在受试者中 治疗代谢病症,或者用于制备在受试者中治疗代谢病症的药物。
在某些优选的实施方案中,所述代谢病症选自肥胖、I型和II型糖 尿病、血脂异常(例如,高脂血症)、非酒精性脂肪肝病(NAFLD)、非 酒精性脂肪性肝炎(NASH)、胰岛素耐受、高胰岛素血症、葡萄糖不耐 受、高血糖、代谢综合征、动脉粥样硬化、冠心病、高血压和其他的代 谢病症,及这些疾病的继发性并发症(例如,糖尿病并发症,如视网膜 病、神经病、肾病以及延缓的创伤愈合)。
在某些优选的实施方案中,所述受试者为哺乳动物,例如人。
在另一个方面,本发明还涉及制备如本文所述的培养上清的方法, 其包括以下步骤:
(1)对本发明的经修饰的间充质干细胞进行培养;和
(2)回收步骤(1)获得的培养物的上清液。
在某些优选的实施方案中,所述方法还包括:(3)对步骤(2)获得的 上清液进行处理,所述处理选自离心、浓缩、溶剂的置换、透析、冷 冻、干燥、冷冻干燥、稀释、脱盐、保存,及其任意组合。
在本发明中,可以使用本领域已知的任何可用于干细胞培养的培养 基以及培养条件对本发明的经修饰的间充质干细胞进行培养。在某些优 选的实施方案中,在步骤(1)中可以使用基础培养基,所述基础培养基任 选地包含一种或多种补充物质(例如血清)。
在某些优选的实施方案中,所述基础培养基选自α-MEM培养基、 DMEM培养基、IMDM培养基、Ham's F12培养基、RPMI1640培养 基,以及上述任一项组合形成的混合培养基(例如,IMDM与HamF12 等量混合而成的IMDM/HamF12培养基)。在某些优选的实施方案中, 所述补充物质可以选自血清(例如,胎牛血清、人血清、羊血清等)、 血清替代物(例如,Knockoutserum replacement(KSR)等)、牛血清白 蛋白(BSA)、抗生素、维生素、矿物质。
在某些示例性实施方案中,在步骤(1)中使用含有或不含有血清的 α-MEM培养基对所述经修饰的间充质干细胞进行培养。
在某些优选的实施方案中,本发明的培养上清不含血清,以提高安 全性。因此,在某些示例性实施方案中,在步骤(1)中,可以使用不含血 清的培养基(例如,基础培养基或无血清培养基)对所述经修饰的间充 质干细胞进行培养,从而获得不含血清的培养上清。在此类实施方案 中,可以在整个培养过程中、或在最后或最后几次的传代培养中使用所述不含血清的培养基进行培养。在某些示例性实施方案中,可以对步骤 (2)获得的培养上清进行透析或溶剂置换,从而去除血清,由此也可得到 不含血清的培养上清。
药物组合物及治疗用途
在另一个方面,本发明提供了一种药物组合物,其包含如本文所述 的经修饰的间充质干细胞、培养物或培养上清。
在某些优选的实施方案中,所述药物组合物包含治疗有效量的所述 经修饰的间充质干细胞或培养物。
在某些优选的实施方案中,所述药物组合物包含如本文所述的经修 饰的间充质干细胞中的一种或多种。
在某些优选的实施方案中,所述药物组合物可以为医学领域已知的 任何形式。例如,所述药物组合物可以是片剂、丸剂、混悬剂、乳剂、 溶液、凝胶剂、胶囊剂、粉剂、颗粒剂、酏剂、锭剂、栓剂、注射剂 (包括注射液、冻干粉剂)等形式。在某些优选的实施方案中,所述药 物组合物为注射剂(包括注射液、冻干粉剂)。
在某些优选的实施方案中,所述药物组合物还包含药学上可接受的 载体或赋形剂。在某些优选的实施方案中,所述药物组合物包含药学上 可接受的无菌等渗水性或非水性溶液(例如,平衡盐溶液或生理盐 水)、分散液、悬浮液或乳液。
在某些优选的实施方案中,所述药物组合物可以以悬浮液、凝胶、 胶体、浆液或混合物的形式进行移植。
关于包含本发明的经修饰的间充质干细胞的药物组合物的配制的一 般原则可参考由G.Morstyn和W.Sheridan编著的《细胞疗法:干细胞 移植,基因疗法和细胞免疫疗法(Cell Therapy:Stem Cell Transplantation,Gene Therapy,and CellularImmunotherapy)》,剑桥 大学出版社,1996;和《造血干细胞疗法(Hematopoietic StemCell Therapy)》,E.D.Ball,J.Lister&P.Law,Churchill Livingstone,2000。
在某些优选的实施方案中,所述药物组合物包含治疗有效量的如本 文所述的培养上清。
在某些优选的实施方案中,所述药物组合物可以为医学领域已知的 任何形式,例如,所述药物组合物可以是片剂、丸剂、混悬剂、乳剂、 溶液、凝胶剂、胶囊剂、粉剂、颗粒剂、酏剂、锭剂、栓剂、注射剂 (包括注射液、冻干粉剂)等形式。在某些优选的实施方案中,所述药 物组合物为注射剂(包括注射液、冻干粉剂)。
在某些优选的实施方案中,所述药物组合物还包含药学上可接受的 载体或赋形剂。在某些优选的实施方案中,所述药物组合物包含药学上 可接受的无菌等渗水性或非水性溶液(例如,平衡盐溶液或生理盐 水)、分散液、悬浮液或乳液。
在某些优选的实施方案中,本发明的药物组合物任选地还包含另外 的药学活性剂。在某些优选的实施方案中,所述另外的药学活性剂选自 抗糖尿病药物、抗肥胖症药物、抗高血压药物、抗动脉粥样硬化药物和 降脂药物。
在本发明中,合适的抗糖尿病药物的非限制性实例包括,噻唑烷二 酮类(如罗格列酮或吡格列酮)、双胍类(如二甲双胍或苯乙双胍)、磺 脲类(如格列美脲、格列本脲、格列齐特、氯磺丙脲或格列吡嗪)、葡 萄糖苷酶抑制剂(如阿卡波糖或米格列醇)、PPAR-α激动剂、PPAR-γ 激动剂、PPAR-α/γ双重激动剂(如莫格他唑)、aP2抑制剂、DPP4抑 制剂(如如西他列汀或维格列汀)、胰岛素敏化剂、胰岛素或氯茴苯酸 类(如瑞格列奈)等。
合适的抗肥胖症药物的非限制性实例包括,β3肾上腺素能激动剂 (如AJ9677(Takeda/Dainippon)、L750355(Merck)或CP331648(Pfize r))、脂酶抑制剂(如奥利司他)、5-羟色胺(和多巴胺)再摄取抑制剂 (如西布曲明或托吡酯)、甲状腺受体β化合物(如WO99/00353和W O 00/039077中公开的化合物)、CB-1拮抗剂(如利莫那班)或厌食药 物(如右旋苯丙胺)。
合适的降脂药物(包括抗动脉粥样硬化药物)的非限制性实例包 括,选自MTP抑制剂、胆固醇酯转移蛋白抑制剂(如CP- 529414(Pfizer))、HMGCoA还原酶抑制剂(如普伐他汀、洛伐他汀、 辛伐他汀、阿托伐他汀、氟伐他汀、西立伐他汀或阿伐他汀)、角鲨烯 合成酶抑制剂(如美国专利US 5,712,396中公开的α-膦酰基-磺酸酯)、 苯乙酸衍生物(如非诺贝特、吉非贝齐、氯贝丁酯、苯扎贝特、环丙贝 特、克利贝特等)、LDL受体活性上调剂(如MD-700(Taisho Pharmaceutical Co.Ltd)和LY295427(Eli Lilly))、脂氧化酶抑制剂(如 WO97/12615中公开的苯并咪唑衍生物、WO 97/12613中公开的15-LO 抑制剂、WO 96/38144中公开的异噻唑酮类)、ACAT抑制剂(如阿伐 麦布)、胆固醇吸收抑制剂、回肠Na<+>/胆汁酸协同转运蛋白抑制剂。
合适的抗高血压药物的非限制性实例包括,β肾上腺素能阻断剂、 钙通道阻断剂(如地尔硫、维拉帕米、硝苯地平、氨氯地平)、利尿剂 (如氯噻嗪、氢氯噻嗪、氟甲噻嗪、氢氟噻嗪、苄氟噻嗪、甲基氯噻 嗪、三氯噻嗪、泊利噻嗪、苄噻嗪、替尼酸、氯噻酮、呋塞米、布美他 尼、阿米洛利或螺内酯)、肾素抑制剂、ACE抑制剂(如卡托普利、佐 芬普利、福辛普利、依那普利、西拉普利、地拉普利、喷托普利、喹那 普利、雷米普利或赖诺普利)、AT-1受体拮抗剂(如氯沙坦、厄贝沙坦 或缬沙坦)、ET受体拮抗剂(如西他生坦或阿曲生坦)、双重ET/AII拮 抗剂(如在WO 00/01389中公开的化合物)、双重NEP-ACE抑制剂 (如奥马曲拉)以及硝酸脂类。
在某些优选的实施方案中,所述药物组合物用于在受试者中治疗代 谢病症。
在某些优选的实施方案中,所述受试者是哺乳动物,例如人。
在某些优选的实施方案中,所述代谢病症选自肥胖、I型和II型糖 尿病、血脂异常(例如,高脂血症)、非酒精性脂肪肝病(NAFLD)、非 酒精性脂肪性肝炎(NASH)、胰岛素耐受、高胰岛素血症、葡萄糖不耐 受、高血糖、代谢综合征、动脉粥样硬化、冠心病、高血压和其他的代 谢病症,及这些疾病的继发性并发症(例如,糖尿病并发症,如视网膜 病、神经病、肾病以及延缓的创伤愈合)。
在另一个方面,本发明涉及如本文所述的经修饰的间充质干细胞、 培养物或培养上清用于在受试者中治疗代谢病症的用途,或者用于制备 在受试者中治疗代谢病症的药物的用途。
在某些优选的实施方案中,所述药物包含治疗有效量的所述经修饰 的间充质干细胞或培养物。
在某些优选的实施方案中,可以组合使用本发明的经修饰的间充质 干细胞。因此,所述药物可以包括本发明的经修饰的间充质干细胞中的 一种或数种。
在某些优选的实施方案中,所述药物可以为医学领域已知的任何形 式。例如,所述药物可以是片剂、丸剂、混悬剂、乳剂、溶液、凝胶 剂、胶囊剂、粉剂、颗粒剂、酏剂、锭剂、栓剂、注射剂(包括注射 液、冻干粉剂)等形式。在某些优选的实施方案中,所述药物为注射剂 (包括注射液、冻干粉剂)。
在某些优选的实施方案中,所述药物还包含药学上可接受的载体或 赋形剂。在某些优选的实施方案中,所述药物包含药学上可接受的无菌 等渗水性或非水性溶液(例如,平衡盐溶液或生理盐水)、分散液、悬 浮液或乳液。
在某些优选的实施方案中,所述药物可以以悬浮液、凝胶、胶体、 浆液或混合物的形式进行移植。
在某些优选的实施方案中,所述药物包含治疗有效量的如本文所述 的培养上清。
在某些优选的实施方案中,所述药物可以为医学领域已知的任何形 式,例如,片剂、丸剂、混悬剂、乳剂、溶液、凝胶剂、胶囊剂、粉 剂、颗粒剂、酏剂、锭剂、栓剂、注射剂(包括注射液、冻干粉剂)等 形式。在某些优选的实施方案中,所述药物为注射剂(包括注射液、冻 干粉剂)。
在某些优选的实施方案中,所述药物还包含药学上可接受的载体或 赋形剂。在某些优选的实施方案中,所述药物包含药学上可接受的无菌 等渗水性或非水性溶液(例如,平衡盐溶液或生理盐水)、分散液、悬 浮液或乳液。
在某些优选的实施方案中,所述药物任选地还包含另外的药学活性 剂。在某些优选的实施方案中,所述另外的药学活性剂选自抗糖尿病药 物、抗肥胖症药物、抗高血压药物、抗动脉粥样硬化药物和降脂药物。
在某些优选的实施方案中,所述代谢病症选自肥胖、I型和II型糖 尿病、血脂异常(例如,高脂血症)、非酒精性脂肪肝病(NAFLD)、非 酒精性脂肪性肝炎(NASH)、胰岛素耐受、高胰岛素血症、葡萄糖不耐 受、高血糖、代谢综合征、动脉粥样硬化、冠心病、高血压和其他的代 谢病症,及这些疾病的继发性并发症(例如,糖尿病并发症,如视网膜 病、神经病、肾病以及延缓的创伤愈合)。
在某些优选的实施方案中,所述受试者是哺乳动物,例如人。
在另一个方面,本发明提供了一种治疗代谢病症的方法,其包括向 有此需要的受试者施用本发明的经修饰的间充质干细胞、培养物、培养 上清、或本发明的药物组合物。
在某些优选的实施方案中,可以组合使用本发明的经修饰的间充质 干细胞。因此,可以向受试者施用本发明的经修饰的间充质干细胞中的 一种或多种。
在某些优选的实施方案中,可以将本发明的经修饰的间充质干细胞 或培养物,作为药物组合物进行配制和施用。这样的药物组合物可包含 治疗有效量的所述经修饰的间充质干细胞或培养物。在某些优选的实施 方案中,所述药物组合物可以是医学领域已知的任何形式。例如,所述 药物组合物可以是片剂、丸剂、混悬剂、乳剂、溶液、凝胶剂、胶囊 剂、粉剂、颗粒剂、酏剂、锭剂、栓剂、注射剂(包括注射液、冻干粉 剂)等形式。在某些优选的实施方案中,所述药物组合物为注射剂(包 括注射液、冻干粉剂)。在某些优选的实施方案中,所述药物组合物还 包含药学上可接受的载体或赋形剂。在某些优选的实施方案中,所述药物组合物包含药学上可接受的无菌等渗水性或非水性溶液(例如,平衡 盐溶液或生理盐水)、分散液、悬浮液或乳液。关于该药物组合物的配 制的一般原则可参考由G.Morstyn和W.Sheridan编著的《细胞疗法: 干细胞移植,基因疗法和细胞免疫疗法(Cell Therapy:Stem Cell Transplantation,Gene Therapy,and Cellular Immunotherapy)》,剑桥 大学出版社,1996;和《造血干细胞疗法(Hematopoietic Stem Cell Therapy)》,E.D.Ball,J.Lister&P.Law,Churchill Livingstone,2000。
在本发明中可以通过各种合适的方式,向受试者施用如本文所述的 经修饰的间充质干细胞或培养物,或包含所述经修饰的间充质干细胞或 培养物的药物组合物。在某些优选的实施方案中,通过局部注射移植 (例如,立体定向脑内注射移植或脊髓局部注射移植)、血液循环途径 移植(例如,静脉内注射移植或动脉内注射移植)或经脑脊液途径移植(例如,腰椎穿刺蛛网膜下腔注射移植)等途径向受试者施用如本文所 述的经修饰的间充质干细胞或药物组合物。本领域技术人员已知如何根 据病灶的位置和性质等选择合适的细胞移植途径。
在某些优选的实施方案中,本发明的经修饰的间充质干细胞、培养 物或药物组合物可以以悬浮液、凝胶、胶体、浆液或混合物的形式进行 移植。
在某些优选的实施方案中,可以将本发明的培养上清,作为药物组 合物进行配制和施用。这样的药物组合物可包含治疗有效量的所述培养 上清。在某些优选的实施方案中,所述药物组合物可以是医学领域已知 的任何形式,例如片剂、丸剂、混悬剂、乳剂、溶液、凝胶剂、胶囊 剂、粉剂、颗粒剂、酏剂、锭剂、栓剂、注射剂(包括注射液、冻干粉 剂)等形式。在某些优选的实施方案中,所述药物组合物为注射剂(包 括注射液、冻干粉剂)。在某些优选的实施方案中,所述药物组合物还 包含药学上可接受的载体或赋形剂。在某些优选的实施方案中,所述药 物组合物包含药学上可接受的无菌等渗水性或非水性溶液(例如,平衡 盐溶液或生理盐水)、分散液、悬浮液或乳液。
在本发明中可以通过各种合适的方式,向受试者施用本发明的培养 上清,或包含所述培养上清的药物组合物。在某些优选的实施方案中, 可以通过皮内注射、皮下注射、肌肉注射、静脉注射、口服给予等途径 施用本发明的培养上清,或包含所述培养上清的药物组合物。
在某些优选的实施方案中,所述方法还包括施用另外的药学活性 剂,所述另外的药学活性剂选自抗糖尿病药物、抗肥胖症药物、抗高血 压药物、抗动脉粥样硬化药物和降脂药物。这种另外的药学活性剂可以 在施用如本文所述的经修饰的间充质干细胞或其培养上清或所述药物组 合物之前、同时或之后施用。
在某些优选的实施方案中,所述方法还包括施用额外的疗法。这种 额外的疗法可以是已知用于代谢病症的任何疗法,例如药物治疗、手术 治疗等。这种额外的疗法可以在施用如上所述的方法之前、同时或之后 施用。
在某些优选的实施方案中,所述受试者是哺乳动物,例如人。
在某些优选的实施方案中,所述代谢病症选自肥胖、I型和II型糖 尿病、血脂异常(例如,高脂血症)、非酒精性脂肪肝病(NAFLD)、非 酒精性脂肪性肝炎(NASH)、胰岛素耐受、高胰岛素血症、葡萄糖不耐 受、高血糖、代谢综合征、动脉粥样硬化、冠心病、高血压和其他的代 谢病症,及这些疾病的继发性并发症(例如,糖尿病并发症,如视网膜 病、神经病、肾病以及延缓的创伤愈合)。
术语定义
在本发明中,除非另有说明,否则本文中使用的科学和技术名词 具有本领域技术人员所通常理解的含义。并且,本文中所用的分子遗 传学、核酸化学、细胞培养、生物化学、细胞生物学等操作步骤均为 相应领域内广泛使用的常规步骤。同时,为了更好地理解本发明,下 面提供相关术语的定义和解释。
如本文中所使用的,术语“外源核酸”是指,人工引入的核苷酸序 列,其相对于未经遗传修饰的细胞而言是外来的。外源核酸包括但不限 于,未在所述细胞基因组中发现的任何基因或核苷酸序列。
如本文中所使用的,术语“FGF21”是指,成纤维细胞生长因子(fib roblastgrowth factor,FGF)蛋白质家族的成员。其氨基酸序列可参见 例如GenBank登录号NP_061986.1,相应的核苷酸序列可参见例如NC BI参考序列号NM_019113.2。
在本发明中,表述“FGF21的变体”是指这样的蛋白,其氨基酸序列 与其所源自的野生型序列(例如,野生型FGF21全长序列,例如,如 SEQ ID NO:1所示的氨基酸序列)相比,具有一个或多个氨基酸的替 换、插入或删除,或者具有至少60%,80%,85%,90%,95%,96%,97%,98%,或99%的序列同一性,并且保留了“FGF21活性”。 因此,本发明所述的“FGF21的变体”也包括野生型蛋白的N端和/或C 端的截短形式。“FGF21变体”的非限制性实例包括,中国专利申请CN2 00980130476.4、CN201180065381.6、CN201280057789.3或CN2015800 70276.X、国际专利申请WO2005/061712、WO2006/028595、WO2006/ 028714、WO2006/065582或WO2008/121563中所描述的那些。所述“F GF21活性”是指天然存在的FGF21的一种或多种生理作用,其是本领 域技术人员熟知的,包括但不限于,结合并激活FGF21受体,例如诱 导不依赖胰岛素的葡萄糖摄入,降低血浆葡萄糖、果糖胺、甘油三酯、胰岛素、高血糖素水平,减少LDL胆固醇和增加HDL胆固醇,增强胰 岛素敏感性等,其详细教导可参见,例如DostálováI等人.Physiol Res. 2009;58(1):1-7;Kharitonenkov A等人.JClin Invest.2005Jun;115(6):1 627-35.
如本文中所使用的,术语“GLP-1”是指,胰高血糖素样肽-1 (glucagon-likepeptide-1)。本领域已知,GLP-1是经翻译后修饰获得 的,并且源自前胰高血糖素原(glucagon preproprotein)。前胰高血糖 素原(glucagon preproprotein)的野生型序列具有NCBI登录号 NP_002045,并且可见于国际专利申请WO98/19698和 WO87/06941A。GLP-1是由前胰高血糖素原的第92-128位氨基酸残基 构成的片段。GLP-1野生型序列的第6位和第7位残基之间的内源性裂 解产生了两种活性形式(天然截短形式):GLP-1(7-37)OH(其野生型 序列如SEQ ID NO:4所示),以及末端进一步酰胺化后形成的GLP- 1(7-36)NH2。
在本发明中,表述“GLP-1的变体”是指这样的蛋白,其氨基酸序列 与其所源自的野生型序列(例如,活性形式GLP-1(7-37)OH的野生型 序列,例如SEQ ID NO:4所示的氨基酸序列)相比,具有一个或多个 氨基酸的替换、插入或删除,或者具有至少60%,80%,85%,90%, 95%,96%,97%,98%,或99%的序列同一性,并且保留了“GLP-1 活性”。因此,本发明所述的“GLP-1的变体”也包括野生型蛋白的N端 和/或C端的截短形式,例如如上所述的GLP-1天然截短形式。“GLP-1 变体”的非限制性实例包括,中国专利申请CN200910173888.8、CN201 010508567.1中所描述的那些。所述“GLP-1活性”是指天然存在的GLP- 1的一种或多种生理作用,其是本领域技术人员已知的,包括但不限 于,结合并激活GLP-1受体,例如对胰岛素分泌的葡萄糖依赖性刺 激、对高血糖素分泌的阻抑、胰岛素(原)生物合成的刺激、食物摄取减 少、胃排空减速等,其详细教导可参见例如Nauck MA等人.Exp Clin Endocrinol Diabetes.1997;105(4):187-95.。
如本文中所使用的,表述“延长蛋白在体内的半衰期”是指,能够阻 止或减缓该蛋白在体内的水解和酶促降解,增加半衰期,和/或改进或 改变其他药代动力学或生物物理学特性,包括但不限于增加吸收速率、 降低毒性、改进溶解度、减少蛋白质聚集等。能够用于延长半衰期的物 质是本领域技术人员熟知的,其非限制性实例包括,免疫球蛋白的Fc结构域、血清白蛋白、转铁蛋白等。
如本文中所使用的,术语“Fc结构域”具有免疫学领域通常赋予该 术语的涵义,尤其指不含有来自该抗体两个抗原结合区(Fab片段)的抗 体片段。Fc结构域由通过非共价相互作用和二硫键结合的抗体的两个 重链恒定区组成。Fc结构域可以包含铰链区,并经CH2和CH3结构域 延伸到抗体C末端。Fc结构域还可以包含一个或多个糖基化位点。Fc 结构域的效应子功能通常由与Fc受体(FcγR)的相互作用或通过结合Clq 和固定补体介导。与FcγR的结合可以导致抗体依赖性细胞介导的细胞 毒性(ADCC),而与补体因子的结合可以导致补体依赖的细胞毒性 (CDC)。因此,当仅利用Fc结构域的延长半衰期活性时,尽量减小效应子功能是重要的,例如可以使用结合FcγR和补体因子的能力相对较 低的免疫球蛋白亚型的Fc结构域(例如IgG4的Fc),或者在天然Fc 结构域进入突变(例如,一个或多个氨基酸的替换)来减小效应子功 能。因此,在本发明中,术语“Fc结构域”包括天然Fc或其变体。所述 变体与其所源自的野生型序列相比,具有一个或多个突变(如,氨基酸 替换、插入或删除),该突变可能影响或参与,或者不影响不参与:(1) 二硫键形成,(2)与选择的宿主细胞的不相容性,(3)在选择的宿主细胞 表达时N-末端异质性,(4)糖基化作用,(5)与补体的相互作用,(6)与补 救受体以外的Fc受体结合,或(7)抗体依赖性的细胞毒性(ADCC)。
如本文中所使用的,术语“接头”是指,由多个氨基酸残基通过肽键 连接形成的线性多肽。本发明的接头可以为人工合成的氨基酸序列,或 天然存在的多肽序列,例如具有铰链区功能的多肽。此类接头多肽是本 领域众所周知的(参见例如,Holliger,P.等人(1993)Proc.Natl.Acad.Sci. USA90:6444-6448;Poljak,R.J.等人(1994)Structure 2:1121-1123)。
如本文中所使用的,术语“培养物”是指,将细胞(例如,本发明的 经修饰的间充质干细胞)在培养基中培养后获得的产物。
如本文中所使用的,术语“培养上清”是指,对细胞(例如,本发明 的经修饰的间充质干细胞)进行培养而得到的不含细胞本身的培养液。 因而,例如可以通过在培养后分离去除细胞成分来得到可用于本发明的 培养上清。该培养上清也可以经过其他处理,例如离心、浓缩、溶剂的 置换、透析、冷冻、干燥、冷冻干燥、稀释、脱盐、保存等。
如本文中所使用的,术语“载体(vector)”是指,可将多聚核苷酸插 入其中的一种核酸运载工具。当载体能使插入的多核苷酸编码的蛋白获 得表达时,载体称为表达载体。载体可以通过转化,转导或者转染导入 宿主细胞,使其携带的遗传物质元件在宿主细胞中获得表达。载体是本 领域技术人员公知的,包括但不限于:质粒;噬菌粒;柯斯质粒;人工染色体,例如酵母人工染色体(YAC)、细菌人工染色体(BAC)或P1来源 的人工染色体(PAC);噬菌体如λ噬菌体或M13噬菌体及动物病毒等。 可用作载体的动物病毒包括但不限于,逆转录酶病毒(包括慢病毒)、腺 病毒、腺相关病毒、疱疹病毒(如单纯疱疹病毒)、痘病毒、杆状病毒、 乳头瘤病毒、乳头多瘤空泡病毒(如SV40)。一种载体可以含有多种控制 表达的元件,包括但不限于,启动子序列、转录起始序列、增强子序 列、选择元件及报告基因。另外,载体还可含有复制起始位点。
如本文中所使用的,术语“启动子”具有本领域技术人员公知的含 义,其是指一段位于基因的上游能启动下游基因表达的非编码核苷酸序 列。组成型(constitutive)启动子是这样的核苷酸序列:当其与编码或者 限定基因产物的多核苷酸可操作地相连时,在细胞的大多数或者所有生 理条件下,其导致细胞中基因产物的产生。诱导型启动子是这样的核苷 酸序列,当可操作地与编码或者限定基因产物的多核苷酸相连时,基本 上只有当对应于所述启动子的诱导物在细胞中存在时,其导致所述基因 产物在细胞内产生。组织特异性启动子是这样的核苷酸序列:当可操作 地与编码或者限定基因产物的多核苷酸相连时,基本上只有当细胞是该 启动子对应的组织类型的细胞时,其才导致在细胞中产生基因产物。
如本文中所使用的,术语“药学上可接受的载体或赋形剂”是指,在 药理学和/或生理学上与受试者和活性成分相容的载体和/或赋形剂,其 是本领域公知的(参见例如Remington's Pharmaceutical Sciences. Edited by Gennaro AR,19thed.Pennsylvania:Mack Publishing Company,1995),并且包括但不限于:pH调节剂,表面活性剂,离子 强度增强剂,维持渗透压的试剂,延迟吸收的试剂,稀释剂,佐剂,防 腐剂等。例如,pH调节剂包括但不限于磷酸盐缓冲液。表面活性剂包 括但不限于阳离子,阴离子或者非离子型表面活性剂,例如Tween- 80。离子强度增强剂包括但不限于氯化钠。维持渗透压的试剂包括但不 限于糖、NaCl及其类似物。延迟吸收的试剂包括但不限于单硬脂酸盐和明胶。稀释剂包括但不限于水,水性缓冲液(如缓冲盐水),醇和多元 醇(如甘油)等。佐剂包括但不限于铝佐剂(例如氢氧化铝),弗氏佐剂 (例如完全弗氏佐剂)等。防腐剂包括但不限于各种抗细菌试剂和抗真 菌试剂,例如硫柳汞,2-苯氧乙醇,对羟苯甲酸酯,三氯叔丁醇,苯 酚,山梨酸等。在某些实施方案中,所述药学上可接受的载体或赋形剂 是无菌等渗水性或非水性溶液(例如,平衡盐溶液或生理盐水)、分散 液、悬浮液或乳液。
如本文中所使用的,术语“治疗”是指,治疗或治愈疾病(例如代谢 病症),延缓疾病(例如代谢病症)的症状的发作,和/或延缓疾病(例 如代谢病症)的发展。
如本文中所使用的,术语“有效量”是指,足以获得或至少部分获得 期望的效果的量。“治疗疾病有效量”是指,足以治愈或至少部分阻止已 患有疾病(例如,代谢病症)的患者的疾病和其并发症的量。测定这样 的有效量完全在本领域技术人员的能力范围之内。例如,对于治疗用途 有效的量将取决于待治疗的疾病的严重度、患者自己的免疫系统的总体状态、患者的一般情况例如年龄、体重和性别,药物的施用方式,以及 同时施用的其他治疗等等。
如本文中所使用的,术语“受试者”包括但不限于各种动物,例如哺 乳动物,例如牛科动物、马科动物、羊科动物、猪科动物、犬科动物、 猫科动物、兔科动物、啮齿类动物(例如,小鼠或大鼠)、非人灵长类 动物(例如,猕猴或食蟹猴)或人。在某些实施方式中,所述受试者 (例如人)患有代谢病症,或者,具有患代谢病症的风险。
发明的有益效果
与现有技术相比,本发明的经修饰的间充质干细胞具有显著的有利 方面。特别地,本发明的经修饰的间充质干细胞展现出显著的协同效 应,能够显著降低受试动物的血糖、血脂,减轻体重,且可安全地施用 给人受试者,而不引发免疫原性反应。因此,本发明的经修饰的间充质 干细胞能够用于治疗代谢病症,具有重大的临床价值。
下面将结合附图和实施例对本发明的实施方案进行详细描述,但是 本领域技术人员将理解,下列附图和实施例仅用于说明本发明,而不是 对本发明的范围的限定。根据附图和优选实施方案的下列详细描述,本 发明的各种目的和有利方面对于本领域技术人员来说将变得显然。
附图说明
图1为PCR扩增产物的电泳图谱,M代表Marker,kFG代表克 隆的FGF21/GLP1-Fc基因片段。
图2为pCDH-FG质粒图谱。
图3为MSC和MSC-FG细胞表面标志流式检测图。
图4为MSC和MSC-FG细胞成脂和成骨分化染色结果图。
图5为Western blot检测MSC和MSC-FG细胞及细胞上清中 FGF21和GLP1-Fc表达量的检测结果。
图6为MSC-FGF21、MSC-GLP1-Fc、MSC-FG的培养上清对葡 萄糖刺激后INS-1细胞Insulin分泌量影响的检测结果。
图7为MSC-FGF21、MSC-GLP1-Fc、MSC-FG的培养上清对固 醇代谢基因SREBP1CmRNA表达水平的影响的检测结果。
图8为糖尿病模型鼠空腹体重趋势图,Liraglutide为药物阳性对照 组,箭头代表给予药物和细胞的时间点,*代表和Con组相比差异显 著,**代表和Con组相比差异极显著。
图9为糖尿病模型鼠空腹血糖趋势图,Liraglutide为药物阳性对照 组,箭头代表给予药物和细胞的时间点,*代表和Con组相比差异显 著,**代表和Con组相比差异极显著。
图10为细胞治疗28天后不同实验组糖尿病模型鼠体型对比图, Liraglutide为药物阳性对照组。
图11为细胞治疗28天后不同实验组糖尿病模型鼠肝脏和腹部皮下 脂肪HE染色图,Liraglutide为药物阳性对照组。
图12为细胞治疗28天后不同实验组糖尿病模型鼠血清中胰岛素水 平检测柱状图,Liraglutide为药物阳性对照组。
图13为细胞治疗28天后不同实验组糖尿病模型鼠血清中血脂水平 检测柱状图,Liraglutide为药物阳性对照组。
序列信息
本发明涉及的部分序列的信息提供于下面的表1中。
表1:序列的描述
具体实施方式
现参照下列意在举例说明本发明(而非限定本发明)的实施例来 描述本发明。
除非特别指明,否则基本上按照本领域内熟知的以及在各种参考 文献中描述的常规方法进行实施例中描述的实验和方法。实施例中未 注明具体条件者,按照常规条件或制造商建议的条件进行。所用试剂 或仪器未注明生产厂商者,均为可以通过市购获得的常规产品。本领域 技术人员知晓,实施例以举例方式描述本发明,且不意欲限制本发明所 要求保护的范围。本文中提及的全部公开案和其他参考资料以其全文通 过引用合并入本文。
实施例1.FGF21/GLP1-Fc修饰的间充质干细胞的制备
1.1自体脂肪干细胞分离培养
采用混合胶原酶消化法分离培养脂肪间充质干细胞(Adipose derivedmesenchymal stem cells,AD-MSCs),具体方法如下:
将吸脂手术吸取的健康成人脂肪组织,转移至50mL离心管中,加 入PBS充分洗涤,1500rpm,离心5分钟,获取上层脂肪组织。按照 1:1:1比例将I、II及IV型胶原酶混合,配制为0.2%混合胶原酶,并按 脂肪组织:胶原酶=1:1的比例将脂肪组织加入混合胶原酶消化液中,置 于37℃摇床中消化脂肪组织30分钟。将消化好的脂肪组织立刻加入 10%FBS的α-MEM细胞培养基(购自Gibco),1500rpm,离心10分 钟,沉降细胞及组织团块。用α-MEM完全培养基重悬细胞,通过 100μm孔径的尼龙网去除未消化的组织。将细胞接种于培养瓶,置于37℃,饱和湿度,5%CO2培养箱中静止培养。2天后,将未贴壁的细胞 倒掉,PBS轻轻洗一遍,加入干细胞完全培养基,待细胞克隆长至 80%融合时,0.05%胰酶消化传代至新培养瓶中。选择P3代细胞,用 0.05%胰酶消化,PBS洗两遍后分别用小鼠抗人CD11b-PE、CD45- PE、HLA-DR-PE、CD73-PE、CD90-PE、CD105-PE、CD34-FITC及 CD19-FITC抗体标记5×105个MSCs,室温避光放置30min,再用PBS 洗两遍后,4%多聚甲醛固定,FACS检测。鉴定合格的细胞冻存于液氮 罐中,用时复苏并做后期处理。
1.2FGF21/GLP1-Fc基因的克隆与载体构建
由中美泰和生物技术(北京)有限公司全基因合成编码FGF21/GLP1- Fc的DNA分子,其中,FGF21(SEQ ID NO:2,编码序列为SEQ ID NO:3)与GLP1-Fc融合蛋白(SEQ ID NO:10,编码序列为SEQ ID NO:11)通过T2A序列(SEQ ID NO:12,编码序列为SEQ ID NO: 13)连接,GLP1-Fc融合蛋白从N端至C端由GLP1(SEQ ID NO: 5)、接头(SEQ ID NO:9)及IgG4-Fc(SEQ ID NO:7)组成,并且其 N端连接有信号肽(SEQ ID NO:22)。该编码FGF21/GLP1-Fc的DNA 分子,命名为pGSI-seq,其核苷酸序列如SEQ ID NO:15所示, FGF21/GLP1-Fc的氨基酸序列如SEQ ID NO:14所示。
以100 ng/μl pGSI-seq为模板,用引物对kspFGF21BamHIF(5’→ 3’:CGCGGATCCGCCACCATGGACTCGGACGAGACC)+IgG4FcSa lIR(5’→3’:ACGCGTCGACTCATTTACCCGGAGACAG)扩增目的 片段kFG(1578bp),并通过琼脂糖凝胶电泳分析扩增产物,其结果如 图1所示,正反向引物分别引入BamHI和SalI酶切位点。将PCR产 物切胶回收后,用BamHI和SalI双酶切,将重组慢病毒载体质粒pCD H-EF1(购自Addgene)也用BamHI和SalI双酶切,酶切产物胶回收后用T4 DNA连接酶连接,4℃连接过夜,转化DH5α感受态细胞,取 100μL菌液涂布至含有氨苄抗性的LB板上,37℃过夜培养。挑取单克 隆进行菌落PCR,将阳性克隆送样测序,保存测序结果正确的克隆并 提取质粒,命名为pCDH-FG,该质粒示意图如图2所示。
1.3携带FGF21/GLP1-Fc的慢病毒载体的制备
从液氮中取出1支冻存的293T细胞(东北农业大学Lab217胚胎 工程实验室赠予)迅速放到37℃水浴中直至冰块消失,逐滴加入含有 5ml预热培养基的15ml离心管中,1200rpm离心3min,弃上清,用 293T培养基(10%FBS+DMEM)重悬细胞接种至150mm培养皿中, 37℃、5%CO2饱和湿度培养。待细胞汇合度达90%以上时,弃去旧培 养基,加入5ml灭菌PBS溶液,轻轻晃动,洗涤细胞后弃去PBS溶 液,加入2ml 0.25%Trypsin-EDTA消化液,消化1-2min直到细胞完全 消化下来。加入含血清的培养基终止消化,细胞悬液1200rpm离心3min,离心所得细胞用培养基重悬,每个150mm培养皿细胞接种 1.2×107细胞用于包装慢病毒,37℃、5%CO2饱和湿度培养,20ml培养 基/皿。
转染前2h,将293T细胞培养基更换为18ml DMEM培养基,向A 灭菌离心管中加入1ml预热的DMEM培养基,然后加入上述1.2中所 制备的pCDH-FG质粒、pHelper1质粒和pHelper2质粒(pCDH-FG: pHelper1:pHelper2=1:1:1,共54μg,pHelper1和pHelper2质粒为慢 病毒包装的辅助质粒,由东北农业大学Lab217胚胎工程实验室赠予), 混合均匀。向B灭菌离心管中加入1ml预热的DMEM培养基,然后加 入108μl Lipofectamin 2000(购自Invitrogen)溶液,混合均匀。A管 和B管在室温下温育5分钟。将B管中的液体成滴的加入到A管中, 混合均匀,室温孵育20min,以便形成DNA-脂质体转染复合物。
将DNA-脂质体混合液转移至预先换液的293T细胞中,混匀, 37℃、5%CO2饱和湿度培养。培养6-8h后吸弃含有转染混和物的培养 基,每皿细胞加入20ml预热的含5%FBS的DMEM培养基,37℃、 5%CO2饱和湿度培养。换液后分别在24h和48h,收集上清液暂存储 于4℃,并换20ml新鲜培养基。将收集到的液体4℃、3500rpm离心 15min,弃沉淀,将上清用Millipore蛋白超滤柱(10KD)进行浓缩, 从而获得携带FGF21/GLP1-Fc的慢病毒载体(Lenti-FGF21/GLP1- Fc);同时进行病毒滴度测定,根据测定结果将病毒稀释为1×108TU/ml,分装后的病毒置于-80℃保存。
1.4间充质干细胞的基因修饰
复苏预先冻存的P3代脂肪间充质干细胞至一个150mm培养皿, 20ml无血清培养基37℃、5%CO2饱和湿度培养。待复苏细胞长满后, 0.05%胰蛋白酶消化细胞,用含血清的培养基终止消化,细胞悬液 800rpm离心5min,离心所得细胞用MSC无血清培养基(购自Bioind)重悬。
每个150mm培养皿细胞接种2-2.5×106细胞,接种后的第二天吸取 细胞的培养基弃掉,更换为无血清的α-MEM培养基,20ml培养基/ 皿,加入16μl Polybrene(购自Sigma),按照40MOIs感染复数加入 1.3中获得的Lenti-FGF21/GLP1-Fc慢病毒(滴度为1×108U/ml), 37℃、5%CO2饱和湿度培养6-8h。6-8小时后弃掉含有病毒的α-MEM 培养基,更换为无血清培养基,37℃5%CO2饱和湿度继续培养2-3 天。待基因编辑后的细胞长满,0.05%胰蛋白酶消化细胞,用含血清的 培养基终止消化,细胞悬液800rpm离心5min,离心所得细胞用无血清 培养基重悬,按照1:6的传代比例进行传代,无血清培养基37℃、 5%CO2培养3天。FGF21/GLP1-Fc基因修饰的间充质干细胞命名为 MSC-FG。
另外,按照上述1.1-1.4中描述的方法制备获得FGF21单基因修饰 的间充质干细胞(MSC-FGF21)以及GLP1-Fc单基因修饰的间充质干 细胞(MSC-GLP1-Fc)。
1.5MSC-FG生物学功能的验证
细胞表型鉴定:选择P6代MSC和MSC-FG,用0.05%胰酶消 化,PBS洗两遍后用小鼠抗人CD14-PerCp-Cy5.5、CD19-PE、CD34- PE、CD45-PE或CD45-FITC、HLA-DR-PE、CD73-PE、CD90-PE及 CD105-PE(Becton,Dickinson and Company)抗体标记MSC,每个 待测样品约1×106个细胞,室温避光孵育30min,PBS洗两遍后,用 2%多聚甲醛固定,用流式细胞仪检测,结果如图3所示。结果显示 Lenti-FGF21/GLP1-Fc慢病毒感染后的MSC细胞(MSC-FG)其表面 marker仍然保持MSC细胞的特性,即CD73、CD90和CD105呈阳性 (>90%),CD14、CD19、CD34、CD45和HLA-DR呈阴性(<1%)。
定向分化诱导:即成脂和成骨诱导,取P6代MSC和MSC-FG, 用0.05%胰酶消化,按照2×105个/孔的细胞密度铺于12孔板中,第2 天更换为成脂诱导培养基和成骨诱导培养基(购买自BI公司),之后每 隔2天换液,成脂诱导于18天后进行油红O染色,成骨诱导于23天后 进行茜素红-S染色,结果如图4所示。结果显示,Lenti-FGF21-GLP1- Fc慢病毒感染后的MSC细胞(MSC-FG)仍然具有成脂和成骨分化能 力。
FGF21及GLP1-Fc表达情况:取MSC和MSC-FG细胞裂解液, 以及MSC和MSC-FG浓缩10倍后的细胞培养上清进行15%SDS- PAGE凝胶电泳,湿转至PVDF膜。5%脱脂牛奶封闭,加入抗体 FGF21(1:3000,Abcam,检测FGF21蛋白表达)和抗体IgG4-HRP (1:3000,Abcam,检测GLP1-Fc蛋白表达),4℃过夜;TBST洗膜 三次,二抗孵育1h;TBST洗膜三次后,用化学发光试剂盒显色,用 计算机图像分析系统曝光,结果如图5所示。结果显示,FGF21/GLP1- Fc双基因修饰的MSC细胞(MSC-FG)上清中有高量的FGF21和 GLP1-Fc存在,细胞内检测到的较少。
实施例2.FGF21/GLP1-Fc修饰的间充质干细胞的体外生物学活性 评价
2.1MSC-FG对葡萄糖刺激的胰岛素分泌的影响
预先准备:在100mm培养中,分别培养实施例1中所获得的 MSC、MSC-FG、MSC-FGF21及MSC-GLP1-Fc细胞,当细胞汇合度 达70%-80%时,吸弃原有MSC无血清培养基,10mlα-MEM培养基, 37℃、5%CO2饱和湿度继续培养48h。收集四种细胞的培养上清,用 超滤柱浓缩10倍,4℃保存备用。长期保存需放置于-80℃冰箱。
从液氮中取出1支冻存的INS-1细胞(大鼠胰岛素瘤细胞,由军事 医学科学院赠予)迅速放入37℃水浴中直至冰块消失,逐滴加入含有 5ml预热培养基的15ml离心管中,1200rpm离心3min,弃上清,用 INS-1培养基(10%FBS+1mM丙酮酸钠+2mM谷氨酰胺+50μM巯基乙 醇+1640培养基)重悬细胞接种至100mm培养皿中,37℃、5%CO2饱 和湿度培养。一般情况下两到三天传一次,传代比例1:3。细胞长满 后,弃去旧培养基,加入2ml灭菌PBS溶液,轻轻晃动,洗涤细胞后 弃去PBS溶液,加入2ml 0.25%Trypsin-EDTA消化液,消化2-3min直到细胞完全消化下来。加入含血清的培养基终止消化,细胞悬液 1200rpm离心3min,离心所得细胞用培养基重悬,在6孔板每孔中接 种为1×106个细胞,加入2ml INS-1培养基,37℃、5%CO2饱和湿度培 养,待细胞密度达70%-80%时即可用于功能验证。
吸弃原有6孔板中INS-1培养基,加入2ml预热的低糖KRBH缓 冲液(129mM NaCl+4.8mM KCl+1.2mM KH2PO4+1.2mM MgSO4+2mM CaCl2+20mM HEPES+24mM NaHCO3+0.2%BSA+0.4 mg/ml glucose)饥饿处理INS-1细胞两小时。吸弃低糖KRBH缓冲 液,加入2ml预热的高糖KRBH缓冲液(129mM NaCl+4.8mM KCl+1.2mM KH2PO4+1.2mM MgSO4+2mM CaCl2+20mMHEPES+24mM NaHCO3+0.2%BSA+3mg/ml glucose),分别加入500 μl预先收集的浓缩的MSC、MSC-FGF21、MSC-GLP1-Fc和MSC-FG 的培养上清,37℃、5%CO2饱和湿度培养2小时。
收集上清,利用放射性免疫原法检测检测培养液中Insulin含量, 结果如图6所示。结果显示,FGF21/GLP1-Fc双基因修饰的MSC细胞 (MSC-FG)的培养上清能够显著刺激INS-1分泌表达胰岛素,且其值 显著高于FGF21单基因修饰的MSC(MSC-FGF21)的培养上清以及 GLP1-Fc单基因修饰的MSC(MSC-GLP1-Fc)的培养上清。由此可 见,FGF21/GLP1-Fc双基因修饰的MSC细胞在调节胰岛素分泌方面展 现出显著的协同作用。
2.2MSC-FG对固醇代基因SREBP1c表达水平的影响
预先准备:在100mm培养中,分别培养实施例1中所获得的 MSC、MSC-FG、MSC-FGF21及MSC-GLP1-Fc细胞,当细胞汇合度 达70%-80%时,吸弃原有MSC无血清培养基,10mlα-MEM培养基, 37℃、5%CO2饱和湿度继续培养48h。收集四种细胞的培养上清,4℃ 保存备用。长期保存需放置于-80℃冰箱。
从液氮中取出的1支冻存的HePG2细胞(人肝癌细胞,由军事医 学科学院赠予)迅速的放37℃水浴中直到冰块消失,逐滴加入含有 5ml预热培养基的15ml离心管中,1200rpm离心3min,弃上清,用 HePG2培养基(10%FBS+DMEM)重悬细胞接种至100mm培养皿 中,37℃、5%CO2饱和湿度培养。一般情况下两到三天传一次,传代 比例1:6。细胞长满后,弃去旧培养基,加入2ml灭菌PBS溶液,轻轻 晃动,洗涤细胞后弃去PBS溶液,加入2ml 0.25%Trypsin-EDTA消化 液,消化2-3min直到细胞完全消化下来。加入含血清的培养基终止消化,细胞悬液1200rpm离心3min,离心所得细胞用培养基重悬,在6 孔板每孔中接种为1×106-2×106个细胞,加入2ml培养基,37℃、 5%CO2饱和湿度培养,待细胞密度达70%-80%时即可用于功能验证。
吸弃原有6孔板中HePG2培养基,加入2ml预先收集的MSC、 MSC-FGF21、MSC-GLP1-Fc和MSC-FG的培养上清,37℃、5%CO2饱和湿度培养24小时。消化细胞,终止离心后,收集细胞用于TRIzol 法RNA提取,测量RNA浓度后,利用反转录试剂盒(All-in-OnecDNASynthesis SuperMix)将500ng总RNA反转为cDNA。
进行RT-qPCR检测,根据Takara的荧光实时定量试剂盒( Premix ExTaqTM)说明书进行。引物序列(5’→3’):SEBP1C-F:CA CTGTGACCTCGCAGATCC;SEBP1C-R:ATAGGCAGCTTCTCCG CATC;β-Actin-F:CCTGGCACCCAGCACAAT;β-Actin-R:GGGCCGGACTCGTCATAC
结果如图7所示,FGF21/GLP1-Fc双基因修饰的MSC细胞(MS C-FG)的培养上清能够显著抑制SREBP1c(肝组织固醇调节元件结合 蛋白-1C)的mRNA表达水平,其抑制活性显著高于MSC-FGF21及M SC-GLP1-Fc的培养上清。由此可见,FGF21/GLP1-Fc双基因修饰的 MSC细胞在调节脂代谢方面展现出显著的协同作用。
实施例3.FGF21/GLP1-Fc修饰的间充质干细胞的体内生物学活性 评价
3.1实验分组
选取30只5周龄的雄性糖尿病模型鼠BKS.Cg- Dock7m+/+Leprdb/Nju(购自南京大学模式动物研究所)。实验分为: 对照组(生理盐水)、利拉鲁肽药物组(药物)、MSC组(细胞)、 MSC-FGF21组(细胞)、MSC-FG组(细胞)和MSC-GLP1-Fc组 (细胞),共6个组,每组5只小鼠。
3.2治疗方案
利拉鲁肽药物组(Liraglutide)给药方式为皮下注射,其余各组给 药方式均为腹腔注射,所有组均要求上午给药。
给药时间:细胞组要求每7天注射一次细胞,一共给予3次细胞。 利拉鲁肽药物组要求每周给予两次药物。
各组给药剂量:
对照组(生理盐水组):每只小鼠每次注射100μl生理盐水,腹腔 注射。
细胞组:每只小鼠每次注射量为1×106细胞/100ul,每7天一次, 腹腔注射。
利拉鲁肽药物组:药物作用浓度为0.5mg/Kg,每3-4天一次,皮下 注射。
3.3检测指标
空腹血糖和空腹体重的测量:注射细胞当天晚上小鼠进行饥饿处理 (断食、水正常供应),小鼠饥饿处理12小时,次日早上进行血糖测量 和体重称重。根据小鼠平均血糖和体重绘制体重变化曲线。
血清生化指标检测:治疗28天后,小鼠眼球取血,3000rpm离心 10min分离血清,样品送至北京北方生科医学技术有限公司进行甘油三 脂(TG)、总胆固醇(TG)、高密度脂蛋白(HDL)、低密度脂蛋白 (LDL)和胰岛素(INS)指标检测。
动物组织苏木素-伊红(HE)染色:治疗28天后,小鼠断颈处死 后,做腹部正中切口,充分暴露腹部,取出小鼠肝脏、和腹部皮下脂 肪,以10倍体积的4%多聚甲醛固定24小时,并进行石蜡包埋、苏木 素-伊红(HE)染色。
3.4实验结果
对BKS糖尿病小鼠进行3次细胞治疗,并从第一次治疗开始每周 测量一次小鼠空腹血糖和体重,停止治疗后继续观测两周数据。小鼠平 均体重和血糖变化曲线分别如图8及图9所示。结果显示,治疗28天 后,MSC-FG细胞治疗组小鼠与对照组小鼠相比体重明显减轻 (*P<0.05),其数值与阳性对照药物Liraglutide相近,且明显优于 MSC-FGF21和MSC-GLP1-Fc组(图8);同时,MSC-FG细胞治疗组 小鼠与对照组小鼠相比空腹血糖差异极显著(*P<0.01),且在第三次细 胞治疗就呈现明显的治疗效果,其趋势与阳性对照药物Liraglutide相 同,且明显优于MSC-FGF21和MSC-GLP1-Fc组(图9)。
治疗28天后,MSC-FG细胞治疗组小鼠的体型也明显小于对照小 鼠体型,且腹部皮下脂肪含量明显减少(图10)。肝组织病理切片HE 染色显示(图11),Con小鼠肝脏呈现严重的脂肪变性,肝组织为脂肪 细胞填充,肝细胞大片坏死,而经MSC-FG细胞治疗后肝脏脂肪变性 明显改善,纤维化程度下降。腹部皮下脂肪HE染色显示(图11), Con组小鼠脂肪细胞过度膨大,且细胞核较不规则;经MSC-FG治疗 后,脂肪细胞体积显著减小。
治疗28天后,经小鼠血清生化检测发现,经MSC-FG治疗后小鼠 在进食后,血清中胰岛素含量明显上升,甚至明显优于阳性对照药物 Liraglutide(图12);并且,经MSC-FG治疗后,小鼠血清中TC(总 胆固醇),LDL(低密度脂蛋白)和HDL(高密度脂蛋白)等物质均显著下降,且要优于MSC-FGF21和MSC-GLP1-Fc组(图13)。
由此可见,MSC-FGF1可明显降低小鼠体重和血糖,同时能够降低 血脂含量,缓解脂肪肝发生,改善血脂代谢异常,修复胰岛细胞功能, 且其疗效要优于MSC-FGF21和MSC-GLP1-Fc组,具备显著的协同作 用,在改善血脂方面也明显优于降糖药物Liraglutide。因此,本发明的 经修饰的MSC特别适用于治疗代谢病症。
尽管本发明的具体实施方式已经得到详细的描述,但本领域技术人 员将理解:根据已经公布的所有教导,可以对细节进行各种修改和变 动,并且这些改变均在本发明的保护范围之内。本发明的全部分为由所 附权利要求及其任何等同物给出。
序列表
<110> 北京吉源生物科技有限公司
<120> 一种双基因修饰的干细胞及其用途
<130> IDC180042
<150> CN 201711374615.0
<151> 2017-12-19
<160> 22
<170> PatentIn version 3.5
<210> 1
<211> 209
<212> PRT
<213> 人工序列
<220>
<223> 野生型FGF21全长序列
<400> 1
Met Asp Ser Asp Glu Thr Gly Phe Glu His Ser Gly Leu Trp Val Ser
1 5 10 15
Val Leu Ala Gly Leu Leu Leu Gly Ala Cys Gln Ala His Pro Ile Pro
20 25 30
Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr
35 40 45
Leu Tyr Thr Asp Asp Ala Gln Gln Thr Glu Ala His Leu Glu Ile Arg
50 55 60
Glu Asp Gly Thr Val Gly Gly Ala Ala Asp Gln Ser Pro Glu Ser Leu
65 70 75 80
Leu Gln Leu Lys Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly Val
85 90 95
Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly Ala Leu Tyr Gly
100 105 110
Ser Leu His Phe Asp Pro Glu Ala Cys Ser Phe Arg Glu Leu Leu Leu
115 120 125
Glu Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala His Gly Leu Pro Leu
130 135 140
His Leu Pro Gly Asn Lys Ser Pro His Arg Asp Pro Ala Pro Arg Gly
145 150 155 160
Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro Ala Leu Pro Glu
165 170 175
Pro Pro Gly Ile Leu Ala Pro Gln Pro Pro Asp Val Gly Ser Ser Asp
180 185 190
Pro Leu Ser Met Val Gly Pro Ser Gln Gly Arg Ser Pro Ser Tyr Ala
195 200 205
Ser
<210> 2
<211> 205
<212> PRT
<213> 人工序列
<220>
<223> FGF21v氨基酸序列
<400> 2
Met Asp Ser Asp Glu Thr Gly Phe Glu His Ser Gly Leu Trp Val Ser
1 5 10 15
Val Leu Ala Gly Leu Leu Leu Gly Ala Cys Gln Ala Asp Ser Ser Pro
20 25 30
Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr Leu Tyr Thr Asp
35 40 45
Asp Ala Gln Gln Thr Glu Ala His Leu Glu Ile Arg Glu Asp Gly Thr
50 55 60
Val Gly Gly Ala Ala Asp Gln Ser Pro Glu Ser Leu Leu Gln Leu Lys
65 70 75 80
Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly Val Lys Thr Ser Arg
85 90 95
Phe Leu Cys Gln Arg Pro Asp Gly Ala Leu Tyr Gly Ser Leu His Phe
100 105 110
Asp Pro Glu Ala Cys Ser Phe Arg Glu Leu Leu Leu Glu Asp Gly Tyr
115 120 125
Asn Val Tyr Gln Ser Glu Ala His Gly Leu Pro Leu His Cys Pro Gly
130 135 140
Asn Lys Ser Pro His Arg Asp Pro Ala Pro Arg Gly Pro Cys Arg Phe
145 150 155 160
Leu Pro Leu Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly Ile
165 170 175
Leu Ala Pro Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ala Met
180 185 190
Val Gly Pro Ser Gln Gly Arg Ser Pro Ser Tyr Ala Ser
195 200 205
<210> 3
<211> 615
<212> DNA
<213> 人工序列
<220>
<223> FGF21v编码核苷酸序列
<400> 3
atggactcgg acgagaccgg gttcgagcac tcaggactgt gggtttctgt gctggctggt 60
cttctgctgg gagcctgcca ggcagactcc agtcctctcc tgcaattcgg gggccaagtc 120
cggcagcggt acctctacac agatgatgcc cagcagacag aagcccacct ggagatcagg 180
gaggatggga cggtgggggg cgctgctgac cagagccccg aaagtctcct gcagctgaaa 240
gccttgaagc cgggagttat tcaaatcttg ggagtcaaga catccaggtt cctgtgccag 300
cggccagatg gggccctgta tggatcgctc cactttgacc ctgaggcctg cagcttccgg 360
gagctgcttc ttgaggacgg atacaatgtt taccagtccg aagcccacgg cctcccgctg 420
cactgcccag ggaacaagtc cccacaccgg gaccctgcac cccgaggacc atgccgcttc 480
ctgccactac caggcctgcc ccccgcactc ccggagccac ccggaatcct ggccccccag 540
ccccccgatg tgggctcctc ggaccctctg gccatggtgg gaccttccca gggccgaagc 600
cccagctacg cttcc 615
<210> 4
<211> 31
<212> PRT
<213> 人工序列
<220>
<223> 野生型GLP-1(7-37)OH氨基酸序列
<400> 4
His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Gly
20 25 30
<210> 5
<211> 31
<212> PRT
<213> 人工序列
<220>
<223> GLP-1v氨基酸序列
<400> 5
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly
20 25 30
<210> 6
<211> 93
<212> DNA
<213> 人工序列
<220>
<223> GLP-1v编码核苷酸序列
<400> 6
catggcgaag ggacctttac cagtgatgta agttcttatt tggaagagca agctgccaag 60
gaattcattg cttggctggt gaaaggcggc gga 93
<210> 7
<211> 228
<212> PRT
<213> 人工序列
<220>
<223> IgG4 Fc 氨基酸序列
<400> 7
Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Ala
1 5 10 15
Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
20 25 30
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
35 40 45
Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val
50 55 60
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser
65 70 75 80
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
85 90 95
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser
100 105 110
Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
115 120 125
Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln
130 135 140
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
145 150 155 160
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
165 170 175
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu
180 185 190
Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser
195 200 205
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
210 215 220
Leu Ser Leu Gly
225
<210> 8
<211> 687
<212> DNA
<213> 人工序列
<220>
<223> IgG4 Fc 编码核酸序列
<400> 8
gagtccaaat atggtccccc atgcccaccc tgcccagcac ctgaggccgc cgggggacca 60
tcagtcttcc tgttcccccc aaaacccaag gacactctca tgatctcccg gacccctgag 120
gtcacgtgcg tggtggtgga cgtgagccag gaagaccccg aggtccagtt caactggtac 180
gtggatggcg tggaggtgca taatgccaag acaaagccgc gggaggagca gttcaacagc 240
acgtaccgtg tggtcagcgt cctcaccgtc ctgcaccagg actggctgaa cggcaaggag 300
tacaagtgca aggtctccaa caaaggcctc ccgtcctcca tcgagaaaac catctccaaa 360
gccaaagggc agccccgaga gccacaggtg tacaccctgc ccccatccca ggaggagatg 420
accaagaacc aggtcagcct gacctgcctg gtcaaaggct tctaccccag cgacatcgcc 480
gtggagtggg aaagcaatgg gcagccggag aacaactaca agaccacgcc tcccgtgctg 540
gactccgacg gctccttctt cctctacagc aggctaaccg tggacaagag caggtggcag 600
gaggggaatg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacacag 660
aagagcctct ccctgtctct gggttga 687
<210> 9
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> Linker
<400> 9
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 10
<211> 276
<212> PRT
<213> 人工序列
<220>
<223> GLP1-Fc氨基酸序列
<400> 10
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Gly Gly Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu
35 40 45
Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro Glu Phe Leu
50 55 60
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
65 70 75 80
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
85 90 95
Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
100 105 110
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
115 120 125
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
130 135 140
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
145 150 155 160
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
165 170 175
Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val
180 185 190
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
195 200 205
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
210 215 220
Pro Val Leu Asp Ser Asp Gly Ser Phe Ala Ala Tyr Ser Arg Leu Thr
225 230 235 240
Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
245 250 255
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
260 265 270
Ser Pro Gly Lys
275
<210> 11
<211> 831
<212> DNA
<213> 人工序列
<220>
<223> GLP1-Fc编码核苷酸序列
<400> 11
catggcgaag ggacctttac cagtgatgta agttcttatt tggaagagca agctgccaag 60
gaattcattg cttggctggt gaaaggcggc ggaggcggag gcggaagcgg aggcggagga 120
agcggcggtg gcggcagcgc tgagtccaaa tatggtcccc catgcccatc atgcccagca 180
cctgagttcc tggggggacc atcagtcttc ctgttccccc caaaacccaa ggacactctc 240
atgatctccc ggacccctga ggtcacgtgc gtggtggtgg acgtgagcca ggaagacccc 300
gaggtccagt tcaactggta cgtggatggc gtggaggtgc ataatgccaa gacaaagccg 360
cgggaggagc agttcaacag cacgtaccgt gtggtcagcg tcctcaccgt cctgcaccag 420
gactggctga acggcaagga gtacaagtgc aaggtctcca acaaaggcct cccgtcctcc 480
atcgagaaaa ccatctccaa agccaaaggg cagccccgag agccacaggt gtacaccctg 540
cccccatccc aggaggagat gaccaagaac caggtcagcc tgacctgcct ggtcaaaggc 600
ttctacccca gcgacatcgc cgtggagtgg gagagcaatg ggcagccgga gaacaactac 660
aagaccacgc ctcccgtgct ggactccgac ggctccttcg ccgcatacag caggctaacc 720
gtggacaaga gcaggtggca ggaggggaat gtcttctcat gctccgtgat gcatgaggct 780
ctgcacaacc actacacaca gaagagcctc tccctgtctc cgggtaaatg a 831
<210> 12
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> T2A氨基酸序列
<400> 12
Glu Gly Arg Gly Ser Leu Leu Thr Cys Gly Asp Val Glu Glu Asn Pro
1 5 10 15
Gly Pro
<210> 13
<211> 54
<212> DNA
<213> 人工序列
<220>
<223> T2A编码核酸序列
<400> 13
gagggcagag gaagtctgct aacatgcggt gacgtcgagg agaatcctgg acct 54
<210> 14
<211> 519
<212> PRT
<213> 人工序列
<220>
<223> FGF21-GLP1-Fc氨基酸序列
<400> 14
Met Asp Ser Asp Glu Thr Gly Phe Glu His Ser Gly Leu Trp Val Ser
1 5 10 15
Val Leu Ala Gly Leu Leu Leu Gly Ala Cys Gln Ala Asp Ser Ser Pro
20 25 30
Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr Leu Tyr Thr Asp
35 40 45
Asp Ala Gln Gln Thr Glu Ala His Leu Glu Ile Arg Glu Asp Gly Thr
50 55 60
Val Gly Gly Ala Ala Asp Gln Ser Pro Glu Ser Leu Leu Gln Leu Lys
65 70 75 80
Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly Val Lys Thr Ser Arg
85 90 95
Phe Leu Cys Gln Arg Pro Asp Gly Ala Leu Tyr Gly Ser Leu His Phe
100 105 110
Asp Pro Glu Ala Cys Ser Phe Arg Glu Leu Leu Leu Glu Asp Gly Tyr
115 120 125
Asn Val Tyr Gln Ser Glu Ala His Gly Leu Pro Leu His Cys Pro Gly
130 135 140
Asn Lys Ser Pro His Arg Asp Pro Ala Pro Arg Gly Pro Cys Arg Phe
145 150 155 160
Leu Pro Leu Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly Ile
165 170 175
Leu Ala Pro Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ala Met
180 185 190
Val Gly Pro Ser Gln Gly Arg Ser Pro Ser Tyr Ala Ser Glu Gly Arg
195 200 205
Gly Ser Leu Leu Thr Cys Gly Asp Val Glu Glu Asn Pro Gly Pro Met
210 215 220
Arg Ala Leu Leu Ala Arg Leu Leu Leu Cys Val Leu Val Val Ser Asp
225 230 235 240
Ser Lys Gly His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr
245 250 255
Leu Glu Glu Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly
260 265 270
Gly Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
275 280 285
Ser Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro
290 295 300
Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
305 310 315 320
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
325 330 335
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
340 345 350
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
355 360 365
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
370 375 380
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
385 390 395 400
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
405 410 415
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
420 425 430
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
435 440 445
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
450 455 460
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Ala Ala Tyr Ser
465 470 475 480
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
485 490 495
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
500 505 510
Leu Ser Leu Ser Pro Gly Lys
515
<210> 15
<211> 1560
<212> DNA
<213> 人工序列
<220>
<223> FGF21-GLP1-Fc编码核苷酸序列
<400> 15
atggactcgg acgagaccgg gttcgagcac tcaggactgt gggtttctgt gctggctggt 60
cttctgctgg gagcctgcca ggcagactcc agtcctctcc tgcaattcgg gggccaagtc 120
cggcagcggt acctctacac agatgatgcc cagcagacag aagcccacct ggagatcagg 180
gaggatggga cggtgggggg cgctgctgac cagagccccg aaagtctcct gcagctgaaa 240
gccttgaagc cgggagttat tcaaatcttg ggagtcaaga catccaggtt cctgtgccag 300
cggccagatg gggccctgta tggatcgctc cactttgacc ctgaggcctg cagcttccgg 360
gagctgcttc ttgaggacgg atacaatgtt taccagtccg aagcccacgg cctcccgctg 420
cactgcccag ggaacaagtc cccacaccgg gaccctgcac cccgaggacc atgccgcttc 480
ctgccactac caggcctgcc ccccgcactc ccggagccac ccggaatcct ggccccccag 540
ccccccgatg tgggctcctc ggaccctctg gccatggtgg gaccttccca gggccgaagc 600
cccagctacg cttccgaggg cagaggaagt ctgctaacat gcggtgacgt cgaggagaat 660
cctggaccta tgagagccct gctggcgcgc ctgcttctct gcgtcctggt cgtgagcgac 720
tccaaaggcc atggcgaagg gacctttacc agtgatgtaa gttcttattt ggaagagcaa 780
gctgccaagg aattcattgc ttggctggtg aaaggcggcg gaggcggagg cggaagcgga 840
ggcggaggaa gcggcggtgg cggcagcgct gagtccaaat atggtccccc atgcccatca 900
tgcccagcac ctgagttcct ggggggacca tcagtcttcc tgttcccccc aaaacccaag 960
gacactctca tgatctcccg gacccctgag gtcacgtgcg tggtggtgga cgtgagccag 1020
gaagaccccg aggtccagtt caactggtac gtggatggcg tggaggtgca taatgccaag 1080
acaaagccgc gggaggagca gttcaacagc acgtaccgtg tggtcagcgt cctcaccgtc 1140
ctgcaccagg actggctgaa cggcaaggag tacaagtgca aggtctccaa caaaggcctc 1200
ccgtcctcca tcgagaaaac catctccaaa gccaaagggc agccccgaga gccacaggtg 1260
tacaccctgc ccccatccca ggaggagatg accaagaacc aggtcagcct gacctgcctg 1320
gtcaaaggct tctaccccag cgacatcgcc gtggagtggg agagcaatgg gcagccggag 1380
aacaactaca agaccacgcc tcccgtgctg gactccgacg gctccttcgc cgcatacagc 1440
aggctaaccg tggacaagag caggtggcag gaggggaatg tcttctcatg ctccgtgatg 1500
catgaggctc tgcacaacca ctacacacag aagagcctct ccctgtctcc gggtaaatga 1560
<210> 16
<211> 33
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 16
cgcggatccg ccaccatgga ctcggacgag acc 33
<210> 17
<211> 28
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 17
acgcgtcgac tcatttaccc ggagacag 28
<210> 18
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 18
cactgtgacc tcgcagatcc 20
<210> 19
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 19
ataggcagct tctccgcatc 20
<210> 20
<211> 18
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 20
cctggcaccc agcacaat 18
<210> 21
<211> 18
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 21
gggccggact cgtcatac 18
<210> 22
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 信号肽
<400> 22
Met Arg Ala Leu Leu Ala Arg Leu Leu Leu Cys Val Leu Val Val Ser
1 5 10 15
Asp Ser Lys Gly
20
Claims (28)
1.一种经修饰的间充质干细胞,其能够表达:(1)第一蛋白,其如SEQ ID NO:2所示;和,(2)第二蛋白,其如SEQ ID NO:10所示;并且,所述第一蛋白和第二蛋白由SEQ ID NO:15编码。
2.权利要求1所述的经修饰的间充质干细胞,其中,所述间充质干细胞来源于脂肪组织、脐带、骨髓或脐血。
3.权利要求1所述的经修饰的间充质干细胞,其中,所述间充质干细胞来源于脂肪组织。
4.一种培养物,其包含权利要求1-3任一项所述的经修饰的间充质干细胞,以及培养基。
5.权利要求4所述的培养物,其中,所述培养基为含有或不含有血清的α-MEM培养基。
6.一种培养上清,其为权利要求4所述的培养物的上清液。
7.权利要求6所述的培养上清,其中,所述培养上清不含所述经修饰的间充质干细胞。
8.权利要求6或7所述的培养上清,其中,所述培养上清不含血清。
9.制备权利要求6-8任一项所述的培养上清的方法,其包括以下步骤:
(1)对权利要求1-3任一项所述的经修饰的间充质干细胞进行培养;和
(2)回收步骤(1)获得的培养物的上清液。
10.权利要求9所述的方法,其中,所述方法还包括:(3)对步骤(2)获得的上清液进行处理,所述处理选自离心、浓缩、溶剂的置换、透析、冷冻、干燥、稀释、脱盐、保存,及其任意组合。
11.权利要求9或10所述的方法,其中,在步骤(1)中使用含有或不含有血清的α-MEM培养基对所述经修饰的间充质干细胞进行培养。
12.一种药物组合物,其包含权利要求1-3任一项所述的经修饰的间充质干细胞、权利要求4或5所述的培养物或权利要求6-8任一项所述的培养上清,以及药学上可接受的载体或赋形剂。
13.权利要求12所述的药物组合物,其中,所述药物组合物包含治疗有效量的所述经修饰的间充质干细胞、培养物或培养上清。
14.权利要求12所述的药物组合物,其中,所述药物组合物为注射剂。
15.权利要求12所述的药物组合物,其中,所述药物组合物包含药学上可接受的无菌等渗水性或非水性溶液、分散液、悬浮液或乳液。
16.权利要求15所述的药物组合物,其中,所述无菌等渗水性或非水性溶液为平衡盐溶液或生理盐水。
17.权利要求12所述的药物组合物,其中,所述药物组合物任选地还包含另外的药学活性剂;其中,所述另外的药学活性剂选自抗糖尿病药物、抗肥胖症药物、抗高血压药物、抗动脉粥样硬化药物和降脂药物。
18.权利要求1-3任一项所述的经修饰的间充质干细胞、权利要求4或5所述的培养物、权利要求6-8任一项所述的培养上清或权利要求12-17任一项所述的药物组合物用于制备在受试者中治疗代谢病症的药物的用途;其中,所述代谢病症选自肥胖、I型和II型糖尿病、血脂异常、胰岛素耐受、高胰岛素血症、葡萄糖不耐受、高血糖、动脉粥样硬化、冠心病。
19.权利要求1-3任一项所述的经修饰的间充质干细胞、权利要求4或5所述的培养物、权利要求6-8任一项所述的培养上清或权利要求12-17任一项所述的药物组合物用于制备在受试者中治疗代谢病症的药物的用途;其中,所述代谢病症是代谢综合征。
20.权利要求18或19所述的用途,其中,所述药物包含治疗有效量的所述经修饰的间充质干细胞培养物、培养上清或药物组合物。
21.权利要求18或19所述的用途,其中,所述药物为注射剂。
22.权利要求18或19所述的用途,其中,所述药物还包含药学上可接受的载体或赋形剂。
23.权利要求18或19所述的用途,其中,所述药物包含药学上可接受的无菌等渗水性或非水性溶液、分散液、悬浮液或乳液。
24.权利要求23所述的用途,其中,所述无菌等渗水性或非水性溶液是平衡盐溶液或生理盐水。
25.权利要求18或19所述的用途,其中,所述药物任选地还包含另外的药学活性剂;其中,所述另外的药学活性剂选自抗糖尿病药物、抗肥胖症药物、抗高血压药物、抗动脉粥样硬化药物和降脂药物。
26.权利要求18所述的用途,其中,所述血脂异常是高脂血症。
27.权利要求18或19所述的用途,其中,所述受试者是哺乳动物。
28.权利要求18或19所述的用途,其中,所述受试者是人。
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WO2019119673A1 (zh) | 2017-12-19 | 2019-06-27 | 北京吉源生物科技有限公司 | 一种双基因修饰的干细胞及其用途 |
CN112279920B (zh) * | 2019-07-25 | 2024-01-16 | 安源医药科技(上海)有限公司 | FGF21 Fc融合蛋白、GLP-1 Fc融合蛋白及它们的组合治疗剂和用途 |
CN110423728A (zh) * | 2019-08-27 | 2019-11-08 | 吉林大学 | 一种间充干细胞的制备方法 |
CN110749579A (zh) * | 2019-08-29 | 2020-02-04 | 西安医学院 | 一种通过免疫荧光检测药物对胰岛细胞摄脂影响的方法 |
CN111849911A (zh) * | 2020-06-28 | 2020-10-30 | 北京纽莱福生物科技有限公司 | 一种经修饰的干细胞及其制备方法和用途 |
CN112175978A (zh) * | 2020-09-22 | 2021-01-05 | 北京贝来生物科技有限公司 | 用于治疗高级别脑胶质瘤的基因修饰间充质干细胞及其制备方法 |
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CN112138025A (zh) * | 2020-09-27 | 2020-12-29 | 东北师范大学 | 一种长效glp-1基因修饰的干细胞制剂、制备方法及其应用 |
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CN112553165A (zh) * | 2020-12-11 | 2021-03-26 | 北京双因生物科技有限公司 | 以修饰的msc培养nk细胞的方法 |
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