CN1469752A - 通过给予igf结构类似物治疗中枢神经系统疾病的方法 - Google Patents
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Abstract
本发明涉及治疗哺乳动物包括人脑或脊髓疾病或失调的方法，包括在血－脑、血－中枢神经系统或血－脊髓屏障外的一点给予有效量的胰岛素－样生长因子(IGF)结构类似物。
Description
本专利申请以2000年8月29日递交的美国专利临时申请系列号No.60/228,633的申请为基础。
根据国家神经性疾病和中风研究所拨款Nos.5 RO1 NS24327和9 RO1DK53922，以及疾病控制中心拨款R49 CCR811509，美国政府对本发明享有一定的权利。
发明概述
本发明涉及通过非颅内和非脊柱内给予一种或多种IGF结构类似物来治疗中枢神经系统疾病的方法。更特别地，本发明涉及通过非颅内和非脊柱内给予一种或多种IGF结构类似物来治疗脑部或脊髓失调或疾病的方法。
附图说明
图1.采用ELISA，浓度依赖性检测(A)hIGF-I，(B)Des(1-3)hIGF-I，(C)[Leu24]hIGF-I和(D)[Leu60]hIGF-I。在各个浓度下一式三份测试样品。利用计算机软件程序通过线性回归测定校正系数r。
图2.对成年大鼠皮下注射之后，在CSF和血浆中免疫反应性hIGF-I的剂量-依赖性分布。以一次大剂量皮下注射指定剂量的hIGF-I之后90分钟抽取血浆和CSF进行ELISA试验，每个样品都一式三份进行测试。给出了每组平均值±SEM(n＝3只大鼠/剂量)。A部分，CSF hIGF-I。B部分，血浆hIGF-I。利用线性回归对数据作图，r＝0.97。
图3.皮下给予hIGF-II对于hIGF-I吸收进入CSF的影响。对大鼠皮下注射单独的150微克hIGF-I(n＝8)或者150微克hIGF-I和400微克hlGF-II的组合(n＝6)。于90分钟后抽取血浆和CSF进行测试。测定值是平均值±SEM。利用t-检验比较每组的平均值。*P＜0.02。
图4.给予(Des)(1-3)hIGF-I(n＝4)、hIGF-I(n＝3)或溶媒(n＝2)之后在CSF和血浆中的相对分布。皮下注射等量的(200微克/大鼠）Des(1-3)hIGF-I或hIGF-I90分钟后，抽取血浆和CSF进行测试。采用Newman-Keuhl＇s posthoc检验比较每组平均值之间的差异。相对于CSF中的对照物来说，对于Des和hIGF-I分别是*P＜0.002和0.003。相对于血浆中的对照物来说，对于hIGF-I的*P＜0.002。
图5.[Leu24]hIGF-I和[Leu60]hIGF-I吸收到CSF中。皮下注射[Leu24]hIGF-I(200微克/大鼠；n＝3只大鼠、[Leu60]hIGF-I(100微克/大鼠；n＝4)或hIGF-I(200微克/大鼠；n＝3)或溶媒(n＝9)，90分钟之后抽取血浆和CSF进行测试。A部分，CSF；B部分，血浆。利用Newman-Keuhl＇s posthoc检验确定每组平均值之间的差异。CSF中hIGF-I对[Len24]hIGF-I是*P＜0.002。CSF中[Leu24]和[Leu60]对对照物的*P＜0.0004，hIGF-I对对照物的*P＜0.0007。在血浆中，[Leu24]和[Leu60]对hIGF-I分别是*P＜0.0002和0.0005。[Leu60]和hIGF-I对对照物分别是*P＜0.0005和0.0002。
发明的详细描述
本发明涉及通过非颅内和非脊柱内给予一种或多种IGF结构类似物来治疗中枢神经系统疾病的方法。更特别地，本发明涉及通过非颅内或非脊柱内给予一种或多种IGF结构类似物来治疗脑部或脊髓失调或疾病的方法。对于本发明的目的而言，″IGF结构类似物″定义为具有与天然存在的胰岛素-样生长因子(IGFs)，包括人和动物(包括但不限于牛，猪，狗，羊，马，鹿，山羊，大鼠，小鼠和鸡)的IGF-I和IGF-II，具有基本上序列同源性的分子。更优选地，所述IGF结构类似物具有通过少于15个氨基酸的缺失，替代和/或附加而修饰的IGF分子的氨基酸序列。
在根据本发明的方法中，给予IGF结构类似物的优选途经是从血-脑屏障(BBB)，血-中枢神经系统-屏障(B-CNS-B)和血-脊髓-屏障(B-SC-B)外的一点。可以使用制药学公知的能够将IGF结构类似物传递到循环系统中的任何常规给药途经，包括但不限于经皮，真皮内，皮下，静脉内，肌内，动脉内，腹膜内，肠胃外，口腔，舌下，直肠，口服，鼻，通过吸入，从皮下植入泵或基质，或者从在BBB，B-CNS-B和B-SC-B之外的一给予的包含IGF结构类似物基因的质粒构建体给予。例如，鼻腔和肺血管丰富，并且装IGF结构类似物给予鼻腔或者通过吸入法可以被局部微血管系统快速吸收，导致IGF类似物穿BBB或B-CNS-B吸收到脑脊髓液(CSF)中。除了给药是从BBB，B-CNS-B和B-SC-B外部的一点，本发明不局限于特定的给药途经。
在优选的实施方案中，可以单独地或者与其它IGF类似物联合给予IGF结构类似物。IGF类似物也可以与一种或多种赋形剂，着色剂，盐，溶剂，载体，稳定剂，和可以在配方中使用的并且是药学上公知的其它成分混合。在另一个优选的实施方案中，以大约0.01微克/千克/天直到大约4毫克/千克/天的量给予所述IGF结构类似物。
在优选的实施方案中，本发明涉及治疗出生后脑或脊髓失调或疾病的方法，所述疾病是例如早老性痴呆，帕金森氏病，AIDS-相关性痴呆，老年性痴呆，中风，外伤，皮层基底神经节综合症，渐进性痴呆，带有痉挛性下肢轻瘫的家族性痴呆，渐进性核上性麻痹，多发性硬化，肝脑病变，皮克病，亨廷顿舞蹈病，弥散性希尔德脑硬化，急性引起坏死性出血的脑脊髓炎，脑肿瘤等。本发明不包括肌萎缩性侧索硬化。
可以在本发明中使用的IGF结构类似物包括但不限于des(1-3)IGF-I，其是缺失N-末端三肽的IGF-I类似物；[Arg3]IGF-I，其是其中Arg取代3位的Glu的IGF-I类似物；[Leu24]IGF-I，其是其中Leu取代24位的Thr的IGF-I类似物；[Leu60]IGF-I其是Leu取代60位的Tyr的突变型IGF-I；长链R3IGF-I，其是Arg取代3位的Glu并且在N-末端延长13个氨基酸的突变型IGF-I；des(1-6)IGF-II，其是缺失N-末端六肽的IGF-II类似物；[Gly1]IGF-II，其是Gly取代1位Ala的IGF-II突变型；[Arg6]IGF-II，其是Arg取代6位的Glu的IGF-II突变型；和[Leu27]IGF-II，其是Leu取代27位Tyr的IGF-II突变型。这些IGF结构类似物是商业上可获得的，例如，从GroPep，Pty.Ltd.(澳大利亚)获得。要明白本领域中有可能产生各种另外的IGF结构类似物。
本发明中使用的IGF结构类似物具有生物学活性。例如，已知对眼给予des(1-3)IGF-I能够增强移植的脊髓，大脑皮质和眼中顶骨皮质的生长。其能够增强培养的脊髓中胆碱乙酰基转移酶活性，并且增强培养的嗅球细胞的生长。[Arg3]IGF-I，长链R3IGF-I，[Leu24]IGF-I，[Leu60]IGF-I，des(1-6)IGF-II，[Gly1]IGF-II，[Arg6]IGF-II，和[Leu27]IGF-II能够与I型IGF受体，II型IGF受体，或IGF结合蛋白质结合，并且改变细胞中蛋白质的合成。因此，跨越BBB，B-CNS-B或B-SC-B的IGF结构类似物可以用于本发明的目的。
脑和脊髓的治疗比末梢神经系统的治疗更复杂，因为B-CNS-B，B-SC-B和BBB造成药物特别是蛋白质和肽传递到中枢神经系统的一个障碍。普遍相信这些障碍阻碍蛋白质和肽例如IGFs的吸收和穿入，并且这些担心同样适用IGF结构类似物。申请人以前证明IGF-I或IGF-II能够从血液进入CSF并且使疾病状态下的脑生物化学正常化，防止脊髓中的轴突损失，并且防止对中枢神经系统的功能损伤。因此，以下面的研究为基础，预期IGF结构类似物同样能够从血液进入脑脊髓液(CSF)中，并且可以预防中枢神经系统损伤、疾病或失调。
下面的实施例证明IGF结构类似物能够从循环系统中进入CSF。结果，IGF结构类似物可以影响中枢神经系统中的变化或治疗中枢神经系统疾病。实施例证明有一种载体携带IGFs从循环系统进入CSF，并且这种载体的性质与已知的IGF结合蛋白和IGF受体，例如I型IGF受体或II型IGF受体不同。实施例中被吸收进入CSF的IGF类似物包括des(1-3)IGF-I，[Leu24]IGF-I和[Leu60]IGF-I。此外，IGF-II诱导IGF-I吸收到CSF中，这与通过普IGF载体吸收的竞争相一致。本发明在更广义方面不局限于描述的具体细节或者代表性实施例。因此，以下面的研究为基础，预期通过这种载体吸收到CSF中的IGF结构类似物可以用于本发明的目的。吸收到CSF中的那些IGF结构类似物可以用作激动剂或拮抗剂。拮抗剂可以用于抑制例如可能是IGF-依赖性的脑肿瘤的生长。激动剂可以用于治疗各种脑部疾病和失调，例如帕金森氏病，早老性痴呆，多发性硬化，中风，外伤，老年性痴呆等。
在这些实施例中，对大鼠皮下注射IGF结构类似物。90分钟之后抽取血浆和CSF并且通过ELISA分析(表I)。
表1.通过ELISA对hIGF-I及其类似物的选择性检测
| 样品 | OD(450)平均值±SEM | P值 |
| 空白 | 0.0±0 | |
| 人IGF-I(150pg) | 0.568±0.113 | 0.001 |
| Des(1-3)hIGF-I(150pg) | 0.276±0.047 | 0.001 |
| Leu24hIGF-I(150pg) | 0.661±0.072 | 0.001 |
| 人IGF-II(150pg) | 0.004±0.017 | 0.959 |
| 胰岛素(150pg) | 0.016±0.006 | 0.903 |
| 大鼠CSF(提取) | 0.018±0.034 | 0.971 |
| 大鼠血浆(提取) | 0.051±0.037 | 0.818 |
如图1所示对hIGF-I和其它蛋白质进行ELISA。这些实验自始至终以相同的检测体积测试未处理大鼠CSF和血浆。注意在ELISA中CSF和血浆中大鼠IGF-I-I，IGF-II，胰岛素和IGFBP不干扰测试。测定值是一式四份测定的平均值±SEM。
ELISA检测人IGF-I和IGF结构类似物。但是，ELISA不检测IGF-II或胰岛素。此外，未处理大鼠CSF或血浆中没有物质干扰ELISA，表明该项试验对于人IGF-I和IGF结构类似物是特异性的。换句话说，CSF或血浆中内源性大鼠IGF-I，大鼠IGF-II，大鼠胰岛素和其它大鼠物质不干扰ELISA。图1说明对于不同浓度的人IGF-I，des(1-3)IGF-I，[Leu24]IGF-I和[Leu60]IGF-I的标准ELISA曲线。
对成年大鼠皮下注射各种剂量的人IGF-I。图2说明血浆中IGF-I随着剂量线性增加。但是，IGF-I吸收到随渐增剂量饱和的CSF中，说明吸收是通IGF吸收载体。图3说明对于吸收到CSF中，IGF-II与IGF-I竞争。
实施例
实施例1.Des(1-3)IGF-I从N-末端缺失头3个氨基酸，导致对于IGF结合蛋白-3(IGFBP-3)，IGFBP-4和IGFBP-5的亲合力降低至少25-倍。与IGFBP-1的结合也降低。Des(1-3)IGF-I与I型IGF受体结合，并且对于神经元有增强的生物学活性。由于与IGFBP的结合降低，其更具有效力。图4说明皮下给予的Des(1-3)IGF-I被成年大鼠脑脊髓液吸收。因此，吸收到CSF中不需要IGF和突变型IGFs与IGFBP-1、-3、-4和-5的结合，IGF吸收载体分子不具有IGFBP-1、-3、-4或-5的特征。
实施例2.Leu取代[Leu24]IGF-I中24位的Thr。对成年大鼠皮下注射[Leu24]IGF-I之后，在脑脊髓液中容易检测它(图5)。该实施例和实施例1和3一起，说明具有各种缺失或替代的IGF结构类似物能够从循环系统中吸收到CSF中。
实施例3.Leu取代[Leu60]IGF-I中60位的Tyr，对于I型IGF受体来说，其具有20-倍降低的亲合力。对成年大鼠皮下注射[Leu60]IGF-I之后，在脑脊髓液中容易检测它(图5)。这说明与I型IGF受体结合对于IGFs吸收不是必需的，并且IGF载体分子不具有I型IGF受体的特征。
Des(1-3)IGF-I和IGF-I不与II型IGF受体发生可察觉的结合，然而在皮下给药之后这两种配体都被吸收到CSF中。因此，与II型IGF受体结合不要求IGFs吸收到CSF中，并且IGF载体分子不具有II型IGF受体的特征。
胰岛素-样生长因子(IGFs)从循环系统吸收到脑脊髓液(CSF)中与运输载体蛋白相一致。这种载体蛋白与I型或II型IGF受体，或IGF结合蛋白不具有相同的性质。结果，该载体具有和先前表征过的IGF结合分子不一样的性质。
因此，证明IGF结构类似物在哺乳动物中跨越BBB、B-CSF-B和/或B-SC-B进入CSF。本发明具有可以从BBB，B-CSF-B和B-SC-B外部给予突变型IGFs和IGF类似物的优点，并且不需要使用侵入性和危险性更大的给药方法例如颅内或鞘内给药。本发明可以避免手术风险和费用和CNS感染的风险。
Claims (15)
1.一种治疗中枢神经系统疾病的方法，包括给予有效量的IGF结构类似物来治疗或预防中枢神经系统中的神经元损伤。
2.权利要求1的方法，其中对中枢神经系统的神经元损伤是由于出生后脑或脊髓失调或疾病所引起。
3.权利要求2的方法，其中脑部的神经元损伤是由于早老性痴呆、帕金森氏病、AIDS-相关性痴呆、老年性痴呆、中风、外伤、皮层基底神经节综合症、渐进性痴呆、带有痉挛性下肢轻瘫的家族性痴呆、渐进性核上性麻痹、多发性硬化、肝脑病变、皮克病、亨廷顿舞蹈病、弥散性希尔德脑硬化或急性引起坏死性出血的脑脊髓炎所引起。
4.权利要求2的方法，其中所述脑或脊髓神经元损伤是肿瘤或癌症。
5.权利要求1的方法，其中所述IGF结构类似物是des(1-3)IGF-I。
6.权利要求1的方法，其中IGF结构类似物是[Arg3]IGF-I、[Leu24]IGF-I、[Leu60]IGF-I、长链R3IGF-I、des(1-6)IGF-II、[Gly1]IGF-II、[Arg6]IGF-II或[Leu27]IGF-II。
7.权利要求1的方法，其中以大约0.01微克/千克/天直到大约4毫克/千克/天的量给予所述突变型IGF或IGF类似物。
8.权利要求1的方法，其中通过非颅内和非脊柱内给药来给予IGF结构类似物。
9.一种治疗中枢神经系统疾病的方法，包括通过非颅内和非脊柱内给予有效量的IGF结构类似物来治疗或预防中枢神经系统神经元损伤。
10.权利要求9的方法，其中所述损伤是由于中枢神经系统失调或疾病，除了所述疾病是肌萎缩侧索硬化所引起。
11.权利要求9的方法，其中所述损伤是由于肿瘤或癌症所引起。
12.权利要求9的方法，其中所述突变型IGF或IGF类似物是des(1-3)IGF-I。
13.权利要求9的方法，其中所述IGF结构类似物是[Arg3]IGF-I、[Leu24]IGF-I、[Leu60]IGF-I、长链R3IGF-I、des(1-6)IGF-II、[Gly1]IGF-II、[Arg6]IGF-II或[Leu27]IGF-II。
14.权利要求9的方法，其中以大约0.01微克/千克/天直到大约4毫克/千克/天的量给予所述突变型IGF或IGF类似物。
15.权利要求9的方法，其中所述非颅内和非脊柱内给予是经皮、皮下、肌内、静脉内、动脉内、通过吸入者鼻内给药。
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| CN108114271A (zh) * | 2016-11-29 | 2018-06-05 | 中国科学院上海生命科学研究院 | 含胰岛素样生长因子-2的药物组合物及其应用 |
| WO2018099363A1 (zh) * | 2016-11-29 | 2018-06-07 | 中国科学院上海生命科学研究院 | 含胰岛素样生长因子-2的药物组合物及其应用 |
| CN109562145A (zh) * | 2016-11-29 | 2019-04-02 | 中国科学院上海生命科学研究院 | 含胰岛素样生长因子-2的药物组合物及其应用 |
| AU2017370226B2 (en) * | 2016-11-29 | 2021-05-20 | Shanghai Institute of nutrition and health, Chinese Academy of Sciences | Pharmaceutical composition containing insulin-like growth factor-2 and use thereof |
| CN109562145B (zh) * | 2016-11-29 | 2023-01-06 | 中国科学院上海营养与健康研究所 | 含胰岛素样生长因子-2的药物组合物及其应用 |
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| WO2002017951A1 (en) | 2002-03-07 |
| AU8844301A (en) | 2002-03-13 |
| ATE463252T1 (de) | 2010-04-15 |
| EP1313499A4 (en) | 2004-05-26 |
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