CN111655228A - 预防和治疗听力损失的组合物和方法 - Google Patents
预防和治疗听力损失的组合物和方法 Download PDFInfo
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Abstract
描述使用EGFR信号传导抑制剂进行预防听力损失、或使用EGFR信号传导抑制剂和编码无调相关因子的核酸分子治疗听力损失的方法和组合物。
Description
本专利申请要求2017年5月3日提交的美国临时专利申请序列号62/500,667的优先权权益,其全部内容通过引用合并于此。
本发明是在政府的支持下完成的,并获得了美国国立卫生研究院授予的编号为DC006471、DC015010、DC015444、DC013879、DC013232和CA021765的专利,编号为N00014-09-V-1014、N00014-12-V-0191、N00014-12-V-0775和N00014-16-V-2315由海军研究办公室授予。政府拥有本发明的某些权利。
背景技术
耳朵是一个复杂的器官,由迷宫般的结构组成,负责听觉和平衡。听力和平衡感都在于内耳结构将机械刺激转换为大脑识别的冲动的能力。负责听力的感觉感受器位于耳蜗中,耳蜗是充满液体的螺旋形管。耳蜗内是Corti器官,内衬有桥接基底膜和盖膜的柱状感觉毛细胞。当声波通过Corti器官时,基底膜振动,导致毛细胞来回弯曲。运动使毛细胞去极化,导致神经递质释放到听觉神经,后者将冲动传递给大脑。
内耳蜗的感觉上皮在出生后是有丝***后的,并且在小鼠中,在出生后的第一周内仅表现出有限的自发再生。Atonal BHLH转录因子1(Atoh1)是感觉毛细胞的谱系特异性转录因子,可将人工耳蜗外植体培养物中和体内的非感觉支持细胞直接转化为感觉毛细胞(Gubbels,et al.(2008)Nature 455(7212):537-41;Kelly,et al.(2012)J.Neurosci.32(19):6699-710;Liu,et al.(2012)J.Neurosci.32(19):6600-10;Liu,et al.(2014)PLoSOne 9(2):e89377;Zheng&Gao(2000)Nature Neurosci.(6):580-6)。此外,FDA已经批准了一项临床试验(NCT02132130),用于评估CGF166的安全性、耐受性和功效,CGF166是一种重组腺病毒5(Ad5)载体,含有编码人Atoh1的cDNA。但是,尚不清楚体内Atoh1介导的非感觉支持细胞到感觉毛细胞的转换是否有效和完整,以及这种转换是否绕过祖细胞状态或精确地遵循正常的发育谱系。在几种小鼠模型中,Atoh1转化的感觉毛细胞表现出不成熟的毛细胞形态,并且不表达几种末端分化标记(例如,编码Prestin的Slc26a5和编码癌调节蛋白的Ocm),并且转化率很低(6%–20%)(Kelly,et al.(2012)J.Neurosci.32(19):6699-710;Liu,et al.(2012)J.Neurosci.32(19):6600-10;Liu,et al.(2014)PLoS One 9(2):e89377)。此外,在以p75标记的部分支持细胞中,表皮生长因子受体(EGFR)信号已被证明是增殖和下调细胞周期抑制剂p27Kip1(CDKN1b)所必需的,以使其能够重新进入细胞周期(White,et al.(2012)Dev.Biol.363:191-200)。
发明概述
本发明提供一种用于通过向有需要的动物施用表皮生长因子受体(EGFR)信号传导抑制剂来治疗或预防听力损失的方法。依照本治疗,该方法还可包括施用表达载体和/或其他再生剂,该表达载体携带编码无调相关因子的核酸分子。在其他实施方案中,该方法还包括施用一种或多种耳保护剂或再生剂。在进一步实施方案中,EGFR信号传导抑制剂抑制EGFR、Ras、Raf、MEK、ERK/MAPK、JAK、STAT、PI3K、AKT、mTOR、NCK、PAK、JNK、PLC、PKC或细胞周期相关蛋白激酶抑制剂(例如Her-2、Aurora激酶、B-Raf或PDGFR)的表达或活性。在其他实施方案中,抑制剂是抑制性RNA、抗体或有机小分子。还提供药物组合物和试剂盒,包含携带编码无调相关因子的核酸分子的表达载体、联合表皮生长因子受体(EGFR)信号转导抑制剂和任选的一种或多种再生剂组合。
附图简述
图1A-1D显示,在新生小鼠耳蜗外植体中,EGFR信号传导的药理作用抑制作用增强了Atoh1诱导的毛细胞(HC)转化。代表性图像显示了用Atoh1-IRES-GFP转染并经媒介物(图1A和1C)或100nM AG1478(图1B和1D)处理的耳蜗外植体的免疫染色。显示了毛细胞标记物Myo6(↑)和Atoh1转染的细胞(GFP,)的表达。图1C和1D分别表示图1A和1B中正方形区域的高放大倍率。比例尺:图1A和1B中为100μm,图1C和1D中为20μm。
图2显示了在所示的不同处理下(每种处理的n=1-5)Atoh1诱导的HC转化率(Myo6+;GFP+/GFP+细胞百分比)的定量。在所有条件下都将Atoh1转染(O/E)。
图3显示,EGFR抑制剂MUBRITINIB(显示出其结构)可防止顺式铂诱导的小鼠耳蜗外植体毛细胞丢失,IC50为2.5nM,LD50为>500nM(治疗指数>200)。外植体数量:每个剂量1-4个;分析了采用150μM顺铂处理和中间回合的FVB耳蜗外植体;曲线拟合,R2为0.86。请注意,MUBRITINIB的IC50值在所有测定中均一致,表明其特异性和效力。
图4显示EGFR抑制剂Pelitinib(显示了其结构)可以防止顺铂诱导的毛细胞丢失。Pelitinib是一种不可逆的EGFR抑制剂,对HEI-OC1细胞中顺铂诱导的Caspase-3/7活性具有保护作用,IC50为0.6μM(cisplatin-Glo3/7),LD50>40μM(CELLTITER-GLO)。
发明详述
现已发现,在顺铂、抗生素、噪音、衰老或其他耳毒性损伤中,EGFR及其下游或与其相关的蛋白质的抑制剂可保护受损的毛细胞,并可在耳蜗外植体培养中与Atoh1过表达一起显着诱导毛细胞形成。因此,本发明提供了组合物和方法,所述组合物和方法用于使用EGFR抑制剂预防听力损失和/或使用EGFR抑制剂与无调相关因子基因疗法组合治疗听力损失。理想地,本发明的方法预防或治疗动物,优选哺乳动物(例如人)的至少一种与感觉毛细胞丧失或损害有关的疾病,例如与感觉毛细胞损害有关的耳朵疾病(例如听力损失或平衡障碍)。本发明的方法还可用于维持感觉水平,即控制由例如老化过程或耳毒性剂引起的对环境刺激的感觉丧失。
EGFR信号传导。表皮生长因子受体(EGFR;ErbB-1;人的HER1)是一种细胞表面受体,通过其特定配体的结合而激活,包括表皮生长因子(EGF)、转化生长因子α(TGFα)、HB-EGF、双调蛋白、betacellulin、epigen和epiregulin。EGFR是ErbB受体家族的成员,该家族是四个紧密相关的受体酪氨酸激酶的一个亚家族:EGFR、HER2/c-neu(ErbB-2)、Her3(ErbB-3)和Her4(ErbB-4)。通过其生长因子配体激活后,EGFR会从无活性的单体形式过渡到有活性的同型二聚体。除了在配体结合后形成同型二聚体外,EGFR还可以与ErbB受体家族的另一个成员(例如ErbB2/Her2/neu)配对,以产生活化的异二聚体。EGFR二聚化刺激其固有的细胞内蛋白酪氨酸激酶活性。结果,在EGFR的C端结构域中发生了几个酪氨酸(Y)残基的自磷酸化。这些包括Y992、Y1045、Y1068、Y1148和Y1173。这种自磷酸化引起Ras/Raf/MEK/ERK/MAPK、JAK/STAT、PI3K/AKT/mTOR、NCK-PAK-JNK、PLC-DAG-PKC和/或许多与细胞周期相关的蛋白激酶蛋白/途径的下游激活、信号传导和/或表达。这些信号事件引发了多个信号转导级联反应,从而导致DNA合成以及细胞迁移、粘附和增殖。因此,“EGFR信号传导”或“EGFR信号传导途径”在本文中是指通过EGFR本身以及Ras/Raf/MEK/ERK/MAPK、JAK/STAT、PI3K/AKT/mTOR、NCK-PAK-JNK、PLC-DAG-PKC、细胞周期相关的蛋白激酶途径/下游蛋白进行的信号传导。
Ras/Raf/MEK/ERK/MAPK途径。Ras/Raf/MEK/ERK/MAPK途径(也称为MAPK/ERK途径)在本领域中是众所周知的,并且通过传递来自配体结合的细胞表面酪氨酸激酶受体(例如EGFR)的细胞外信号,在调节哺乳动物细胞的生长中起着重要作用。MAPK/ERK(促***原激活的蛋白激酶/细胞外信号调节激酶)途径的激活是通过从激活Ras(例如,HRas(GENBANK登录号为NP_001123914、NP_001304983或NP_789765),KRas(GENBANK登录号为NP_004976或NP_203524)或NRas(GENBANK登录号为NP_002515))开始的一系列磷酸化事件。Ras的激活导致Raf(例如c-Raf或Raf-1(GENBANK登录号为NP_002871)、A-Raf(GENBANK登录号为NP_001243125、NP_001645或NP_001243126)或B-Raf(GENBANK登录号为NP_004324))的募集和激活。然后,激活的Raf磷酸化并激活MEK1/2(即MAPK/ERK激酶-1和-2;GENBANK登录号分别为NP_002746和NP_109587),然后磷酸化并激活ERK1/2(即MAPK3/MAPK1;UniProt登录号分别为P28482和P27361)。从Ras到ERK的蛋白质链将信号从细胞表面受体传递到DNA。ERK通过控制细胞周期进程、分化、蛋白质合成、代谢、细胞存活、细胞迁移以及侵袭和衰老的转录因子介导的基因表达发生广泛变化。
JAK/STAT途径。Janus激酶/信号转导子和转录激活子(JAK/STAT)通路刺激细胞增殖、分化、细胞迁移和凋亡。从机制上讲,JAK/STAT信令由一些主要组件组成。在哺乳动物中,JAK家族包括四个成员:JAK1(GENBANK登录号为NP_001307852)、JAK2(GENBANK登录号为NP_001309123或NP_001309127)、JAK3(GENBANK登录号为NP_000206)和Tyk2(GENBANK登录号为NP_003322)。JAK活化在配体介导的受体多聚化时发生,从而允许反磷酸化。随后,激活的JAK磷酸化其他靶标,特别是STAT。STAT是潜伏的转录因子,在激活之前一直存在于细胞质中。哺乳动物STAT(即STAT1,GENBANK登录号为NP_009330或NP_644671;STAT2,GENBANK登录号为NP_005410或NP_938146;STAT3,GENBANK登录号为NP_003141、NP_644805或NP_998827;STAT4,GENBANK登录号为NP_001230764或NP_003142;STAT5A,GENBANK登录号为NP_001275647、NP_001275648或NP_001275649;STAT5B,GENBANK登录号为NP_036580;STAT6,GENBANK登录号为NP_001171549、NP_001171550、NP_001171551或NP_001171552)在C端附近带有一个保守的酪氨酸残基,该残基被JAK磷酸化。该磷酸酪氨酸通过与保守的SH2结构域相互作用而使STAT二聚化。磷酸化的STAT进入细胞核并结合特定的调控序列以激活或抑制靶基因的转录。因此,JAK/STAT级联提供了将细胞外信号翻译成转录反应的直接机制。
PI3K/AKT/mTOR途径。PI3K/AKT/mTOR途径是在调节细胞周期中重要的细胞内信号传导途径。EGFR的配体结合激活导致PI3K(磷脂酰肌醇-4,5-二磷酸3激酶,例如1类酶,如PIK3CA、PIK3CB、PIK3CG、PIK3CD、PIK3R1、PIK3R2、PIK3R3、PIK3R4、PIK3R5和PIK3R6;2类酶,例如PIK3C2A、PIK3C2B和PIK3C2G;以及3类酶PIK3C3)的激活。PI3K随后磷酸化Akt(即,蛋白激酶B或PKB包括AKT1,UniProt登录号P31749;AKT2,UniProt登录号P31751;AKT3,UniProt登录号Q9Y243)。PIK3随后激活各自参与细胞生长的mTOR复合物mTORC1和mTORC2。mTORC1由mTOR、Raptor、GβL(具有SEC13蛋白8的哺乳动物致死性)和含域的mTOR相互作用蛋白(DEPTOR)组成,它们统一表明多种信号,这些信号指示生长因子、营养素和能量的可用性,以促进压力下的细胞生长和分解代谢过程。活跃的mTORC1发挥许多下游生物学作用,包括通过磷酸化下游靶标(例如4E-BP1和p70 S6激酶)来翻译mRNA、通过Atg13和ULK1抑制自噬、核糖体生物发生以及导致线粒体活性或脂肪形成增加的转录激活。由mTOR、Rictor、GβL、Sin1、PRR5/Protor-1和DEPTOR组成的mTORC2通过激活Akt促进细胞存活。mTORC2通过激活PKCα和磷酸化SGK1来调节细胞骨架动力学、离子转运和生长。
NCK-PAK-JNK途径。已知Nck(酪氨酸激酶衔接子蛋白1的非催化区域;GENBANK登录号为NP_001177725或NP_001278928)通过其SH2结构域与活化的EGFR结合。Nck通过PAK1的第一N末端多脯氨酸域和Nck的SH3域与PAK1(p21/CDC42/Rac1激活的激酶1;GENBANK登录号为NP_001122092或NP_002567)相关。Nck激活PAK,PAK随后通过MEKK1(MAP/ERK激酶激酶1;GENBANK登录号NP_005912)和MKK4/7(MAP激酶激酶4/7;GENBANK登录号NP_1268364、NP_003001、NP_001284484或NP_001284485)激活JNK(c-Jun激酶)。激活的JNK进入细胞核并引起c-Fos和c-Jun等转录因子的磷酸化。
PLC-DAG-PKC途径。磷脂酶C(PLC)将EGFR激活与次级信使的产生和钙代谢联系起来。EGFR募集PLC-γ1并使其磷酸化(GENBANK登录号NP_002651或NP_877963),然后从PtdIns(4,5)P2生成二酰基甘油(DAG)和肌醇-1,4,5-三磷酸酯(IP3)。DAG激活蛋白激酶C(PKC)的许多同工型,包括常规同工型α、β和γ,以及PKC-ε和PKC-θ。PKC-α、PKC-β、PKC-γ和PKC-ε磷酸化并激活c-Raf-1,从而扩增HRas/MEK1和MEK2/ERK1/2激酶级联反应。PKC-θ激活核因子NF-kappa-B抑制剂激酶beta(IKK-beta),导致核因子NF-kappa-B(NF-kB)激活。
细胞周期相关蛋白激酶。EGFR下游或与EGFR相互作用的蛋白激酶在真核细胞周期的调控中起着核心作用。更具体地说,这些蛋白激酶参与信号转导、染色体凝缩、中心体成熟、纺锤体组装、纺锤体定向、减数***成熟和胞质***。因此,“细胞周期相关的蛋白激酶”是指在EGFR下游或与EGFR相互作用的激酶,其调节细胞周期进程、细胞***、细胞增殖和细胞周期机制中的一种或多种。在某些实施方案中,本发明的细胞周期相关的蛋白激酶是Her2/neu、Aurora激酶、B-raf(如本文所讨论)或血小板衍生的生长因子受体(PDGFR)。
Her2/neu激酶。Her2/neu是由位于染色体17q21-22上的erbB2癌基因编码的185-kDa跨膜蛋白(GENBANK登录号NP_001005862、NP_001276865、NP_001276866、NP_001276867或NP_004439)。Her2/neu在细胞表面的正常表达对于调节细胞生长和上皮细胞存活至关重要。虽然尚未鉴定出Her2/neu的天然配体,但已知Her2/neu是与EGFR和Her3形成有效异二聚体的优选二聚体伴侣(Lenferink,et al.(1998)EMBO J.17:3385-97)。
Aurora激酶。Aurora激酶是高度保守的丝氨酸/苏氨酸激酶家族,对通过有丝***的忠实过渡非常重要(Bischoff,et al.(1998)EMBO J.17:3052–65;Carmena&Earnshaw(2003)Nat.Rev.Mol.Cell Biol.4:842–54;Giet&Prigent(1999)J.Cell Sci.112:3591–601)。Aurora A的基因映射到20q13.2染色体区域,该区域已在不同的人类癌症中扩增。Aurora A(GENBANK登录号NP_001310232、NP_001310233、NP_001310234、NP_003591或NP_940835)在中心体成熟、纺锤体组装、减数***成熟和中期I纺锤体定向中起重要作用(Carmena&Earnshaw(2003)Nat.Rev.Mol.Cell Biol.4:842–54)。Aurora A功能受降解,磷酸化和去磷酸化的调节,其激酶活性取决于激活环中苏氨酸288(Thr288)的磷酸化。选择性抑制Aurora A导致抑制Thr288、单极纺锤体和G2-M阻滞时Aurora A的自磷酸化(Girdler,et al.(2006)J.Cell Sci.119:3664–75;Carpinelli&Moll(2008)ExpertOpin.Ther.Targets 12:69–80)。Aurora B(GENBANK登录号NP_001243763、NP_001271455、NP_001300879、NP_001300880或NP_001300881)基因定位到染色体区域17p13.1,该激酶形成具有三个非酶亚基的染色体乘客复合物(CPC)的一部分:内部着丝粒蛋白(INCENP)、Survivin和Borealin(Vader,et al.(2006)J.Cell Biol.173:833–7)。高动态的CPC对染色体凝结、有丝***纺锤体上的染色体方向,通过校正染色体-微管附着错误,纺锤体装配检查点(SAC)以及胞质***的最后阶段至关重要(Sampath,et al.(2004)Cell 118:187–20;Terada,et al.(1998)EMBO J.17:667–76;Carmena,et al.(2012)Nat.Rev.Mol.CellBiol.13:789–803;Tanenbaum,et al.(2011)Curr.Biol.21:1356–6)。据报道,Aurora C(GENBANK登录号NP_001015878、NP_001015879或NP_003151)在睾丸、甲状腺和胎盘以及减数***的配子中表达(Ulisse,et al.(2006)Int.J.Cancer 119:275–82;Bernard,et al.(1998)Genomics 53:406–9;Kimura,et al.(1999)J.Biol.Chem.274:7334–40;Yang,etal.(2010)Mol.Biol.Cell21:2371–83)。此外,已证明与STAT5相关的核EGFR结合并增加Aurora-A基因表达(Hung,et al.(2008)Nucl.Acids Res.36(13):4337-51)。提示Aurora C的过表达会诱导异常细胞***,从而导致中心体扩增和细胞中的多核化。
PDGFR激酶。PDGFR参与控制脊椎动物各种组织中的细胞增殖、分化和存活。活化的PDGFR使自身和其他蛋白质磷酸化,从而参与触发细胞反应(例如迁移和增殖)的细胞内信号传导途径。PDGFRα(UniProtKB登录号P16234)和PDGFRβ(GENBANK登录号NP_002600)在迅速生长的卵囊中在胚胎的第12-14天高表达,此后微弱表达(Lee,et al.(2004)Acta Oto-Laryng.124:558-62)。基于该分析,表明PDGF信号传导的完整性是发育中的耳蜗毛细胞的增殖所必需的(Lee,et al.(2004)Acta Oto-Laryng.124:558-62)。此外,先前的研究表明PDGF信号传导对于新生小鼠内耳的血管和间质隔室的营养作用以及间接地对感觉上皮的生存是必需的(Hayashi,et al.(2008)Hear.Res.245:73–81)。值得注意的是,PDGFRβ与EGFR之间的异二聚化和串扰表明了EGFR反式激活在PDGF刺激的细胞迁移中的作用(Saito,et al.(2001)Mol.Cell Biol.21(19):6387-94)。
EGFR信号传导抑制剂。EGFR信号传导抑制剂是指能降低、阻断或降低EGFR蛋白或与EGFR下游通路相互作用或在其下游通路中的蛋白的表达或活性的任何分子,例如Ras、Raf、MEK、ERK/MAPK、JAK、STAT、PI3K、AKT、mTOR(包括mTOR复合体的蛋白质)、NCK、PAK、JNK、PLC、PKC或与细胞周期相关的蛋白激酶(例如Her-2、Aurora激酶、B-Raf或PDGFR)。EGFR信号传导抑制剂还包括阻断EGFR配体例如EGF、TGF-α、HB-EGF、AR、BTC、EPR或表观基因的表达或活性的抑制剂。在某些实施方案中,EGFR信号传导抑制剂抑制或降低EGFR、PLC、STAT3、JAK2、PI3K、MEK、Her-2、Aurora激酶、B-Raf或PDGFR的表达或活性。
本发明的抑制剂可以选择性地降低或阻断EGFR信号传导蛋白的表达(即该蛋白的转录或翻译),降低或阻断EGFR信号传导蛋白的活性(即与配体的结合、酪氨酸激酶活性、磷酸化、蛋白-蛋白相互作用和/或下游信号传导),降低或阻断EGFR信号传导蛋白的生物学效应,和/或修饰EGFR信号传导蛋白的半衰期或亚细胞定位(膜与细胞质或核的定位、内化和再循环)。特别地,EGFR信号传导抑制剂是选择性降低或阻断以下一种或多种的活性剂:转录或翻译、配体结合、磷酸化、多聚化、酪氨酸激酶活性、内在化和/或易位入核内。
理想地,与正常的生理水平相比,EGFR信号传导抑制剂的抑制剂完全阻断EGFR信号传导或将其减少至少10%、至少20%、至少30%、至少40%、至少50%、至少60%、至少70%、至少75%、至少80%、至少85%、至少90%、至少92.5%、至少95%、至少97%、至少98%、至少98、5%、至少99%、至少99.25%、至少99.5%或至少99.75%。
本发明的EGFR信号传导抑制剂通常具有在1pM至100μM范围内的一半最大(50%)抑制浓度(IC50)。优选地,EGFR信号传导抑制剂具有小于10μM、小于5μM、小于1μM或小于100nM的IC50值。此外,在一些实施方案中,EGFR信号传导抑制剂对一种或多种目的EGFR信号传导蛋白是特异的/选择性的,并且不能抑制其他非EGFR途径蛋白或在很大程度上抑制其他非EGFR途径蛋白。在这方面,优选EGFR信号传导抑制剂是EGFR信号传导的选择性抑制剂。优选地,选择性是针对一种、两种、三种或四种EGFR信号传导蛋白,并且不能抑制或基本上不抑制其他非EGFR途径蛋白。举例来说,抑制剂可以是双重EGFR和ERBB2抑制剂,两者都是EGFR信号传导蛋白。选择性评估抑制剂的方法是本领域已知的,并且可以基于任何常规测定法,包括但不限于测定IC50、抑制剂的结合亲和力(即Ki)和/或与另一种蛋白质(比较蛋白)相比目标EGFR信号传导蛋白抑制剂的半数最大有效浓度(EC50)。在特定的实施方案中,EGFR信号传导的选择性抑制剂是这样的抑制剂:其所关注的EGFR信号传导蛋白的IC50值比比较蛋白质的相应IC50值低至少两倍,或更理想地,至少低三倍、四倍、五倍或六倍。最合乎需要的是,EGFR信号传导的选择性抑制剂具有的EGFR信号传导蛋白的IC50值比比较蛋白质的IC50值低至少一个数量级或至少两个数量级。
本发明的抑制剂可以是基于核酸的抑制剂,例如抑制性RNA分子(例如,反义分子、核酶、siRNA、shRNA、miRNA等);影响剪接或3'加工(例如,聚腺苷酸化)或细胞内另一个基因表达水平的蛋白(即,广泛认为基因表达包括从转录起始到过程蛋白产生的所有步骤),例如通过介导mRNA积累或转运速率的改变或转录后调控的改变;抗体(包括片段或模拟物);肽;有机小分子;或其组合。
术语siRNA是指具有降低靶基因表达活性的双链RNA或RNA和DNA种类。这些分子被称为“小干扰RNA”、“短干扰RNA”或“沉默RNA”。siRNA链通常长20-25个核苷酸,尽管可在体内裂解形成活性物质的较大前体分子在本文所用术语的范围内。
如本文所用,“miRNA分子”或“miRNA”是小RNA分子,通常约20至25个核苷酸,由动物的基因组编码或合成产生,其序列对应于动物的基因组编码的序列。如本文所用,miRNA分子可以是单链或双链的。
当抑制剂是例如抑制性RNA、肽或蛋白质时,编码这种抑制剂的核酸分子可以由编码无调相关因子的相同核酸分子携带,或者可以是存在于相同表达载体上或不同表达载体一部分上的独立核酸分子。基于本文公开的核酸序列可以容易地制备抑制性RNA分子。或者,可从商业来源例如Dharmacon(参见例如ON-TARGET plus siRNA SMART pools)、Invitrogen或Zyagen获得抑制性RNA分子例如siRNA。可以使用常规技术,例如斑点印迹、RNA印迹、ELISA或蛋白质印迹分析来测量蛋白质表达的降低。
EGFR抑制剂。选择性降低或阻断EGFR本身表达的EGFR抑制剂包括但不限于EGFR反义、siRNA和miRNA分子。降低EGFR表达的示例性反义和siRNA公开于例如美国专利2011/0046067和Kang,et al.(2006)Cancer Gene Ther.13(5):530-8。降低EGFR表达的示例性miRNA在例如美国专利8,673,872中公开,其通过引用整体并入本文。
EGFR抑制剂也可以是特异性结合EGFR并通过例如阻断配体结合、活化、磷酸化或蛋白质-蛋白质相互作用来拮抗其活性的抗体、抗体片段或抗体模拟物。西妥昔单抗(IgG1)和帕尼单抗(IgG2)是EGFR的单克隆抗体抑制剂的实例。其他拮抗性单克隆抗体包括Zalutumumab、Nimotuzumab、Matuzumutab、ICR62和mAb806。参见US 6,506,883、US 6,235,883、US 5,891,996、US 4,943,533、WO 2004/056847、WO 2002/092771、WO 2002/66058和WO1995/20045。这样的抗体阻断细胞外配体结合结构域,从而阻断酪氨酸激酶激活。
调节EGFR多聚和激活的EGFR肽抑制剂也用于本发明。EGFR的示例性肽抑制剂可以基于以下来自EGFR的近膜序列:LLLWALGIGLFMRRRHIVRKRTLRRLLQERELVEPLTPS(SEQ ID NO:2),并且可以任选地包括细胞穿透组分,例如蛋白质转导域(PTD),以促进向细胞中的递送。参见美国专利2016/0311884。
更进一步,EGFR抑制剂可以是抑制EGFR的酪氨酸激酶活性的小分子。没有激酶活性,EGFR将无法激活自身,这是结合下游衔接子蛋白的先决条件。EGFR小分子抑制剂的实例包括但不限于埃洛替尼(CAS 183321-74-6)、吉非替尼(CAS 184475-35-2)、拉帕替尼(CAS231277-92-2、EGFR和ERBB2双重抑制剂)、纳拉替尼(CAS 698387-09-6)、坎尼替尼(CAS267243-28-7)、凡德他尼(CAS 443913-73-3)、阿法替尼(CAS 439081-18-2)、AG 1478(CAS153436-53-4)、TAK-285(CAS 871026-44-7、HER2和EGFR双重抑制剂)、ARRY334543(CAS845272-21-1、双重EGFR磷酸化抑制剂)、达科替尼(CAS 1110813-31-4、EGFR和ERBB2抑制剂)、AZD3759(CAS 1626387-80-1)、NT113(CAS 1398833-56-1、pan-ERBB抑制剂)、OSI-420(去甲基厄洛替尼、CAS 183321-86-0、EGFR抑制剂)、AZD8931(CAS 848942-61-9、EGFR、HER2和HER3抑制剂)、AEE788(CAS 497839-62-9、EGFR、HER2和VEGFR 1/2抑制剂)、培利替尼(EKB-569、CAS 257933-82-7、pan-ErbB抑制剂)、CUDC-101(CAS 1012054-59-9、EGFR、HER2和HDAC抑制剂)、XL647(CAS 651031-01-5、HER2和EGFR双重抑制剂)、BMS-599626(CAS714971-09-2、EGFR和HER2双重抑制剂)、PKC412(CAS 120685-11-2、EGFR、PKC、环AMP依赖性蛋白激酶和S6激酶抑制剂)、BIBX1382(CAS 196612-93-8、EGFR抑制剂)和AP26113(CAS1197953-54-0、ALK和EGFR抑制剂),及其衍生物和组合。在一些实施方案中,EGFR抑制剂不是培利替尼。
Ras/Raf/MEK/ERK/MAPK抑制剂。选择性降低或阻断Ras、Raf、MEK、ERK/MAPK表达的该途径的抑制剂包括但不限于反义、siRNA和miRNA分子。举例说明,在US 6,096,543中公开了对MEK1的反义抑制,其通过引用整体并入本文。
Ras抑制剂的实例包括但不限于R115777(CAS 192185-72-1)、BMS-214662(CAS195987-41-8)、SCH66336(CAS 193275-84-2)、FTI-277(CAS 1217447-06-7)、manumycin A(CAS 52665-74-4)、FTI-276(CAS 170006-72-1)、RasCAAX(拟肽)、L-744,832(CAS1177806-11-9)及其衍生物和其组合。
在本发明中使用的Raf抑制剂包括但不限于Bay43-9006(索拉非尼、CAS 284461-73-0、对B-Raf和C-Raf的选择性抑制剂)、维拉非尼(CAS918504-65-1、B-Raf抑制剂)、达拉非尼(CAS 1195764-45-7、B-Raf抑制剂;另请参见US 7,994,185和US 8,415,345)、LY3009120(CAS 1454682-72-4、pan-Raf抑制剂)、GW 5074(CAS 220904-83-6、C-Raf-1抑制剂)、ZM 336372(CAS 208260-29-1、Raf-1抑制剂)、2-溴二甲胺(CAS 96562-96-8、RAF/MEK-1/MAPK途径抑制剂)、L-779,450(CAS 303727-31-3)、AZ628(CAS 878739-06-1、Raf-1抑制剂)、RAF265(CAS 927880-90-8、B-Raf和VEGFR-2抑制剂)、恩可拉非尼(LGX818、CAS1269440-17-6、B-Raf抑制剂)及其衍生物和组合。
MEK抑制剂包括但不限于SL-327(CAS 305350-87-2、MEK1和MEK2抑制剂)、PD 184,352(CAS 212631-79-3)、2-溴二甲胺(CAS 96562-96-8、Raf/MEK-1/MAPK途径抑制剂)、PD198306(CAS 212631-61-3、非ATP竞争性MEK1/2抑制剂)、PD 0325901(CAS 391210-10-9、MEK抑制剂和ERK磷酸化抑制剂)、MEK抑制剂II(CAS 623163-52-0)、PD 184161(CAS212631-67-9、MEK1和MEK2的选择性抑制剂)、U-0126(CAS 109511-58-2、MEK1/2的抑制剂)、PD 98059(CAS 167869-21-8、MEK1的选择性抑制剂)、AS703026(CAS 1236699-92-5、MEK1/2抑制剂)、BAY 869766(CAS 923032-37-5、MEK-1和MEK-2的非ATP竞争性抑制剂)、PD 318088(CAS 391210-00-7、MEK1/2抑制剂)、塞鲁替尼(CAS 606143-52-6、MEK-1非ATP竞争性抑制剂)、TAK-733(CAS 1035555-63-5、MEK的变构抑制剂)、曲美替尼(CAS 871700-17-3、MEK1/MEK2的变构抑制剂)及其衍生物和组合。还参见WO 1998/037881、WO 1999/901426、WO2000/041505、WO 2000/041994、WO 2000/042002、WO 2000/042003、WO 2000/042022、WO2000/042029、WO 2001/068619和WO 2002/036570,用于其他MEK抑制剂。
ERK抑制剂包括,例如,SCH772984(CAS 942183-800-4、ERK1/2抑制剂)、DEL-22379(CAS 181223-80-3、ERK二聚抑制剂)、VX-11e(CAS 896720-20-0、ERK2抑制剂)、多效素(SC1、CAS 839707-37-8、ERK1和RasGAP双重抑制剂)、乌利替尼(BVD-523、VRT752271、CAS869886-67-9、ERK1/ERK2抑制剂)、FR 180204(CAS 865362-74-9、ATP竞争性ERK抑制剂)、GDC-0994(CAS 1453848-26-4、ERK1/2抑制剂)、KO-947(Kura Oncology、ERK1/2抑制剂)及其衍生物和组合。有关其他ERK抑制剂,另请参见JP 2005-330265。
JAK/STAT抑制剂。选择性降低或阻断JAK或STAT表达的抑制剂包括但不限于反义、siRNA和miRNA分子。作为说明,分别在US 2004/0101853、US 6,159,694、US 6,479,465、US8,722,873和WO 1998/040478中公开了STAT-2、STAT-3、STAT-4、STAT-5和STAT-6的反义抑制。同样,在US 9,198,911中公开了用于降低STAT-1和STAT-2表达的siRNA。在US 2010/0298409中描述了STAT-3siRNA,在WO 2009/039199中描述了STAT-5siRNA,在US 7,566,700中描述了STAT-6siRNA。在US 9,198,911中公开了用于抑制Jak1和Jak3表达的SiRNA分子,其全部内容通过引用并入本文。
STAT抑制剂的非限制性实例包括但不限于WP-1034(CAS 857064-42-7、Jak-Stat抑制剂)、氟达拉滨(CAS 21679-14-1、STAT1抑制剂)、S3I-201(CAS 501919-59-1、STAT3DNA结合活性抑制剂)、Stattic(CAS 19983-44-9、STAT3抑制剂)、APTSTAT3-9R(STAT结合肽)、STA-21(CAS 28882-53-3、STAT3抑制剂)、SH-4-54(CAS 1456632-40-8)、那巴布星(CAS83280-65-3、STAT3抑制剂)、隐丹参酮(CAS 35825-57-1、STAT3抑制剂)、烟酰胺(CAS 50-65-7、STAT3抑制剂)、NSC 74859(CAS 501919-59-1、STAT3抑制剂)、HO-3867(CAS 1172133-28-6、STAT3抑制剂)及其衍生物和组合。
Jak1/Jak2抑制剂包括但不限于AG-490(CAS 133550-30-8),CYT387(CAS1056634-68-4),SB1518(Pacritinib,CAS 937272-79-2),LY3009104(INCB28050,Baricitinib,CAS 1187594-09-7),TG101348(CAS 936091-26-8),BMS-911543(CAS1271022-90-2),AZD1480(CAS 935666-88-9),Ruxolitinib(INCB018424,CAS 941678-49-5),CEP-701(CAS 111358-88-4),TG101348(Fedratinib,CAS 936091-26-8),SD 1008(CAS960201-81-4,JAK2/STAT3抑制剂),WP-1066(CAS 857064-38-1,JAK2/STAT3抑制剂)及其衍生物和组合。JAK3抑制剂包括但不限于Janex1(WHI-P131,CAS 202475-60-3),PF-956980(CAS 1262832-74-5),WHI-P154(CAS 211555-04-3),VX-509(Decernotinib,CAS 944842-54-0),JAK3抑制剂IV(ZM-39923,CAS 1021868-92-7),托法替尼(CP-690550,CAS 540737-29-9)及其衍生物和组合。
PI3K/AKT/mTOR抑制剂。选择性降低或阻断PI3K、AKT或mTOR表达的抑制剂包括但不限于反义、siRNA和miRNA分子。作为说明,分别在例如US 2005/0272682、US 2008/0161547和US 9,012,622中公开了对PI3K、AKT和mTOR的siRNA抑制。
用于抑制PI3K的小分子包括但不限于SF1101(LY 294002、CAS 154447-36-6)、BKM120(CAS 944396-07-0)、BYL719(CAS 1217486-61-7)、XL-147(CAS 956958-53-5)、ZSTK-474(CAS 475110-96-4)、PX-866(CAS 502632-66-8)、PI-103(CAS 371935-74-9)及其衍生物和组合。
示例性的AKT抑制剂包括,例如AZD5363(CAS 1143532-39-1)、GDC-0068(CAS1001264-89-6、ATP竞争性pan-Akt抑制剂)、MK-2206(CAS 1032350-13-2)、Perifosine(CAS157716-52-4)、PBI-05204(Oleandrin、CAS 465-16-7)、GSK2141795(CAS 1047634-65-0)和SR13668(CAS 637774-61-9)及其衍生物和组合。另外的AKT抑制剂描述于US 2010/0009397、US 2007/0185152、US 6,960,584、US 7,098,208、US 7,223,738、US 7,304,063、US 7,378,403、US 7,396,832、US 7,399,764、US 7,414,055、US 7,544,677、US 7,576,209、US 7,579,355、US 7,589,068、US 7,638,530、US 7,655,649、US 7,705,014、US 7,750,151、US 7,943,732、US 8,003,643、US 8,003,651、US 8,008,317、US 8,168,652、US8,263,357、US 8,273,782和US 8,324,221。
示例性的双重mTOR/PI3K抑制剂包括,例如SF1126(CAS 936487-67-1)、BEZ235(CAS 915019-65-7)、BGT-226(CAS 1245537-68-1)、PF-04691502(CAS 1013101-36-4)、GNE-477(CAS 1032754-81-6)、XL765(CAS 1349796-36-6)、GDC-0941(CAS 957054-30-7)、GDC-0980(CAS 1032754-93-0)、PF-05212384(CAS 1197160-78-3)及其衍生物和组合。
可以使用以下一种或多种抑制剂来实现mTOR的抑制,例如OSI-027(CAS 936890-98-1)、INK-128(CAS 1224844-38-5)、AZD-8055(CAS 1009298-09-2)、AZD-2014(CAS1009298-59-2)、Palomod 529(CAS 914913-88-5)、Pp-242(CAS 1092351-67-1)、GSK2126458(CAS 1086062-66-9)、PF-04691502(CAS 1013101-36-4)、渥曼青霉素(CAS19545-26-7)、Ku-0063794(CAS 938440-64-3)、WAY-600(CAS 1062159-35-6)、WYE-687(CAS1062161-90-3)、WYE-354(CAS 1062169-56-5)、雷帕霉素(CAS 53123-88-9)及其衍生物和组合。雷帕霉素衍生物在例如US 5,258,389、US 5,100,883、US 5,118,678、US 5,151,413、US 5,256,790、US 5,120,842、US 2011/0178070、WO 1994/09010、WO 1992/05179、WO1993/11130、WO 1994/02136、WO 1994/02485、WO 1994/02136、WO 1995/16691、WO 1996/41807、WO 1996/41807、WO 1998/02441、WO 2001/14387和WO 1995/14023中进一步描述。关于其他PI3K/AKT/mTOR抑制剂,也请参阅US 2016/0244424。
NCK-PAK-JNK抑制剂。选择性降低或阻断NCK、PAK或JNK表达的抑制剂包括但不限于反义、siRNA和miRNA分子。作为说明,在例如WO 2013/135745中公开了对Pak1的siRNA抑制。类似地,在例如US 2015/0361184中公开了对JNK1、JNK2和JNK3的siRNA抑制。
PAK激酶的抑制剂在本领域中是已知的,包括但不限于2-氨基吡啶并[2,3-d]嘧啶-7(8H)-ones,例如WO 2009/086204、WO 2010/071846、WO 2011/044535、WO 2011/156646、WO 2011/156786、WO 2011/156640、WO 2011/156780、WO 2011/156775和WO 2011/044264中公开的那些;1H-噻吩并[3,2-c]吡唑,3-氨基-四氢吡咯并[3,4-c]吡唑和N4-(1H-吡唑-3-基)嘧啶-2,4-二胺,如WO 2004/007504,WO 2007/023382,WO 2007/072153和WO2006/072831所公开;N4-(1H-吡唑-3-基)嘧啶-2,4-二胺的N2-双环吲哚基、吲唑基和苯并咪唑基衍生物,如美国专利8,637,537PF-3758309(CAS 898044-15-0)中所述;IPA-3(CAS42521-82-4);FRAX597(CAS 1286739-19-2);FRAX486(CAS 1232030-35-1);FRAX1036(CAS1432908-05-8);及其衍生物和组合。
JNK1、JNK2和/或JNK3抑制剂的非限制性实例包括但不限于JNK抑制剂V(CAS345987-15-7)、JNK抑制剂VII(TAT-TI-JIPi53-163、CAS 305350-87-2)、JNK抑制剂VIII(CAS894804-07-0)、JNK-IN-7(CAS 1408064-71-0)、JNK抑制剂IX(CAS 312917-14-9)、JNK抑制剂XI(CAS 2207-44-5)、JNK抑制剂XVI(CAS 1410880-22-6)、AEG 3482(CAS 63735-71-7)、多拉吡莫德(CAS 285983-48-4、p38αMAPK和JNK2抑制剂)、CC-401(CAS 395104-30-0)、SP600125(CAS 129-56-6)、AS601245(CAS 345987-15-7)及其衍生物和组合。在一些实施方案中,抑制剂不是来氟米特。
PLC-DAG-PKC抑制剂。选择性降低或阻断PLC或PKC表达的抑制剂包括但不限于反义、siRNA和miRNA分子。作为说明,在US 9,546,367中公开了PLC的siRNA抑制,其siRNA分子通过引用并入本文。
抗PLCγ抗体在本领域中还已知用于调节PLCγ的结合和/或催化活性。抗PLCγ抗体的实例描述于例如Lee,et al.(2002)Mol.Vis.8:17-25和Buckley,et al.(2004)J.Biol.Chem.279:41807-14。
PLC的小分子抑制剂的例子包括但不限于D609(CAS 83373-60-8)、依德福星(ET-18-OCH3、CAS 77286-66-9、PLC/PKC双重抑制剂)、马诺利德(CAS 75088-80-1)、NCDC(CAS10556-88-4)、U-73122(CAS 112648-68-7)及其衍生物和组合。
Her2/neu抑制剂。选择性降低或阻断Her2/neu表达的抑制剂包括但不限于反义、siRNA和miRNA分子。通过举例说明,在例如Faltus,et al.(2004)Neoplasia 6(6):786-95;Choudhury,et al.(2004)Int.J.Cancer 108:71-77,公开了Her2/neu的siRNA抑制。
抗-Her2/neu抗体在本领域中还已知用于调节Her2/neu的活性。抗Her2/neu抗体的实例包括但不限于曲妥珠单抗(HERCEPTIN、CAS 180288-69-1)和帕妥珠单抗(PERJETA、CAS 380610-27-5)。参见Schroeder,et al.(2014)Molecules 19:15196-15212进行审查。
Her2/neu的小分子抑制剂的例子包括但不限于拉帕替尼(TYKERP、CAS 231277-92-2、EGFR/Her2双重抑制剂)、阿法替尼(GIOTRIF、CAS 439081-18-2、不可逆泛抑制剂)、AZD8931(CAS 848942-61-0、EGFR/Her2/ErbB3抑制剂)、AST-1306(CAS 897383-62-9、不可逆的EGFR和Her2抑制剂)、AEE-788(CAS 497839-62-0、EGFR和Her2激酶双重抑制剂)、CI-1033(Canertinib、CAS 289499-45-2、EGFR和Her2抑制剂)、TAK-165(Mubritinib、CAS366017-09-6、Her2抑制剂、参见US 6,716,863和US 7,005,526)、CP-724714(CAS 383432-38-0、Her2抑制剂)、CUDC-101(CAS 1012054-59-9、不可逆HDAC/EGFR/Her2抑制剂)、TAK-285(CAS 871026-44-7、EGFR/Her2双重抑制剂)、AC-480(BMS-599626、CAS 714971-09-2、可逆EGFR/Her2/HER4抑制剂)、PF299804或PF299(Dacomitinib、CAS 1110813-31-4、不可逆EGFR/Her2/Her4抑制剂)和EKB-569(Perlitinib、CAS 257933-82-7、双重EGFR/Her2抑制剂),及其衍生物和组合。在某些实施方案中,该抑制剂对Her2具有选择性,并且对其他激酶几乎没有或没有活性。
Aurora激酶抑制剂。选择性降低或阻断Aurora激酶表达的抑制剂包括但不限于反义、siRNA和miRNA分子。举例说明,在例如Tao,et al.(2007)Br.J.Cancer 97(12):1664-1672;Umene,et al.(2015)Int.J.Oncol.46(4):1498-1506中公开了对Aurora激酶的siRNA抑制。
Aurora激酶的小分子抑制剂的实例包括但不限于SNS314甲磺酸酯(CAS 1146618-41-8,pan Aurora抑制剂,请参见US 2016/0287602,US 2015/0329828和US 2011/0014191),PHA-680632(CAS 398493-79-3,pan Aurora抑制剂),VE-465(Tozasertib,VX-680或MK0457,CAS 639089-54-6),Barasertib(AZD1152,CAS 722544-51-6,Aurora B激酶抑制剂),Alisertib(MLN8237,CAS 1028486-01-2,Aurora A激酶抑制剂),Danusertib(PHA-739358,CAS 827318-97-8,pan Aurora抑制剂),PF-03814735(CAS 942487-16-3,Aurora A/B双重抑制剂),AMG 900(CAS 945595-80-2,pan Aurora抑制剂)及其衍生物和组合。在某些实施方案中,抑制剂对Aurora激酶具有选择性,并且对其他激酶几乎没有或没有活性。
PDGFR抑制剂。选择性降低或阻断PDGFR表达的抑制剂包括但不限于反义、siRNA和miRNA分子。举例说明,在例如Chen,et al.(2008)Liver Int.28(10):1446-1457;Kaulfuβ,et al.(2013)Oncotarget 4(7):1037-49;Yeh,et al.(2011)BMC Cancer 11:139中公开了对PDGFR的siRNA抑制。
抗PDGFR抗体在本领域中还已知用于调节PDGFR的活性。抗PDGFR抗体的实例包括但不限于IMC-3G3(抗PDGFRα抗体;EP 2100618)和IMC-2C5(PDGFRβ抗体;Shen,et al.(2009)Neoplasia 11(6):594-604)。
PDGFR的小分子抑制剂的例子包括但不限于Ki11502(CAS 347155-76-4)、伊马替尼(GLEEVEC/ST571、CAS 220127-57-1、PDGFRα/BCR-ABL/c-kit抑制剂)、Ponatinib(AP24534、CAS 943319-70-8、Abl/PDGFRα/VEGFR2/FGFR1/Src抑制剂)、Telatinib(CAS332012-40-5、VEGFR/c-Kit/PDGFRα抑制剂)、Amuvatinib(MP-470、CAS 850879-09-3、c-Kit/PDGFRα/Flt3抑制剂)、克仑诺尼(CP-868596、CAS 670220-88-9、PDGFRα/β的选择性抑制剂、参见US 7,071,337、US 7,183,414、US 2015/0238479和US 2010/0016353)、阿昔替尼(CAS 319460-85-0、VEGFR1/VEGFR2/VEGFR3/PDGFRβ/c-Kit抑制剂)、CP-673451(CAS343787-29-1、PDGFRα/β抑制剂)、Nintedanib(BIBF 1120、CAS 656247-17-5、VEGFR/FGFR/PDGFRα/β抑制剂)、马赛替尼(CAS 790299-79-5、Kit/PDGFRα/β抑制剂)、舒尼替尼(SUTENT/SU11248、CAS 557795-19-4、VEGFR2/PDGFRβ抑制剂)、TSU-68(SU6668或Orantinib、CAS252916-29-3)、Linifanib(ABT-869、CAS 796967-16-3、VEGFR/PDGFR抑制剂)、AC 710(CAS1351522-04-7、选择性PDGFR家族抑制剂)、DMPQ二盐酸盐(CAS 137206-97-4、PDGFRβ抑制剂)、GSK 1363089(CAS 849217-64-7、PDGFR/MET/VEGFR2/Ron/AXL抑制剂)、PD 166285(CAS212391-63-4、PDGFRβ/FGFR/Src抑制剂)和Toceranib(CAS 356068-94-5、PDGFR和VEGFR抑制剂)及其衍生物和组合。
无调相关因子。无调相关因子是转录因子家族,其将支持细胞转分化为耳朵的感觉毛细胞。无调相关因子是基本螺旋-环-螺旋(bHLH)蛋白质家族的转录因子。蛋白质的基本结构域负责蛋白质的DNA结合和功能。果蝇bHLH蛋白(ato)激活与昆虫的感觉器官,特别是腱索器官发育相关的基因。在各种动物和昆虫中都发现了与无调相关因子,也称为无调同源1(Atoh1)蛋白,包括小鼠(小鼠无调同源物1(Math1)),鸡(鸡无调同源物1(Cath1)),非洲爪蟾(非洲爪蟾无调同源物1(Xath1))和人类(人类无调同源物1(Hath1))。Math1与bHLH域中的ato高度同源(82%的氨基酸相似性),基本域的100%保守,并且在确定小鼠的细胞命运中起作用。Math1已被证明对于毛细胞的发育至关重要,并且可以刺激耳朵中的毛细胞再生。Math1的特征还在于,例如,Ben-Arie,et al.(1996)Human Mol.Genet.5:1207-1216;Bermingham,et al.(1999)Science 284:1837-1841;Zheng&Gao(2000)Nature Neurosci.3(2):580-586;和Chen,et al.(2002)Development 129:2495-2505。Hath1是Math1的人类对应物。在某些实施方案中,无调相关因子是Math1或Hath1或与Math1和Hath1具有显着氨基酸序列相似性的蛋白质。无调相关因子在WO 2000/73764中进一步描述。
Hath1和Math1的氨基酸序列是本领域已知的,并且分别在GENBANK登录号NP_005163(基因ID:474)和NP_031526(基因ID:11921)下可获得。期望与Math1和Hath1具有显着氨基酸序列相似性的蛋白质具有与Hath1(NP_005163)或Math1(NP_031526)的氨基酸序列至少约50%相同的氨基酸序列,并具有将支持细胞分化为感觉毛细胞的能力。理想地,无调相关因子具有与Hath1(NP_005163)或Math1(NP_031526)氨基酸序列至少约60%的氨基酸序列同一性(例如,至少约65%或至少约70%的序列同一性),优选至少约75%的氨基酸序列同一性(例如,至少约80%或至少约85%的序列同一性),最优选至少约90%的氨基酸序列同一性(例如,至少约95%的序列同一性)。观察编码无调相关因子的核酸序列,优选该核酸序列编码Hath1(NP_005163)或Math1(NP_031526)氨基酸序列(即,缺少与该基因相关的调控序列的编码Hath1和Math1蛋白的Hath1或Math1基因的部分)或编码Hath1或Math1蛋白的cDNA。编码Hath1和Math1的核酸序列分别可在GENBANK登录号NM_005172和NM_031526下获得。
尽管野生型Hath1或Math1蛋白和核酸特别有用,但是在本发明的上下文中,Hath1或Math1序列的许多修饰和变化(例如,突变)是可能的并且合适的。例如,遗传密码的简并性允许在整个编码序列中以及在翻译终止信号中取代核苷酸,而不改变所编码的多肽。可以从无调相关因子的已知氨基酸序列或编码无调相关因子的核酸序列推导此类取代,并且可以通过常规的合成或位点特异性诱变方法构建。合成DNA的方法可以按照Itakura,etal.(1977)Science 198:1056-1063或Crea,et al.(1978)Proc.Natl.Acad.Sci.USA 75:5765-5769的方法进行。在Maniatis,et al.(1989)Molecular Cloning:A LaboratoryManual,2nd Ed.,Cold Spring Harbor,NY中描述了位点特异性诱变程序。或者,该核酸序列可以编码在该蛋白质的N-或C-末端具有延伸的无调相关肽,只要所得的无调相关因子保持活性即可。
无调相关因子的功能取决于蛋白质的螺旋-环-螺旋(HLH)部分,尤其是HLH域的基本区域(Chien,et al.(1996)Proc.Natl.Acad.Sci.93:13239-13244),该区域包括氨基酸序列AANARERRRMHGLNHAFDQLR(SEQ ID NO:1)。因此,理想的是,对无调相关因子氨基酸序列的修饰位于蛋白质的基本结构域之外。WO 2004/076626提供了携带编码无调相关因子的核酸的示例性构建体和表达载体。
感官知觉。本发明通过向内耳施用EGFR信号传导抑制剂和任选地包含携带编码无调相关因子和/或耳保护剂的核酸分子的表达载体(例如表达病毒载体),来调节动物的感官知觉。“调节感官知觉”是指至少部分地实现识别和适应环境变化的能力。就感觉毛细胞功能而言,感官知觉的调节与感觉毛细胞的产生或保护有关,这些感觉毛细胞将内耳的机械刺激转换为神经冲动,然后在大脑中进行处理,从而使动物意识到环境变化,例如声音、语言或身体/头部位置。感觉毛细胞优选在Corti和/或前庭装置的器官中产生。在预防的情况下,通过施用EGFR信号传导抑制剂和任选的耳保护剂来保护最初或由于例如耳毒性试剂会进一步损坏或丢失的感觉毛细胞免受损伤或损失。在治疗的背景下,EGFR信号传导抑制剂与表达无调相关因子的核酸分子的组合可提高重编程效率和/或某些重编程细胞的终末分化,从而促进允许感知(或识别)内耳的刺激的感觉毛细胞的产生。
感觉毛细胞的产生可以使用多种手段来确定,例如本领域技术人员已知的那些手段。毛细胞可以通过扫描电子显微镜和/或通过肌球蛋白VIIa的检测来检测,所述肌球蛋白VIIa是通过免疫化学检测到的毛细胞特异性蛋白。然而,仅仅存在感官毛细胞并不一定暗示用于识别环境刺激的功能***。功能性感觉毛细胞必须与神经通路有效连接,这样机械刺激才能转化为大脑可以识别的神经冲动。因此,虽然毛细胞生成的检测适合于确定与靶组织相关的无调核酸序列的成功表达,但是受试者意识的检查是感觉知觉变化的更理想的指标。
通过简单的听力测试,例如通常由听觉医师进行的语气测试,可以容易地实现受试者检测声音的能力的改变。在大多数哺乳动物中,对不同频率的反应表明感觉知觉的变化。在人类中,理解语言也是适当的。例如,对象可能会听不懂语音。感知能力的变化通过区分不同类型的声音刺激(例如区分语言和背景噪音)的能力以及理解语音来表示。语音阈值和辨别力测试对于此类评估很有用。
还可以使用多种技术来评估平衡,运动意识和/或对运动刺激的响应时间的变化。前庭功能也可以通过比较对运动刺激的响应幅度(增益)或响应开始的时间(相位)来测量。可以使用巩膜搜索线圈测试动物的眼动反射(VOR)增益和相位,以评估感觉知觉的改善。脑电描记术(ENG)记录眼球对刺激(例如,移动或闪烁的灯光、身体重新定位、半圆管内的液体运动等)的反应。在这方面,使用旋转椅子或移动平台评估运动过程中的平衡也很有用。
为了检测感觉知觉的变化,在本发明方法之前使用任何适当的感觉测试来记录基线值。在本发明方法之后的适当时间段对受试者进行重新评估(例如本发明方法后1小时、6小时、12小时、18小时、1天、3天、5天、7天、14天、21天、28天、2个月、3个月或更长时间),将其结果与基线结果进行比较,以确定感官知觉的变化。
预防或治疗方法。本发明的方法促进了感觉性毛细胞的保护和/或产生,所述感觉性毛细胞允许感知刺激。因此,本发明提供了通过给予需要治疗的受试者EGFR信号传导抑制剂和任选地携带编码无调相关因子和/或一种或多种耳保护/再生剂的核酸分子的表达载体(例如表达病毒载体)来预防、治疗、控制、改善或降低听力障碍、丧失和障碍的风险的方法。理想地,本发明的方法预防或治疗动物至少一种与失落、损伤、缺少感官毛细胞有关的疾病,例如听力损失和平衡疾病。听力损失可能是由于细菌或病毒感染、遗传、身体伤害、听觉创伤、耳毒性药物(例如氨基糖苷抗生素或顺铂)等引起的Corti器官的毛细胞受损而引起的。虽然可以轻松地识别出听力损失,但平衡障碍表现为多种并发症,很容易归因于其他疾病。平衡障碍的症状包括迷失方向、头晕、眩晕、恶心、视力模糊、笨拙和频繁跌倒。通过本发明的方法治疗的平衡失调优选涉及周围的前庭失调(即,前庭装置的失调),该失调涉及由于损伤或缺乏感觉毛细胞而导致机械刺激向神经冲动的功能失调。
一方面,提供了防止或预防听力损失或障碍的方法。按照这样的方法,需要治疗的对象被给予有效量的EGFR信号传导抑制剂。在一些实施方案中,EGFR信号传导抑制剂抑制EGFR、Ras/Raf/MEK/ERK/MAPK蛋白、JAK/STAT蛋白、PI3K/AKT/mTOR蛋白、NCK-PAK-JNK蛋白、PLC-DAG-PKC蛋白或与EGFR相关或下游的细胞周期相关蛋白激酶的表达或活性。在其他实施方案中,通过向需要治疗的受试者施用与EGFR相关或下游的细胞周期相关蛋白激酶抑制剂来实现预防听力损失。在某些实施方案中,通过向需要治疗的受试者施用Her-2、Aurora激酶、B-Raf或PDGFR表达或活性的抑制剂来预防听力损失。EGFR信号传导的抑制剂可以单独给药或与一种或多种耳保护剂组合给药。术语“耳保护剂”是指减少或预防噪声引起的听力损失、化学引起的听力损失或年龄引起的听力障碍或以其他方式防止听力障碍的药剂。耳保护剂的实例包括但不限于PARP-1抑制剂;哌仑西平LS-75、otenzepad、AQ-RA741、viramune、BIBN 99、DIBD、Telenzepine(参见US 2011/0263574);蛋氨酸(见美国专利7,071,230);IGF-1、FGF-2、阿司匹林、还原型谷胱甘肽、N-甲基-(D)-葡糖胺二硫代氨基甲酸酯,和铁螯合剂,如酒石酸盐和马来酸盐。关于其他的耳保护剂,也参见US 2005/0101534。
在另一方面,提供了治疗听力损失或障碍的方法。根据这样的方法,将需要治疗的对象与携带用于表达无调相关因子的核酸分子的表达载体组合给予有效量的EGFR信号传导抑制剂。在一些实施方案中,EGFR信号传导抑制剂抑制EGFR、Ras/Raf/MEK/ERK/MAPK蛋白、JAK/STAT蛋白、PI3K/AKT/mTOR蛋白、NCK-PAK-JNK蛋白、PLC-DAG-PKC蛋白或与EGFR相关或下游的细胞周期相关蛋白激酶的表达或活性。在其他实施方案中,通过向需要治疗的受试者施用EGFR、Ras/Raf/MEK/ERK/MAPK蛋白、JAK/STAT蛋白、PI3K/AKT/mTOR蛋白、NCK-PAK-JNK蛋白或PLC-DAG-PKC蛋白抑制剂来治疗听力损失。在某些实施方案中,通过向需要治疗的受试者施用EGFR、PLC、STAT3、JAK2、PI3K或MEK表达或活性的抑制剂来实现听力损失的治疗。可以单独或与一种或多种再生剂组合施用EGFR信号传导抑制剂和携带表达无调相关因子的核酸分子的表达载体。术语“再生剂”是指刺激或促进感觉毛细胞再生的试剂。再生剂的实例包括但不限于烟酰胺核糖苷(参见US 2015/0174148);和靶向Hes1的siRNA(参见US9,101,647);PKA抑制剂(参见US 6,268,351);Myc家族蛋白,例如c-Myc、N-Myc或L-Myc(请参阅US 2015/0079110);玫瑰树碱衍生物和/或GSK-3抑制剂(参见US 9,370,510)。
预防和预防或治疗听力损失或障碍的情况可能包括但不限于耳鸣、鸣响、老花眼、听觉神经病、听觉创伤、听神经瘤、Pendred综合征、Usher综合征、Wardenburg综合征、非综合征性感音神经性耳聋、中耳炎、耳硬化症、美尼尔氏病、耳毒性、迷路炎以及由感染(例如麻疹、腮腺炎或脑膜炎)、抗生素等药物和某些癌症治疗(例如化学疗法和放射疗法)引起的听力障碍。
在某些实施方案中,听力障碍是药物诱导的。在另一方面,所述药物是化学治疗剂。更具体地,该药物是铂基化学治疗剂,例如卡铂、顺铂、反铂、奈达铂、奥沙利铂、吡铂、沙特铂、反铂和三雷铂、或其药学上可接受的盐。在一个具体的实施方案中,基于铂的化学治疗剂是顺铂或其药学上可接受的盐。在另一个实施方案中,药物是抗生素,包括但不限于柔红霉素、阿霉素、表柔比星、伊达比星、放线菌素-D、博来霉素、丝裂霉素-C、阿米卡星、阿普霉素、阿贝卡星、阿霉素、贝卡那霉素、地贝卡星、曲霉菌素、庆大霉素、潮霉素B、异帕米星、卡那霉素、新霉素、奈替米星、巴龙霉素、杜鹃链霉素、核糖霉素、西索米星、壮观霉素、链霉素、妥布霉素和维达霉素或其药学上可接受的盐。
在另一方面,听力障碍是与年龄有关的、由噪声引起的或与平衡或取向有关的障碍。平衡障碍的例子包括但不限于诱发或自发性眩晕、不平衡、对晕车的易感性增加、恶心、呕吐、共济失调、迷路炎、骨骼肌、眼球震颤、晕厥、头昏眼花、头晕、摔倒、夜间行走困难、美尼尔氏病,以及视觉追踪和处理困难。此外,由噪声引起的听力损失可能是暂时的或永久的。
根据世界卫生组织最近的报告,全世界有超过十亿的青少年因暴露于响亮的音乐而有听力损失的风险。许多其他噪音暴露,包括职业环境和消费者操作的设备,也会引起噪音引起的听力损失,这是最常见的身体不适,并且大大降低了与人交谈、交流和参与日常生活的能力(因此降低了个人和家庭的总体生活质量)。急性或慢性声音过度暴露使超过4000万美国工人面临永久性听力损失的风险(Kopke,et al.(2007)Hear.Res.226:114-125)。
创伤性脑损伤(TBI)和***相关的伤害最常发生在无法预测***危险、创伤强度超过防护装置的有效性或没有防护装置的军事场合。TBI通常伴随着对听觉感觉***的各种破坏或损害,这很容易受到***伤害。极高的物理***力会导致各种类型的周围听觉***受损,包括鼓膜破裂(TM,耳膜)、中耳骨骨折、感觉毛细胞从基底膜脱位以及使神经细胞受神经支配的螺旋神经节丢失。在***冲击的人体研究中,约17-29%的病例涉及严重的TM破裂,而33-78%的病例涉及中度至重度的感音神经性听力损失(毛细胞和神经节损失)。因此,TBI和***伤是听力损失的常见(尽管极端)原因。
听力的生物保护比目前可用的机械保护装置更有希望。助听器由于其高成本和许多技术问题而经常出现问题。理想情况下,服役的男性和女性可以在进入高风险或高噪声环境之前服用保护性药物,然后受到保护免受噪音伤害,而不会影响工作表现。迄今为止,还没有获得FDA批准的抗噪音和TBI相关听力损失的药物。
根据本发明的方法,可以将EGFR信号传导抑制剂和携带表达无调相关因子的核酸分子的任选表达载体局部施用,例如施用于受试者的内耳。或者,可以全身性施用EGFR信号传导抑制剂和携带表达无调相关因子的核酸分子的任选表达载体。此外,EGFR信号传导抑制剂和携带表达无调相关因子的核酸分子的任选表达载体可通过注入鼓膜、鼓膜、耳蜗、前庭的一种或多种、内耳道的听神经干或跨鼓膜/耳鼓的中耳间隙来给药。此外,当组合使用时,可以通过相同或不同的途径来施用携带用于表达无调相关因子的核酸分子的EGFR信号传导和表达载体。
在各个方面,所公开的分子可以与一种或多种其他药物组合用于治疗、预防、控制、改善或降低听力受损和障碍的风险,其中所公开的分子或其他药物可以对其有用,其中药物组合在一起比单独使用任何一种药物更安全或更有效。这些其他药物可以通过本发明化合物同时或依次通过其通常使用的途径和量来施用。当本发明的分子与一种或多种其他药物同时使用时,优选单位剂型的包含此类其他药物和所公开的化合物的药物组合物。然而,组合疗法还可包括其中所公开的分子和一种或多种其他药物以不同的重叠时间表施用的疗法。还可以预期的是,当与一种或多种其他活性成分组合使用时,所公开的分子和其他活性成分可以以比单独使用时更低的剂量使用。
本文的方法可用于预防或治疗与功能性感觉毛细胞缺乏或损害有关的急性和持续性进行性疾病。对于急性疾病,本文中的药物可以在短时间内使用单次施用或多次施用来施用。对于持续性疾病,例如听力损失或由于感觉性毛细胞的大量丧失而引起的疾病,可能需要多次给药本文的药物以实现治疗效果。
在适当的情况下,在治疗之后,可以测试受试者(例如人或其他动物)的听力或与听力障碍有关的其他症状的改善。受益于治疗的受试者包括那些有脱发风险的患者和/或有脱发患者的患者。例如,患有或有发展听力损失的风险的受试者的听力比普通受试者(例如,普通人)的听力差,或者与经历听力损失的受试者的听力差。例如,听力可降低至少5%、10%、30%、50%或更多。测量听力的方法是众所周知的,包括纯音测听、空气传导和骨传导测试。这些检查测量的是人类可以听到的响度(强度)和音高(频率)的极限。人类的听力测试包括行为观察测听法(适用于婴儿至七个月),视觉强化定向测听法(适用于7个月至3个月的儿童)和3岁以上儿童的游戏测听法。耳声发射测试可用于测试耳蜗毛细胞的功能,而耳蜗电描记术可提供有关耳蜗功能以及通向大脑的神经通路的第一部分的信息。在各个方面,可以在进行修饰或不进行修饰的情况下继续治疗,或者可以停止治疗。
在各个方面,本文所述的方法可用于在耳朵中产生毛细胞生长和/或增加耳朵(例如,内、中和/或外耳中)的毛细胞数量。在这方面,与治疗前的毛细胞数量相比,本文描述的分子的有效量是使耳朵中的毛细胞数量增加约2倍、3倍、4倍、6倍、8倍或10倍或更多倍的量。这种新的毛细胞生长可以有效地恢复或建立至少部分改善受试者的听觉能力。例如,施用本发明的刺激剂和抑制剂可将听力损失改善约5%、10%、15%、20%、40%、60%、80%、100%或更多。
表达载体。本领域普通技术人员将理解,本领域已知的多种表达载体中的任何一种都适合于将核酸序列引入内耳。合适的表达载体的例子包括,例如质粒,质粒-脂质体复合物和病毒载体,例如基于细小病毒的载体(即基于腺相关病毒(AAV)的载体),逆转录病毒载体,基于单纯疱疹病毒(HSV)的载体,AAV腺病毒嵌合载体和基于腺病毒的载体。这些表达载体均可以使用例如在Sambrook,et al.(1989)Molecular Cloning,A LaboratoryManual,2nd Ed.,Cold Spring Harbor Press,Cold Spring Harbor,NY;和Ausubel,et al.(1994)Current Protocols in Molecular Biology,Greene Publishing Associates和John Wiley&Sons,New York,NY所述的标准重组DNA技术制备。
经基因工程改造的环状双链DNA分子质粒可设计为包含表达盒,用于将核酸序列递送至内耳。尽管质粒是描述用于治疗性核酸给药的第一个载体,但与其他技术相比,转染效率水平较差。通过将质粒与脂质体复合,通常可以提高基因转移的效率。尽管用于质粒介导的基因转移策略的脂质体具有多种组成,但它们通常是合成的阳离子脂质。质粒-脂质体复合物的优点包括其转移编码治疗性核酸的大片段DNA的能力和相对较低的免疫原性。如US 6,165,754中所述,还可以修饰质粒以延长转基因表达。已经描述了使用质粒在耳朵中表达转基因(参见,例如,Jero,et al.(2001)Human Gene Ther.12:539-549)。尽管质粒适合用于本发明的方法,但是优选地,表达载体是病毒载体。
AAV载体是用于基因治疗方案中特别感兴趣的病毒载体。AAV是一种DNA病毒,未知会导致人类疾病。为了有效复制,AAV需要与辅助病毒(即腺病毒或疱疹病毒)共同感染,或表达辅助基因。用于给予治疗性核酸的AAV载体已删除约96%的亲本基因组,因此仅保留了末端重复序列(ITR),其中包含用于DNA复制和包装的识别信号。这消除了由于病毒基因表达而引起的免疫或毒性副作用。包含整合的AAV基因组的宿主细胞在细胞生长或形态上没有显示变化(参见,例如,US 4,797,368)。虽然有效,但对辅助病毒或辅助基因的需求可能成为该载体广泛使用的障碍。
逆转录病毒是一种RNA病毒,能够感染多种宿主细胞。感染后,逆转录病毒基因组整合到其宿主细胞的基因组中,并与宿主细胞DNA一起复制,从而不断产生病毒RNA和掺入逆转录病毒基因组的任何核酸序列。当使用病原性逆转录病毒时,例如人免疫缺陷病毒(HIV)或人T细胞淋巴营养病毒(HTLV),在改变病毒基因组时必须小心以消除毒性。逆转录病毒载体可以另外***纵以使病毒不能复制。这样,逆转录病毒载体被认为对于体内稳定的基因转移特别有用。慢病毒载体,例如基于HIV的载体,是用于基因递送的逆转录病毒载体的示例。与其他逆转录病毒不同,已知基于HIV的载体会将其过客基因整合到非***细胞中,因此,在感觉细胞无法再生的内耳感觉上皮中特别有用。
基于HSV的病毒载体适合用作表达载体,以将核酸引入内耳以转导靶细胞。成熟的HSV病毒体由包膜的二十面体衣壳和病毒基因组组成,病毒基因组由152kb的线性双链DNA分子组成。大多数复制缺陷型HSV载体均包含缺失,以删除一个或多个中间早期基因以防止复制。疱疹载体的优势在于其能够进入潜在阶段(可导致长期DNA表达)的能力,以及其大型病毒DNA基因组(可容纳高达25kb的外源DNA)。当然,就短期治疗方案而言,这种能力也是不利的。对于适用于本发明方法的基于HSV的载体的描述,参见,例如,US 5,837,532、US 5,846,782、US 5,849,572、US 5,804,413、WO 1991/02788、WO 1996/04394、WO 1998/15637和WO 1999/06583。
腺病毒(Ad)是一种36kb的双链DNA病毒,可将DNA有效地体内转移到各种不同的靶细胞类型。为了用于本发明的方法,优选通过缺失病毒复制所需的选择基因使病毒复制缺陷。消耗性的非复制必需E3区也经常被删除,以为更大的DNA***留出更多空间。该载体可以高滴度生产,并且可以有效地将DNA转移至复制和非复制细胞。通过腺病毒载体转移到细胞的遗传信息仍然是染色体外的,因此消除了随机***诱变和靶细胞基因型永久改变的风险。但是,如果需要,可以通过构建AAV-Ad嵌合载体将AAV的整合特性赋予腺病毒。例如,AAV反向末端重复序列(ITR)和编码掺入到腺病毒载体中的Rep蛋白的核酸使腺病毒载体能够整合到哺乳动物细胞基因组中。因此,AAV-Ad嵌合载体是用于本发明上下文中的令人感兴趣的选择。
优选地,本发明方法的表达载体是病毒载体,更优选地,表达载体是腺病毒载体。任何来源,任何亚型、亚型混合物或任何嵌合腺病毒的腺病毒都可以用作本发明腺病毒载体的病毒基因组来源。优选将人腺病毒用作复制缺陷型腺病毒载体的病毒基因组的来源。腺病毒可以是任何亚型或血清型。例如,腺病毒可以属于亚组A(例如血清型12、18和31)、亚组B(例如血清型3、7、11、14、16、21、34、35和50)、亚组C(例如血清型1、2、5和6)、亚组D(例如血清型8、9、10、13、15、17、19、20、22-30、32、33、36-39和42-48)、亚组E(例如血清型4)、亚组F(例如血清型40和41)、未分类的血清群(例如血清型49和51)或任何其他腺病毒血清型。腺病毒血清型1到51可从美国典型培养物保藏中心(ATCC,Manassas,VA)获得。优选地,腺病毒载体属于亚组C,尤其是血清型2或什至更期望的血清型5。
但是,非C组腺病毒,甚至非人腺病毒都可以用于制备复制缺陷型腺病毒基因转移载体,以将DNA传递到内耳的靶细胞。用于构建非C组腺病毒基因转移载体的优选腺病毒包括Ad12(A组)、Ad7和Ad35(B组)、Ad30和Ad36(D组)、Ad4(E组)和Ad41(F组)。非C组腺病毒载体、生产非C组腺病毒载体的方法和使用非C组腺病毒载体的方法公开于例如US 5,801,030、US 5,837,511、US 5,849,561、WO 1997/12986和WO 1998/53087。优选的非人腺病毒包括但不限于猿猴(例如SAV 25)、牛、犬、猪腺病毒。
腺病毒载体优选是复制缺陷的。“复制缺陷型”是指腺病毒载体包含缺乏至少一种复制必需基因功能的腺病毒基因组(即,使得腺病毒载体不能在典型的宿主细胞中复制,特别是在根据本发明的治疗过程中可能被腺病毒载体感染的人类患者的那些宿主细胞中)。如本文所用,基因、基因功能或基因或基因组区域的缺陷被定义为病毒基因组足够遗传材料的缺失,以削弱或消除其核酸序列全部或部分缺失的基因的功能。尽管优选遗传物质的缺失,但是通过添加或替代来遗传物质的突变也适合于破坏基因功能。复制必不可少的基因功能是复制(例如繁殖)所必需的那些基因功能,并由例如腺病毒早期区域(例如E1、E2和E4区域)、晚期区域(例如L1-L5区域)、参与病毒包装的基因(例如IVa2基因)和病毒相关的RNA(例如VA-RNA1和/或VA-RNA-2)编码。更优选地,复制缺陷型腺病毒载体包含腺病毒基因组的一个或多个区域的至少一种复制必需基因功能缺陷的腺病毒基因组。优选地,腺病毒载体在病毒复制所需的腺病毒基因组的E1区域或E4区域的至少一种基因功能上是缺陷的(表示为E1缺陷型腺病毒载体或E4缺陷型腺病毒载体)。如在WO 2000/00628中所讨论的,除了E1区域中的缺陷外,重组腺病毒还可以在主要晚期启动子(MLP)中具有突变。最优选地,腺病毒载体在E1区域(希望所有复制必需的基因功能)和非必需E3区域(例如,E3区的XbaI缺失)的至少一部分中至少具有复制必需的基因功能(表示为E1/E3缺陷型腺病毒载体)。关于E1区域,腺病毒载体可以在E1A区域的一部分或全部和E1B区域的一部分或全部上是缺陷的,例如在E1A和E1B区域中的每一个的至少一个复制必需基因功能上。当腺病毒载体在腺病毒基因组的一个区域中缺乏至少一种复制必需的基因功能时(例如,E1或E1/E3缺陷的腺病毒载体),腺病毒载体被称为“单复制缺陷”。
本发明的腺病毒载体可以是“多重复制缺陷型”,意指该腺病毒载体在腺病毒基因组的两个或多个区域的每一个中缺乏一个或多个复制必需的基因功能。例如,上述E1缺陷型或E1/E3缺陷型腺病毒载体可以进一步缺乏E4区的至少一种复制必需基因功能(表示为E1/E4-或E1/E3/E4缺陷型腺病毒载体),和/或E2区域(表示E1/E2或E1/E2/E3缺陷的腺病毒载体),最好是E2A区域(表示E1/E2A-或E1/E2A/E3缺陷的腺病毒载体)。理想地,腺病毒载体仅缺少由腺病毒基因组的早期区域编码的那些复制必需基因功能的复制必需基因功能,尽管这在本发明的所有情况下不是必需的。优选的多重缺陷型腺病毒载体包括具有E1区域的核苷酸457-3332、E3区域的核苷酸28593-30470、E4区域的核苷酸32826-35561以及,任选地,编码VA-RNA1的区域的核苷酸10594-10595的缺失的腺病毒基因组。但是,其他删除可能是合适的。可以去除核苷酸356-3329或356-3510,从而在复制必需的E1基因功能中产生缺陷。核苷酸28594-30469可以从腺病毒基因组的E3区域中缺失。尽管上面列举的特定核苷酸名称对应于腺病毒5型血清基因组,但本领域普通技术人员可以容易地确定非血清5型腺病毒基因组的相应核苷酸。
腺病毒载体在多重复制缺陷时,特别是在E1和E4区的复制必不可少的基因功能中,优选包含间隔子元件,以在补体细胞系中提供病毒生长,类似于单复制缺陷型腺病毒载体,特别是E1缺陷型腺病毒载体。间隔元件可包含具有所需长度的任何一个或多个序列,例如至少约15个碱基对的序列(例如,在约15个碱基对与约12,000个碱基对之间),优选约100个碱基对至约10,000个碱基对,更优选为约500个碱基对至约8,000个碱基对,甚至更优选为约1,500个碱基对至约6,000个碱基对,最优选为约2,000个至约3,000个碱基对。间隔元件序列相对于腺病毒基因组可以是编码的或非编码的,并且可以是天然的或非天然的,但是不能将复制必需的功能恢复到缺陷区。在US 5,851,806中描述了在腺病毒载体中间隔基的使用。在本发明方法的一个实施方案中,复制缺陷型或条件复制型腺病毒载体是E1/E4缺陷型腺病毒载体,其中保留了L5纤维区域,并且间隔物位于L5纤维区域和右侧ITR之间。更优选地,在这种腺病毒载体中,在L5纤维区域和右侧ITR之间存在单独的E4聚腺苷酸化序列,或者最优选地,与另一个序列组合,从而使保留的L5纤维区域与右侧ITR充分分离,从而使这种载体的病毒产生量接近单复制缺陷型腺病毒载体,特别是E1缺陷型腺病毒载体的病毒产量。
腺病毒载体可能仅在腺病毒基因组的早期区域,仅腺病毒基因组的晚期区域以及腺病毒基因组的早期和晚期区域都缺乏复制必需的基因功能。腺病毒载体还可以基本上除去整个腺病毒基因组,在这种情况下,优选至少使病毒ITR和一个或多个启动子或病毒ITR和包装信号保持完整(即,腺病毒扩增子)。包含ITR和包装序列的腺病毒基因组的5'或3'区域不必与病毒基因组的其余部分源自相同的腺病毒血清型。例如,腺病毒血清型5基因组的5'区域(即,基因组5'到腺病毒E1区域的区域)可以被腺病毒血清型2基因组的相应区域替换(例如,将腺病毒基因组E1区域的Ad5基因组区域5'替换为Ad2基因组的核苷酸1-456)。合适的复制缺陷型腺病毒载体,包括多重复制缺陷型腺病毒载体,公开于US 5,837,511、US5,851,806、US 5,994,106、US 2001/0043922、US 2002/0004040、US 2002/0031831、US2002/0110545、WO 1995/34671、WO 1997/12986和WO 1997/21826。理想地,复制缺陷型腺病毒载体存在于实际上没有复制能力的腺病毒(RCA)污染的药物组合物中(例如,药物组合物包含少于约1%的RCA污染)。最期望地,药物组合物是无RCA的。在US 5,944,106、US 6,482,616、US 2002/0110545和WO 1995/34671中描述了无RCA的腺病毒载体组合物和原种。
因此,在一个优选的实施方案中,本发明方法的表达载体是缺乏E1区域的全部或部分、E3区域的全部或部分、E4区域的全部或部分、以及E2区域的全部或部分(可选)的多重复制缺陷型腺病毒载体。据信,多缺陷载体特别适合于将外源核酸序列递送至耳朵。缺乏E1区域的至少一种复制必需基因功能的腺病毒载体最常用于体内基因转移。然而,当前使用的单复制缺陷型腺病毒载体可能对内耳上皮的敏感细胞有害,从而损害了要治疗的细胞。缺乏E4区域的至少一种复制必需基因功能的腺病毒载体,特别是缺乏E4区域和E1区域的复制必需基因功能的腺病毒载体,对细胞的毒性比缺乏E1区域的腺病毒载体低(参见,例如,Wang,et al.(1996)Nature Med.2(6):714-716和US 6,228,646)。因此,可以通过使用E1、E4缺陷型腺病毒载体将编码无调相关因子的核酸序列递送至内耳细胞来最小化对现有毛细胞和支持细胞的损害。
在这方面,已经观察到至少E4缺陷型腺病毒载体在体内有限的时间内高水平表达转基因,并且至少E4缺陷型腺病毒载体中转基因表达的持久性可以通过反式作用因子(例如HSV ICPO、Ad pTP、CMV-IE2、CMV-IE86、HIV tat、HTLV-tax、HBV-X、AAV Rep 78)、功能类似于HSV ICPO的U205骨肉瘤细胞系中的细胞因子、或神经生长因子诱导的PC12细胞中的细胞因子等的作用来调节。有鉴于此,多重缺陷型腺病毒载体(例如,至少E4缺陷型腺病毒载体)或第二表达载体包含编码反式作用因子的核酸序列,所述反式作用因子调节编码非调子相关因子的核酸序列的表达的持久性,如在例如US 6,225,113、US 6,660,521、US 6,649,373和WO 2000/34496中所述。
复制缺陷型腺病毒载体通常在互补细胞系中产生,所述互补细胞系提供适当水平的复制缺陷型腺病毒载体中不存在但病毒繁殖所需的基因功能,以产生高滴度的病毒载体原种。优选的细胞系对复制缺陷型腺病毒中不存在的至少一种并且优选所有复制必需基因功能进行补充。互补细胞系可以弥补由早期区域,晚期区域,病毒包装区域,病毒相关RNA区域或其组合所编码的至少一种复制必需基因功能的缺陷,包括所有腺病毒功能(例如,以使腺病毒扩增子能够繁殖)。最优选地,互补细胞系补充腺病毒基因组E1区域的至少一种复制必需基因功能(例如,两个或多个复制必需的基因功能)的缺陷,特别是E1A和E1B区域中的每一个的复制必需基因功能的缺陷。另外,所述互补细胞系可以补充腺病毒基因组的E2(特别是关于腺病毒DNA聚合酶和末端蛋白)和/或E4区域的至少一种复制必需基因功能的缺陷。理想地,补充E4区域的缺陷的细胞包含E4-ORF6基因序列并产生E4-ORF6蛋白。期望这样的细胞至少包含腺病毒基因组的E4区域的ORF6而不包含其他ORF。优选地,所述细胞系的特征还在于,其以非重叠的方式包含与腺病毒载体的互补基因,这使载体基因组与细胞DNA重组的可能性最小化,并且实际上消除了该可能性。因此,如果不避免,在载体原液中复制感受态腺病毒(RCA)的存在被最小化,因此,其适合于某些治疗目的,尤其是基因治疗目的。载体原种中RCA的缺乏避免了腺病毒载体在非补体细胞中的复制。这样的互补细胞系的构建涉及标准的分子生物学和细胞培养技术,例如Sambrook,et al.(1989)MolecularCloning,a Laboratory Manual,2d edition,Cold Spring Harbor Press,Cold SpringHarbor,NY;和Ausubel,et al.(1994)Current Protocols in Molecular Biology,GreenePublishing Associates和John Wiley&Sons,New York,NY描述的那些。
用于产生腺病毒载体的互补细胞系包括但不限于293细胞(参见,例如,Graham,etal.(1977)J.Gen.Virol.36:59-72)、PER.C6细胞(参见,例如,WO 1997/00326、US 5,994,128和US 6,033,908)和293-ORF6细胞(参见,例如,WO 1995/34671和Brough等人(1997)J.Virol.71:9206-9213)。在某些情况下,补体细胞将不能补充所有必需的腺病毒基因功能。可以使用辅助病毒来提供反式的基因功能,这些基因功能不是由细胞或腺病毒基因组编码的,从而能够复制腺病毒载体。腺病毒载体可以使用例如在US 5,965,358、US 5,994,128、US 6,033,908、US 6,168,941、US 6,329,200、US 6,383,795、US 6,440,728、US 6,447,995、US 6,475,757、US 2002/0034735、WO 1998/53087、WO 1998/56937、WO 1999/15686、WO 1999/54441、WO 2000/12765、WO 2001/77304和WO 2002/29388以及本文中确定的其他参考文献中阐述的材料和方法来构建、繁殖和/或纯化。可以使用例如在US 5,837,511、US 5,849,561、WO 1997/12986和WO 1998/53087中阐述的方法来产生非C类腺病毒载体,包括腺病毒血清型35载体。此外,许多腺病毒载体可商购获得。
可以修饰腺病毒载体的外壳蛋白,以降低腺病毒载体被针对野生型外壳蛋白的中和抗体识别的能力或不能被识别。这样的修饰对于多轮给药是有用的。类似地,可以操纵腺病毒载体的外壳蛋白来改变腺病毒载体对潜在宿主细胞上病毒受体的结合特异性或识别。这样的操作可以包括纤维、五邻体、六邻体、pIIIa、pVI和/或pIX的区域的缺失或取代、各种天然或非天然配体***外壳蛋白的部分中,等等。外壳蛋白的操纵可以拓宽腺病毒载体感染的细胞范围,或使腺病毒载体靶向特定的细胞类型。无需对外壳蛋白进行遗传操作,即通过使用双特异性分子,就可以调节腺病毒载体识别潜在宿主细胞的能力。例如,使腺病毒与双特异性分子复合,该双特异性分子包含五烯酮碱基或纤维结合域和选择性结合特定细胞表面结合位点的域,使得能够将腺病毒载体靶向特定细胞类型。
优选地,腺病毒衣壳被修饰以显示非天然氨基酸序列。可以将非天然氨基酸序列***内部外壳蛋白序列中或代替内部外壳蛋白序列(例如,在腺病毒纤维蛋白的暴露环内),或融合至腺病毒外壳蛋白的末端(例如,融合至腺病毒纤维蛋白的C端,任选地使用接头或间隔序列)。可以将非天然氨基酸序列与任何腺病毒外壳蛋白缀合以形成嵌合外壳蛋白。因此,例如,本发明的非天然氨基酸序列可以缀合、***或附着于纤维蛋白、彭顿基蛋白、六邻体蛋白、蛋白IX、VI或IIIa等。此类蛋白质的序列以及将其用于重组蛋白质的方法是本领域众所周知的(参见,例如,US 5,543,328、US 5,559,099、US 5,712,136、US 5,731,190、US 5,756,086、US 5,770,442、US 5,846,782、US 5,962,311、US 5,965,541、US 5,846,782、US 6,057,155、US 6,127,525、US 6,153,435、US 6,329,190、US 6,455,314、US6,465,253、US 6,576,456、US 2001/0047081、US 2003/0099619、WO 1996/07734、WO 1996/26281、WO 1997/20051、WO 1998/07877、WO 1998/07865、WO 1998/40509、WO 1998/54346、WO 2000/15823、WO 2001/58940和WO 2001/92549)。嵌合外壳蛋白的外壳蛋白部分可以是全长的腺病毒外壳蛋白,在其上附加了配体结构域,或者可以例如在内部或在C-和/或N-末端被截短。外壳蛋白部分本身不必是腺病毒载体天然的。
当配体连接到纤维蛋白上时,优选它不干扰病毒蛋白或纤维单体之间的相互作用。因此,非天然氨基酸序列优选本身不是寡聚结构域,因为这样可能与腺病毒纤维的三聚结构域不利地相互作用。优选地,将配体添加到病毒体蛋白中,并以易于暴露于底物的方式掺入(例如,在蛋白质的N或C末端、附着于面对底物的残基、位于肽间隔子上以接触底物等),以最大程度地将非天然氨基酸序列呈现给底物。理想地,将非天然氨基酸序列掺入到纤维蛋白C端的腺病毒纤维蛋白中(并通过间隔基连接)或掺入纤维的裸露环中(例如HI环)以产生嵌合外壳蛋白。当非天然氨基酸序列连接或替代戊烯碱基的一部分时,优选其在高变区内,以确保其接触底物。当非天然氨基酸序列连接至六邻体时,优选其在高变区内(Miksza,et al.(1996)J.Virol.70(3):1836-44)。使用间隔子序列使非天然氨基酸序列远离腺病毒颗粒的表面延伸可能是有利的,因为非天然氨基酸序列可以更易于结合受体,并且减少了非天然氨基酸序列与腺病毒纤维单体之间的任何空间相互作用。
期望地,包含非天然配体的嵌合病毒外壳蛋白能够引导包含外壳蛋白的病毒(即腺病毒)载体进入细胞,该病毒比包含野生型病毒外壳蛋白而不是嵌合病毒外壳蛋白的相同载体的细胞更有效地进入。优选地,嵌合病毒外壳蛋白结合存在于细胞表面上的新的内源性结合位点,所述内源结合位点未被包含野生型外壳蛋白的载体识别或识别不佳。
另外,可以改变腺病毒衣壳蛋白以减少或消除与天然腺病毒受体(即,野生型腺病毒结合的受体)的结合。特别地,与柯萨奇和腺病毒受体(CAR)相互作用的腺病毒纤维蛋白的部分可以通过缺失、取代、在纤维蛋白内重新定位等进行突变,使得腺病毒纤维蛋白不结合CAR。同样,可以改变与整联蛋白相互作用的腺病毒戊聚糖蛋白的部分,以消除天然的整联蛋白结合。为了减少复制缺陷或条件复制的腺病毒载体的天然结合和转导,不存在或破坏位于介导细胞进入的腺病毒外壳蛋白上的天然结合位点,例如纤维和/或戊烯基。据信两种或更多种腺病毒外壳蛋白介导附着于细胞表面(例如,纤维和戊烯基)。可以采用任何合适的技术来改变与宿主细胞(例如间皮细胞或肝细胞)的天然结合。例如,利用不同的纤维长度来消融与细胞的天然结合可以通过将结合序列添加到戊烯基或纤维瘤上来实现。该添加可以通过双特异性或多特异性结合序列直接或间接进行。备选地,可以修饰腺病毒纤维蛋白以减少纤维轴中的氨基酸数目,从而产生“短轴”纤维(例如,在US 5,962,311中描述)。某些腺病毒血清型的纤维蛋白自然比其他类型短,这些纤维蛋白可以代替天然纤维蛋白用于减少腺病毒与其天然受体的天然结合。例如,可以将血清型5腺病毒衍生的腺病毒载体的天然纤维蛋白与腺病毒血清型40或41的纤维蛋白进行交换。
在这方面,可以修饰腺病毒载体以包括来自不同血清型腺病毒的腺病毒外壳蛋白(例如,纤维、戊烯或六邻体蛋白)。例如,可以修饰腺病毒血清型5腺病毒以展示腺病毒血清型35纤维,该纤维又可以任选地包含一种或多种非天然氨基酸配体。可以利用不自然感染内耳细胞类型的腺病毒载体将载体靶向特定细胞类型。或者,可以修饰天然转导内耳细胞的腺病毒载体以显示衍生自对靶细胞无天然嗜性的腺病毒的腺病毒纤维蛋白和/或腺病毒Penton碱基,该腺病毒载体可以显示能够转导靶细胞的非天然氨基酸序列。
在另一个实施方案中,与天然底物结合相关的核酸残基可以被突变(参见,例如,WO 2000/15823;Einfeld,et al.(2001)J.Virol.75(23):11284-11291;van Beusechem,etal.(2002)J.Virol.76(6):2753-2762),使得掺入突变的核酸残基的腺病毒载体较不能够结合其天然底物。例如,腺病毒血清型2和5通过腺病毒纤维蛋白与柯萨奇病毒和腺病毒受体(CAR)的结合以及戊烯蛋白与位于细胞表面的整联蛋白的结合来转导细胞。因此,本发明方法的复制缺陷型或条件复制型腺病毒载体可能缺乏与CAR的天然结合和/或显示出与整联蛋白的天然结合降低。为了减少复制缺陷型或条件复制型腺病毒载体与宿主细胞的天然结合,去除或破坏天然CAR和/或整联蛋白结合位点(例如,位于腺病毒戊烯碱基中的RGD序列)。
腺病毒外壳蛋白的修饰可以增强所得腺病毒载体逃避宿主免疫***的能力。在一个实施方案中,通过消融腺病毒载体与CAR和/或整联蛋白的天然结合并且将一种或多种非天然配体掺入腺病毒衣壳中,将腺病毒载体选择性地靶向于瘢痕上皮细胞(例如上皮区域缺少内源性功能性毛细胞)。可以使用常规文库展示技术(例如噬菌体展示)来确定介导经由特定受体转导的合适的配体,并且包括例如,由EGF结合的配体和来自FGF家族的肽的配体。非天然氨基酸序列及其底物的其他实例包括但不限于被整联蛋白识别的氨基酸的短(例如6个或更少的氨基酸)线性延伸,以及诸如聚赖氨酸、聚精氨酸等的聚氨基酸序列。非天然氨基酸序列在US6,455,314和WO 2001/92549中进一步描述了用于产生嵌合腺病毒外壳蛋白的方法。
对腺病毒载体的合适修饰描述于US 5,543,328、US 5,559,099、US 5,712,136、5,731,190、US 5,756,086、US 5,770,442、US 5,846,782、US 5,871,727、US 5,885,808、US5,922,315、US 5,962,311、US 5,965,541、US 6,057,155、US 6,127,525、US 6,153,435、US6,329,190、US 6,455,314、US 6,465,253、US 2001/0047081、US 2002/0099024、US 2002/0151027、WO 1996/07734、WO 1996/26281、WO 1997/20051、WO 1998/07865、WO 1998/07877、WO 1998/40509、WO 1998/54346、WO 2000/15823、WO 2001/58940和WO 2001/92549。腺病毒载体的构建是本领域众所周知的。腺病毒载体可以使用例如在US 5,965,358、US 6,168,941、US 6,329,200、US 6,383,795、US 6,440,728、US 6,447,995、US 6,475,757、WO1998/53087、WO 1998/56937、WO 1999/15686、WO 1999/54441、WO 2000/12765、WO 2001/77304和WO 2002/29388以及本文中确定的其他参考文献中所述的方法构建和/或纯化。此外,许多表达载体,包括腺病毒载体,可商购获得。可以使用例如在US 4,797,368和Laughlin,et al.(1983)Gene 23:65-73中所述的方法来构建和/或纯化与腺相关的病毒载体。
用于本发明方法的表达载体的选择取决于多种因素,例如宿主、载体的免疫原性、所需的蛋白质生产持续时间、靶细胞等。由于每种类型的表达载体具有不同的特性,因此可以将本发明的方法适应于任何特定情况。此外,可以使用一种以上类型的表达载体来将核酸序列递送至靶细胞。因此,本发明提供了改变动物的感觉知觉和预防或治疗听力损失的方法,其中所述方法包括向内耳施用至少两种不同的表达载体,所述至少两种不同的表达载体包括编码无调相关因子的核酸序列和/或编码EGFR信号传导抑制剂的核酸序列。优选地,内耳中的靶细胞,例如支持细胞,与腺病毒载体和HSV载体接触,因为腺病毒载体有效地转导支持细胞并且HSV载体有效地转导神经元。本领域普通技术人员将理解利用多个递送***的有利特性来治疗或研究内耳感觉障碍的能力。
核酸分子。本发明的表达载体包含核酸分子,其表达促进毛细胞的再生和听力恢复。理想地,所述核酸分子编码无调相关因子并且可以进一步编码EGFR信号传导抑制剂。本领域普通技术人员将理解,任何转录因子,例如Math1或Hath1或EGFR信号传导抑制剂,可被修饰或截短并保留活性。因此,治疗性片段(即那些具有足以激活转录的生物学活性的片段)也适合掺入表达载体中。同样,由转录因子或其治疗片段和例如稳定肽构象的部分组成的融合蛋白也可以存在于表达载体中。
核酸分子(即编码无调相关因子和/或EGFR信号传导抑制剂)理想地作为表达盒的一部分存在,即具有促进核酸分子的亚克隆和恢复(例如,一个或多个限制位点)或核酸分子表达(例如,聚腺苷酸化或剪接位点)的功能的特定碱基序列。当表达盒是腺病毒载体时,感兴趣的核酸分子(例如,编码无调相关因子和/或EGFR信号传导抑制剂)可以位于腺病毒基因组的E1区域(例如,全部或部分替换E1区域)或可以位于腺病毒基因组的E4区域。当位于E4区域时,不需要间隔序列。表达盒优选以3'->5'方向***,例如以使得表达盒的转录方向与周围腺病毒基因组的转录方向相反的方向***。尽管可以将单个表达盒***腺病毒载体中以表达无调相关因子和/或EGFR信号传导抑制剂,但在其他实施方案中,腺病毒载体可以包括多个表达盒,其携带编码编码无调相关因子和/或EGFR信号传导抑制剂的核酸分子,其中所述表达盒可以替代腺病毒基因组的任何缺失的区域。表达盒向腺病毒基因组(例如,基因组的E1区域)的***可以通过已知方法来促进,例如,通过在腺病毒基因组的给定位置引入独特的限制性位点。如上所述,优选地,腺病毒载体的E3区被缺失,并且E4区被间隔元件替代。
为了表达,将目的核酸分子可操作地连接至所述表达所需的调控序列,例如启动子。“启动子”是指导RNA聚合酶结合从而促进RNA合成的DNA序列。当启动子能够指导该核酸分子的转录时,该核酸分子与该启动子“可操作地连接”。启动子对于与其可操作连接的核酸分子可以是天然的或非天然的。任何启动子(即,无论是从自然界中分离出来的,还是通过重组DNA或合成技术产生的)都可以与本发明结合使用以提供核酸分子的转录。该启动子优选能够指导真核(期望是哺乳动物)细胞中的转录。启动子的功能可以通过一种或多种增强子(例如CMV立即早期增强子)和/或沉默子的存在而改变。
本发明优先采用病毒启动子。合适的病毒启动子是本领域已知的,包括例如巨细胞病毒(CMV)启动子,例如CMV立即早期启动子,衍生自人免疫缺陷病毒(HIV)的启动子,例如HIV长末端重复启动子,劳斯肉瘤病毒(RSV)启动子,例如RSV长末端重复序列,小鼠乳腺肿瘤病毒(MMTV)启动子,HSV启动子,例如Lap2启动子或疱疹胸苷激酶启动子(Wagner,etal.(1981)Proc.Natl.Acad.Sci.USA 78:144-145),衍生自SV40或Epstein Barr病毒的启动子,腺相关病毒启动子,例如p5启动子等。优选地,病毒启动子是腺病毒启动子,例如Ad2或Ad5主要晚期启动子和三方前导子,CMV启动子(鼠源或人源)或RSV启动子。
启动子不必是病毒启动子。例如,启动子可以是细胞启动子,即驱动细胞蛋白表达的启动子。用于本发明的优选的细胞启动子将取决于所需的表达谱以产生治疗剂。一方面,细胞启动子优选是在多种细胞类型中起作用的组成型启动子。合适的组成型启动子可以驱动编码转录因子的基因、持家基因或真核细胞共有的结构基因的表达。例如,Ying Yang 1(YY1)转录因子(也称为NMP-1、NF-E1和UCRBP)是一种普遍存在的核转录因子,是核基质的固有成分(Guo,et al.(1995)Proc.Natl.Acad.Sci.USA 92:10526-10530)。JEM-1(也称为HGMW和BLZF-1;Tong,et al.(1998)Leukemia 12(11):1733-1740;Tong,et al.(2000)Genomics 69(3):380-390),泛素启动子,特别是UbC(Marinovic,et al.(2002)J.Biol.Chem.277(19):16673-16681),β-肌动蛋白启动子,例如衍生自鸡的启动子,以及适用于本发明的方法的启动子。
上述许多启动子是组成型启动子。该启动子可以是诱导型启动子(即响应适当信号而被上调和/或下调的启动子),而不是组成型启动子。例如,合适的诱导型启动子***包括但不限于IL-8启动子、金属硫氨酸诱导型启动子***、细菌lacZYA表达***、四环素表达***和T7聚合酶***。此外,可以使用在不同发育阶段(例如,珠蛋白基因从胚胎和成体中与珠蛋白相关的启动子中差异转录)被选择性激活的启动子。调节核酸分子表达的启动子序列可以包含至少一种异源调节序列,其响应于外源试剂的调节。调节序列优选对外源试剂例如但不限于药物、激素或其他基因产物有反应。例如,调节序列,例如启动子,优选对糖皮质激素受体-激素复合物有响应,这反过来又增强了治疗性肽或其治疗性片段的转录水平。
优选地,启动子是组织特异性启动子,即在给定组织中优先被激活并导致基因产物在被激活的组织中表达的启动子。本领域技术人员可以根据靶组织或细胞类型来选择用于本发明的组织特异性启动子。合适的启动子包括但不限于BRN.3C、BRN 3.1、POU ORF3因子启动子、BRK1、BRK3、chordin启动子、noggin启动子、jagged1启动子、jagged2启动子和notch1启动子。用于本发明的优选的组织特异性启动子对于支持细胞或感觉毛细胞是特异的,例如在毛细胞中起作用的无调启动子或肌球蛋白VIIa启动子,或在支持细胞中起作用的hes-1启动子。理想地,选择在疤痕上皮中促进转基因表达的启动子。
也可以通过使启动子的特定活性模式与所需蛋白的所需模式和表达水平相匹配来选择用于本发明的启动子(例如,无调相关因子)。或者,可以构建结合了多个启动子的期望方面的杂种启动子。例如,在本发明方法的许多实施方案中,特别优选将CMV启动子的初始活性急升与RSV启动子的高活性保持水平相结合的CMV-RSV杂交启动子。还可以选择具有可由研究者操纵的表达谱的启动子。
沿着这些路线,为了优化蛋白质生产,优选地,核酸分子在核酸分子的编码区之后还包括聚腺苷酸化位点。可以使用任何合适的聚腺苷酸化序列,包括合成的优化序列,以及BGH(牛生长激素)、多瘤病毒、TK(胸苷激酶)、EBV(Epstein Barr病毒)和***瘤病毒(包括人***瘤病毒和BPV(牛***瘤病毒))的聚腺苷酸化序列。优选的聚腺苷酸化序列是SV40(人肉瘤病毒-40)聚腺苷酸化序列。而且,优选地,所有适当的转录信号(和翻译信号,如果合适的话)被正确地排列,使得核酸分子在其被引入的细胞中被正确表达。如果需要,核酸分子还可掺入剪接位点(即,剪接受体和剪供***点)以促进mRNA产生。此外,如果核酸分子编码是加工或分泌的蛋白质或在细胞内起作用的蛋白质或肽,则优选核酸分子进一步包括用于加工、分泌、细胞内定位等的适当序列。
在某些实施方案中,调节无调相关因子和/或EGFR信号传导抑制剂的表达可能是有利的。调节核酸分子表达的特别优选的方法涉及在表达载体上添加位点特异性重组位点。通过重组事件使具有位点特异性重组位点的表达载体与重组酶接触,将上调或下调编码序列的转录,或者同时上调一个编码序列的转录,同时下调另一个编码序列的转录。在例如US 5,801,030、US 6,063,627和WO 97/09439中描述了使用位点特异性重组来调节核酸序列的转录。
有几种选择可用于将编码无调相关因子和/或EGFR信号传导抑制剂的核酸分子传递到内耳。编码无调相关因子的核酸分子还可编码EGFR信号传导抑制剂。表达载体可替代地或另外地可以包括编码无调子相关因子和/或EGFR信号传导抑制剂的多个表达盒。多个编码序列可以可操作地连接至不同的启动子,例如具有不同水平和活性模式的不同启动子。或者,多个编码序列可以可操作地连接至相同的启动子以形成多顺反子元件。本发明还考虑了向内耳施用表达载体的混合物,其中每个表达载体编码无调相关因子和/或EGFR信号传导抑制剂。表达载体的混合物可以进一步包括不同类型的表达载体,例如腺病毒载体和腺相关病毒载体。
有鉴于此,本发明进一步提供了一种腺病毒载体,该腺病毒载体携带编码无调相关因子(例如Math1或Hath1)和/或EGFR信号传导抑制剂的核酸分子,其中该核酸分子可操作地连接至表达无调相关因子和/或EGFR信号传导抑制剂所必需的调节序列。腺病毒载体在至少E4区的至少一种复制必需的基因功能上不足。核酸分子可以从任何来源获得,例如,从自然界中分离,合成产生,从基因工程生物体分离等。本文讨论了合适的腺病毒载体和调控序列。
此外,本发明进一步提供了一种在体内分化的感觉上皮细胞中产生毛细胞的方法。该方法涉及使分化的感觉上皮细胞与腺病毒载体接触,所述腺病毒载体(a)缺乏E1区域、E4区域的一种或多种复制必需基因功能,以及任选地,缺乏E3区域的一种或多种基因功能,(b)在E4区域具有间隔子,和(c)携带编码无调相关因子和/或EGFR信号传导抑制剂的核酸分子。表达该核酸分子以产生无调相关因子和/或EGFR信号传导抑制剂,从而产生毛细胞。虽然腺病毒载体可用于体内生成毛细胞(因此可用于预防或治疗听力障碍或平衡障碍),但支持细胞的转分化可在体外发生,因此可用于研究方法。
管理途径。本领域技术人员将认识到,向内耳施用药物或表达载体(例如腺病毒载体)的合适方法是可用的。尽管可以使用一种以上的途径来施用特定的药物或表达载体,但是与另一种途径相比,特定的途径可以提供更直接、更有效的反应。因此,所描述的给药途径仅是示例性的,绝不是限制性的。
无论给药途径如何,本发明方法的药物或表达载体理想地到达内耳的感觉上皮。因此,最直接的给药途径需要允许进入内耳结构内部的外科手术程序。通过耳蜗切开术接种允许将表达载体直接施用于与听力相关的内耳区域。耳蜗切开术包括在耳蜗壁上钻一个孔,例如在Kawamoto,et al.((2001)Molecular Therapy 4(6):575-585)描述的在骨动脉下方的耳囊中,然后释放含有该药物或表达载体的药物组合物。向内淋巴隔室给药对于向负责听力的内耳区域给药腺病毒载体特别有用。备选地,可以通过输卵管切开术将药物或表达载体给予半圆形管。吻合口切开术在前庭***和耳蜗中提供转基因表达,而耳蜗切开法不能在前庭空间中提供有效的转导。使用导管切开术降低了耳蜗功能受损的风险,因为直接注射到耳蜗间隙中会导致对毛细胞的机械损害(Kawamoto等人,同上)。给药程序也可以在液体(例如人工外周淋巴液)下进行,其可以包括减轻治疗或给药程序副作用的因素,例如细胞凋亡抑制剂或抗炎药。
向内耳给药的另一种直接途径是通过圆形窗口,通过注射或局部施用于圆形窗口。为了将药物或腺病毒载体递送至淋巴间隙,特别优选通过圆形窗口给药。在经由圆形窗口施用表达载体后,已经观察到在耳蜗和前庭神经元中以及在耳蜗感觉上皮中的转基因表达(Staecker等人,(2001)Acta Otolaryngol.121:157-163)。值得注意的是,内耳细胞中表达载体,特别是非靶向腺病毒载体的摄取似乎不是受体介导的。换句话说,内耳细胞的腺病毒感染似乎不是由CAR或整联蛋白介导的。为了在给予淋巴周区室后增加Corti器官中的细胞转导,腺病毒载体可以展示一种或多种配体,这些配体增强腺病毒载体对靶细胞的吸收(例如,支持细胞、血管纹样细胞等)。在这方面,腺病毒载体可以编码一种或多种腺病毒外壳蛋白,这些蛋白经修饰可减少天然结合(例如CAR和/或整联蛋白结合)并具有非天然氨基酸序列,从而增强了内耳靶细胞对腺病毒载体的吸收。
药物或表达载体(例如,腺病毒载体)可以存在于药物组合物中以施用于内耳。在某些情况下,给予多种应用和/或采用多种途径(例如,结肠造口术和耳蜗造口术)以确保支持细胞充分暴露于药物或表达载体可能是合适的。
药物或表达载体可以存在于允许受控或持续释放该药物或表达载体的装置中或该装置上,例如海绵、网状物、机械容器或泵或机械植入物。例如,将浸泡在含有药物或表达载体的药物组合物中的生物相容性海绵或凝胶状体与圆形窗相邻放置,药物或表达载体通过该圆形窗渗透以到达耳蜗(如Jero等人,见上文)。微型渗透泵可在较长的时间段内(例如五至七天)持续释放药物或表达载体,从而允许施用含有该药物或表达载体的少量组合物,从而可以防止对内源性感觉细胞的机械损伤。药物或表达载体也可以以包含例如明胶、硫酸软骨素、聚磷酸酯例如双-2-羟乙基对苯二甲酸酯(BHET),或聚乙醇酸的持续释放制剂的形式给药(参见例如US5,378,475)。
或者,可以胃肠外、肌肉内、静脉内、口服或腹膜内施用药物或表达载体。优选地,肠胃外给予患者以在耳朵中产生感觉毛细胞的药物或表达载体被特异性地靶向感觉上皮细胞,例如支持细胞。理想地,表达载体靶向于瘢痕的感觉上皮,以促进外源性毛细胞的生成以替代受损的内源性毛细胞。如本文所述,可以修饰表达载体以改变表达载体对潜在宿主细胞上受体的结合特异性或识别。对于腺病毒,这样的操作可以包括删除纤维、戊烯或六邻体的区域,将各种天然或非天然配体***外壳蛋白的一部分中,等等。本领域普通技术人员将理解,肠胃外施用可能需要大剂量或多次施用以有效地将表达载体递送至合适的宿主细胞。用于组合物的药学上可接受的载体是本领域普通技术人员众所周知的(参见Pharmaceutics and Pharmacy Practice,(1982)J.B.Lippincott Co.,Philadelphia,PA,Banker和Chalmers,eds.,238-250页;ASHP Handbook on Injectable Drugs(1986)Toissel,4th ed.,622-630页)。尽管不太优选,但表达载体也可以通过粒子轰击,即基因枪,在体内施用。
本领域普通技术人员还将理解,可以选择剂量和施用途径以使由于宿主的免疫***引起的表达载体的损失最小化。例如,为了在体内接触靶细胞,在进行本发明的方法之前向宿主施用无效表达载体(即不携带目标核酸分子的表达载体)可能是有利的。无效表达载体的先前施用可用于在宿主中产生对表达载体的免疫,所述免疫阻碍身体的先天清除机制,从而减少免疫***清除的载体的量。
剂量。根据本发明,施用于动物,特别是人的药物或表达载体的剂量应足以在合理的时间内影响动物所需的反应。本领域技术人员将认识到剂量将取决于多种因素,包括年龄、种类、受损的感觉上皮细胞的位置、所讨论的病理学(如果有的话)以及状况或疾病状态。剂量还取决于无调相关因子、EGFR信号传导抑制剂和/或细胞周期相关蛋白激酶抑制剂,以及要转导的感觉上皮的量。剂量的大小也将由给药途径、时间和频率以及给药特定表达载体(例如手术创伤)可能引起的任何不良副作用的存在、性质和程度或药物以及所需的生理效果来确定。本领域普通技术人员将认识到,各种病症或疾病状态,特别是慢性病症或疾病状态,可能需要涉及多次施用的延长治疗。
合适的剂量和剂量方案可以通过本领域普通技术人员已知的常规测距技术来确定。当表达载体是病毒载体,最优选腺病毒载体时,将约105个病毒颗粒至约1012个病毒颗粒递送给患者。换句话说,可以施用包括约105个颗粒/ml至约1013个颗粒/ml的表达载体浓度(包括在约105个颗粒/ml至约1013个颗粒/ml的范围内的所有整数)的药物组合物,优选约1010个颗粒/ml至约1012个颗粒/ml,并且通常涉及将约0.1μl至约100μl的这种药物组合物直接施用于内耳。考虑到上述情况,一次给药的剂量优选为至少约1×106个颗粒(例如,约4×l06-4×1012个颗粒),更优选至少约1×107个颗粒,更优选至少约1×108个颗粒(例如约4×108-4×l011个颗粒),最优选腺病毒载体的至少约1×109个颗粒至至少约1×1010个颗粒(例如约4×l09-4×l010个颗粒),所述腺病毒载体携带编码基因沉默复合物的无调相关因子和/或共转录因子和/或抑制剂的核酸分子。或者,药物组合物的剂量包括不超过约1×1014个颗粒,优选不超过约1×1013个颗粒,甚至更优选不超过约1×1012个颗粒,甚至更优选不超过约1×1011个颗粒,最优选不超过约1×1010个颗粒(例如,不超过约1×109个颗粒)。换句话说,单剂量的药物组合物可以是腺病毒载体(例如,复制缺陷型腺病毒载体)的约1×106个颗粒单位(pu)、4×l06pu、l×l07pu、4×l07pu、l×l08pu、4×l08pu、l×l09pu、4×l09pu、l×l010pu、4×l010pu、l×l011pu、4×l011、l×l011pu、4×l011pu、l×l012pu或4×1012pu。当表达载体是质粒时,优选施用约0.5ng至约1000μg的DNA。更优选地,施用约0.1μg至约500μg的DNA,甚至更优选地施用约1μg至约100μg的DNA。最优选地,向内耳施用约50μg的DNA。当然,其他给药途径可能需要较小或较大剂量才能达到治疗效果。剂量和给药途径的任何必要的变化可以由本领域普通技术人员使用本领域已知的常规技术来确定。
内耳的结构的内部空间是有限的。直接施用于内耳结构的药物组合物的体积应仔细监控,因为强加过多的组合物会损害感觉上皮。对于人类患者,施用的体积优选为约10μl至约2ml(约25μL至约1.5ml)的组合物。例如,可以施用约50μl至约1ml(约100μL、200μL、300μL、400μL、500μL、600μL、700μL、800μL或900μL)的组合物。在一个实施方案中,用药物组合物代替内耳结构例如耳蜗或半圆形管的全部流体内容物。在另一个实施方案中,本发明的药物组合物缓慢释放到内耳结构中,使得机械损伤最小。
施用两剂或更多剂(即,多剂)的药物或表达载体可能具有优势,所述药物或表达载体携带编码无调相关因子和/或EGFR信号传导抑制剂的核酸分子。本发明的方法提供了多剂量的药物或表达载体的施用,以在感觉上皮中产生毛细胞,从而改变动物的感觉。例如,可以将至少两次剂量的药物或表达载体施用于同一只耳朵。优选地,在保持基因表达高于背景水平的同时给予多剂量。还优选地,内耳的感觉上皮在约30天内与两种或更多剂量的药物或表达载体接触。更优选地,在约90天内向内耳施用两次或更多次施用。但是,可以在任何时间范围内(例如,两次给药之间间隔2、7、10、14、21、28、35、42、49、56、63、70、77、85天或更长时间)服用3、4、5、6或更多剂量。
药物组合物。本发明的药物或表达载体期望以药物组合物的形式施用,所述药物组合物包括药学上可接受的载体和药物或表达载体。在本发明的范围内可以使用任何合适的药学上可接受的载体,并且这种载体是本领域众所周知的。载体的选择将部分地由将组合物施用至的特定部位和用于施用组合物的特定方法来确定。理想地,在腺病毒载体的情况下,药物组合物优选不含能复制的腺病毒。
合适的制剂包括水溶液和非水溶液,等渗无菌溶液,其可以包含抗氧化剂、缓冲液、抑菌剂和使制剂与预期受体内耳的血液或液体等渗的溶质,以及可以包括悬浮剂、增溶剂、增稠剂、稳定剂和防腐剂的水性和非水性无菌悬浮液。所述制剂可包括可商购的人工内淋巴或外淋巴。制剂可以装在单位剂量或多剂量密封的容器中,例如安瓿和小瓶,并在即将使用之前可以冷冻干燥(冻干)条件保存,仅需添加无菌液体载体,例如水。临时溶液和悬浮液可以由前述类型的无菌粉末、颗粒和片剂制备。优选地,药学上可接受的载体是缓冲盐溶液。更优选地,用于本发明方法的表达载体以配制为在给药前保护表达载体不受损害的药物组合物中给药。例如,可以配制药物组合物以减少表达载体在用于制备、储存或施用表达载体的装置(例如玻璃器皿、注射器或针头)上的损失。可以配制药物组合物以降低表达载体的光敏感性和/或温度敏感性。为此,药物组合物优选包含药学上可接受的液体载体,例如上述那些,以及选自聚山梨酯80、L-精氨酸、聚乙烯吡咯烷酮、海藻糖及其组合的稳定剂。这种药物组合物的使用将延长载体的保存期限,促进给药,并提高本发明方法的效率。在这方面,还可以配制药物组合物以增强转导效率。另外,本领域普通技术人员将理解,表达载体,例如病毒载体,可以与其他治疗或生物活性剂一起存在于组合物中。例如,可以存在可用于治疗特定适应症的治疗因子。控制炎症的因素,例如布洛芬或类固醇,可以是组合物的一部分,以减少与体内施用病毒载体有关的肿胀和炎症。免疫***抑制剂可以与本发明的方法组合施用,以减少对载体本身或与内耳疾病有关的任何免疫应答。药物组合物中可以存在血管生成因子、神经营养因子、增殖剂等。同样,维生素和矿物质、抗氧化剂和微量营养素也可以共同使用。可以存在抗生素,即杀微生物剂和杀真菌剂,以降低与基因转移程序和其他疾病相关的感染风险。
其他注意事项。本发明的方法包括给予EGFR信号传导抑制剂和/或携带编码无调相关因子的核酸分子的表达载体,以通过在内耳的感觉上皮细胞中产生毛细胞来改变动物的感觉。编码无调相关因子的核酸分子可编码多个(例如2、3或更多)无调相关因子和/或EGFR信号传导的抑制剂。然而,仅产生毛细胞并不能确保动物的感觉知觉的改变。应该生成足够数量的毛细胞,并且这些感觉性毛细胞应该链接到能够将信号传输到大脑的神经网络。因此,尽管不是必需的,但是提供附加的因素以确保信号正确地接收和传输到大脑可能是有利的。
如本文所讨论的,几个选项可用于将多个编码序列传递到内耳。编码无调相关因子和/或EGFR信号传导抑制剂的核酸分子可以编码其他基因产物。表达载体可替代地或另外地可以包括编码不同基因产物的多个表达盒。多个编码序列可以可操作地连接至不同的启动子,例如具有不同水平和活性模式的不同启动子。或者,多个编码序列可以可操作地连接至相同的启动子以形成多顺反子元件。本发明还考虑了将表达载体的混合物给予内耳,其中每个表达载体编码无调相关因子或另一种有益于感觉感知的基因产物。表达载体的混合物可以进一步包含不同类型的表达载体,例如腺病毒载体和腺相关病毒载体。
替代地,或除了施用EGFR信号传导抑制剂和/或携带编码无调相关因子的核酸分子的表达载体外,本发明方法还包括与不由表达载体编码的与EGFR信号传导抑制剂联合施用携带编码无调相关因子的核酸分子的表达载体。在这方面,本文公开的方法和药物组合物可被修饰以包括表达载体,所述表达载体携带编码无调相关因子的核酸分子,其与抑制EGFR信号传导的分离的抑制性RNA分子、蛋白质、肽、抗体或有机小分子结合。此外,本文公开的方法和药物组合物可以被修饰为包括(i)携带编码无调相关因子的核酸分子的表达载体和/或与(ii)抑制EGFR信号传导的分离的抑制性RNA分子、蛋白质、肽、抗体或有机小分子组合的EGFR信号传导抑制剂。
为了进行本文公开的方法,本发明还提供了一种试剂盒。理想地,该试剂盒包括编码无调相关因子的核酸分子,和(i)编码表皮生长因子受体(EGFR)信号转导抑制剂的核酸分子;(ii)分离的EGFR信号抑制剂(例如,抑制EGFR、Ras、Raf、MEK、ERK/MAPK、JAK、STAT、PI3K、AKT、mTOR、NCK、PAK、JNK、PLC、PKC或细胞周期相关激酶中的一种或多种的抑制性RNA或有机小分子);或(iii)(i)和(ii)的组合。另外,试剂盒可包括含有冻干或液体形式的活性成分的容器(例如,小瓶、瓶、注射器或管),以及使用试剂盒组分的说明,包括关于剂量、给药、给药时间等的信息。试剂盒可进一步包括活性成分的指示、参考科学文献、包装材料、临床试验结果等。该信息可以基于各种研究的结果,例如,使用涉及体内模型的实验动物进行的研究以及基于人类临床试验的研究。
在一个优选的实施方案中,本发明的方法还考虑了编码至少一种神经营养剂的核酸分子的递送。理想地,神经营养剂是神经生长刺激剂,其诱导神经过程的生长、发育和/或成熟。也可以给予神经营养因子以保护或维持现有和发育中的神经元。为了使新生成的毛细胞正常工作,应建立神经网络以将神经冲动传递到大脑。因此,有利的是在产生新的毛细胞的同时保护与内耳的感觉上皮相关的现有神经元,诱导新的神经过程的生长和成熟,和/或简单地将现有的神经过程引导至感觉的毛细胞。神经营养因子分为三个亚类:神经细胞因子;神经营养蛋白;和成纤维细胞生长因子。睫状神经营养因子(CNTF)是神经生成细胞因子的示例。CNTF促进睫状神经节神经元的存活,并支持某些对NGF敏感的神经元。神经营养蛋白包括,例如,脑源性神经营养因子(BDNF)和神经生长因子(NGF),它们刺激神经突生长。其他神经营养因子包括例如转化生长因子、神经胶质细胞系衍生的神经营养因子(GDNF)、神经营养蛋白3、神经营养蛋白4/5和白介素1-β。神经营养因子提高神经元的存活率,并且也适用于本发明的方法。据推测,神经营养因子实际上可以逆转神经元的降解。可以想象,这些因素可用于治疗与年龄、感染或创伤有关的神经元变性。优选的神经营养因子是色素上皮衍生因子(PEDF)。PEDF在Chader(1987)Cell Different.20:209-216;Pignolo,et al.(1998)J.Biol.Chem.268(12):8949-8957;US 5,840,686、WO 1993/24529、WO 1999/04806和WO 2001/58494中有进一步的描述。
增殖剂诱导细胞增殖,优选内耳中支持细胞的增殖。乘以毛细胞祖细胞的数量可使基因沉默复合物的无调相关因子和/或共转录因子和/或抑制剂的生物学作用最大化。支持细胞的增殖由有丝***生长因子诱导,例如成纤维细胞生长因子(FGF,特别是FGF-2)、血管内皮生长因子(VEGF)、表皮生长因子(EGF)、E2F、细胞周期上调剂等。在本发明的方法中,可以将编码增殖剂的核酸序列与编码无调相关因子和/或EGFR信号传导抑制剂的核酸分子联合施用。如果需要的话,可以对编码增殖剂的核酸分子进行改造,使其仅对要复制的细胞类型发挥其生物学作用。对于支持细胞,核酸可以包括在支持细胞中优先被激活的调节序列。所得的增殖剂也可以被工程化以防止分泌到细胞环境中。或者,可以向内耳施用物质以促进细胞增殖或增强表达载体的摄取。
本发明的方法可以是涉及其他治疗方式的治疗方案的一部分。因此,如果采用本发明的方法预防或治疗已被治疗,正在治疗或将要用许多其他疗法(例如药物疗法或手术)治疗的感觉障碍,即听力障碍或平衡障碍。本发明的方法也可以结合听力装置的植入,例如耳蜗植入。本发明的方法还特别适用于涉及干细胞以再生内耳内细胞群的程序。在这方面,可以离体实践本发明的方法以转导干细胞,然后将其植入内耳中。
确定已经确定动物,例如哺乳动物,特别是人,处于感觉毛细胞变性的风险(预防治疗)或已证明感觉毛细胞数量减少或受损(治疗)之后,优选尽快施用表达载体。治疗将部分取决于所用的特定核酸分子,所表达的特定无调相关因子和/或EGFR信号抑制剂,表达载体,给药途径以及实现的毛细胞损失或损害的原因和程度(如果有)。
可以将携带编码无调相关因子和/或EGFR信号传导抑制剂的核酸分子的表达载体离体引入先前从给定动物特别是人中去除的细胞中。此类转导的自体或同源宿主细胞可以是祖细胞,其被重新引入动物或人的内耳以表达与无调相关的因子和/或EGFR信号传导抑制剂,并在体内分化为成熟的毛细胞。本领域普通技术人员将理解,此类细胞不需要与患者分离,而是可以与另一个个体分离并植入患者体内。
本发明的方法还可以涉及其他药物活性化合物的共同给药。“共同施用”是指在如上所述的相同表达或分开的表达中,在与表达载体组合之前,同时,例如与表达载体组合同时或在施用表达载体之后施用。例如,可以共同施用控制炎症的因子,例如布洛芬或类固醇,以减少与表达载体的施用相关的肿胀和炎症。可以共同施用免疫抑制剂以减少与内耳疾病或本发明方法的实施有关的不适当的免疫反应。同样,维生素和矿物质,抗氧化剂和微量营养素也可以共同使用。可以共施用抗生素,即杀微生物剂和杀真菌剂,以减少与外科手术相关的感染风险。
提供以下非限制性实施例以进一步说明本发明。
实施例1:EGFR信号传导的小分子抑制,促进毛细胞再生
Atoh1是一种转录因子,可以将新生儿和少年哺乳动物耳蜗中的非感觉支持细胞(SC)转换为毛细胞(HC)(Izumikawa,et al.(2005)Nature Med.11:271-6;Kelly,et al.(2012)J.Neurosci.32:6699-710;Liu,et al.(2012)J.Neurosci.32:6600-10)。Atoh1的异位表达已被批准用于基因治疗的临床试验。但是,Atoh1诱导的HC转化效率低(<17%)、不完全(缺乏成熟的HC标记)和年龄依赖性(成年耳蜗无反应)(Izumikawa,et al.(2008)Hearing Res.240:52-6;Liu,et al.(2012)J.Neurosci.32:6600-10)。使用RNA序列分析比较成年小鼠耳蜗中SC的转录组、内源性外HC(OHC)和Atoh1诱导的HC(cHC)的转录组,观察到表皮生长因子受体(EGFR)信号使用基因集富集分析(GSEA)富含SC和cHC。为验证离体EGFR途径的作用,新生小鼠耳蜗外植体用强效EGFR抑制剂(AG1478)处理。该分析表明,AG1478本身对7天后内源性SC和HC的增殖和分化没有影响。但是,将AG1478与Atoh1组合使用时,从植株SC到Atoh1诱导的HC转化率显着增加(从24.7%增至80.6%;图1A-1D)。此外,测试了靶向EGFR信号传导下游蛋白的抑制剂,包括高于各自EC50值的各种剂量的WP1066(STAT3抑制剂)、LY 294002(PI3K抑制剂)、U0126(MEK抑制剂)和U73122(PLC抑制剂)。除PLC抑制外,还观察到了Atoh1诱导的HC转化率的类似提高(图2)。该分析表明,EGFR信号传导通路在SC转化为HC中发挥了新作用。尽管已知在发育中很重要(Doetzlhofer,et al.(2004)Dev.Biol.272:432-47;Yamashita&Oesterle(1995)Proc.Natl.Acad.Sci.USA92:3152-5),EGFR信号传导以前并未涉及HC再生。
为了进一步评估EGFR信号传导抑制剂在HC再生中的用途,评估了AG1478对新生小鼠和成年小鼠的毒性。根据此分析,通过腹膜内(IP)注射,FVB小鼠在出生后第1天(P1)的AG1478的中位致死剂量(LD50)估计为30mg/kg。对于成年(>P21)FVB小鼠,在经鼓膜(TT)注射后7天,10μgAG1478导致听觉脑干反应(ABR)阈值无明显变化。
实施例2:Atoh1过表达小鼠的EGFR缺乏模型
Prox1-CreER(Prox1)、CAG-loxp-stop-loxp-Atoh1-HA(HA)和EGFRflox/flox杂交产生诱导小鼠系(Prox1;HA;EGFRflox/flox或PHER),其中在他莫昔芬诱导后,在新生儿和青少年SC(外HC(OHC)下方的Deiters细胞(DC)和柱状细胞(PC))中可以特别实现Atoh1过表达和EGFR缺失。诱导后3周和6周,通过免疫组织化学分析HC标志物的表达(早期和晚期)和形态,并用HA染色检查新产生的HC的电生理特征。
同样,Glast-CreER(Glast)已与HA和EGFRflox/flox一起使用,以生成特异性靶向内部HCs(IHC)下方的指骨内和边界细胞的小鼠系(Glast;HA;EGFRflox/flox或GHER)。另外,产生了Fgfr3-CreER;HA;EGFRflox/flox或FHER小鼠,以靶向成年deiter和柱状细胞。Cre活性将在P28成年时诱导,并在3周和6周后调查HC再生。预期在缺乏EGFR表达的小鼠中观察到SC向HC的转化增加。
此外,一个月大的小鼠将在120dB SPL下暴露于8-16kHz倍频程噪声2小时,以引起OHC丧失和听力损失。随后,在暴露后7天,用他莫昔芬诱导HC再生。将在噪声损伤之前,噪声损伤后7天和他莫昔芬诱导后3周测试动物的ABR,以进一步确定小鼠模型中HC再生的分子途径。
实施例3:EGFR抑制剂在Atoh1过表达小鼠中的治疗潜力
将在具有Atoh1过表达(PH、GH和FH)的小鼠模型中测试所选的EGFR抑制剂,以确定其模仿上面实例2中所述遗传模型的潜力(分别为PHER、GHER和FHER)。将分别测试六种高效和特异的EGFR抑制剂,包括厄洛替尼、吉非替尼、阿法替尼、NT-113、AZD3759和达可替尼,其EC50值为0.2-33nM。这些化合物已获得FDA的批准或正在其他疾病的临床试验中,并且在各个物种之间具有相对较好的吸收、分布、代谢、***和毒性(ADMET)特性。对于此分析,在小鼠模型(PH、GH和FH)中,用他莫昔芬在SC中诱导Atoh1过表达。随后,所选化合物将通过IP或TT注射进行递送。将评估血浆、耳蜗匀浆或淋巴液中每种化合物的ADMET特性,并检查NIHL后在再生功能性HC和恢复听力方面的暴露-疗效关系。
预期在新生儿和成人耳蜗中,EGFR抑制剂与Atoh1(EGFRi/Atoh1)的过表达一起使用会产生比单独的Atoh1多得多的HC。进一步预期这些HC的一部分将表达成熟的HC标志物(Prestin、癌调节蛋白、vGlut3),并表现出与正常成熟HC类似的电生理学。EGFRi/Atoh1介导的功能性HC转换甚至发生在噪音引起的听力损失中。如果在过表达Atoh1的成年SC中EGFR敲除和/或EGFR抑制剂的效率低于最佳效果,则可以使用过表达Atoh1/Pou4f3的小鼠模型,当在成年年龄诱导时,每只耳蜗的SC含量约为150cHC(在许多型号中最高)。预期EGFR抑制将与Pou4f3和Atoh1的过表达协同促进SC到HC的转化。
实施例4:用于防止听力损失的EGFR抑制剂
进行了由75种激酶抑制剂组成的文库筛选,以鉴定可防止顺铂诱导的毛细胞丢失的抑制剂。此筛查确定了四种化合物:(1)Her2抑制剂MUBRITINIB(TAK 165),(2)Pan-AUR抑制剂SNS314(3)BRAF-V600E抑制剂GSK2118436A(DABRAFENIB)和(4)PDGFR抑制剂CRENOLANIB,其在小鼠耳蜗来源的细胞系(HEI-OC1)中有效保护顺铂诱导的细胞死亡,以及在耳蜗外植体中顺铂诱导的毛细胞损失。Her2抑制剂MUBRITINIB(TAK 165)对HEI-OC1细胞中顺铂诱导的Caspase-3/7活性具有保护作用,IC50为4nM,LD50>55μM,并能保护顺铂诱导的小鼠耳蜗外植体毛细胞丢失,IC50为2.5nM,LD50>500nM(治疗指数>200)(图3)。同样,发现泛ErbB抑制剂PELITINIB在HEI-OC1细胞丢失中表现出针对顺铂诱导的Caspase-3/7活性的保护作用,IC50为0.6μM,LD50为40μM(图4)。此外,在预孵育1小时后,PELITINIB在小鼠耳蜗外植体中显示出49%的外部毛细胞抵抗顺铂诱导的毛细胞丢失(N=3)。
实施例5:在成年小鼠模型中针对由噪声和***伤害引起的听力损失的体内保护
在成年小鼠模型中,对局部给药(鼓膜注射入中耳)的EGFR信号传导抑制剂进行了测试,以对抗NIHL和***损伤引起的听力损失。使用局部传递途径是因为它在哺乳动物的听力研究中经常被使用,因为它提供了最小的侵入性和简单的程序。具体而言,儿科医生和耳鼻喉科医生通常通过这种途径向不同年龄的患者给药(Banerjee&Parnes(2005)Otol.Neurotol.26:878-881;Dodson,et al.(2004)Ear Nose Throat J.83:394-398;McCall,et al.(2010)Ear Hear.31:156-165;Muller&Barr-Gillespie(2015)Nat.Rev.Drug Discov.14:346-365;Rauch(2004)Otolaryngol.Clin.North Am.37:1061-1074)。在临床试验中,可以直接测试在鼠模型中显示出功效的化合物是否可以预防顺铂相关的听力损失。此外,鼓膜输送使化合物易于通过圆窗膜扩散到淋巴液中(Borkholder(2008)Curr.Opin.Otolaryngol.Head Neck Surg.16:472-477;Mizutari,et al.(2013)Neuron 77:58-69;Swan,et al.(2008)Adv.Drug Deliv.Rev.60:1583-1599;Tamura,etal.(2005)Laryngoscope 115:2000-2005),从而可以直接在体内测试其效价和毒性,而无需担心血迷宫屏障(BLB)。还可以考虑口服途径和其他途径的体内特性(例如溶解性、渗透性、药代动力学/药效学(PK/PD)以及吸收、分布、代谢、***和毒理学(ADMET))。
可以基于以下条件选择待测试的化合物:(1)表现出有效的IC50值和最小的毒性(即,高LD50/IC50值,最好>50-100μM);(2)针对几种不同的生物学目标/途径;(3)可以通过其他途径(例如口头)提供的能力。
为了进行噪音损伤测试,当听力成熟但很久以后才出现与年龄有关的重大听力损失时,在P28岁时使用野生型FVB小鼠(Kermany,et al.(2006)Hear Res.220:76-86;Maison,et al.(2002)J.Neurosci.22:10838-10846;Maison,et al.(2007)J.Neurophysiol.97:2930-2936;Zheng,et al.(1999)Hearing Research 130:94-107)。先前已经在来自FVB背景的各种转基因小鼠品系中测试了标准的噪声暴露方案(94、100、106、116和120dB声压级(SPL)倍频带8-16kHz噪声持续2小时)(Maison,et al.(2002)J.Neurosci.22:10838-10846;Maison,et al.(2007)J.Neurophysiol.97:2930-2936)。这些噪声损伤方案导致CBA/CaJ小鼠的听力损失(ABR)(Wang,et al.(2002)J.Assoc.Res.Otolaryngol.3:248-268)。
在135-155dB SPL处反复施加脉冲可以有效地概括成年小鼠耳蜗的***损伤效应。先前在动物模型中***冲击的研究表明,以147-160dB SPL反复进行50-160次冲击,会对黄鼠、绵羊和猪的耳蜗造成生理和形态上的损害,类似于对大鼠14psi冲击波的3-4次脉冲(Choi,et al.(2008)Free Radic.Biol.Med.44:1772-1784;Hamernik,et al.(1987)J.Acoust.Soc.Am.81:1118-1129;Henselman,et al.(1994)Hear.Res.78:1-10;Kopke,etal.(2005)Acta Otolaryngol.125:235-243;Roberto,et al.(1989)Ann.Otol.Rhinol.Laryngol.Suppl.140:23-34)。更有趣的是,在***后21天,大鼠受到3-4次14psi冲击的脉冲,导致43%的OHC损失和30-40dB的ABR阈值升高,类似于在龙猫中以4kHz为中心连续6个小时暴露于105dB SPL倍频程频带噪声引起的损害(Choi,et al.(2008)FreeRadic.Biol.Med.44:1772-1784;Ewert,et al.(2012)Hear.Res.285:29-39;Kopke,et al.(2005)Acta Otolaryngol.125:235-243)。根据这些结果,使用了持续时间约10毫秒的135-155dB SPL倍频程8-16kHz噪声脉冲范围,可以在小鼠模型中以1-s间隔重复100次,以模拟外伤性***伤害(Choi,et al.(2008)Free Radic.Biol.Med.44:1772-1784;Ewert,et al.(2012)Hear.Res.285:29-39;Henselman,et al.(1994)Hear.Res.78:1-10;McFadden,etal.(2000)J.Acoust.Soc.Am.107:2162-2168)。
实验设计。立即将暴露于噪音或***中的小鼠的一只耳朵中的单个化合物与另一只耳朵中的媒介物对照(0.5%DMSO)一起处理。DMSO或化合物以最高可行剂量(应比人工耳蜗外植体中的IC50高得多,但在体内本身无毒)以每耳~5μL的剂量经鼓室局部注射。在噪音前或TBI以及注射后1和2周测量ABR和失真产物的耳声发射(DPOAE)。在通过ABR和DPOAE进行听力测试后,对小鼠进行心脏灌流以固定和收获耳蜗。使用整装制剂和切片对耳蜗进行分析,并使用免疫荧光检测HC/SC标记物(如鬼笔环肽、Myo7a、Prestin和Sox2等)和突触标记物(Ctbp2、GluR2/3和Tuj1)(Liu,et al.(2014)PLoS One 9:e89377)。
整个过程是双盲的:一者编码DMSO或化合物,而另一者随机注射同一只小鼠的左耳和右耳,而记录ABR和DPOAE者直到整个实验完成才知道向哪个耳朵注射了化合物。
成年小鼠的ABR/DPOAE测量。先前已经详细介绍了ABR测量(Dallos,et al.(2008)Neuron 58:333-339;Gao,et al.(2007)Mol.Cell Biol.27:4500-4512;Liberman,et al.(2002)Nature 419:300-304;Liu,et al.(2014)PLoS One 9:e89377;Wu,et al.(2004)Brain Res.Mol.Brain Res.126:30-37;Yamashita,et al.(2012)PLoS One 7:e45453)。简而言之,通过腹膜内注射AVERTIN(0.5mg/kg体重)麻醉小鼠,并使用恒温毯***(哈佛仪器有限公司)将其放在电加热垫上以维持体温。在实验过程中死亡或显示中耳功能障碍迹象的小鼠被排除在分析之外。所有录音均在录音棚(Industrial Acoustic Company)中进行。为了进行声学刺激和测量,将两个扬声器(f1和f2;EC1)和一个麦克风(ER-10B,EtymoticResearch,Elk Grove Village,IL)连接到一个短的柔性耦合管,该耦合管的锥形塑料尖端***外耳道。在耦合器处于测量位置的情况下,对麦克风进行原位校准。在高于22kHz的频率下,测量麦克风(ER10B+)的频率响应低于参考麦克风(ACO-7017;ACO Pacific,Inc.,Belmont,CA)的频率响应。因此,使用TDT BioSig III***(TDT)在5454-18180Hz的频率f1范围内记录DPOAE 2f1-f2响应。信号持续时间为83.88ms,重复频率为11.92/s。f1和f2响应分别通过RX6多功能处理器(TDT)传递,以将数字/模拟转换为PA5可编程衰减器。以5dB的步长将刺激强度从90dB降低到0dB,以建立阈值,并以200kHz的频率进行数字采样,并从100个离散频谱中求平均值。信号通过ED1扬声器驱动器传递,该驱动器馈入耦合到耳道的EC1静电扬声器。所产生的耳道声压由ER10B+低噪声麦克风(增益为0×)和探头(Etymotic)记录,该探头与f1和f2扬声器安装在同一耦合器中。ER10B+放大器的输出直接路由到RX6多功能处理器(TDT),以进行模/数转换,以200kHz采样。使用TDT BioSigRP软件对所得波形(TDT)生成平均响应的快速傅立叶变换(FFT)。本底噪声是通过对2f1-f2频率档上方和下方的10个频率档的声音水平进行平均来确定的。在评估耳后验尸中未发现仪器失真产物。
成年小鼠的噪声损伤。将小鼠单独放置在定制丙烯酸室中的笼子中,该笼子的两侧都不平行。声音刺激是由RZ6处理器(Tucker-Davis Technologies,Gainesville FL)产生,经过滤波(Frequency Devices,Inc.,Haverhill,MA),放大(Crown XTi 1000放大器;Crown,Elkhart,IN),然后通过扬声器喇叭(JBL,Northridge,CA)传递到丙烯酸室。声压级通过1/4英寸自由场麦克风(ACO Pacific,Belmont,CA)进行测量,并校准为124dB活塞式电话(Bruel和Kjaer,Denmark)。在进行实验性噪声暴露之前,使用1/4英寸麦克风对腔室的四个象限进行采样,以确保在测量位置上声压的变化小于0.5dB。
经鼓室注射成年小鼠。通过腹膜内(i.p.)注射AVERTIN或***和甲苯噻嗪麻醉小鼠。在手术过程中,将体温保持在加热垫上。由于在手术过程中眨眼反射消失,因此润滑性眼药膏可用于预防角膜溃疡。鼓膜可通过手术体视显微镜观察。使用33号套管,将5μL的PBS中的化合物或DMSO轻轻地通过鼓膜注射,然后通过手术立体显微镜确认溶液在中耳腔中。然后将小鼠放在加热垫上的笼子中再放置30分钟。手术后,允许所有小鼠在加热垫上康复,然后再返回动物***。
序列表
<110> 圣祖德儿童研究医院
J·左
F·郑
T·山下
Z·卡拉德
T·泰兹
J·闵
T·S·陈
<120> 预防和治疗听力损失的组合物和方法
<130> SJ0072WO
<150> US 62/500,667
<151> 2017-05-03
<160> 2
<170> PatentIn version 3.5
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<213> 人工序列(Artificial Sequence)
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Ala Ala Asn Ala Arg Glu Arg Arg Arg Met His Gly Leu Asn His Ala
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Phe Asp Gln Leu Arg
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Claims (14)
1.一种用于治疗或预防听力损失的方法,所述方法包括向有需要的动物施用表皮生长因子受体(EGFR)信号传导抑制剂。
2.根据权利要求1所述的方法,其中所述治疗还包括施用表达载体,该表达载体携带编码无调相关因子的核酸分子。
3.根据权利要求1所述的方法,还包括施用一种或多种耳保护剂或再生剂。
4.根据权利要求1所述的方法,其中所述EGFR信号传导抑制剂抑制EGFR、Ras、Raf、MEK、ERK/MAPK、JAR、STAT、PI3K、AKT、mTOR、NCR、PAR、JNR、PLC、PRC或细胞周期相关蛋白激酶抑制剂的表达或活性。
5.根据权利要求4所述的方法,其中所述细胞周期相关蛋白激酶是Her-2、Aurora激酶、B-Raf或PDGFR。
6.根据权利要求1所述的方法,其中所述抑制剂是抑制性RNA、抗体或有机小分子。
7.一种药物组合物,包含携带编码无调相关因子的核酸分子的表达载体和表皮生长因子受体(EGFR)信号转导抑制剂。
8.根据权利要求7所述的药物组合物,其中所述EGFR信号传导抑制剂抑制EGFR、Ras、Raf、MEK、ERK/MAPK、JAK、STAT、PI3K、AKT、mTOR、NCK、PAK、JNK、PLC、PKC或细胞周期相关蛋白激酶抑制剂的表达或活性。
9.根据权利要求7所述的药物组合物,其中所述抑制剂是抑制性RNA、抗体或有机小分子。
10.根据权利要求7所述的药物组合物,还包含一种或多种再生剂。
11.试剂盒,包含:编码无调相关因子的核酸分子;和
(i)编码表皮生长因子受体(EGFR)信号转导抑制剂的核酸分子;
(ii)分离的EGFR信号抑制剂;或
(iii)(i)和(ii)的组合。
12.根据权利要求11所述的试剂盒,其中所述EGFR信号传导抑制剂抑制EGFR、Ras、Raf、MEK、ERK/MAPK、JAK、STAT、PI3K、AKT、mTOR、NCK、PAK、JNK、PLC、PKC或细胞周期相关蛋白激酶抑制剂的表达或活性。
13.根据权利要求11所述的试剂盒,其中所述抑制剂是抑制性RNA、抗体或有机小分子。
14.根据权利要求11所述的试剂盒,还包含一种或多种再生剂。
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN112755026A (zh) * | 2021-03-01 | 2021-05-07 | 滨州医学院 | 雷帕霉素在制备治疗中耳炎药物中的应用 |
Also Published As
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EP3618807A4 (en) | 2021-01-20 |
CN111655228B (zh) | 2024-02-09 |
JP2023024984A (ja) | 2023-02-21 |
US11883491B2 (en) | 2024-01-30 |
JP7291399B2 (ja) | 2023-06-15 |
WO2018204226A1 (en) | 2018-11-08 |
EP3618807A1 (en) | 2020-03-11 |
US20200093923A1 (en) | 2020-03-26 |
JP2020518642A (ja) | 2020-06-25 |
WO2018204226A8 (en) | 2019-01-03 |
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