CN101227928A - 软骨形成组合物及其使用方法 - Google Patents
软骨形成组合物及其使用方法 Download PDFInfo
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Abstract
本发明提供了治疗关节和盘疾病的方法,该方法包括给予需要这种治疗的对象一种新型的组合物,所述组合物包含基本上纯的细胞群和至少一种生物活性因子,所述生物活性因子能使所述多种细胞的至少一部分细胞表达提高量的至少一种软骨形成标志。
Description
相关申请的交叉引用
本申请要求2005年5月27日提交的临时申请60/685,224的优先权,该使其结合于此作为参考。
发明领域
本发明涉及向盘提供相对容易获得的软骨细胞样细胞来上调基质产生,从而防止盘进一步变性的组合物和方法。
背景
认为椎间盘随年龄增长的进行性变性与细胞密度的降低和软骨特异性基质组分,尤其是蛋白聚糖的合成减少有关。例如,参见S.J.Lipson & H.Muir H.沃尔沃(Volvo)基础科学奖:实验椎间盘变性中的蛋白聚糖(Proteoglycans inExperimental Intervertebral Disc Degeneration),6 SPINE 194-210(1981);A.G.Nerlich等,沃尔沃基础科学研究奖获得者:人体腰椎间盘年龄相关变化的免疫组织学标志(Immunohistologic Markers for Age-related Changes of HumanLumbar Intervertebral Disc),22SPINE 2781-95(1997);R.H.Pearce等,人腰椎间盘的退变及化学组成(Degeneration and the Chemical Composition of theHuman Lumbar Intervertebral Disc),5J.ORTHOP.RES.198-205(1987)。蛋白聚糖减少的一种解决办法是将自体盘细胞植入变性盘。认为这些植入细胞通过上调基质产生来刺激盘。测试了自体盘细胞的植入,表明技术上可行并且生物学上与修复盘损伤和延迟盘变性相关。参见T.Ganey等,犬类模型中的盘软骨细胞移植:治疗变性或受损椎间盘(Disc Chondrocyte Transplantation in a CanineModel:A Treatment for Degenerated or Damaged Intervertebral Disc),28 SPINE2609-20(2003)。然而,采集自体细胞所致供体部位病态和免疫应答的风险限制了这些方法在临床实践中的应用。
发明概述
因此,本发明的目的是向盘提供相对容易获得的软骨细胞样细胞来上调基质产生,从而防止盘进一步变性。
一方面,本发明提供一种包含基本上纯的细胞群和用至少一种生物活性因子强化的组合物,所述生物活性因子能使所述细胞群的至少一部分表达改变量的至少一种软骨形成标志。在本发明的各种实施方式中,所述细胞群选自:骨髓细胞、脂肪细胞和肌细胞。并且,在本发明的一个实施方式中,所述至少一种生物活性因子是LMP-1。
另一方面,本发明提供包含上述组合物与合适的运载体或稀释剂的制剂。在本发明各实施方式中,本发明组合物用适合肌内、静脉内、髓内或关节内注射的液体或半固体运载体配制。
另一方面,本发明提供治疗软骨细胞衍生组织的方法,所述方法包括给予需要这种治疗的对象有效量的上述实施方式之一所述的组合物。在本发明各实施方式中,在有利于分化形成软骨形成细胞的条件下培养所述细胞群。
又一方面,本发明提供治疗软骨细胞衍生组织的方法,所述方法包括给予需要这种治疗的对象有效量的编码所述至少一种生物活性因子的载体。在一个实施方式中,所述至少一种生物活性因子是LMP-1。
附图简要说明
图1是显示Ad-f35-LMP1对盘细胞产生硫酸化-葡萄糖胺聚糖(sGAG)的作用的柱状图。数据按对照组的sGAG值标准化(均值±SEM,每组n=6)。符号“*”表示与对照组相比P<0.05。
图2是显示Ad-LMP1-GFP对盘细胞LMP-1mRNA水平的作用的柱状图。数据按对照组的mRNA表达标准化(均值±SD,每组n=6)。符号“*”表示与对照组相比P<0.05。
图3是显示Ad-f35-LMP1对盘细胞聚集蛋白聚糖mRNA水平的作用的柱状图。数据按对照组的聚集蛋白聚糖值标准化(均值±SEM,每组n=6)。符号“*”表示与对照组相比P<0.05。
图4是显示Ad-f35-LMP1对盘细胞BMP-2mRNA水平的作用的柱状图。数据按对照组的BMP-2mRNA表达标准化(均值±SEM,每组n=6)。符号“*”表示与对照组相比P<0.05。
图5是显示Ad-f35-LMP1对盘细胞BMP-7mRNA水平的作用的柱状图。数据按对照组的BMP-7mRNA表达标准化(均值±SEM,每组n=6)。符号“*”表示与对照组相比P<0.05。
图6是显示Ad-f35-LMP1对盘细胞BMP-9mRNA水平的作用的柱状图。数据按对照组的BMP-9mRNA表达标准化(均值±SEM,每组n=6)。符号“*”表示与对照组相比P<0.05。
发明详述
在本发明中,提供了以下非限制性定义。
本文所用术语“软骨”指关节腔、椎间盘及人体内所有软骨组织。
术语“同种异体移植”和“同种异体”指从相同种类的供体获得的但与受体具有不同遗传组成的组织移植物,例如两人之间的组织移植。
术语“自体移植”和“自体”指同一个体来源或转移。
术语“异种移植”和“异种”指来源于与受体不同种的供体。
术语“椎间盘”和“椎间盘组织”包括终板、髓核和/或纤维环。
术语“载体”指能够将基因序列转运到靶细胞的核酸集合(例如,病毒载体、非病毒载体、微粒载体和脂质体)。术语“表达载体”指包含能够介导感兴趣序列或基因在细胞中表达的启动子的核酸集合。载体的核酸序列通常包含编码可用于选择载体转染细胞的选择性标志。通常,“载体构建物”、“表达载体”和“基因转运载体”指能够介导感兴趣核酸序列表达并且能够将基因序列转运至靶细胞的任何核酸构建物。因此,该术语包括克隆和表达载体以及病毒载体。
术语“治疗”或疾病“疗法”指一种执行方案,包括给予患者(人或其它动物)一种或多种药物来缓解疾病征兆或症状。缓解可在疾病征兆或症状出现之前,以及出现之后发生。因此,“治疗”或“疗法”包括“预防”疾病。此外,“治疗”或“疗法”不要求完全缓解征兆或症状,不要求治愈,具体地包括对患者只有边缘治疗效应的方案。
术语“实施人员”指对患者采用本发明方法和组合物的人。该术语包括但不限于医生、护士、科学家及其它医疗或科研人员。
术语“多能细胞”指能够分化成一种以上细胞类型的细胞。如本文所用,多能细胞包括但不限于间充质细胞。
本文所用术语“LMP-1”包括能使各成员细胞表达至少一种软骨形成标志的生物活性片段及其衍生物和类似物。LMP-1还包括美国专利20030125248(Hair)中使用的LMP,LMP剪接变体包括但不限于WO00/66178(申请号PCT/US00/11664)中描述的物质。如本文所用,LMP还包括美国专利20030180266(McKay)所述的LIM矿化蛋白。所有上述出版物的全部公开内容结合于此作为参考。
本发明方法采用分子生物学领域中的常规技术。一般分子生物学方法的基本书籍包括Sambrook等,Molecular Cloning,A Laboratory Manual(第3版,2001)和Ausubel等,Current Protocols In Molecular Biology(1994)。
一方面,本发明提供一种包含基本上纯的细胞群和用至少一种能使该细胞群中至少一部分细胞分化成软骨形成细胞或软骨形成样细胞的生物活性因子强化的组合物。所述至少一种生物活性因子可刺激本发明细胞群产生至少一种软骨形成标志。所述至少一种生物活性因子包括能直接或间接使所述细胞群的成员表达至少一种软骨形成标志的分子。例如,已知骨形态形成性蛋白2、7和9(分别为BMP-2、BMP-7和BMP-9)能诱导蛋白聚糖的表达。因此,当分子诱导这些或其它BMP的表达时,进而能诱导蛋白聚糖的表达,认为这种分子即是所述的至少一种生物活性因子。在一些实施方式中,所述至少一种生物活性因子指氨基酸序列、其生物活性片段及其衍生物或类似物。在其它实施方式中,所述至少一种生物活性因子包括核酸序列,该核酸序列包含编码能直接或间接使所述细胞群的成员表达至少一种软骨形成标志的核酸序列。因此,包括编码能使细胞群各成员表达至少一种软骨形成标志的LMP-1或其片段的核酸的载体(例如逆转录病毒载体)包括在术语“至少一种生物活性剂因子”的涵义范围内。
文献中,刺激蛋白聚糖合成的一种方法是使用细胞因子。采用几种候选细胞因子如转化生长因子-β(TGF-β1)、BMP-2和BMP-7的初步试验表明,它们能够刺激盘细胞中聚集蛋白聚糖合成速率。参见S.T.Yoon,基因治疗盘变性的前景(The Potential of Gene Therapy for the Treatment of Disc Degeneration),35ORTHOP.CLIN.N.AM.95-100(2004);Y.Zhang等,生长因子成骨蛋白-1:对牛椎间盘中三个不同区域细胞的分化作用(Growth Factor Osteogenic Protein-1:Differing Effects on Cells from Three Distinct Zones in the Bovine IntervertebralDisc),83AM.J.PHYS.MED.REHABIL.515-21(2004);J.Yung Lee等,人椎间盘细胞的三维团粒培养系统的新应用:组织工程的初步表征与潜在应用(NewUse of a Three-dimensional Pellet Culture System for Human Intervertebral DiscCells:Initial Characterization and Potential Use for Tissue Engineering),26 SPINE2316-22(2001)。
本领域技术人员将理解,蛋白聚糖(包括聚集蛋白聚糖)不是唯一的软骨形成标志。在本发明各个实施方式中,至少一种软骨形成标志选自:II型胶原、蛋白聚糖如聚集蛋白聚糖、多能聚糖、或纤维调节素、膜聚糖(lumican)、SOX-9、硫酸化-葡萄糖胺聚糖、软骨细胞增殖、细胞凝集、碱性磷酸酶、X型胶原、以及它们的任意组合。
在本发明一个实施方式中,所述至少一种生物活性因子包括LIM矿化蛋白-1(LMP-1)。LMP-1是一种新的高度保守的细胞内调节蛋白,申请人发现其通过上调多种BMP而促进蛋白聚糖产生。参见S.T.Yoon等,ISSLS奖获得者:体内外试验中LMP-1能上调椎间盘细胞蛋白聚糖BMP的产生(LMP-1Upregulates Intervertebral Disk Cell Production of Proteoglycan s and BMPs InVitro and In Vivo),29SPINE 2603-11(2004)。认为LMP-1是治疗变性盘的优良候选物质,通过上调蛋白聚糖或其它相关胞外基质分子而发挥作用。
本领域普通技术人员将毫无疑问地理解,可用一种核酸序列转化下述适用于本发明的细胞,所述核酸序列包含编码至少一种生物活性因子的核酸序列。所述包含编码至少一种生物活性因子的核酸序列可通过多种方式引入细胞。引入外源性核酸序列的适当方法参见Sambrook和Russel的《分子克隆:实验室手册》(Molecular Cloning:A Laboratory Manual)(第3版),Cold Spring HarborPress,NY,2000。这些方法包括但不限于:物理转移技术,例如显微注射或电穿孔;转染,例如磷酸钙转染;采用脂质体的膜融合转移;病毒转运,例如采用DNA或逆转录病毒载体的转运。
将本发明核酸序列引入适当细胞的其它方法如电穿孔(例如参见Iversen等,核转染电穿孔是人体内皮细胞和平滑肌细胞的最佳非病毒转染技术(Electroporation by nucleofector is the best nonviral transfection technique inhuman endothelial and smooth muscle cells),GENETIC VACCINES AND THER.3:2-14(2005))是本领域普通技术人员显而易见的。所有这些方法在本发明的范围内。
在一个实施方式中,编码至少一种生物活性因子的核酸是病毒载体。适用于本发明的载体包括但不限于:质粒载体和病毒载体。病毒表达载体尤其适用于心脏细胞的有效转导(例如,α病毒、慢病毒、逆转录病毒、腺病毒、腺伴随病毒(AAV)),例如参见Williams和Koch,Annu.Rev.Physiol.66:49(2004);del Monte和Hajjar,J.Physiol.546.1:49(2003)。
在一个实施方式中,载体包括来自细小病毒家族的腺伴随病毒(AAV)。这些载体能将遗传物质插入染色体19上特定位置。本领域普通技术人员将理解,AAV的优点在于,AAV无致病性,大多数用AAV治疗的人不会产生免疫应答清除该病毒。
已证明腺病毒和AAV载体能将转基因有效递送至(包括将转基因导入所需处)心脏细胞,包括衰竭的心肌细胞(例如参见Iwanaga等,J.Clin.Invest.113:727(2004);Seth等,Proc.Natl.Acad.Sci.USA 101:16683(2004);Champion等,Circulation 108:2790(2003);Li等,Gene Ther.10:1807(2003);Vassalli等,Int.J.Cardiol.90:229(2003);del Monte等,Circulation 105:904(2002);Hoshijima等,Nat.Med.8:864(2002);Eizema等,Circulation 101:2193(2000);Miyamoto等,Proc.Natl.Acad.Sci.USA 97:793(2000);He等,Circulation 100:974(1999)。近来报道显示,采用AAV载体在小鼠和仓鼠心肌膜和动脉中持续基因表达超过1年(Li等,Gene Ther.10:1807(2003);Vassalli等,Int.J.Cardiol.90:229(2003))。具体地,已证明基于AAV血清6型的表达载体能有效转导骨骼肌和心肌(例如,Blankinship等,Mol.Ther.10:671(2004))。
包含编码至少一种生物活性因子核酸序列的核酸序列可通过本领域普通技术人员已知的方法来构建,例如参见Sambrook等,Molecular Cloning,ALaboratory Manual(第3版.2001)和Ausubel等,Current Protocols in MolecularBiology(1994)。而且,尤其在包括病毒载体的实施方式中,包含编码至少一种本发明生物活性因子核酸序列的核酸序列可通过多种方法产生,最显著性是采用包装细胞株,例如J.M.Coffin,S.H.Hughes & H.E.Varmus(编),Retroviruses所述的细胞株,冷泉港实验室出版。产生逆转录病毒和体内外感染细胞的其它方法参见Ausubel,F.M.等(编)的《当前的分子生物学方案》(Current Protocols inMolecular Biology),Greene Publishing Associates,(1989),Sections 9.10-9.14。
本领域普通技术人员毫无疑问将理解,至少在一些本发明实施方式中,宜配制能提高转染效率的核酸序列。仅仅通过例子的方式而非限制性的,可将此种核酸序列放在脂质体中。脂质体可通过本领域已知的方法制备,例如Epstein等,Proc.Natl.Acad.Sci.USA,82:3688(1985);Hwang等,Proc.Natl.Acad.Sci.USA,77:4030(1980);美国专利4、485、045和美国专利4、544、545。循环时间延长的脂质体在美国专利5、013、556中描述。
关于LMP-1刺激蛋白聚糖和BMP上调的研究过去仅集中在椎间盘细胞或骨髓细胞上。然而,本发明并不仅限于这些细胞。本发明可采用多种细胞类型,例如不同种类的多能细胞。多能细胞可来源于体内各种组织。在不同的实施方式中,细胞群分离自供体离体组织或尸体组织。组织来源包括但不限于:脂肪组织、肌肉组织、外周血、脐带血、血管、骨骼肌、皮肤、肝和心脏。在本发明的实践中,细胞来源包括全细胞、浓集细胞、滤过细胞、分离细胞以及从组织来源分离的和培养扩增的细胞群。
在一个实施方式中,细胞群的成员是骨髓细胞。这些细胞容易从已有来源获得,可从最不可能发病的人体获得。如果本发明实践中采用骨髓细胞,细胞来源可以是全骨髓、浓集骨髓、滤过骨髓、分离的骨髓细胞以及从骨髓来源分离的和培养扩增的细胞群。注意,骨髓含有间充质细胞群。据报道,移植到软骨中的人间充质干细胞可位点专一地分化成软骨细胞。参见K.W.Liechty等,人间充质干细胞移植入羊子宫内之后显示位点专一性分化(HumanMesenchymal Stem Cells Engraft and Demonstrate Site-specific DifferentiationAfter In Utero Transplantation in Sheep),6 NAT.MED.1282-6(2000)。重要地是,采用人骨髓细胞可消除自体或同种异体盘细胞采集的实际问题而大大缩短临床移植过程中制备细胞所需的时间。
体内外试验显示成人骨髓细胞能分化成软骨细胞。参见D.J.Prockop,骨髓基质细胞可用作非造血组织干细胞(Marrow Stromal Cells as Stem Cells forNon hematopoietic Tissues),276 SCIENCE 71-4(1997);M.F.Pittenger等,成人间充质干细胞的多谱系(分化)潜力(Multilineage Potential of Adult HumanMesenchymal Stem Cells),284 SCIENCE 143-7(1999);P.Bianco等,骨髓基质干细胞:性质、生物学及可能的应用(Bone Marrow Stromal Stem Cells:Nature,Biology,and Potential Applications),19 STEM CELLS 180-92(2001)。据报道表达软骨形成基因的经工程改造的成人骨髓细胞能原位分化成软骨从而修复软骨。参见N.Adachi等,用于治疗全厚度关节软骨缺损的离体基因治疗的肌肉来源细胞(Muscle Derived,Cell Based Ex Vivo Gene Therapy for Treatment ofFull Thickness Articular Cartilage Defects),29 J.RHEUMATOL.1920-30(2002);Y.Gafni等,干细胞用作矫形外科基因疗法的载体(Stem Cells as Vehicles forOrthopedic Gene Therapy),11 GENE THER.417-26(2004)。BMP能够促进间充质干细胞的骨形成分化,但由于盘内环境无血管和氧张力低,间充质干细胞更可能分化成软骨细胞。参见D.A.Puleo,体外间充质细胞反应依赖于与骨形态发生蛋白-2接触的持续时间(Dependence of Mesenchymal Cell Responses onDuration of Exposure to Bone Morphogenetic Protein-2 In Vitro),173 J.CELL.PHYSIOL.93-101(1997);O.Fromigue等,骨形态发生蛋白-2与转化生长因子β2相互作用来调节人骨髓基质细胞增殖与分化(Bone Morphogenetic Protein-2 andTransforming Growth Factor-β2 Interact to Modulate Human Bone Marrow StromalCell Proliferation and Differentiation),68 J.CELL.BIOCHEM.411-26(1998);A.H.Reddi,骨形态发生蛋白、骨髓基质细胞和间充质干细胞:(Bone MorphogeneticProteins,Bone Marrow Stromal Cells,and Mesenchymal Stem Cells):MaureenOwen Revisited,1995 CLIN.ORTHOP.115-9;M.K.Majumdar等,BMP-2和BMP-9促进人多能间充质细胞的软骨形成分化和克服IL-1的抑制作用(BMP-2and BMP-9 Promotes Chondrogenic Differentiation of Human MultipotentialMesenchymal Cells and Overcomes the Inhibitory Effect of IL-1),189 J.CELL.PHYSIOL.275-84(2001)。
总之,LMP-1能够诱导人骨髓细胞,通过上调多种BMP来提高蛋白聚糖和其它软骨形成标志的合成。因此,骨髓细胞是盘变性离体基因疗法的优良候选细胞。
因此,如果能刺激骨髓,尤其是人骨髓(细胞)使之选择性分化成软骨细胞,无论是植入关节或盘或是离体维持,都可用作有效的治疗剂。
本发明细胞群的成员不仅可以是自体来源,也可以是同种异体或者甚至是异种来源。然而,本领域技术人员将理解,采用自体来源的细胞群将能最低程度地减少本发明组合物引起的免疫应答和其它不良反应。
LMP-1植入椎间盘后增强的骨髓细胞可防止和/或逆转盘变性。申请人认为,用LMP-1增强骨髓将产生治疗性软骨形成基质。在一个具体的实施方式中,植入受损盘之后,它能够修复该盘。
在本发明一个实施方式中,如上所述用LMP-1转化的骨髓细胞和间充质细胞一旦植入受损盘将表达能够介导间充质细胞原位分化为软骨的基因,从而修复受损盘软骨。而且,上调的蛋白聚糖,尤其是聚集蛋白聚糖将保护盘免于进一步蛋白水解变性。
本领域普通技术人员毫无疑问将理解,已有一些收集细胞制备本发明细胞群的方法。例如,在以下“实施例”章节中描述了骨髓细胞,包括间充质细胞富集组分的收集。在另一个实施方式中,细胞可来自脂肪细胞。如果选择该实施方式,可在美国专利20050282275(Katz)所述条件下纯化和培养所述细胞。简言之,为了分化为软骨形成细胞,优选以高密度培养细胞(例如,约几百万个细胞/毫升或采用微量压迫技术),也可在低含量血清存在下(例如,约1%到约5%)培养。而且,可在支架上培养细胞形成所需形状。半月板修复治疗可采用的合适方法的非限制性例子,例如可参见美国专利20050234549(Kladakis)。而且,可在生物反应器中培养细胞,例如美国专利6,875,605所述的生物反应器。
如上所述,培养条件对于使本发明细胞群的成员分化成软骨细胞至关重要的。高密度种板,例如约105到约107细胞/毫升,在低氧张力下培养,例如约1%-5%O2有利于刺激培养的细胞群的成员分化成为软骨形成细胞谱系。而且,本领域普通技术人员将发现,在流体静压下培养细胞群的成员然后引入对象具有优点,这种流体静压模拟了日常生活正常活动的物理刺激。在一个实施方式中,流体静压约为1-10MPa。
而且,本领域普通技术人员将理解,甚至可将尚未完全分化的细胞群的成员给予需要的对象。对象体内植入区域的某些物理和化学特征条件将会导致尚未完全分化的细胞群的成员分化成为软骨细胞或软骨细胞样细胞,从而导致对象修复或形成软骨。这些物理和化学特征条件包括压迫力、剪切力、低氧张力(约1%-5%)、相对高压。这些条件组合的合适的非限制性例子包括1,800循环/天或7,200循环/天的1Hz正弦流体静压至5MPa。Elder等,周期性流体静压刺激C3H/10T1/2细胞形成软骨(Cyclic hydrostatic compression stimulateschondroinduction of C3H/10T1/2 cells)BIOMECH MODEL MECHANOBIOL.3(3):141-6(2005).2005年1月25日电子出版。关节和椎间盘具有这种特征条件,因此,如果给予对象时细胞群的成员尚未完全分化,此种条件能刺激细胞群的成员分化成软骨细胞或软骨细胞样细胞。
本领域普通技术人员将理解,本发明组合物可进一步包含至少一种添加剂。所述至少一种添加剂合适的例子包括但不限于:润滑剂、抗炎剂、抗生素、镇痛剂以及它们的组合。
合适的润滑剂的例子包括但不限于:透明质酸、透明质烷、润滑素(lubricin)、聚乙二醇及其任意组合。
合适的抗炎化合物包括甾体和非甾体结构的化合物。合适的甾体抗炎化合物的非限制性例子有皮质类固醇类如氢化可的松、皮质醇、羟基曲安西龙、α-甲基地塞米松、磷酸地塞米松、倍氯美松双丙酸酯、氯倍他索戊酸酯、地奈德、去氧米松、醋酸脱氧皮质酮、地塞米松、二氯松、双醋二氟拉松、二氟可龙戊酸酯、氟羟可舒松(fluadrenolone)、氟氯奈德、氟氢可的松、特戊酸二氟美松、氟西奈德、氟轻松、氟米松丁酯(flucortine butylesters)、氟可龙、醋酸氟泼尼定、氟羟可舒松、哈西奈德、醋酸氢化可的松、氢化可的松丁酸酯、甲泼尼龙、曲安奈德、可的松、可托多松、氟奈德(flucetonide)、氟氢可的松、双醋二氟拉松、氟羟可舒松、氟氢可的松、双醋二氟拉松、氟轻松、丙酮缩氟氢羟龙、甲羟松、安西法尔、安西非特、倍他米松及其酯平衡、氯泼尼松、醋酸氯泼尼松、氯可托龙、地西龙、二氯松、二氟泼尼酯、氟二氯松、氟尼缩松、氟米龙、氟培龙、氟泼尼龙、戊酸氢化可的松、氢化可的松环戊丙酸酯、氢可他酯、甲泼尼松、帕拉米松、泼尼松龙、泼尼松、倍氯美松双丙酸酯、曲安西龙。也可使用上述甾体抗炎化合物的混合物。
非甾体抗炎化合物的非限制性例子包括:萘丁美酮、塞来考昔、依托度酸、尼美舒利、阿帕松(apasone)、金、昔康类如吡罗昔康、伊索昔康、美洛昔康、替诺昔康、舒多昔康和CP-14、304;水杨酸类,例如阿司匹林、双水杨酯、贝诺酯、三水杨酸胆碱镁、萨法波林(safapryn)、搜普林(solprin)、二氟尼柳和芬度柳;醋酸衍生物,例如双氯芬酸、芬氯酸、吲哚美辛、舒林酸、托美丁、伊索克酸、呋罗芬酸、硫平酸、齐多美辛、阿西美辛、芬替酸、佐美酸、环氯茚酸、奥昔平酸、联苯乙酸和酮咯酸;灭酸酯类,例如甲灭酸、甲氯芬那酸、氟芬那酸、尼氟灭酸和托芬那酸;丙酸衍生物,例如布洛芬、萘普生、苯噁洛芬、氟比洛芬、酮洛芬、非诺洛芬、芬布芬、吲哚洛芬、吡洛芬、卡洛芬、奥沙普秦、普拉洛芬、咪洛芬、硫噁洛芬、舒洛芬、阿明洛芬和噻洛芬酸;以及吡唑类,例如保泰松、羟布宗、非普拉宗、阿扎丙宗和三甲保泰松。
该组包括的化合物是本领域技术人员熟知的。非甾体抗炎化合物的化学结构、合成、副作用等详细内容参见一般参考文献,包括《抗炎药与抗风湿药》(Anti-inflammatory and Anti-Rheumatic Drugs),K.D.Rainsford,第I-III卷,CRC出版,Boca Raton,(1985)以及《抗炎药,化学与药学》Anti-inflammatory Agents,Chemistry and Pharmacology 1,R.A.Scherrer等,Academic Press,NewYork(1974),其内容结合于此作为参考。
也可采用这些非甾体抗炎化合物的混合物,以及这些化合物药学上可接受的盐。此外,所谓“天然”抗炎化合物也适用于本发明方法。这些化合物可通过合适的物理和/或化学分离方法从天然来源(例如,植物、真菌、微生物的副产物)提取得到。这些化合物合适的非限制性例子包括:小烛树蜡、α没药醇、芦荟、Manjistha(从茜草属植物提取,尤其是红根(Rubia Cordifolia))和Guggal(从没药属植物提取,尤其是印度穆库尔没药)、可乐树提取物、甘菊、柳珊瑚提取物、甘草家族(甘草属/种植物)的化合物,包括甘草次酸、甘草酸及其衍生物(例如盐和酯)。上述化合物合适的盐包括金属盐和铵盐。合适的酯包括C2-C24饱和或不饱和酸,优选C10-C24,更优选C16-C24的酯。具体例子包括油溶性甘草浸液、甘草酸和甘草次酸本身、甘草酸单铵、甘草酸单钾、甘草酸二钾、1-β-甘草次酸、甘草次酸硬脂酸酯、3-硬脂酰-甘草次酸以及3-琥珀酰氧-β-甘草次酸二钠。
通常,“镇痛剂”的定义包括非甾体抗炎药,因为它们能够缓解疼痛。然而,在本说明书中,非甾体抗炎药包括在抗炎化合物的定义中。因此,本说明书中术语“镇痛剂“的定义不包括抗炎化合物。因此,合适的镇痛剂包括其它类型的化合物,例如阿片类(例如吗啡和纳洛酮)、局部麻醉剂(例如,利多卡因)、谷氨酸受体拮抗剂、α-肾上腺素受体激动剂、腺苷、大麻素、胆碱能和GABA受体激动剂及各种神经肽。各种镇痛剂的详细论述参见Sawynok等,(2003)Pharmacological Reviews,55:1-20,其内容结合于此作为参考。
合适的抗生素包括但不限于:硝基咪唑类抗生素、四环素类、青霉素类、先锋霉素类、碳青霉烯类、氨基糖甙类、大环内酯类抗生素、林肯酰胺类抗生素、4-喹诺酮类、利福霉素类和呋喃妥因类。具体合适的化合物包括但不限于:氨苄西林、阿莫西林、青霉素、苯氧甲基青霉素、巴氨西林、呋喃妥因、羧苄西林、氯唑西林、氨环己青霉素、双氯西林、甲氧西林、苯唑西林、哌拉西林、替卡西林、氟氯西林、头孢呋辛、头孢他美、头孢他美(cefetrame)、头孢克肟(cefixine)、头孢西丁、头孢他啶、头孢唑肟、拉氧头孢、头孢哌酮、头孢曲松、头孢磺啶、头孢噻肟、头孢氨苄、头孢克洛、头孢羟氨苄、头孢噻吩、头孢唑林、头孢泊肟、头孢布烯、氨曲南、替吉莫南、红霉素、地红霉素、罗红霉素、阿奇霉素、克拉霉素、克林霉素、帕地霉素、林可霉素、万古霉素、林可霉素、妥布拉霉素、巴龙霉素、双唑泰栓、替硝唑、奥硝唑、氨氟沙星、西诺沙星、环丙沙星、二氟沙星、依诺沙星、氟罗沙星、诺氟沙星、氧氟沙星、替马沙星、多西环素、米诺环素、四环素、金霉素、土霉素、美他环素、罗利环素、呋喃妥因、萘啶酸、庆大霉素、利福平、阿米卡星、奈替米星、亚胺培南、西司他丁、氯霉素、呋喃唑酮、硝呋齐特、磺胺嘧啶、磺胺甲噁唑、碱式水杨酸铋、胶体次枸橼酸铋、短杆菌肽、美西林、氯羟喹、氯己定、二氯苄醇、甲基-2-苯基酚或它们的任意组合。
而且,此组合物中可加入至少一种能防止细胞外基质裂解的试剂或与能与此组合物一起递送或者在给予本发明组合物之前或之后短时间内递送(例如,8小时内、或4小时、或2小时或1小时内)的试剂。在本发明一个实施方式中,所述至少一种试剂是基质金属蛋白酶(MMP)下调试剂。合适的MMP下调试剂是本领域公知的,非限制性地包括:ONO-4817、金属蛋白酶-1(TIMP-1)的组织抑制剂、金属蛋白酶-2(TIMP-2)的组织抑制剂、金属蛋白酶-3(TIMP-3)的组织抑制剂、金属蛋白酶-4(TIMP-4)的组织抑制剂、化学修饰的四环素-3(CMT-3)、基质金属蛋白酶的5-氨基-2-巯基-1,3,4-噻二唑基抑制剂、多西他赛、槲皮素、绿茶提取物、TNF-α抑制剂、IL-1β抑制剂、p38抑制剂、普啉司他、P16、异黄酮、PCK3145以及它们的任意组合。这些化合物更详细的说明以及合适的非限制性治疗方案例如参见Kim等,抑制通气装置诱导肺损伤的基质金属蛋白酶-9可防止嗜中性炎症(Inhibition of Matrix Metalloprotease-9 Prevents NeutrophilicInflammation in Ventilator-Induced Lung Injury),AM.J.PHYSIOL.LUNG CELLMOL PHYSIOL,2006年5月12日,电子公开早于印刷(Epub ahead of print);Jamloki等,基质金属蛋白酶和细菌胶原酶的某些5-氨基-2-巯基-1,3,4-噻二唑基抑制剂的QSAR分析(QSAR analysis of some 5-amino-2-mercapto-1,3,4-thiadiazole based inhibitors of matrix metalloproteases and bacterial collagenase),BIOORG MED CHEM LETT.2006年5月6日,电子公开早于印刷;Li等,前列腺癌中染料木黄酮通过调节骨保护素/核因子-κB(RANK)/RANK配基/MMP-9信号转导来增强多西他赛的抗肿瘤和抗转移活性(Antitumor andantimetastatic activities of Docetaxel are enhanced by genistein through regulationof osteoprotegerin/receptor activator of nuclear factor-kappaB(RANK)/RANKligand/MMP-9 signaling in prostate cancer),CANCER RES-66(9):4816-25(2006);Vijayababu等,槲皮素下调前列腺癌(PC-3)细胞的基质金属蛋白酶2和9蛋白表达(Quercetin downregulates matrix metalloproteases 2 and 9 proteinsexpression in prostate cancer cells(PC-3)),MOL CELL BiOCHEM.2006年4月28日,电子公开早于印刷;Roomi等,抗坏血酸、赖氨酸、脯氨酸、精氨酸和绿茶提取物对人纤维肉瘤细胞HT-1080的体内外抗肿瘤作用(In vivo and invitro antitumor effect of ascorbic acid,lysine,proline,arginine,and green teaextract on human fibrosarcoma cells HT-1080),MED ONCOL.23:105-11(2006);Sang等,基质金属蛋白酶抑制剂在预防和治疗心血管和肿瘤疾病中的可能应用(Matrix metalloprotease inhibitors as prospective agents for the prevention andtreatment of cardiovascular and neoplastic diseases),CURR TOP MED CHEM.6:289-316(2006);Puli等,异黄酮抑制基质降解酶和侵入人胶质母细胞瘤(U87MG)细胞(Inhibition of matrix degrading enzymes and invasion in humanglioblastoma(U87MG)Cells by isoflavones),J NEUROONGOL.2006年4月6日,电子公开早于印刷,Wang等,P16通过抑制Sp1-介导的基因转录抑制基质金属蛋白酶-2表达(P16 inhibits matrix metalloproteinase-2 expression viasuppression of Sp1-mediated gene transcription),J CELL PHYSIOL.208:246-52(2006);Annabi等,抗转移性PSP94衍生肽PCK3145抑制MMP-9分泌需要细胞表面层粘连蛋白受体信号转导(Inhibition of MMP-9 secretion bythe anti-metastatic PSP94-derived peptide PCK3145 requires cell surface lamininreceptor signaling),ANTICANCER DRUGS,17:429-438(2006)。
另一方面,本发明提供了治疗软骨细胞衍生组织的方法,所述方法包括给予需要的对象有效量的上述任一实施方式所述的组合物。并且,所述组合物可用药学上可接受的运载体或稀释剂来配制。在一个实施方式中,药学上可接受的运载体或稀释剂是液体或半固体。而且,制剂适用于肌内、静脉内、髓内或关节内注射。
可通过几种方式递送组合物,包括但不限于:注入对象体内所需部位(例如关节或椎间盘)、外科手术设置、肌内、静脉内、髓内、或关节内注射、或是上述方式的组合。外科手术设置尤其适合细胞在支架上生长而形成合适的形状。
在另一个实施方式中,本发明提供治疗软骨细胞衍生组织的方法,所述方法包括给予需要的对象有效量的核酸序列,所述核酸序列包含编码至少一种生物活性因子的核酸序列。在该实施方式中,可将包含编码至少一种生物活性因子核酸序列的核酸序列直接注入需要治疗的对象体内。或者,所述核酸序列从位于对象体内需要治疗部位的储器释放。而且,如上所述,此核酸序列包含编码至少一种生物活性因子的核酸序列。
实施例
实施例1
不希望受单一理论的束缚,如果用LMP-1诱导植入的骨髓细胞产生其它BMP,如BMP-2、BMP-7和BMP-9或者甚至是盘基质,则这些细胞提供了离体治疗盘变性的实际细胞来源。如下所述,申请人进行了试验测试人供体的骨髓细胞是否能被过度表达的LMP-1刺激而产生蛋白聚糖和BMP。
人骨髓细胞的制备
通过CBSW有限公司(Cambrex Bio Science Walkersville INC),从3位女性(年龄分别为21、25和35)采集人骨髓和匹配的外周血。该研究得到人类机构调查委员会(Institutional Review Board)批准。后侧髂嵴用骨髓活检穿刺针获取骨髓。进行多次穿刺抽吸30cm3体积的骨髓液,用肝素作为抗凝剂。此外,从同一供体获取约60cm3的外周血,采用柠檬酸盐作为抗凝剂。采集后24小时内,将骨髓和外周血混合并在Magellan系统(美敦力SD公司(Medtronic Sofamor Danek),Memphis,TN)中离心。按标准器材方案离心细胞。取出浓集的人骨髓细胞,包括间充质细胞富集层。用血细胞计数器和Hemavit计数法(CDC Tech INC,Oxford,CT)计数对照孔确定细胞数量。
细胞培养与Ad-f35-LMP1腺病毒转染
由美敦力S有限公司(Medtronic Sofamor Inc)提供含血清型35纤维(F35)的复制缺陷5型腺病毒,该病毒携带有人LMP-1 cDNA,由CMV启动子驱动。该嵌合腺病毒能够通过独立于CAR受体的机制感染人细胞,认为具有较高的感染性。病毒剂量以感染复数(MOI),噬斑形成单位(pfu)/细胞表示。
37℃,在0.5毫升无血清AMEM/F 12间充质干细胞培养基(Cambrex,Walkersville,MD)中,用不同MOI(3.3,10,33和100)的Ad-f35-LMP1病毒感染细胞30分钟。无病毒组用作对照。每管400,000个细胞,治疗组和对照组分别制备六管。然后将细胞以400,000细胞/孔的密度接种到装有1.5毫升含10%胎牛血清(FBS)培养基的6孔板中,治疗组和对照组各6孔。37℃5%CO2湿度下培养细胞6天。第6天,分别合并治疗组和对照组三个孔的细胞和培养基。离心后,收集培养基作蛋白聚糖分析,收集细胞提取RNA。
蛋白聚糖试验
采用1,9二甲基亚甲基蓝(DMMB)试验测定培养液的蛋白聚糖(PG)含量。每孔取20微升(20μl)培养液,在96-孔微量滴定板中与200μl DMMB染料溶液轻轻混合,立即检测520nm波长光密度(OD)。采用硫酸软骨素(西格玛化学公司(Sigm a Chemical),圣路易斯(St.Louis),MO)系列稀释液构建标准曲线。培养液中的PG含量定义为Ad0 5-LMP1处理样品高于对照的倍数。
逆转录和实时PCR
第6天,采用生产商(安氏公司(Ambion inc.),奥斯汀(Austin),TX,美国)指定的RNAqueous试剂盒分离RNA。用DNA酶(安氏公司,奥斯汀,TX,美国)处理RNA去除样品中的DNA污染。用RNA 6000纳米试验方案(安捷仑科技(Agilent Technologies),Waldbronn,德国)测定分离的RNA的浓度。采用以下逆转录反应试剂(应用生物系统公司(Applied Biosystem),福斯特城(Fostercity),CA)。2.5μl 50U/μl Multiscribe逆转录酶;2μl 20U/μl RNA酶抑制剂;22μl 25mM MgCl2溶液;5μl 50μM随机六聚物;10μl IOX PCR缓冲剂II和20gl 12.5mM dNTP与dUTP的混合物,总RNA含量500ng以体积100μl进行逆转录。反应条件为25℃下10分钟,48℃下30分钟,95℃下5分钟。为了证实没有DNA污染。对没有用逆转录酶处理的RNA样品也进行PCR:PCR产物的缺失证实没有DNA污染。
采用SYBR Green实时PCR试剂盒(应用生物系统,福斯特城,CA),用实时PCR方法测定LMP-1、聚集蛋白聚糖、BMP-2、BMP-7和BMP-9的mRNA水平。每份样品25微升(25μl)反应体积包含5μl cDNA、3.75皮可摩尔引物和12.5μl SYBR Green主体混合物。通过以下3步方案进行实时PCR;步骤1:50℃下2分钟,步骤2:95℃下10分钟,步骤3:采用Gene Amp;5700序列检测系统(应用生物系统,福斯特城,CA),(95℃下15秒,60℃下1分钟)×40个循环。为了证实扩增的特异性,对PCR产物进行解离曲线分析。采用比较-ΔΔCt法,按18S标准化各反应的临界循环值(Ct),如上所述。参见S.T.Yoon等,ISSLS获奖者:LMP-1体内外上调椎间盘细胞产生蛋白聚糖和BMP(LMP-1Upregulates Intervertebral Disk Cell Production of Proteoglycans and BMPs In Vitroand In Vivo),29 SPINE 2603-11(2004)。通过在琼脂糖凝胶上测定产物大小和扩增子的DNA序列测定来验证所有基因的引物。
统计学分析
整个实验在三位具有类似结果的人供者中重复6次。提供的所有数据为与对照的比率。用双尾student检验计算p值。数据表示为均值±SEM。采用P<0.05作为统计学显著性的截止点。
DMMB试验表明,与对照组相比,MOI 3.3、10、33和100时蛋白聚糖的产生分别增加1.35、1.58、1.39和1.46倍(图1)。MOI 10时增加具有显著性(P<0.05)。
实时PCR数据表明,与对照组相比,LMP-1的mRNA水平以剂量依赖性方式增加;MOI 3.3、10、33和100时分别为3.28、12.79、18.99和17.65倍;MOI 10、33和100时增加具有显著性(P<0.05)(图2)。
与对照组相比,MOI 3.3、10、33和100时聚集蛋白聚糖的mRNA水平分别增加1.21、2.61、1.78和1.26倍;MOI 10时增加具有显著性(P<0.05)(图3)。
与对照组相比,MOI 3.3、10、33和100时BMP-2的mRNA水平分别增加1.05、2.03、1.15和1.02倍;MOI 10时增加具有显著性(P<0.05)(图4)。
与对照组相比,MOI 3.3、10、33和100时BMP-7的mRNA水平分别为0.88、1.72、0.95和0.78倍;MOI 10时增加具有显著性(P<0.05)(图5)。
最后,与对照组相比,MOI 3.3、10、33和100时BMP-9的mRNA水平为1.23、2.98、1.36和0.87倍;MOI 10时增加具有显著性(P<0.05)(图6)。
结论
已表明,在兔椎间盘细胞中LMP-1的过度表达通过上调BMP-2和BMP-7可提高蛋白聚糖的产生。本文的研究显示采用非盘细胞,尤其是人骨髓细胞结果非常类似。
此外,在此研究中首次检测到LMP-1上调了BMP-9 mRNA水平。据报道BMP-2和BMP-9能促进人多功能间充质细胞的软骨形成(细胞)分化和克服IL-1的抑制作用。参见M.K.Majumdar等,BMP-2和BMP-9促进人多功能间充质细胞的软骨形成(细胞)分化和克服IL-1的抑制作用(BMP-2 and BMP-9 PromotesChondrogenic Differentiation of Human Multipotential Mesenchymal Cells andOvercomes the Inhibitory Effect of IL-1),189 J.CELL.PHYSIOL.275-84(2001)。因此,多种BMP的上调在蛋白聚糖的合成中起着重要作用并导致人骨髓细胞分化为软骨形成细胞。
总之,人骨髓细胞能够被LMP-1诱导通过上调多种BMP而提高蛋白聚糖的合成。因此,这些细胞是椎间盘变形的细胞治疗和基因治疗(包括但不限于离体基因治疗)优良的候选细胞。
本文提及的专利和科技文献建立了本领域技术人员可获得的认知。本文引用的所有美国专利和出版或未出版的美国专利申请结合在此作为参考。本文引用的所有出版的外国专利和专利申请结合在此作为参考。所有其它出版文献、资料、手稿和科技文献结合在此作为参考。
虽然参照优选实施方式具体显示和描述了本发明,本领域技术人员应理解,可对实施形式和细节进行各种改变而不背离权利要求书所涵盖的本发明的范围。
Claims (67)
1.一种组合物,其包含基本上纯的细胞群和至少一种生物活性因子,所述生物活性因子能使所述细胞群的至少一部分表达改变量的至少一种软骨形成标志。
2.如权利要求1所述的组合物,其特征在于,所述基本上纯的细胞群包括至少一种多能细胞。
3.如权利要求2所述的组合物,其特征在于,所述至少一种多能细胞是骨髓细胞。
4.如权利要求3所述的组合物,其特征在于,所述骨髓细胞的提取来源选自:全骨髓、浓集骨髓、滤过骨髓、分离的骨髓以及从骨髓分离和培养扩增的细胞群。
5.如权利要求2所述的组合物,其特征在于,所述至少一种多能细胞是间充质细胞。
6.如权利要求1所述的组合物,其特征在于,所述基本上纯的细胞群的成员是人体细胞。
7.如权利要求6所述的组合物,其特征在于,所述人体细胞获自同种异体移植来源。
8.如权利要求6所述的组合物,其特征在于,所述人体细胞获自自体移植来源。
9.如权利要求1所述的组合物,其特征在于,所述基本上纯的细胞群的成员来源于异种来源。
10.如权利要求1所述的组合物,其特征在于,所述至少一种软骨形成标志选自:II型胶原、蛋白聚糖如聚集蛋白聚糖、多能聚糖、或纤维调节素、膜聚糖、SOX-9、硫酸化-葡萄糖胺聚糖、软骨细胞增殖、细胞凝集、碱性磷酸酶、X型胶原及其任意组合、以及它们的任意组合。
11.如权利要求1所述的组合物,其特征在于,所述至少一种生物活性因子选自:LMP-1、BMP-2、BMP-7、GDF-5、BMP-12、BMP-13、MIA/CD-RAP、TGF-β、FGF、IGF、地塞米松以及它们的任意组合。
12.如权利要求1所述的组合物,其特征在于,所述至少一种生物活性因子是LMP-I。
13.如权利要求1所述的组合物,其特征在于,所述细胞群是培养的。
14.如权利要求1所述的组合物,其特征在于,所述细胞群生长成预先设计的形状。
15.如权利要求14所述的组合物,其特征在于,所述细胞群的成员形成软骨或软骨-样组织。
16.如权利要求15所述的组合物,其特征在于,所述软骨形成在选自以下的人体内:关节腔、椎间盘组织和人体内的软骨组织。
17.如权利要求16所述的组合物,其特征在于,所述椎间盘组织选自终板、核髓和纤维环。
18.如权利要求1所述的组合物,其特征在于,所述组合物还包含至少一种选自以下的添加剂:润滑剂、抗炎剂、抗生素、镇痛剂及其任意组合。
19.一种组合物,其包含基本上纯的细胞群和至少一种生物活性因子,所述生物活性因子能使所述细胞群的至少一部分分化成软骨形成或软骨形成样细胞。
20.如权利要求19所述的组合物,其特征在于,所述基本上纯的细胞群包括至少一种多能细胞。
21.如权利要求20所述的组合物,其特征在于,所述至少一种多能细胞是骨髓细胞。
22.如权利要求21所述的组合物,其特征在于,所述骨髓细胞的提取来源选自:全骨髓、浓集骨髓、滤过骨髓、分离的骨髓以及从骨髓分离和培养扩增的细胞群。
23.如权利要求20所述的组合物,其特征在于,所述至少一种多能细胞是间充质细胞。
24.如权利要求19所述的组合物,其特征在于,所述基本上纯的细胞群的成员是人体细胞。
25.如权利要求24所述的组合物,其特征在于,所述人体细胞获自同种异体移植来源。
26.如权利要求25所述的组合物,其特征在于,所述人体细胞获自自体移植来源。
27.如权利要求19所述的组合物,其特征在于,所述基本上纯的细胞群的成员来源于异种来源。
28.如权利要求19所述的组合物,其特征在于,所述至少一种生物活性因子选自:LMP-1、BMP-2、BMP-7、GDF-5、BMP-12、BMP-13、MIA/CD-RAP、TGF-β、FGF、IGF、地塞米松以及它们的任意组合。
29.如权利要求19所述的组合物,其特征在于,所述至少一种生物活性因子是LMP-1。
30.如权利要求19所述的组合物,其特征在于,所述细胞群是培养的。
31.如权利要求19所述的组合物,其特征在于,所述细胞群生长成预先设计的形状。
32.如权利要求31所述的组合物,其特征在于,所述细胞群的成员形成软骨或软骨-样组织。
33.如权利要求32所述的组合物,其特征在于,所述软骨形成在选自以下的人体内:关节腔、椎间盘组织和人体内的软骨组织。
34.如权利要求33所述的组合物,其特征在于,所述椎间盘组织选自终板、核髓和纤维环。
35.如权利要求19所述的组合物,其特征在于,所述组合物还包含至少一种选自下组的添加剂:润滑剂、抗炎剂、抗生素、镇痛剂及其任意组合。
36.一种包含如权利要求1或权利要求19所述组合物与药学上可接受的运载体或稀释剂的制剂。
37.如权利要求36所述的制剂,其特征在于,所述药学上可接受的运载体或稀释剂是液体或半固体。
38.适用于肌内、静脉内、髓内或关节内注射的如权利要求36所述的制剂。
39.一种治疗软骨细胞衍生组织的方法,所述方法包括给予需要这种治疗的对象有效量的如权利要求1所述的组合物。
40.一种治疗软骨细胞衍生组织的方法,所述方法包括给予需要这种治疗的对象有效量的如权利要求18所述的组合物。
41.如权利要求40所述的方法,其特征在于,权利要求1或权利要求18所述的组合物中所述细胞群的至少一部分用包含编码至少一种生物活性因子的核酸序列的载体转化。
42.如权利要求41所述的方法,其特征在于,所述至少一种生物活性因子是LMP-1。
43.如权利要求40所述的方法,其特征在于,所述权利要求1的组合物包含至少一种间充质细胞。
44.如权利要求40所述的方法,其特征在于,所述细胞群在治疗前获自对象。
45.如权利要求40所述的方法,其特征在于,所述细胞群获自同种异体来源。
46.如权利要求40所述的方法,其特征在于,所述细胞群获自异种来源。
47.如权利要求40所述的方法,其特征在于,所述软骨细胞衍生组织是软骨或软骨样组织。
48.如权利要求40所述的方法,其特征在于,所述软骨细胞衍生组织是椎间盘组织。
49.如权利要求40所述的方法,其特征在于,所述方法还包括给予蛋白聚糖上调因子。
50.如权利要求40所述的方法,其特征在于,所述方法还包括给予至少一种能防止细胞外基质破坏的试剂。
51.如权利要求50所述的方法,其特征在于,所述至少一种试剂是基质金属蛋白酶(MMP)下调试剂。
52.如权利要求50所述的方法,其特征在于,所述至少一种试剂选自:ONO-4817、TIMP-1、TIMP-2、TIMP-3、TIMP-4、CMT-3、基质金属蛋白酶的5-氨基-2-巯基-1,3,4-噻二唑基抑制剂、多西他赛、槲皮素、绿茶提取物、TNF-α抑制剂、IL-1β抑制剂、p38抑制剂、普啉司他、P16、异黄酮、PCK3145以及它们的任意组合。
53.如权利要求50所述的方法,其特征在于,所述细胞外基质位于软骨组织或椎间区域中。
54.如权利要求40所述的方法,其特征在于,所述对象患有盘变形疾病。
55.如权利要求40所述的方法,其特征在于,所述细胞群的成员在体内与生物活性因子接触。
56.如权利要求40所述的方法,其特征在于,所述细胞群的成员在引入受体之前与培养液中的生物活性因子接触。
57.如权利要求40所述的方法,其特征在于,所述组合物在流体静压力下给予对象。
58.如权利要求40所述的方法,其特征在于,所述细胞群的成员在引入对象之前在流体静压力下培养。
59.如权利要求58所述的方法,其特征在于,所述流体静压力模拟日常生活正常活动的物理刺激。
60.如权利要求58所述的方法,其特征在于,所述流体静压力约为1-10MPa。
61.如权利要求40所述的方法,其特征在于,将所述权利要求1的组合物给予对象的低氧张力部位。
62.如权利要求40所述的方法,其特征在于,将所述权利要求1的组合物给予一部位,所述部位的压力能使所述细胞群的成员分化成软骨细胞或软骨细胞样细胞从而修复对象的软骨或形成软骨。
63.如权利要求40所述的方法,其特征在于,所述方法还包括给予对象至少一种选自下组的添加剂:润滑剂、抗炎剂、抗生素、镇痛剂及其任意组合。
64.一种在对象中修复或形成肌腱或韧带的方法,所述方法包括在所述对象肌腱或韧带损伤部位给予所述对象如权利要求1所述的组合物,所述部位的剪切力和张力能使所述工程改造的骨髓细胞分化成软骨细胞或软骨细胞样细胞从而在对象中修复或形成肌腱或韧带。
65.一种在对象中修复或形成肌腱或韧带的方法,所述方法包括在所述对象肌腱或韧带损伤部位给予所述对象如权利要求18所述的组合物,所述部位的剪切力和张力能使所述工程改造的骨髓细胞分化成软骨细胞或软骨细胞样细胞从而在对象中修复或形成肌腱或韧带。
66.一种治疗软骨细胞衍生组织的方法,所述方法包括给予需要这种治疗的对象有效量的多个多能细胞以及有效量的包含编码至少一种生物活性因子的核酸序列的核酸序列。
67.如权利要求65所述的方法,其特征在于,所述至少一种生物活性因子是LMP-1。
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105308176A (zh) * | 2013-03-15 | 2016-02-03 | 迪斯吉尼科斯有限公司 | 从哺乳动物组织分离的椎间盘细胞、使用方法及其制备方法 |
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Families Citing this family (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20080193500A1 (en) * | 2007-02-14 | 2008-08-14 | Mckay William F | Effect of LMP-1 overexpression on large and small proteoglycans of the disc |
EP1986657A4 (en) * | 2006-02-16 | 2011-07-20 | Discogen Llc | METHOD OF TREATING A SUBJECT SUFFERING FROM DEGENERATIVE DISCOPATHY BY A MATRIX METALLOPROTEASE INHIBITOR |
US20070287991A1 (en) * | 2006-06-08 | 2007-12-13 | Mckay William F | Devices and methods for detection of markers of axial pain with or without radiculopathy |
US20080082170A1 (en) * | 2006-09-29 | 2008-04-03 | Peterman Marc M | Apparatus and methods for surgical repair |
CN101678250B (zh) | 2007-03-02 | 2013-04-24 | 史密夫及内修公开有限公司 | 用于在生物样品过滤中通过超声、回洗和过滤器运动进行过滤器清洁的装置和方法 |
US20090110637A1 (en) * | 2007-10-26 | 2009-04-30 | Warsaw Orthopedic, Inc. | LMP and Regulation of Tissue Growth |
KR102006014B1 (ko) * | 2008-03-21 | 2019-08-30 | 코오롱 티슈진 인크. | 추간디스크 퇴행 치료용 조성물 |
CN105030828B (zh) * | 2008-06-25 | 2020-10-02 | 麦瑟布莱斯特公司 | 椎间盘的修复和/或重建 |
AU2009275287B2 (en) | 2008-07-25 | 2015-07-23 | Smith & Nephew Plc | Controller for an acoustic standing wave generation device in order to prevent clogging of a filter |
WO2010109736A1 (ja) * | 2009-03-25 | 2010-09-30 | 国立大学法人鳥取大学 | 軟骨生成促進剤および軟骨損傷由来疾病の予防治療剤 |
US20120114755A1 (en) * | 2009-06-22 | 2012-05-10 | Mayo Foundation For Medical Education And Research | Methods and materials for tissue repair |
JPWO2021100796A1 (zh) * | 2019-11-20 | 2021-05-27 | ||
KR102307115B1 (ko) * | 2021-05-12 | 2021-10-01 | 주식회사 스마트셀랩 | 시프로플록사신에 의한 줄기세포의 연골전구세포로의 유도 및 연골세포로의 분화 |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20030225021A1 (en) * | 2001-11-14 | 2003-12-04 | Mckay William F. | Methods of inducing the expression of bone morphogenetic proteins (BMPs) and transforming growth factor-beta proteins (TGF-betas) in cells |
US7923250B2 (en) * | 1997-07-30 | 2011-04-12 | Warsaw Orthopedic, Inc. | Methods of expressing LIM mineralization protein in non-osseous cells |
EP1007673B1 (en) * | 1997-07-30 | 2008-12-17 | Emory University | Novel bone mineralization proteins, dna, vectors, expression systems |
US6077987A (en) * | 1997-09-04 | 2000-06-20 | North Shore-Long Island Jewish Research Institute | Genetic engineering of cells to enhance healing and tissue regeneration |
US6197586B1 (en) * | 1997-12-12 | 2001-03-06 | The Regents Of The University Of California | Chondrocyte-like cells useful for tissue engineering and methods |
US6849255B2 (en) * | 1998-08-18 | 2005-02-01 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Methods and compositions for enhancing cartilage repair |
US6315992B1 (en) * | 1999-06-30 | 2001-11-13 | Tissuegene Co. | Generating cartilage in a mammal using fibroblasts transfected with a vector encoding TGF-β-1 |
DE60137430D1 (de) * | 2000-07-29 | 2009-03-05 | Smith & Nephew | Gewebeimplant zur wiederherstellung von knorpelgewebe |
CN1281739C (zh) * | 2002-02-19 | 2006-10-25 | 美迪宝斯特有限公司 | 从脐带血中分离并扩大培养间充质干细胞/祖细胞及将脐带血来源的间充质干细胞/祖细胞分化成各种间充质组织的方法 |
EP1660663A4 (en) * | 2003-08-12 | 2007-07-11 | Brigham & Womens Hospital | METHODS AND COMPOSITIONS FOR TISSUE REGENERATION |
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CN111534483B (zh) * | 2020-05-23 | 2020-12-18 | 广东壹加再生医学研究院有限公司 | 一种胰岛素样生长因子结合蛋白7激活剂在人脐带间充质干细胞成软骨分化中的应用 |
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AU2006249302A1 (en) | 2006-11-30 |
WO2006128100A2 (en) | 2006-11-30 |
JP2009518283A (ja) | 2009-05-07 |
US20080292599A1 (en) | 2008-11-27 |
EP1907014A2 (en) | 2008-04-09 |
EP1907014A4 (en) | 2009-03-04 |
US20070009493A1 (en) | 2007-01-11 |
WO2006128100A3 (en) | 2007-03-29 |
CA2609849A1 (en) | 2006-11-30 |
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