CN113499450B - 用于治疗疼痛的组合物 - Google Patents
用于治疗疼痛的组合物 Download PDFInfo
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- CN113499450B CN113499450B CN202110999106.7A CN202110999106A CN113499450B CN 113499450 B CN113499450 B CN 113499450B CN 202110999106 A CN202110999106 A CN 202110999106A CN 113499450 B CN113499450 B CN 113499450B
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Abstract
本发明涉及一种用于缓解或治疗疼痛的组合物,该组合物包括谷氨酸脱羧酶和编码抗炎细胞因子的基因;本发明还涉及一种使用该组合物缓解或治疗疼痛的方法。本发明的药物组合物通过联合施用GAD和IL‑10的组合,即使在较小的剂量下也表现出优异的镇痛功效,因此它显示了通过低剂量给药降低常规副作用和毒性的协同效应。
Description
相关申请
本申请是申请号为201680053704.2的专利申请的分案申请。原申请的发明名称为《用于治疗疼痛的组合物》,申请日为2016年9月20日。
技术领域
本发明涉及一种用于缓解或治疗疼痛的组合物,该组合物包括编码谷氨酸脱羧酶的基因和编码抗炎细胞因子的基因;本发明还涉及一种使用该组合物缓解或治疗疼痛的方法。
背景技术
国际疼痛研究协会(International Association for the Study of Pain)使用的术语“疼痛”(pain)被定义为“实际或潜在的组织损伤或与之相关的不愉快的感觉和情感体验”。在损伤愈合过程中,疼痛可保护部分受损的身体免受损伤的发生,并激励人类避免将来出现类似的体验。如果刺激的来源被消除,大多数疼痛会逐渐缓解,但有时即使受损部位因刺激消失而明显愈合,疼痛仍然存在,或者疼痛在没有发生刺激、损伤或疾病的状态下仍然产生。
神经病理性疼痛(Neuropathic pain)是一种由神经、脊髓或大脑异常引起的非恶性(non-malignant)慢性疼痛,并且认为有1%或更多的人正在遭受这种疼痛。神经病理性疼痛的最常见原因是创伤、代谢疾病和缺血性疾病等,它们引起的病理性神经冲动(nerveimpulses)通过脊髓传递到大脑,从而导致疼痛发生。根据受影响的部位,神经病理性疼痛可分为周围神经性疼痛和中枢神经性疼痛。
如果这种神经病理性疼痛持续很长一段时间,则可能导致患者精神痛苦和身体疼痛,从而可能导致患者的生活质量下降。因此,应该进行缓解疼痛的积极治疗。目前,由于疼痛本身被认为是一种疾病,以及人们对疼痛的兴趣正在蔓延,预计未来镇痛药的需求量将稳步增加。主要地,镇痛药如乙酰水杨酸(acetylsalicylic acid)、布洛芬(ibuprofen)和对乙酰氨基酚(acetaminophen)被广泛用于目前的疼痛治疗中。如果主要成分为乙酰水杨酸的阿司匹林(aspirin)用于镇痛目的,应给予至少500毫克的高剂量。然而,由于阿司匹林是非甾体抗炎镇痛药(NSAIDs),它通过抑制酶(COX-1)来干扰胃黏膜的产生,该酶(COX-1)促进前列腺素的产生,而前列腺素起到保护胃粘膜的作用,因此胃易被胃酸损伤,容易引起胃肠道出血。此外,由于阿司匹林可防止血栓形成,因此可导致出血。布洛芬也是一种非甾体抗炎镇痛药成分,因此也会引起胃病。对于主要成分为对乙酰氨基酚的镇痛药如泰诺(Tylenol),由于对乙酰氨基酚主要在肝中代谢,肝脏可能受损。因此,存在安全问题,需要降低其最大剂量等。此外,长期使用上述镇痛药即使在早期有效,也常常导致抗药性和功效丧失,特别是在神经病理性疼痛的情况下。非甾体抗炎剂即使在最大剂量下也是无效的,这是对每个患者都存在的问题,因此规定了短期的高剂量给药。因此,迫切需要开发一种新的用于神经病理性疼痛的镇痛药,其在低剂量下表现出优异的镇痛功效且没有副作用。
目前,正在开发几种新物质作为治疗神经病理性疼痛的镇痛剂。最近,钠通道阻滞剂已经被开发出来,但它们大多数是小分子的形式,对某些亚型的选择性很低。此外,它们表现出诸如心脏毒性、运动障碍等副作用,因此将来需要更多的研究。至于基因治疗剂,Periphagen控股公司开发了一种治疗剂,其中将编码脑啡肽(一种阿片肽)的基因插入单纯疱疹病毒(HSV)基因载体中。然而,在临床试验中,已经发现其镇痛功效下降的问题,因此,在2期研究中其进展已停止。即使在皮下给药时,HSV具有将基因递送至末梢神经的优点,但实际上,基因递送效率较差,并且似乎难以仅用脑啡肽(一种阿片肽)来抑制疼痛。
发明内容
技术问题
本发明的一个实施例涉及一种用于缓解或治疗疼痛的组合物,其包括编码谷氨酸脱羧酶(GAD)的基因和编码抗炎细胞因子的基因。
本发明的另一个实施例是提供一种用于缓解或治疗疼痛的方法,其包括将编码GAD的基因和编码抗炎细胞因子的基因施用于有需要的受试者。
解决问题的方案
本发明提供一种用于缓解或治疗疼痛的药物组合物,其包括编码谷氨酸脱羧酶(GAD)的基因和编码抗炎细胞因子的基因,以及提供一种用于缓解或治疗疼痛的方法,所述方法包括将所述药物组合物施用于有需要的受试者。
本发明的有益效果
本发明的药物组合物在只有少量的基因递送下即可表现出镇痛效果,与单独给药相比,即使基因递送量较少,也可以观察到疼痛缓解效果。GAD基因的产物GABA具有阻断疼痛信号传导的功效,但GABA过量会引起诸如瘙痒、头晕、困倦等症状,以及诸如心率增加或呼吸率增加的副作用。已知IL-10是显示出抗炎作用的细胞因子,但是当全身使用高剂量IL-10时,观察到了例如RBC水平降低等副作用。另一方面,与单独给药相比,本发明的药物组合物通过联合施用GAD和IL-10的组合,即使在较小的剂量下也表现出优异的镇痛功效,因此它显示了通过低剂量给药降低常规副作用和毒性的协同效应。
附图说明
图1显示了用于产生重组腺相关病毒的质粒pAAV-hGAD65的载体图谱。
图2显示了用于产生重组腺相关病毒的质粒pAAV-rIL-10的载体图谱。
图3显示了用于产生重组腺相关病毒的质粒pAAV-rIL-4的载体图谱。
图4是通过蛋白质印迹证实每种蛋白质的表达水平的图,其中制备了分别插入了GAD65、IL-10和IL-4基因的腺相关病毒,然后用病毒处理293T细胞(一种人胚胎肾细胞系),48小时后收集细胞或培养基。
图5显示了由重组腺相关病毒AAV-hGAD65引起的GABA表达,该图显示了通过ELISA测量的培养基中的GABA水平,其中用AAV-GAD65处理293T细胞(一种人胚肾细胞系),48小时后收集培养基。对于每个实验组分别制备两个相同的样品,图中的条表示每个样品的值。
图6显示了AAV-GAD65和AAV-IL-10联合给药与加巴喷丁(gabapentin)给药的比较效果的结果,该图证实了与市场上用作神经病理性疼痛缓解剂的加巴喷丁相比,AAV-GAD65和AAV-IL-10联合给药的协同效应的差异。
图7显示了AAV-GAD65和AAV-IL-10根据其组合比例的功效。特别地,该图显示在AAV-IL-10与AAV-GAD的组合比例为1:1、1:5和1:30下的动物行为分析中的协同效应。
图8是显示通过经椎间孔硬膜外注射(transforaminal epidural injection)以1:10和1:30的比例联合施用AAV-GAD65和AAV-IL-10时的协同效应的图。
图9显示了AAV-GAD65和AAV-IL-10与AAV-GAD65和AAV-IL-4的功效的比较结果,这说明当IL-10和IL-4分别与GAD65联合施用时,在动物行为分析中的协同效应。
实施本发明的最佳方式
在下文中,将详细描述本发明。
在本发明的一个实施例中,编码GAD的基因和编码抗炎细胞因子的基因以包含在载体中的形式提供,载体包括病毒载体和非病毒载体,例如质粒,脂质体等等。
编码GAD的基因可包含在第一载体中,并且编码抗炎细胞因子的基因可包含在第二载体中。
病毒载体可以是选自腺病毒、腺相关病毒、单纯疱疹病毒、慢病毒、逆转录病毒和痘病毒中的至少一种。
含有编码本发明的GAD的基因的载体(例如第一载体)和含有编码抗炎细胞因子的基因的载体(例如第二载体)可以具有单位体积下基于病毒滴度的混合比为1:1至1:100、1:1至1:80、1:1至1:60、1:1至1:40、1:1至1:20、1:1至1:10、1:3至1:100、1:3至1:80、1:3至1:60、1:3至1:40、1:3至1:20或1:3至1:10的比例,更优选1:1至1:50,最优选1:5至1:30。
本发明的药物组合物可以仅用少量基因或含有它们的载体就可表现出镇痛效果。本发明的组合物由含有编码GAD的基因的载体和含有在神经组织中有抗炎作用基因的载体组成,与单独给药相比,通过联合施用具有不同镇痛机制的物质可以以较少的用量实现疼痛缓解或治疗效果。因此,由于本发明的组合物使用少量基因或含有它们的载体,可显示出优异的镇痛效果的协同作用,同时降低了毒性。
根据本发明的一个实施例,第一载体和第二载体可以是腺相关病毒。腺相关病毒不限于特定的血清型,并且优选地,它可以是AAV1至AAV5中的任何一种。
本发明的GAD是使谷氨酸脱羧生成GABA(γ-氨基丁酸)的酶。编码适用于本发明的GAD的基因可以是GAD65和GAD67中的一种,它们是两种亚型(isoforms)。GAD65可以是人或大鼠蛋白质或编码它的基因,其具体实例可以由NCBI登录号为NM_000818的SEQ ID NO:1的氨基酸序列组成,也可以由SEQ ID NO:2或SEQ ID NO:3的碱基序列组成。GAD67可以是人或大鼠蛋白质或编码它的基因,其具体实例可以由NCBI登录号为NM_000817的SEQ ID NO:4的氨基酸序列组成,也可以由SEQ ID NO:5的碱基序列组成。
在本发明的药物组合物中,炎性细胞因子可以是白细胞介素-10(IL-10),并且通过联合施用IL-10和GAD65表现出协同的疼痛缓解功效。
IL-10是一种抗炎细胞因子,也被称为细胞因子合成抑制因子(CSIF)。IL-10属于II类细胞因子,是由2个长度为178个氨基酸的亚基组成的同源二聚体(homodimer)。IL-10具有抑制NK(自然杀伤)细胞在免疫反应中的活性的功能,并且通过与IL-10受体形成复合物参与信号转导。IL-10可以是人或大鼠蛋白质或编码它的基因,其具体实例可以由NCBI登录号为NM_012854的SEQ ID NO:6的氨基酸序列组成,或由NCBI登录号为NM_000572的SEQID NO:9的氨基酸序列组成,也可以由SEQ ID NO:7、SEQ ID NO:8或SEQ ID NO:10的碱基序列组成。
编码本发明的GAD的基因和/或编码IL-10的基因的碱基序列包括其突变体,其可以是通过对大鼠或人进行密码子优化而修饰的碱基序列。具体而言,与其具有至少60%序列同源性的碱基序列也包含在内,优选为70%或更多的序列同源性,更优选为80%或更多的序列同源性,甚至更优选为90%或更多的序列同源性,最优选为95%或更多的序列同源性。其中“序列同源性%”是通过比较两个最佳排列的序列和比较区域来鉴定,与关于两个序列的最佳排列的参考序列(不包括插入或缺失)相比较,比较区域中的部分序列可包括插入或缺失(即缺口)。
本发明还提供了一种用于缓解和/或治疗疼痛的方法,其包括向需要缓解和/或治疗疼痛的患者施用治疗有效量的药物组合物。在施用步骤之前,上述方法可以进一步包括将患者确定为需要缓解和/或治疗疼痛的患者。术语“治疗有效量”可取决于达到所需功效、缓解疼痛和/或治疗效果的活性梯度的量。
根据本发明的疼痛可以包括伤害性疼痛、心因性疼痛、与组织损伤和免疫细胞浸润相关的炎性疼痛、由神经系统损伤或其异常功能引起的疾病状态的病理性疼痛(功能失调性疼痛如纤维肌痛、肠易激综合征、紧张性头痛)等。此外,疼痛可能包括解剖学上的背痛,例如:颈部疼痛、中背痛(middle back pain)、下腰痛或尾骨疼痛(tailbone pain)。此外,疼痛可能包括如神经病理性疼痛、偏头痛(migraine)等疼痛。神经病理性疼痛可以由影响躯体感觉系统的损伤或疾病引起。神经病理性疼痛可能与称为感觉迟钝(dysesthesia)的异常感觉以及可能与异常性疼痛(allodynia)有关,异常性疼痛指的是即使在无痛刺激下也会引起的痛苦感觉。而且,神经病理性疼痛也可以是连续和/或间歇(发作)因素。后者与形象意义上的电击有关。一般特征包括发热或发冷、针刺感(pins and needles)、麻木(numbness)和瘙痒。
相反,伤害性疼痛(nociceptive pain)通常表达为“疼痛”(ache)。此外,偏头痛是一种慢性病,与许多自主神经系统症状(autonomic nervous system symptoms)相关,并会引起一般到严重强度的头痛。这些偏头痛的确切机制尚未阐明。其基本理论与大脑皮层(cerebral cortex)兴奋性增加以及脑干(brainstem)三叉神经核(trigeminal nucleus)中疼痛神经细胞的异常调节有关。
作为具体实施例,疼痛可以是选自神经病理性疼痛、癌症疼痛、术后疼痛、三叉神经痛、特发性疼痛、糖尿病神经病理性疼痛和偏头痛等中的至少一种。作为另一个具体的例子,疼痛可能不是与腰痛相关的肌肉痉挛。
优选地,本发明的组合物可用于缓解或治疗神经病理性疼痛或慢性癌症疼痛。术语“缓解或治疗”是指通过施用本发明的组合物来减轻或改善疼痛症状的任何作用。
本发明的另一实施例涉及一种用于缓解或治疗疼痛的方法,其包括将编码GAD的基因和编码抗炎细胞因子的基因施用于有需要的受试者。受试者可以是包括人的哺乳动物,或者是从包括人在内的哺乳动物分离的细胞和/或组织。此外,受试者可以是非人类动物,术语“非人类动物”包括脊椎动物如哺乳动物和非哺乳动物,例如除人以外的灵长类动物、绵羊、狗、猫、马、牛、鸡、两栖类动物、爬行类动物等。
本发明药物组合物的治疗有效量和给药途径可以由本领域普通技术人员考虑患者的状况,期望的功效等进行适当调整。例如,本发明的组合物可以以注射剂的形式提供,并且可以包括例如神经注射、皮下注射、肌内注射或基因枪注射。
本发明实施例
以下通过实施例详细说明本发明,但下列实施例旨在进一步说明本发明而不限制其范围。
<实施例1>重组腺相关病毒的制备和性质分析
基于AAV无辅助系统(Agilent,美国)制备和生产本发明所需的腺相关病毒。
A.制备pAAV-hGAD65
为了制备图1的pAAV-hGAD65,通过PCR扩增pJDK-rGAD65的CMV启动子区域[Lee B等人,Gene Ther,12:1215-1222(2005)],然后将其插入到pGEM-T(Promega,美国)中,以制备pGEM-T-CMV。用于扩增CMV启动子的引物序列如下。
F-JDK(SEQ ID NO:16):5′-TTCGGCCGTCGAGGAGCTTGGCCCATTG-3′
R-JDK(SEQ ID NO:17):
5′-GACGTCGACCTAGCTAGCGAATTCGGGGCCGCGGAG-3′
基于具有SEQ ID NO:1的氨基酸序列(NCBI NM_000818)的人GAD65序列,进行密码子优化以制备GAD65基因以适合人类,得到SEQ ID NO:3的碱基序列(Bioneer,韩国),用NheI和SalI处理插入到pGEM-T中的hGAD65基因,以获得1.7Kb的DNA片段,将其连接到通过用NheI和SalI处理pGEM-T-CMV获得的3.7Kb的DNA片段上,以完成pGEM-T-CMV-hGAD65的制备。
通过使用pCI(Invitrogen,美国)作为模板进行PCR扩增SV40pA,然后用ClaI和SalI处理,以获得222bp的DNA片段。将上述片段连接到通过用ClaI和SalI切割pGEM-T-CMV-hGAD65制得的5.4Kb DNA片段上,以最终制备pGEM-T-CMV-hGAD65-SV40pA。用于扩增SV40pA的引物序列如下。
F-SV40pA(SEQ ID NO:18):
5′-CCATCGATCAGACATGATAAGATACATTGATGAG-3′
R-SV40pA(SEQ ID NO:19):
5′-GACGTCGACGCGGCCGCTACCACATTTGTAGAGGTTTTACTTG-3′
用卡那霉素抗性基因(kanamycin-resistance gene)代替pAAV-MCS(Agilent,美国)中的氨苄青霉素抗性基因(ampicillin-resistance gene)以制备腺相关病毒载体。使用pET-28(a)(Novagen,美国)作为模板,通过PCR扩增卡那霉素抗性基因,并将扩增的816bp的卡那霉素抗性基因连接至pGEM-T上,以制备pGEM-T-Kanr。用于扩增卡那霉素抗性基因的引物序列如下。
F-Kan(SEQ ID NO:20):5′-AGGCGCCATGAGCCATATTCAACGGGAA-3′
R-Kan(SEQ ID NO:21):5′-TTCATGATTAGAAAAACTCATCGAGCATC-3′
为了插入卡那霉素抗性基因,通过诱变分别在pAAV-MCS中的氨苄青霉素抗性基因的前端和末端产生SpeI和EcoRV位点,并用SpeI和EcoRV处理,然后将其连接到通过用NheI和EcoRV切割上述制备的pGEM-T-Kanr来获得的DNA片段上,以制备pAAV-MCS-Kanr。
用NotI和BamHI处理制备得到的pAAV-MCS-Kanr,然后将其连接到通过用EagI和PvuI切割pGEM-T-CMV-hGAD65-SV40pA获得的2.7Kb DNA片段上,以制备pssAAV-GAD65。
为了将GAD65表达盒插入到pVAX1(Invitrogen,美国)中,通过诱变在bGHpA的末端产生BamHI位点,然后用MluI和NheI切割BhamHI位点以制备DNA片段。使用pssAAV-GAD65作为模板通过PCR扩增LITR和CMV启动子区域,并将其克隆到pGEM-T easy(Promega,美国)中,然后用AscI和NheI切割并连接到上述制备的pVAX1载体上,以制备pVAX1-LITR-CMV。用于扩增LITR和CMV启动子区域的引物序列如下。
F-ITR(SEQ ID NO:22):5′-ATGGCGCGCCCCTGGCCTTTTGCTGGCC-3′
R-JDK(SEQ ID NO:17):
5′-GACGTCGACCTAGCTAGCGAATTCGGGGCCGCGGAG-3′
通过用NotI和NheI切割将pVAX1-LITR-CMV制备成DNA片段,并将其连接到通过用Eagl和Nhel切割pssAAV-GAD65制得的DNA片段上,以制备pVAX1-LITR-CMV-hGAD65-SV40pA。
用HpaI和BamHI切割pVAX1-LITR-CMV-hGAD65-SV40pA,然后将其连接到DNA片段上以完成pVAX1-LITR-CMV-hGAD65-SV40pA-RITR(以下缩写为“pAAV-GAD65”)的制备,该DNA片段是通过用HpaI和BamHI处理pGEM-T easy-SV40pA-RITR获得,pGEM-T easy-SV40pA-RITR已经使用pssAAV-GAD65作为模板通过PCR扩增并克隆到pGEM-T easy中。用于扩增SV40pA和RITR区的引物序列如下。
F-SV40pA(SEQ ID NO:18):
5′-CCATCGATCAGACATGATAAGATACATTGATGAG-3′
R-ITR(SEQ ID NO:23):5′-ATGGATCCGCTAGTAAATACCGCATCAG-3′
pAAV-hGAD65的载体图谱如图1所示。
B.制备pAAV-rIL-10
通过与制备pAAV-hGAD65相似的方法制备pAAV-rIL-10。基于具有SEQ ID NO:6的氨基酸序列的源自大鼠的碱基序列(NCBI NM_012854),进行密码子优化以制备大鼠IL-10基因以适合大鼠,得到具有SEQ ID NO:8的碱基序列(Bioneer,韩国)的基因,使用插入到pGEM-T easy中的大鼠IL-10基因作为模板,通过PCR扩增rIL-10基因,然后用NheI和SalI处理以获得0.5Kb DNA片段,然后将其连接到通过用NheI和SalI切割pGEM-T-CMV获得的3.7Kb的DNA片段上,以制备pGEM-T-CMV-rIL-10。用于扩增rIL10的引物序列如下。
F-rIL-10(SEQ ID NO:24):5′-CCGCTAGCGCCACCATGCCT-3′
R-rIL-10(SEQ ID NO:25):
5′-GACGTCGACGCCATCGATGGCTTAATTAATCAATTCTTC-3′
通过使用pCI作为模板进行PCR扩增SV40pA,随后用NotI和SalI处理以获得222bp的DNA片段。将上述片段连接到4.2Kb DNA片段上,该4.2Kb DNA片段是通过用ClaI和SalI切割上述制备的pGEM-T-CMV-rIL-10制得,以制备pGEM-T-CMV-rIL-10-SV40pA。用于扩增SV40pA的引物序列如下。
F-SV40pA(SEQ ID NO:18):
5′-CCATCGATCAGACATGATAAGATACATTGATGAG-3′
R-SV40pA(SEQ ID NO:19):
5′-GACGTCGACGCGGCCGCTACCACATTTGTAGAGGTTTTACTTG-3′
通过用EagI处理pGEM-T-CMV-rIL-10-SV40pA获得1.6Kb的DNA片段,然后将其连接到通过用NotI和BamHI处理pAAV-MCS-Kanr制得的DNA片段上,以制备pssAAV-CMV-rlL-10-SV40pA(以下简称为“pAAV-rIL-10”)。图2中显示了pAAV-rIL-10的载体图谱。
C.制备pAAV-rIL-4
基于具有SEQ ID NO:11的氨基酸序列的源自大鼠的碱基序列(NCBI NM_201270),进行密码子优化以制备大鼠IL-4基因以适合大鼠,得到具有SEQ ID NO:13的碱基序列(Bioneer,韩国)的基因,使用NheI和NotI处理插入到pGEM-B1(Bioneer,韩国)中的rIL-4基因,以获得0.5Kb的DNA片段。将上述片段连接到通过用NheI和NotI处理pAAV-hGAD65制得的3Kb DNA片段上,以制备pssAAV-CMV-rIL-4-SV40pA(以下缩写为“pAAV-rIL-4”)。图3中显示了pAAV-rIL-4的载体图谱。
D.重组腺相关病毒的性质分析
使用PEI(Polysciences,美国)将上面制备的三种类型的质粒(pAAV-hGAD65,pAAV-rIL-10和pAAV-rIL-4)分别与pHelper和pRC转染到293T细胞(一种人胚胎肾细胞系)中。在此,插入了AAV血清型5的衣壳蛋白基因的pRC5是用于制备hGAD65,而插入了AAV血清型1的衣壳蛋白基因的pRC1是用于制备rIL-10和rIL-4。将转染的细胞在37℃培养箱中培养,48小时后收集,并进行3次冷冻和解冻循环以获得每种粗制病毒。
为了证实递送至细胞的重组腺相关病毒的蛋白质表达,分别用粗制病毒AAV5-hGAD65、AAV1-rIL-10和AAV1-rIL-4处理293T细胞(一种人胚肾细胞系),通过蛋白质印迹证实蛋白质表达。具体而言,将8×105个293T细胞等分到T25烧瓶中,并在第二天用700μL的粗制病毒处理每个烧瓶,然后在37℃培养箱中培养。48小时后,分别收获细胞和培养基,并用增溶剂溶解细胞,用超过滤器(amicon,Merck Millipore,德国)浓缩培养基。将制得的样品分别用GAD65(Cell signaling,美国)、IL-10(Santa Cruz,美国)和IL-4(Santa Cruz,美国)的抗体处理,并进行蛋白质印迹试验。结果如图4所示。
图4是通过对用AAV5-hGAD65、AAV1-rIL-10或AAV1-rIL-4处理的293T细胞系(人胚胎肾细胞系)的细胞裂解物进行蛋白质印迹分析显示每种蛋白质的表达的图。通过确认每种情况下都表达了目标蛋白质,证实了实验中使用的重组腺相关病毒的结构和性质没有问题。
为了确认GABA是由AAV5-hGAD65产生,在与用于蛋白质印迹的样品制备相同的条件下收集用AAV5-GAD65处理的细胞培养基,并进行GABA ELISA(LDN,荷兰)分析。结果如图5所示。每个实验组分别制备两个相同的样品,图中的条表示每个样品的值。结果证实,通过由AAV5-hGAD65病毒引入细胞的GAD65将GABA分泌到培养基中。
E.重组腺相关病毒的制备
通过KRcrogen(韩国)制备和纯化重组腺相关病毒以用于动物功效实验,其制备方法如下。
使用磷酸钙法将上述制备的三种类型的质粒(pAAV-hGAD65,pAAV-rIL-10和pAAV-rIL-4)分别与pHelper和pRC转染到293T细胞(人胚胎肾细胞系)中。在此,插入了AAV血清型5的衣壳蛋白基因的pRC5是用于制备hGAD65,而插入了AAV血清型1的衣壳蛋白基因的pRC1是用于制备rIL-10和rIL-4。将转染的细胞在37℃培养箱中培养,48小时后收集。
然后,根据铯浓度梯度,通过高速离心分离和纯化仅含有病毒的条带,以获得AAV5-hGAD65、AAV1-rIL-10和AAV1-rIL-4。产生的病毒的滴度使用制造商建立的qPCR方法进行测量。
<实施例2>AAV-IL-10和AAV-GAD65的镇痛效力测试
A.给药样品的制备
在动物给药前30分钟,将储存在-80℃的重组腺相关病毒在室温下在1分钟内解冻并通过涡旋充分混合。将10mg的考马斯蓝在1mLPBS中充分混合,然后通过针式过滤器(syringe filters)过滤来制备考马斯蓝染料溶液。在计算每只动物总共获得3μL情况下,将1μL的5.4×105VG/μL的AAV-GAD65、1μL的1.8×107VG/μL的AAV-IL-10和1μL的0.1%考马斯蓝染料混合。将样品制备成所需量的两倍,并给予每只动物3μL的样品。
作为对照组,在给药前1小时将加巴喷丁混合在动物饮用水中,其以10mg/mL的浓度制备。
B.制备神经病理性疼痛动物模型以及样品给药
用吸入麻醉方式麻醉180至200g的雄性SD大鼠,然后切开小腿上部,将腓总神经和胫神经的两端打结,以0.5-1厘米的间隔通过7-0缝线缝合制成结。用剪刀剪断结之间的两个神经束的区域,缝合切口部位。两周后,进行Von Frey纤毛测试以确认疼痛感应,然后施用测试物质(C.J.Woolf,Pain 87,2000)。
将测试物质施用于背根神经节(DRG)。在疼痛动物模型吸入麻醉后,将从L3到L5的腰椎的大鼠的背部线性切开,以暴露脊椎骨,然后将横突(transverse process,一个脊髓的突起)暴露于暴露侧,并且在固定状态下将覆盖DRG的L4段在立体变焦显微镜下由咬骨钳(rongeur)仔细分离,使得DRG不被损坏。DRG周围的区域被操纵,使得在斜线中延伸的DRG像米粒一样暴露。
将汉密尔顿注射器(hamilton syringe)连接到聚乙烯导管上,并准确地收集3μL测试物质。然后,将注射器更换为1mL注射器以给药。将大鼠置于小型动物立体定位仪上,在确认微针在手术镜下准确刺入L4DRG的同时注射样品。在此,证实含有染料的样品不会从DRG泄漏出来并且很好地输送到DRG的内部。在确认整个样品被递送到DRG后,将注射器与DRG分离,并且完成缝合,回收动物。
加巴喷丁口服3mg/kg。
C.使用Von
Frey纤毛测试观察镇痛效力
采用Dixon在1992年建立的50%上下阈值方法(50%up&down thresholdmethod),因为它是一种众所周知的方法。该方法使用总共8根纤毛并根据疼痛反应的预定模式计算阈值,8根纤毛的N值分别为0.4、0.6、1、2、4、6、8和15g。通过改变从最外侧趾部区域到发生疼痛的后脚跟处的位置来搜索疼痛发生区域。
当疼痛发生时,大鼠突然抬起脚掌并缩足或舔脚掌。因此,当发现疼痛发生区域时,下一步用纤毛刺入周围区域5次,如果响应3次或更多,则将其视为疼痛反应,下一步用纤毛观察大鼠。每一步都记录模式。根据S.R.Chaplan(定量评估大鼠爪中的触觉异常性疼痛,Journal of Neuroscience Methods,1994)建立的模式表记录疼痛模式,并使用它计算阈值。动物组的行为分析通过盲法进行4至6周,由至少3人观察,并且记录模式的结果被统计处理以分析疼痛倾向。
图6显示了使用von Frey纤毛测试进行疼痛观察的结果,其中疼痛动物模型被给予样品。图6显示了AAV-GAD65和AAV-IL-10联合给药与加巴喷丁给药之间的比较效果的结果。当联合给予GAD65和IL-10时,与未处理的对照组(阴性对照)相比,观察到统计学显著的疼痛缓解效果,并且发现效果好于加巴喷丁。
<实施例3>AAV-IL-10和AAV-GAD65的镇痛效力测试
A.给药样品的制备
为了制备给药样品,将在实施例1中制得并以冷冻状态保存的rAAV5-GAD65和rAAV1-rIL-10解冻,并按照与实施例2中的给药样品的制备方法基本相同的方法制备样品。具体而言,将单独给药物质AAV-GAD65或AAV-rIL-10和联合给药物质AAV-GAD65与AAV-rIL-10在如表1中所示的基于病毒滴度的混合比例1:1、1:5或1:30下稀释到PBS中,并且在计算每只动物总共获得3μL情况下,每个样品中加入1μL的0.1%考马斯蓝染料。将样品制备成所有动物所需量的两倍,给予每只动物3μL的样品。
表1
B.使用Von
Frey纤毛测试观察镇痛效力
将样品施用于通过与实施例2相同的方法制备的疼痛动物模型,并且使用VonFrey纤毛测试观察疼痛,结果示于图7中。
图7显示了AAV-GAD65和AAV-IL-10根据其组合比例的功效。特别地,与显示无镇痛效力的痕量AAV-GAD65和AAV-rIL-10相比,AAV-rIL-10与AAV-GAD混合组成比为1:1(试验实验例1)、1:5(试验实验例2)和1:30(试验实验例3)的试验在动物行为分析中表现出协同效应。结果表明,本发明的AAV-GAD65和AAV-rIL-10的联合施用组合物随着AAV-rIL-10与AAV-GAD的混合组成比例增加而显示出疼痛治疗功效的增加模式。
<实施例4>使用经椎间孔硬膜外注射(transforaminal epidural injection)的AAV-IL-10和AAV-GAD65的镇痛效力测试
A.给药样品的制备
在动物给药实验前30分钟,将保持在-80℃的试剂在室温下在1分钟内解冻并通过涡旋充分混合。将AAV-GAD65和AAV-IL-10在PBS中稀释以获得表2所示的病毒滴度。为了向每只动物给予5μL样品,将两种病毒稀释溶液混合各半,获得1.5倍所需体积。然后,给予每只动物5μL的样品。
表2
B.制备神经病理性疼痛模型和样品给药
通过与实施例2中描述的相同的方法制备神经病理性疼痛动物模型,然后施用测试物质。
测试物质通过经椎间孔硬膜外注射法在靠近背根神经节(DRG)的位置给药。通过吸入麻醉将神经性疼痛动物模型麻醉后,将从L3至L5的腰椎的大鼠的背部线性切开,以暴露脊椎骨,然后将L4横突(一个脊髓的突起)暴露于暴露侧。将大鼠侧躺以从上方看到其侧面,从而使L4椎间孔可见。
将附在导管上的微针放入制备的样品中。将汉密尔顿注射器连接到导管的另一端并拉动直到达到5μL的标记以将样品注入导管中。从导管上取下汉密尔顿注射器后,止血钳(Halsted-Mosquito)抓住离针头1厘米处的区域。由于L4脊柱被钳子夹住并向上拉,由直止血钳(Halsted-Mosquito Straight)固定的针的尖端区域被放置在L4椎间孔周围。将针的尖端插入到固定空间的椎间孔中,使针前进至椎间孔内的弯曲部,使被夹持的针松开。在确认针固定后,将1mL注射器连接到聚乙烯导管,该聚乙烯导管连接在针的相对一侧。轻压活塞以将稀释的给药物质缓慢地施用于大鼠DRG周围区域,然后缝合,以完成给药程序。按照与实施例2中所述的相同的方法,在施用物质4周后观察使用von Frey纤毛测试的疼痛结果。结果如图8所示。
图8显示出即使通过经椎间孔硬膜外注射方法给药,AAV-GAD65和AAV-IL-10的混合物也表现出功效。另外,在AAV-GAD65与AAV-IL-10的混合组成比为1:10(试验实施例1)和1:30(试验实施例2)时,证实了动物行为分析中的协同效力。
<实施例5>比较AAV-GAD65和AAV-IL-10与AAV-GAD65和AAV-IL-4的效力
用与实施例2基本相同的方法制备疼痛动物模型,并且给药样品的制备方法也相同。将实施例1中描述的AAV1-rIL-4解冻并进行制备以用于如下的动物实验。
在动物DRG给药实验前30分钟,将储存在-80℃的试剂在室温下在1分钟内解冻并通过涡旋充分混合。将10mg考马斯蓝在1mL PBS中充分混合,然后制备通过针式过滤器过滤的染料。在PBS中稀释AAV-GAD65和AAV-rIL-4以获得表3中所示的基于病毒滴度的混合比例,并且在计算每只动物总共获得3μL情况下,在每个样品中加入1μL的0.1%考马斯蓝染料。将样品制备成总动物所需量的两倍,并给予每只动物3μL的样品。
表3
观察采用von Frey纤毛测试的疼痛结果,结果显示在图9中。图9显示了AAV-GAD65和AAV-rIL-10与AAV-GAD65和AAV-rIL-4的效力的比较结果,这说明当IL-10和IL-4(具有抗炎作用的细胞因子)分别与GAD65联合使用时,在动物行为分析中出现相对的协同效力。如图9所示,当单独施用GAD65、IL-10或IL-4时,疼痛治疗效果不显著或未被观察到,与单独施用GAD65或IL-4的情况相比,当联合施用GAD65和IL-4时未观察到显著的镇痛效力。另一方面,当联合施用GAD65和IL-10时,证实了与其他对比例相比,其具有统计学上显著的更好镇痛效果。特别地,观察到联合施用GAD65和IL-10具有协同的疼痛缓解作用,而当联合施用GAD65和IL-4时没有显示这样的作用。
序列表
<110> 可隆生命科学株式会社
<120> 用于治疗疼痛的组合物
<130> OPP20162511KR
<160> 25
<170> KoPatentIn 2.0
<210> 1
<211> 585
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<213> 智人(Homo sapiens)
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gaagtcaagg agaaaggaat ggctgctctt cccaggctca ttgccttcac gagtgaacac 840
agtcactttt ccctcaagaa gggggctgcc gccttaggga tcggaacaga cagcgtgatt 900
ctgataaagt gcgacgagag agggaaaatg attccatctg atcttgagag aaggattctt 960
gaagccaaac agaaagggtt tgtccctttc ctcgtgagtg ccacagctgg aaccaccgtg 1020
tacggcgcat ttgaccccct cttagctgtc gcggatatat gtaagaagta taagatctgg 1080
atgcacgtgg atgctgcttg gggtggggga ttactgatgt ccaggaaaca caagtggaaa 1140
ctgtctggcg tggagcgcgc caacagcgtg acgtggaatc cacacaaaat gatgggagtc 1200
cctttgcagt gctctgctct cctggttcga gaagagggac tgatgcagaa ttgcaaccaa 1260
atgcatgcct cctacctctt tcagcaggat aaacattatg acctgtctta cgacactggt 1320
gacaaggccc tgcagtgtgg gcgccacgtt gatgtattca agctatggct gatgtggagg 1380
gcaaagggga ctaccggttt tgaagcccat gttgacaaat gtctggagtt ggcagagtat 1440
ttatacaata tcataaaaaa ccgagaagga tatgagatgg tgtttgatgg caagcctcag 1500
cacacaaatg tctgcttctg gtacatccct cccagcctac gtactctgga ggacaacgaa 1560
gagagaatga gtcgcctctc gaaggtggct ccagtgatta aagccagaat gatggagtat 1620
ggaaccacaa tggtcagcta ccaacccttg ggggacaagg taaatttctt ccgcatggtc 1680
atctcaaacc cagcggcaac tcaccaagac attgatttcc tgattgaaga gatcgagcgg 1740
ctcggccagg atctgtga 1758
<210> 4
<211> 594
<212> PRT
<213> 智人(Homo sapiens)
<400> 4
Met Ala Ser Ser Thr Pro Ser Ser Ser Ala Thr Ser Ser Asn Ala Gly
1 5 10 15
Ala Asp Pro Asn Thr Thr Asn Leu Arg Pro Thr Thr Tyr Asp Thr Trp
20 25 30
Cys Gly Val Ala His Gly Cys Thr Arg Lys Leu Gly Leu Lys Ile Cys
35 40 45
Gly Phe Leu Gln Arg Thr Asn Ser Leu Glu Glu Lys Ser Arg Leu Val
50 55 60
Ser Ala Phe Lys Glu Arg Gln Ser Ser Lys Asn Leu Leu Ser Cys Glu
65 70 75 80
Asn Ser Asp Arg Asp Ala Arg Phe Arg Arg Thr Glu Thr Asp Phe Ser
85 90 95
Asn Leu Phe Ala Arg Asp Leu Leu Pro Ala Lys Asn Gly Glu Glu Gln
100 105 110
Thr Val Gln Phe Leu Leu Glu Val Val Asp Ile Leu Leu Asn Tyr Val
115 120 125
Arg Lys Thr Phe Asp Arg Ser Thr Lys Val Leu Asp Phe His His Pro
130 135 140
His Gln Leu Leu Glu Gly Met Glu Gly Phe Asn Leu Glu Leu Ser Asp
145 150 155 160
His Pro Glu Ser Leu Glu Gln Ile Leu Val Asp Cys Arg Asp Thr Leu
165 170 175
Lys Tyr Gly Val Arg Thr Gly His Pro Arg Phe Phe Asn Gln Leu Ser
180 185 190
Thr Gly Leu Asp Ile Ile Gly Leu Ala Gly Glu Trp Leu Thr Ser Thr
195 200 205
Ala Asn Thr Asn Met Phe Thr Tyr Glu Ile Ala Pro Val Phe Val Leu
210 215 220
Met Glu Gln Ile Thr Leu Lys Lys Met Arg Glu Ile Val Gly Trp Ser
225 230 235 240
Ser Lys Asp Gly Asp Gly Ile Phe Ser Pro Gly Gly Ala Ile Ser Asn
245 250 255
Met Tyr Ser Ile Met Ala Ala Arg Tyr Lys Tyr Phe Pro Glu Val Lys
260 265 270
Thr Lys Gly Met Ala Ala Val Pro Lys Leu Val Leu Phe Thr Ser Glu
275 280 285
Gln Ser His Tyr Ser Ile Lys Lys Ala Gly Ala Ala Leu Gly Phe Gly
290 295 300
Thr Asp Asn Val Ile Leu Ile Lys Cys Asn Glu Arg Gly Lys Ile Ile
305 310 315 320
Pro Ala Asp Phe Glu Ala Lys Ile Leu Glu Ala Lys Gln Lys Gly Tyr
325 330 335
Val Pro Phe Tyr Val Asn Ala Thr Ala Gly Thr Thr Val Tyr Gly Ala
340 345 350
Phe Asp Pro Ile Gln Glu Ile Ala Asp Ile Cys Glu Lys Tyr Asn Leu
355 360 365
Trp Leu His Val Asp Ala Ala Trp Gly Gly Gly Leu Leu Met Ser Arg
370 375 380
Lys His Arg His Lys Leu Asn Gly Ile Glu Arg Ala Asn Ser Val Thr
385 390 395 400
Trp Asn Pro His Lys Met Met Gly Val Leu Leu Gln Cys Ser Ala Ile
405 410 415
Leu Val Lys Glu Lys Gly Ile Leu Gln Gly Cys Asn Gln Met Cys Ala
420 425 430
Gly Tyr Leu Phe Gln Pro Asp Lys Gln Tyr Asp Val Ser Tyr Asp Thr
435 440 445
Gly Asp Lys Ala Ile Gln Cys Gly Arg His Val Asp Ile Phe Lys Phe
450 455 460
Trp Leu Met Trp Lys Ala Lys Gly Thr Val Gly Phe Glu Asn Gln Ile
465 470 475 480
Asn Lys Cys Leu Glu Leu Ala Glu Tyr Leu Tyr Ala Lys Ile Lys Asn
485 490 495
Arg Glu Glu Phe Glu Met Val Phe Asn Gly Glu Pro Glu His Thr Asn
500 505 510
Val Cys Phe Trp Tyr Ile Pro Gln Ser Leu Arg Gly Val Pro Asp Ser
515 520 525
Pro Gln Arg Arg Glu Lys Leu His Lys Val Ala Pro Lys Ile Lys Ala
530 535 540
Leu Met Met Glu Ser Gly Thr Thr Met Val Gly Tyr Gln Pro Gln Gly
545 550 555 560
Asp Lys Ala Asn Phe Phe Arg Met Val Ile Ser Asn Pro Ala Ala Thr
565 570 575
Gln Ser Asp Ile Asp Phe Leu Ile Glu Glu Ile Glu Arg Leu Gly Gln
580 585 590
Asp Leu
<210> 5
<211> 1784
<212> DNA
<213> 智人(Homo sapiens)
<400> 5
atggcgtctc gaccccatct tcgtccgcaa cctcctcgaa cgcgggagcg gaccccaata 60
ccactaacct gcgccccaca acgtacgata cctggtgcgg cgtggcccat ggatgcacca 120
gaaaactggg gctcaagatc tgcggcttct tgcaaaggac caacagcctg gaagagaaga 180
gtcgccttgt gagtgccttc aaggagaggc aatcctccaa gaacctgctt tcctgtgaaa 240
acagcgaccg ggatgcccgc ttccggcgca cagagactga cttctctaat ctgtttgcta 300
gagatctgct tccggctaag aacggtgagg agcaaaccgt gcaattcctc ctggaagtgg 360
tggacatact cctcaactat gtccgcaaga catttgatcg ctccaccaag gtgctggact 420
ttcatcaccc acaccagttg ctggaaggca tggagggctt caacttggag ctctctgacc 480
accccgagtc cctggagcag atcctggttg actgcagaga caccttgaag tatggggttc 540
gcacaggtca tcctcgattt ttcaaccagc tctccactgg attggatatt attggcctag 600
ctggagaatg gctgacatca acggccaata ccaacatgtt tacatatgaa attgcaccag 660
tgtttgtcct catggaacaa ataacactta agaagatgag agagatagtt ggatggtcaa 720
gtaaagatgg tgatgggata ttttctcctg ggggcgccat atccaacatg tacagcatca 780
tggctgctcg ctacaagtac ttcccggaag ttaagacaaa gggcatggcg gctgtgccta 840
aactggtcct cttcacctca gaacagagtc actattccat aaagaaagct ggggctgcac 900
ttggctttgg aactgacaat gtgattttga taaagtgcaa tgaaaggggg aaaataattc 960
cagctgattt tgaggcaaaa attcttgaag ccaaacagaa gggatatgtt cccttttatg 1020
tcaatgcaac tgctggcacg actgtttatg gagcttttga tccgatacaa gagattgcag 1080
atatatgtga gaaatataac ctttggttgc atgtcgatgc tgcctgggga ggtgggctgc 1140
tcatgtccag gaagcaccgc cataaactca acggcataga aagggccaac tcagtcacct 1200
ggaaccctca caagatgatg ggcgtgctgt tgcagtgctc tgccattctc gtcaaggaaa 1260
agggtatact ccaaggatgc aaccagatgt gtgcaggata cctcttccag ccagacaagc 1320
agtatgatgt ctcctacgac accggggaca aggcaattca gtgtggccgc cacgtggata 1380
tcttcaagtt ctggctgatg tggaaagcaa agggcacagt gggatttgaa aaccagatca 1440
acaaatgcct ggaactggct gaatacctct atgccaagat taaaaacaga gaagaatttg 1500
agatggtttt caatggcgag cctgagcaca caaacgtctg tttttggtat attccacaaa 1560
gcctcagggg tgtgccagac agccctcaac gacgggaaaa gctacacaag gtggctccaa 1620
aaatcaaagc cctgatgatg gagtcaggta cgaccatggt tggctaccag ccccaagggg 1680
acaaggccaa cttcttccgg atggtcatct ccaacccagc cgctacccag tctgacattg 1740
acttcctcat tgaggagata gaaagactgg gccaggatct gtaa 1784
<210> 6
<211> 178
<212> PRT
<213> 褐家鼠(Rattus norvegicus)
<400> 6
Met Pro Gly Ser Ala Leu Leu Cys Cys Leu Leu Leu Leu Ala Gly Val
1 5 10 15
Lys Thr Ser Lys Gly His Ser Ile Arg Gly Asp Asn Asn Cys Thr His
20 25 30
Phe Pro Val Ser Gln Thr His Met Leu Arg Glu Leu Arg Ala Ala Phe
35 40 45
Ser Gln Val Lys Thr Phe Phe Gln Lys Lys Asp Gln Leu Asp Asn Ile
50 55 60
Leu Leu Thr Asp Ser Leu Leu Gln Asp Phe Lys Gly Tyr Leu Gly Cys
65 70 75 80
Gln Ala Leu Ser Glu Met Ile Lys Phe Tyr Leu Val Glu Val Met Pro
85 90 95
Gln Ala Glu Asn His Gly Pro Glu Ile Lys Glu His Leu Asn Ser Leu
100 105 110
Gly Glu Lys Leu Lys Thr Leu Trp Ile Gln Leu Arg Arg Cys His Arg
115 120 125
Phe Leu Pro Cys Glu Asn Lys Ser Lys Ala Val Glu Gln Val Lys Asn
130 135 140
Asp Phe Asn Lys Leu Gln Asp Lys Gly Val Tyr Lys Ala Met Asn Glu
145 150 155 160
Phe Asp Ile Phe Ile Asn Cys Ile Glu Ala Tyr Val Thr Leu Lys Met
165 170 175
Lys Asn
<210> 7
<211> 682
<212> DNA
<213> 褐家鼠(Rattus norvegicus)
<400> 7
catgcctggc tcagcactgc tatgttgcct gctcttactg gctggagtga agaccagcaa 60
aggccattcc atccggggtg acaataactg cacccacttc ccagtcagcc agacccacat 120
gctccgagag ctgagggctg ccttcagtca agtgaagact ttctttcaaa agaaggacca 180
gctggacaac atactgctga cagattcctt actgcaggac tttaagggtt acttgggttg 240
ccaagccttg tcagaaatga tcaagtttta cctggtagaa gtgatgcccc aggcagagaa 300
ccatggccca gaaatcaagg agcatttgaa ttccctggga gagaagctga agaccctctg 360
gatacagctg cgacgctgtc atcgatttct cccctgtgag aataaaagca aggcagtgga 420
gcaggtgaag aatgatttta ataagctcca agacaaaggt gtctacaagg ccatgaatga 480
gtttgacatc ttcatcaact gcatagaagc ctacgtgaca ctcaaaatga aaaattgaac 540
cacccggcat ctactggact gcaggacata aatagagctt ctaaatctga tccagagatc 600
ttagctaacg ggagcaactc cttggaaaac ctcgtttgta cctctctcca aaatatttat 660
tacctctgat acctcagttc cc 682
<210> 8
<211> 537
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 优化的大鼠 IL-10(Optimized rat IL-10)
<400> 8
atgcctggct cagccctgct atgttgcctt ctcctgctgg cgggagtcaa gacaagcaag 60
ggccattcca tccggggaga taataactgc acccacttcc cagtctctca aacccacatg 120
ttgcgagagc tgagggctgc cttcagtcag gtgaagacgt tcttccagaa gaaggaccag 180
ctggacaaca ttctgctgac tgacagcctg ctgcaggatt tcaagggtta tttggggtgt 240
caagccctgt ctgaaatgat caagttttac ctggtagaag tgatgcccca ggcagagaat 300
catggccccg agatcaagga gcacctcaac tccctggggg agaagctgaa gaccctgtgg 360
attcagctga ggcgctgcca cagatttctc ccctgtgaaa acaagagcaa ggcagtggag 420
caggtgaaga acgattttaa taagctccag gacaagggcg tctacaaggc catgaacgag 480
ttcgacatct ttatcaactg catagaagct tacgttacac tcaagatgaa gaattga 537
<210> 9
<211> 178
<212> PRT
<213> 智人(Homo sapiens)
<400> 9
Met His Ser Ser Ala Leu Leu Cys Cys Leu Val Leu Leu Thr Gly Val
1 5 10 15
Arg Ala Ser Pro Gly Gln Gly Thr Gln Ser Glu Asn Ser Cys Thr His
20 25 30
Phe Pro Gly Asn Leu Pro Asn Met Leu Arg Asp Leu Arg Asp Ala Phe
35 40 45
Ser Arg Val Lys Thr Phe Phe Gln Met Lys Asp Gln Leu Asp Asn Leu
50 55 60
Leu Leu Lys Glu Ser Leu Leu Glu Asp Phe Lys Gly Tyr Leu Gly Cys
65 70 75 80
Gln Ala Leu Ser Glu Met Ile Gln Phe Tyr Leu Glu Glu Val Met Pro
85 90 95
Gln Ala Glu Asn Gln Asp Pro Asp Ile Lys Ala His Val Asn Ser Leu
100 105 110
Gly Glu Asn Leu Lys Thr Leu Arg Leu Arg Leu Arg Arg Cys His Arg
115 120 125
Phe Leu Pro Cys Glu Asn Lys Ser Lys Ala Val Glu Gln Val Lys Asn
130 135 140
Ala Phe Asn Lys Leu Gln Glu Lys Gly Ile Tyr Lys Ala Met Ser Glu
145 150 155 160
Phe Asp Ile Phe Ile Asn Tyr Ile Glu Ala Tyr Met Thr Met Lys Ile
165 170 175
Arg Asn
<210> 10
<211> 1600
<212> DNA
<213> 智人(Homo sapiens)
<400> 10
aaaccacaag acagacttgc aaaagaaggc atgcacagct cagcactgct ctgttgcctg 60
gtcctcctga ctggggtgag ggccagccca ggccagggca cccagtctga gaacagctgc 120
acccacttcc caggcaacct gcctaacatg cttcgagatc tccgagatgc cttcagcaga 180
gtgaagactt tctttcaaat gaaggatcag ctggacaact tgttgttaaa ggagtccttg 240
ctggaggact ttaagggtta cctgggttgc caagccttgt ctgagatgat ccagttttac 300
ctggaggagg tgatgcccca agctgagaac caagacccag acatcaaggc gcatgtgaac 360
tccctggggg agaacctgaa gaccctcagg ctgaggctac ggcgctgtca tcgatttctt 420
ccctgtgaaa acaagagcaa ggccgtggag caggtgaaga atgcctttaa taagctccaa 480
gagaaaggca tctacaaagc catgagtgag tttgacatct tcatcaacta catagaagcc 540
tacatgacaa tgaagatacg aaactgagac atcagggtgg cgactctata gactctagga 600
cataaattag aggtctccaa aatcggatct ggggctctgg gatagctgac ccagcccctt 660
gagaaacctt attgtacctc tcttatagaa tatttattac ctctgatacc tcaaccccca 720
tttctattta tttactgagc ttctctgtga acgatttaga aagaagccca atattataat 780
ttttttcaat atttattatt ttcacctgtt tttaagctgt ttccataggg tgacacacta 840
tggtatttga gtgttttaag ataaattata agttacataa gggaggaaaa aaaatgttct 900
ttggggagcc aacagaagct tccattccaa gcctgaccac gctttctagc tgttgagctg 960
ttttccctga cctccctcta atttatcttg tctctgggct tggggcttcc taactgctac 1020
aaatactctt aggaagagaa accagggagc ccctttgatg attaattcac cttccagtgt 1080
ctcggaggga ttcccctaac ctcattcccc aaccacttca ttcttgaaag ctgtggccag 1140
cttgttattt ataacaacct aaatttggtt ctaggccggg cgcggtggct cacgcctgta 1200
atcccagcac tttgggaggc tgaggcgggt ggatcacttg aggtcaggag ttcctaacca 1260
gcctggtcaa catggtgaaa ccccgtctct actaaaaata caaaaattag ccgggcatgg 1320
tggcgcgcac ctgtaatccc agctacttgg gaggctgagg caagagaatt gcttgaaccc 1380
aggagatgga agttgcagtg agctgatatc atgcccctgt actccagcct gggtgacaga 1440
gcaagactct gtctcaaaaa ataaaaataa aaataaattt ggttctaata gaactcagtt 1500
ttaactagaa tttattcaat tcctctggga atgttacatt gtttgtctgt cttcatagca 1560
gattttaatt ttgaataaat aaatgtatct tattcacatc 1600
<210> 11
<211> 147
<212> PRT
<213> 褐家鼠(Rattus norvegicus)
<400> 11
Met Gly Leu Ser Pro His Leu Ala Val Thr Leu Phe Cys Phe Leu Ile
1 5 10 15
Cys Thr Gly Asn Gly Ile His Gly Cys Asn Asp Ser Pro Leu Arg Glu
20 25 30
Ile Ile Asn Thr Leu Asn Gln Val Thr Glu Lys Gly Thr Pro Cys Thr
35 40 45
Glu Met Phe Val Pro Asp Val Leu Thr Ala Thr Arg Asn Thr Thr Glu
50 55 60
Asn Glu Leu Ile Cys Arg Ala Ser Arg Val Leu Arg Lys Phe Tyr Phe
65 70 75 80
Pro Arg Asp Val Pro Pro Cys Leu Lys Asn Lys Ser Gly Val Leu Gly
85 90 95
Glu Leu Arg Lys Leu Cys Arg Gly Val Ser Gly Leu Asn Ser Leu Arg
100 105 110
Ser Cys Thr Val Asn Glu Ser Thr Leu Thr Thr Leu Lys Asp Phe Leu
115 120 125
Glu Ser Leu Lys Ser Ile Leu Arg Gly Lys Tyr Leu Gln Ser Cys Thr
130 135 140
Ser Met Ser
145
<210> 12
<211> 475
<212> DNA
<213> 褐家鼠(Rattus norvegicus)
<400> 12
tctcacgtca ctgactgtag agagctattg atgggtctca gcccccacct tgctgtcacc 60
ctgttctgct ttctcatatg taccgggaac ggtatccacg gatgtaacga cagccctctg 120
agagagatca tcaacacttt gaaccaggtc acagaaaaag ggactccatg caccgagatg 180
tttgtaccag acgtccttac ggcaacaagg aacaccacgg agaacgagct catctgcagg 240
gcttccaggg tgcttcgcaa attttacttc ccacgtgatg tacctccgtg cttgaagaac 300
aagtctgggg ttctcggtga actgaggaaa ctctgtagag gtgtcagcgg tctgaactca 360
ctgagaagct gcaccgtgaa tgagtccacg ctcacaacac tgaaagactt cctggaaagc 420
ctaaaaagca tcctacgagg gaaatacttg cagtcctgca cttccatgtc ctaac 475
<210> 13
<211> 444
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 优化的大鼠 IL-4(Optimized rat IL-4)
<400> 13
atgggtttaa gcccccacct tgccgtcaca ctgttctgtt ttctcatctg taccgggaac 60
ggaattcatg gctgtaacga cagccctctg agagagatta tcaacacctt gaatcaggtt 120
accgaaaaag gcactccatg caccgagatg tttgtaccag atgtgcttac ggcaacgagg 180
aacaccactg agaatgagct gatctgtcgg gcttctcgag tgctgcgcaa attctacttc 240
cctcgtgatg tgcccccgtg cttgaagaac aagtcaggcg tgctcggaga actgaggaag 300
ctctgcagag gcgtctcagg gctgaattct ctgcgcagct gcaccgtgaa tgaatccaca 360
ctcacaaccc tgaaagactt cctggagagc ctgaagagca tcctacgggg gaagtatctc 420
cagtcctgca cttccatgag ttga 444
<210> 14
<211> 153
<212> PRT
<213> 智人(Homo sapiens)
<400> 14
Met Gly Leu Thr Ser Gln Leu Leu Pro Pro Leu Phe Phe Leu Leu Ala
1 5 10 15
Cys Ala Gly Asn Phe Val His Gly His Lys Cys Asp Ile Thr Leu Gln
20 25 30
Glu Ile Ile Lys Thr Leu Asn Ser Leu Thr Glu Gln Lys Thr Leu Cys
35 40 45
Thr Glu Leu Thr Val Thr Asp Ile Phe Ala Ala Ser Lys Asn Thr Thr
50 55 60
Glu Lys Glu Thr Phe Cys Arg Ala Ala Thr Val Leu Arg Gln Phe Tyr
65 70 75 80
Ser His His Glu Lys Asp Thr Arg Cys Leu Gly Ala Thr Ala Gln Gln
85 90 95
Phe His Arg His Lys Gln Leu Ile Arg Phe Leu Lys Arg Leu Asp Arg
100 105 110
Asn Leu Trp Gly Leu Ala Gly Leu Asn Ser Cys Pro Val Lys Glu Ala
115 120 125
Asn Gln Ser Thr Leu Glu Asn Phe Leu Glu Arg Leu Lys Thr Ile Met
130 135 140
Arg Glu Lys Tyr Ser Lys Cys Ser Ser
145 150
<210> 15
<211> 642
<212> DNA
<213> 智人(Homo sapiens)
<400> 15
tgcatcgtta gcttctcctg ataaactaat tgcctcacat tgtcactgca aatcgacacc 60
tattaatggg tctcacctcc caactgcttc cccctctgtt cttcctgcta gcatgtgccg 120
gcaactttgt ccacggacac aagtgcgata tcaccttaca ggagatcatc aaaactttga 180
acagcctcac agagcagaag actctgtgca ccgagttgac cgtaacagac atctttgctg 240
cctccaagaa cacaactgag aaggaaacct tctgcagggc tgcgactgtg ctccggcagt 300
tctacagcca ccatgagaag gacactcgct gcctgggtgc gactgcacag cagttccaca 360
ggcacaagca gctgatccga ttcctgaaac ggctcgacag gaacctctgg ggcctggcgg 420
gcttgaattc ctgtcctgtg aaggaagcca accagagtac gttggaaaac ttcttggaaa 480
ggctaaagac gatcatgaga gagaaatatt caaagtgttc gagctgaata ttttaattta 540
tgagtttttg atagctttat tttttaagta tttatatatt tataactcat cataaaataa 600
agtatatata gaatctaaaa aaaaaaaaaa aaaaaaaaaa aa 642
<210> 16
<211> 28
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 用于扩增CMV启动子的正向引物
<400> 16
ttcggccgtc gaggagcttg gcccattg 28
<210> 17
<211> 36
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 用于扩增CMV启动子的反向引物
<400> 17
gacgtcgacc tagctagcga attcggggcc gcggag 36
<210> 18
<211> 34
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 用于扩增SV40pA的正向引物
<400> 18
ccatcgatca gacatgataa gatacattga tgag 34
<210> 19
<211> 43
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 用于扩增SV40pA的反向引物
<400> 19
gacgtcgacg cggccgctac cacatttgta gaggttttac ttg 43
<210> 20
<211> 28
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 用于扩增卡那霉素抗性基因的正向引物
<400> 20
aggcgccatg agccatattc aacgggaa 28
<210> 21
<211> 29
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 用于扩增卡那霉素抗性基因的反向引物
<400> 21
ttcatgatta gaaaaactca tcgagcatc 29
<210> 22
<211> 28
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 用于扩增LITR和CMV的正向引物
<400> 22
atggcgcgcc cctggccttt tgctggcc 28
<210> 23
<211> 28
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 用于扩增SV40pA和RITR的反向引物
<400> 23
atggatccgc tagtaaatac cgcatcag 28
<210> 24
<211> 20
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 用于扩增rIL-10的正向引物
<400> 24
ccgctagcgc caccatgcct 20
<210> 25
<211> 39
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 用于扩增rIL-10的反向引物
<400> 25
gacgtcgacg ccatcgatgg cttaattaat caattcttc 39
Claims (12)
1.一种组合物在制备用于缓解或治疗疼痛的药物中的用途,其特征在于,所述组合物包括第一载体和第二载体,所述第一载体含有编码谷氨酸脱羧酶的基因,所述第二载体含有编码白细胞介素-10的基因。
2.如权利要求1所述的用途,其特征在于,所述第一载体和所述第二载体单位体积下基于病毒滴度的混合比为1:1至1:50。
3.如权利要求1所述的用途,其特征在于,所述第一载体和所述第二载体为选自腺病毒、腺相关病毒、单纯疱疹病毒、慢病毒、逆转录病毒和痘病毒中的至少一种病毒载体。
4.如权利要求1所述的用途,其特征在于,所述谷氨酸脱羧酶选自GAD65和GAD67中的至少一种。
5. 如权利要求1所述的用途,其特征在于,所述谷氨酸脱羧酶由SEQ ID NO:1或SEQ IDNO:4的氨基酸序列组成。
6. 如权利要求1所述的用途,其特征在于,所述编码谷氨酸脱羧酶的基因由SEQ IDNO:2、SEQ ID NO:3或SEQ ID NO:5的碱基序列组成。
7. 如权利要求1所述的用途,其特征在于,所述白细胞介素-10由SEQ ID NO:6或SEQID NO:9的氨基酸序列组成。
8. 如权利要求1所述的用途,其特征在于,所述编码白细胞介素-10的基因由SEQ IDNO:7、SEQ ID NO:8或SEQ ID NO:10的碱基序列组成。
9.如权利要求1所述的用途,其特征在于,所述疼痛为伤害性疼痛、心因性疼痛、炎性疼痛或病理性疼痛。
10.如权利要求1所述的用途,其特征在于,所述疼痛为神经病理性疼痛、癌症疼痛、术后疼痛、三叉神经痛、特发性疼痛、糖尿病神经病理性疼痛或偏头痛。
11.如权利要求1所述的用途,其特征在于,所述组合物还包括生理学上可接受的载体。
12.如权利要求1所述的用途,其特征在于,所述组合物为注射剂。
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SG11201802292UA (en) | 2018-04-27 |
CN113499450A (zh) | 2021-10-15 |
EP3354284B1 (en) | 2023-02-22 |
US20180250421A1 (en) | 2018-09-06 |
JP6621916B2 (ja) | 2019-12-18 |
BR112018005602A2 (pt) | 2018-10-09 |
HK1248130A1 (zh) | 2018-10-12 |
ES2939637T3 (es) | 2023-04-25 |
JP2018527400A (ja) | 2018-09-20 |
AU2016327213B2 (en) | 2019-07-25 |
CN108025090B (zh) | 2022-03-22 |
KR20180027598A (ko) | 2018-03-14 |
AU2016327213A1 (en) | 2018-03-22 |
KR20170034701A (ko) | 2017-03-29 |
CN108025090A (zh) | 2018-05-11 |
CA2998470A1 (en) | 2017-03-30 |
US11433145B2 (en) | 2022-09-06 |
KR102050478B1 (ko) | 2019-11-29 |
CA2998470C (en) | 2021-06-15 |
EP3354284A4 (en) | 2019-04-10 |
EP3354284A1 (en) | 2018-08-01 |
WO2017052160A1 (ko) | 2017-03-30 |
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