CN102037119A - 促进再生的方法、组合物及设备 - Google Patents

促进再生的方法、组合物及设备 Download PDF

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CN102037119A
CN102037119A CN2009801188176A CN200980118817A CN102037119A CN 102037119 A CN102037119 A CN 102037119A CN 2009801188176 A CN2009801188176 A CN 2009801188176A CN 200980118817 A CN200980118817 A CN 200980118817A CN 102037119 A CN102037119 A CN 102037119A
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刘易斯·S·格鲁伯
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Abstract

本发明涉及一种去除干扰再生过程的细胞的设备、组合物及方法。相对于功能细胞而言，所述设备、组合物及方法选择性地杀死具有部分功能和/或无功能的细胞，同时保护功能性增殖细胞达到下述程度：一旦通过破碎或清除来去除已经杀死的细胞，功能细胞就替换所述具有部分功能或无功能的细胞。

Description

促进再生的方法、组合物及设备
相关申请的交叉引用
本申请要求2008年5月23日提交的申请号为No.61/055,846、标题为“METHODS，COMPOSITIONS AND APPARATUS FOR FACILITATING REGENERATION”的美国临时申请的优先权，将上述申请通过引用的方式整体并入本文中。
关于联邦政府资助研发的声明
不适用。
通过引用将光盘上所提交的资料结合到本文中
不适用。
技术领域
总体而言，本发明涉及一种用于促进组织和器官再生的方法、组合物及设备。具体地说，本发明涉及阻止细胞抑制再生过程，从而获得健康方面公认的益处以及与再生结果相关的功能。
背景技术
组织和器官再生的研究集中于通过用可溶因子活化干细胞来刺激再生的需求，或通过破坏与损伤相关的交联来处理具有部分功能或无功能的细胞以改善其功能的需求。上述研究忽视了去除抑制效果的需求。
衰老由多种因素引起，但当且仅当再生干细胞是功能性干细胞的情况下，再生能够克服衰老的影响。干细胞在正常的损耗(normal wear-and-tear)后，对细胞进行替换、使机体结构重新生长并使机体组织更新，以生成替换细胞甚至替换结构(如毛囊)。事实上，如果机体内所有干细胞都被破坏，几天内机体就会死亡。
然而，在多种疾病、机能失常(如男性型秃发)及组织损伤中，当细胞受损或无功能时，并未观察到细胞类型被替换。对于上述情况，有人提出采取干细胞移植疗法，尽管该方法并不总能成功。
在本领域中留下了这样的疑问，即机体具有再生机制时，为何还会屈从于损伤及衰老。
发明内容
本发明提供了将干扰再生过程的细胞去除的设备、组合物及方法，所述细胞通过阻断组织中的某些位置(在这些位置，干细胞后代可改善功能)来干扰再生过程。本发明还降低了具有部分功能及无功能的细胞的比例，而不考虑其在组织中的位置。
本发明的功能性(functionality)被定义为在所选择的健康个体中，相同类型的细胞的运行状态(state of operation)。
本发明的设备、组合物及方法反向地(inversely)基于所述细胞的功能性程度(degree of functionality)，区别性地杀死细胞(即功能性越低，越可能被杀死)，以及采用该技术来促进再生过程。这一杀死细胞的技术优先保留增殖细胞。举例来说，可选取脂褐质(lipofuscin)、糖基化终产物或细胞硬度(cell stiffness)作为具有部分功能性或无功能性的增殖维持的标记物。针对上述标记物的杀死细胞的技术分别包括激光/强光、抗体及超声。依照本发明，可通过例如物理技术、电磁技术、化学技术或生物技术杀死细胞。所述物理技术包括但不限于用于扰乱细胞膜或结构从而引起细胞死亡的超声及其它振动(oscillatory)方法。所述电磁技术包括但不限于致敏剂(例如吸收剂纳米颗粒)EMF(参见例如Litovitz，美国专利No.7,367,988关于EMF方法的记载)、高强度光、无线电波微波(radio waves microwaves)、激光、磁以及电离辐射，并被上述技术作为目标。所述化学技术包括但不限于毒性纳米颗粒、化学毒素以及例如β-氨基丙腈等结构去除化合物(structure removal compounds)。所述生物技术包括但不限于针对具有部分功能或无功能的细胞的抗体及其变种或修饰物，如毒素缀合物(toxin conjugates)以及经过修饰以表达靶特异性抗体的天然杀伤细胞。经确认有效，可组合使用上述技术(如：见McHale等，美国专利No.6,821,274关于通过EMF处理的超声致敏的记载)。当监测确定对促进再生有效时，本发明的设备、方法及组合物可以顺序使用，或同时组合使用。
优选地，相对于相同细胞类型的功能细胞而言，所述设备、组合物及方法选择性地杀死具有部分功能和/或无功能的细胞，并达到下述程度：一旦通过破碎(disintegration)或清除(scavenging)将杀死的细胞去除，功能细胞就将部分功能和/或无功能的细胞替换。本发明的杀死细胞的设备、组合物及方法必须优先保留增殖的功能细胞，同时必须在一定程度上避免过度的炎性反应。
对于所需结果的改善或维持的评估，可用于指导再次应用本发明的设备、组合物及方法的频率。所述应用与再次应用可根据逐渐改善的目标来确定，从而避免无法抵抗的自然机制，比如通过清除性细胞(scavenging cell)去除细胞/碎片。
附图说明
附图表示依照本发明的设备。
具体实施方式
高等多细胞有机体表现为共同发挥作用的特化细胞的群体(community)，它们并不保护每个单独的细胞，而是将该有机体作为一个整体进行保护。在发育中的人体内，发育过程中的细胞通过程序性细胞死亡(即凋亡)去除，以使得组织、器官或整个有机体受益。即使当有机体已到达了成熟期，具有一定损伤的细胞(例如损伤的血细胞)也会被机体破坏，从而让步于替换作用。所述替换细胞源自于干细胞。因此，在成熟的有机体中，细胞更新(cell turnover)是维持年轻/有功能的整体的关键。
只要随时间推移，该破坏作用不降低有机体的功能，所述更新便能以破坏功能细胞为代价而进行。因此，上述破坏作用必须优先靶向具有部分功能或无功能的非增殖细胞，但并不需要完全避免杀死功能细胞和增殖细胞。目标在于保护细胞的群体(如有机体)，而不是单独的细胞。增殖的细胞包括两种：正在分裂的细胞；以及在刺激下正常分裂的细胞(例如干细胞)。
当干细胞参与通常的组织替换时，损伤也可成为诱因从而释放刺激干细胞增殖和分化的一个或多个因子。干细胞可以生成治愈损伤(例如，治愈上皮中的伤口)的细胞。
然而，在正常的细胞补充作用的存在下，干细胞的分裂和分化是不正常的，甚至可引起肿瘤。因此，存在着阻止过度增殖的机制。例如，上皮中某位置存在细胞便阻止了在该处的替换。该种现象的实例是接触抑制(contact inhibition)，即当细胞与其它细胞接触时便停止增殖。所述现象可以归纳为如下规律，即，为了促进干细胞的增殖和分化以使细胞在某位置再生，组织中在此位置不能存在细胞或结构。
在某些情况下，人体既包括破坏结构的细胞(如骨中的破骨细胞)，也包括构建结构的细胞(如骨中的成骨细胞)。两类细胞的活性之间的平衡决定了所得结构的程度。在这个意义上，如果任何内在的机制均未去除细胞/结构以实现周期性的更新，本发明提供了去除作用以促进再生。
处于抑制干细胞作用位置的细胞可以是全功能的、部分功能的或无功能的。死细胞可被清除性巨噬细胞去除，从而使替换成为可能，但机能失常的细胞(malfunctioning cells)仍可能被保留，尽管这会对受试者(即，其是有机体的一部分)产生不良影响。具有部分功能或无功能的细胞，即机能失常的细胞不能发生凋亡，因此也无法自发刺激巨噬细胞的清除作用。可依照本发明杀死这种机能失常的细胞，从而实现利用机体的自然进程清除所述细胞。
癌症治疗中治疗性地杀死细胞的目的是针对增殖的细胞，与本发明刚好相反。依照本发明，通过刺激干细胞增殖使得在细胞分裂中发挥功能的纠错(error-correcting)机制可纠正突变，否则所述突变可在非分裂的细胞中发生累积，由此提供了抗癌作用。
不加限制地，依照本发明的具有部分功能或无功能的细胞由于损伤(如自由基损伤)或与糖反应(即糖基化)引起的交联不是全功能的。由于与受试者的干细胞享有相同遗传组成(genetic makeup)而具有部分功能或无功能的细胞，可被具有全功能遗传组成的外源干细胞替换。
通过组织中某位置的细胞或结构阻断干细胞的作用，干扰了内源干细胞及移植干细胞的作用。阻断干细胞作用的结构不需要是细胞。非细胞的物质(如瘢痕组织)也可以阻断这种再生作用。这一点便可解释再生及干细胞移植中的失败。只要在给定情况下可行，便可依照本发明去除非细胞的阻断结构。
去除阻断的细胞物质和/或非细胞物质后，合适的再生细胞(如干细胞)被保留或通过移植进行补充，从而使再生成为可能。“全功能的(fully functional)”定义如下：在进行干细胞移植或未进行干细胞移植的受试者体内，可获得的干细胞后代所展现出的特定细胞类型的指定功能的程度中，程度更高的那种情况。
依照本发明的设备的实例如图1所示。效应器10是杀死细胞的装置。效应器10可以是超声仪器或抗体给予装置(例如滴注设备)，但不限于此。控制器20是依照预设的参数和/或为保证安全性或有效性而修改的参数，调控效应器10运行的装置。控制器20可以是效应器10的控制面板，但不限于此。在效应器10应用于受试者的条件下，监测器30提供关于炎性反应的程度和/或其他重要因子的信息。来自监测器30的信息可用于调节控制器20，由此调节或改变效应器10的运行。监测器30可以是与控制器20相连的温度计，但不限于此。
与对功能细胞有很大影响的无差别杀灭作用(indiscriminate killing)相反，选择依照本发明的技术，用以优先杀死具有部分功能或无功能的细胞，或去除非细胞的组成部分。通过对功能细胞和具有部分功能的细胞和/或无功能的细胞使用本发明的技术，选择浓度、强度以及例如波长、频率、波形、连续性及处理的持续时间等特征，可选定这一技术。相对于功能细胞，对具有部分功能和/或无功能的细胞可接受的选择性的识别为基础，可选择应用于特定受试者的技术。
本领域技术人员很容易获取适当的选择方法及标准。所述选择方法是相关领域技术人员常规采用的方法，如选择用于去除瘢痕(blemish)的激光治疗水平、通过放射疗法治疗癌症、选择单克隆抗体、选择治疗性使用的毒素及选择用于治疗的超声波性质。依照本发明，所选择的技术可以区分功能细胞以及与所述功能细胞的细胞类型相同的无功能的细胞和/或具有部分功能的细胞。
依据具有部分功能或无功能的细胞与功能细胞间的差异发挥作用的技术，可以基于与功能异常相关的细胞特性，例如，与新生细胞、分裂细胞或功能细胞相反，在老化细胞或衰老细胞中的交联、膜硬度和与脂褐质相关的褐色着色。依照本发明，可以采用如超声的技术，其目标是交联的细胞膜或组分的谐振频率。同样地，依照本发明，也可采用如激光或强光的技术，所述激光或强光具有可优先被具有部分功能或无功能的细胞吸收的波长。
依照本发明的技术可用于在需要的地方进行定点治疗(localize therapy)。可以通过计算机辅助断层成像术、磁共振成像及正电子发射断层成像术实现定位，但不限于这些成像技术。更优选地，依照本发明的技术可应用于整个有机体而无需定位。
一旦选定了针对一个或多个靶的技术，所述技术可以周期性地使用，尤其可在低强度或低浓度的条件下周期性使用，以维持或提高功能细胞与具有部分功能或无功能的细胞间的正平衡。与急促的细胞杀伤相比，逐步的细胞杀伤能够避免来自高水平的细胞破坏产品的毒性影响和/或炎性反应的有害影响。
除治疗性的应用之外，非治疗性应用、非人类应用及工业化应用也包括在本发明的范围内。化妆品的应用、诊断的应用及兽医的应用也在本发明的范围内。在低水平下重复实施本发明的方法可与监测相结合，以确定改善的程度，作为比较受损细胞与遗传因子引起的疾病的组分的诊断测量。就组织和细胞培养物的应用而言，例如，对阻断细胞的破坏可使得所得死细胞及碎片能够被冲洗掉。以这种方式，可通过提高生产性细胞相对于非生产性细胞的相对比例，来提高细胞及组织培养物的生产能力。
实施例
以下实施例仅用于说明的目的，不应被理解为对所要求保护的发明的限制。对本领域技术人员而言，还存在多种可替代的技术和方法，所述技术和方法也可类似地使得本领域的技术人员成功完成预期的发明。
实施例1
在本发明一个实施方式中，糖基化终产物、由糖与蛋白结合而产生的交联被选作与部分功能性或无功能性相关的细胞损伤累积的指标。依照本领域技术人员公知的方法，可产生针对上述糖基化终产物的抗体(如：Abed等，美国专利No 6,380,165；Bucala，美国专利No 5,702,704)，还可依照公知的方法，制备注射用的保留了恒定区的人源化单克隆抗体，所述人源化单克隆抗体使得通过免疫系统破坏靶细胞成为可能(如：Basi等，美国专利No.7,256,273)。依照本发明，通过对抗体进行标记并分别应用于未处理的细胞以及用糖(如核糖)培养的细胞(用于诱导形成糖基化终产物)，可对抗体的有效性进行筛选。与未经糖处理的细胞相反，抗体与事先用糖培养的细胞的结合性更高，表明优先针对所选的靶标发挥作用。
如上所述产生的抗体可通过静脉给予受试者，通过监测来确定例如发烧或肿胀等的炎性反应并未超过公认的安全极限。该过程可每隔一定时间重复进行，以维持再生的水平。该过程可关注于去除特定位置的具有部分功能和/或无功能的细胞(如：干细胞移植靶向的位置)。
对于改善或维持的所需结果的评估，可用于指导依照本发明的抗体再次应用的频率。所述应用与再次应用可根据逐渐改善的目标来确定，从而避免无法抵抗的自然机制，比如通过清除性细胞去除细胞/碎片。
实施例2
在本发明另一个实施方式中，糖基化终产物、由糖与蛋白结合而产生的交联被选作与具有部分功能性或无功能性相关的细胞损伤的累积的指标。所述交联以细胞的硬化显现出来。本领域技术人员了解可以通过硬度将增殖细胞及非增殖细胞进行类型区分(如：Kas等，美国专利No.6,067,859)。
依照本领域技术人员公知的实践，可利用超声装置通过振动技术破坏细胞(如：Chapelon等，美国专利No.5,601,526)。依照本发明，可通过将超声应用于未处理的细胞以及用糖(如核糖)孵育的细胞(用于诱导形成糖基化终产物)，针对选择性破坏更硬的细胞(stiffer cells)方面的有效性，对超声参数(如频率、功率和脉冲)进行筛选。依照本发明，相比超声引起的热破坏，优选超声引起的振动破坏。所选的参数用于优先破坏经糖处理的细胞，而不是事先未经糖处理的细胞，表明本发明优先针对所选的靶标发挥作用。
如上所述的超声可应用于受试者，通过监测确定例如发烧或肿胀等的炎性反应并未超过公认的安全极限。该过程可每隔一定时间重复进行，以维持再生的水平。该过程可关注于去除特定位置的具有部分功能或无功能的细胞(如：干细胞移植靶向的位置)。
对于所需结果的改善或维持的评估，可用于指导依照本发明的超声再次应用的频率。所述应用与再次应用可根据逐渐改善的目标来确定，从而避免无法抵抗的自然机制，比如通过清除性细胞去除细胞/碎片。
本发明从优选实施方式的方面进行了描述，并不意味着本发明局限于此处所记载的实施方式，相反，在合理解释的情况下，本发明包括所附权利要求书范围内的所有实施方式。

Claims (9)

1.一种促进受试者体内再生过程的方法，所述方法包括以下步骤：
a)选择区别性地杀死细胞的技术，所述技术反向地基于所述细胞的功能性程度，并正向地基于对受试者体内非增殖细胞的优先作用；以及
b)应用所述技术以提高具有所述功能性程度的细胞的比例。
2.如权利要求1所述的方法，其中，所述区别性地杀死细胞包括对所述细胞施加超声。
3.如权利要求1所述的方法，其中，所述选择的步骤包括选取抗-糖基化终产物的抗体的剂量水平的步骤。
4.如权利要求1所述的方法，其中，所述方法进一步包括监测炎性反应的步骤。
5.如权利要求1所述的方法，其中，所述选择的步骤包括从基本上由以下技术组成的组中进行选择的步骤：用于扰乱细胞膜或结构从而引起细胞死亡的超声及其它振动方法、EMF、高强度光、无线电波、微波、激光、磁以及电离辐射、化学毒素、针对具有部分功能或无功能的细胞的抗体、抗体-毒素缀合物以及经过修饰以表达靶特异性抗体的天然杀伤细胞。
6.一种用于促进再生过程的方法中的组合物，所述组合物的特征在于，当保护功能性增殖细胞时，基于与所述细胞的功能性程度呈反向关系而区别性地杀死细胞。
7.如权利要求6所述的组合物，其中，所述组合物包括抗-糖基化终产物的抗体。
8.一种用于促进再生过程的方法中的设备，所述设备的特征在于，当保护功能性增殖细胞时，基于所述细胞的功能性程度区别性地杀死细胞。
9.如权利要求8所述的设备，其中，所述设备包括破坏细胞的效应器、检测炎性反应的监测器以及决定所述效应器作用水平的控制器。
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