CN109562092A - 治疗普拉德-威利综合症的方法 - Google Patents
治疗普拉德-威利综合症的方法 Download PDFInfo
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Abstract
本发明涉及用于调节激素原转化酶(PC1)的方法以及用于治疗普拉德‑威利综合症(PWS)的增加PC1水平的化合物和治疗。
Description
相关申请案
本申请要求2016年6月3日提交的美国临时专利申请No.62/345,133、2016年8月16日提交的美国临时申请No.62/375,662的优先权,其各自以全文引用的方式并入本文。
政府支持
此工作部分由美国国立卫生研究院R01DK052431授权支持;因此,美国政府可享有本发明中的某些权利。
发明领域
本发明涉及用于调节激素原转化酶(PC1)的方法以及增加PC1水平的化合物和治疗方法。
发明背景
普拉德-威利综合症(PWS)因染色体15q的印记区中损失了父系表达基因而引起。其中典型的表型为贪食性肥胖症、中枢性性腺功能减退以及低生长激素。罕见的微缺失症PWS患者定义一个涵盖3个基因的91kb最小临界缺失区,包括非编码SNORD116。我们已发现,与未受影响的对照物相比,源自PWS iPSC的神经元中的NHLH2和PC1下调。禁食Snord116p-/m+小鼠的下丘脑中的Nhlh2和Pcsk1转录水平降低。
小鼠体内缺乏Nhlh2导致肥胖症、性腺功能减退和生长不足。Nhlh2促使激素原转化酶(PC1)的表达。缺乏PC1的人类和小鼠都由于激素原加工受损而表现出贪食性肥胖症、性腺功能减退、生长激素减少和糖尿病。例如,Snord116p-/m+小鼠在胰岛素原、proGHRH和胃饥饿素原的激素原加工中都显示出与PC1减少相关的体内功能缺陷。
目前尚无用于PWS患者的治疗方法,并且急需有效的治疗方法和模型系统。
发明概要
本发明的方法提供通过施用有效量的磷酸二酯酶4抑制剂(PDE4抑制剂或PDE4i)来调节激素原转化酶。可通过施用治疗有效量的PDE4抑制剂来上调激素原转化酶的表达。PDE4抑制剂可施用于细胞或普拉德-威利综合症患者。PDE4抑制剂可施用于肥胖症受试者。还预期这些方法将适用于治疗患有Schaaf-Yang综合症和自闭症谱系障碍(AutismSpectrum Disorder)的患者。
PDE4抑制剂可经口、静脉内、皮下、鞘内、局部、鼻内施用或施用于肺部。
PDE4抑制剂可包括茶碱、罗氟司特(roflumilast)、阿普司特(apremilast)、异丁司特(ibdulast)、GSK356278、MK0952、IBMX以及这些药物的组合。
在某些实施方案中,PDE4抑制剂可包括表1A或表1B中的任何抑制剂。
在其它实施方案中,本发明的方法中可使用PDE4抑制剂的组合。
本发明的方法还包括施用治疗有效量的腺苷酸环化酶活化剂。腺苷酸环化酶活化剂可施用于细胞或施用于普拉德-威利综合症患者。腺苷酸环化酶活化剂可施用于肥胖症受试者。
腺苷酸环化酶活化剂可经口、静脉内、鞘内、鼻内、局部施用或施用于肺部。腺苷酸环化酶活化剂可包括佛司可林(Forskolin)、FD1、FD2、FD3、FD4、FD5(NKH477)、FD6以及这些药物的组合。
PDE4抑制剂还可与腺苷酸环化酶活化剂一起施用。
本发明的方法还包括施用治疗有效量的MC4R激动剂。MC4R激动剂可施用于细胞或施用于普拉德-威利综合症患者。MC4R激动剂可施用于肥胖症受试者。
MC4R激动剂可经口、静脉内、鞘内、鼻内、局部施用或施用于肺部。MC4R激动剂可包括RM-493(赛特糖苷,Setmelanotide)、TTP2515、2-氨基噻唑衍生物、MK-0493及它们的组合。MC4R激动剂可与本文所述的PDE4抑制剂和/或腺苷酸环化酶活化剂组合施用。
本发明的方法还包括其中施药导致患者的一项或多项以下改进的方法:减少或改善摄食过量;增加PCSK1水平;增加PC1水平和/或活性;减少循环胰岛素原与胰岛素的比率,因此增加胰岛素分泌;减少循环胃饥饿素原与胃饥饿素的比率;减少循环POMC与ACTH的比率;改善甲状腺功能减退、减少催产素原与催产素的循环比率,因此增加大脑中的催产素产量以及增加大脑中的α-MSH产量;减少BDNF原与BDNF的循环比率(增加BDNF的大脑水平);以及增加激素原:激素的比率(减少促成熟激素);其中所述症状、水平或比率均是关于患者的疾病症状、水平或比率。
在某些实施方案中,所述方法提供治疗拉德-威利综合症(PWS),包括向有需要的受试者施用磷酸二酯酶4抑制剂(PDE4i),由此缓解、消除或预防PWS的一种或多种症状。
在某些实施方案中,施用PDE4i使受试者体内的环磷酸腺苷(cAMP)浓度或活性上调。
在某些实施方案中,PWS的特征在于NHLH2的表达减少。
在其它实施方案中,NHLH2的表达减少导致PCSK1的表达减少。
在某些实施方案中,增加cAMP的浓度或活性使Pcsk1的表达上调。
在其它实施方案中,PDE4i为选择性PDE4i。在其它实施方案中,PDE4i为非选择性PDE4i。
在某些实施方案中,所述选择性PDE4i是选自AN2728、阿普司特(apremilast)、西洛司特(cilomilast)、地西泮(diazepam)、异丁司特(ibudilast)、木犀草素、松叶菊酮碱、吡拉米司特(piclamilast)、罗氟司特、咯利普兰(rolipram)、E6005、GSK356278和MK0952。
在某些实施方案中,所述非选择性PDE4i是选自甲基化黄嘌呤及它的衍生物、咖啡因、氨茶碱、3-异丁基-1-甲基黄嘌呤、副黄嘌呤、已酮可可碱、可可碱和茶碱。
又在其它实施方案中,所述一种或多种症状包括摄食过量、代谢率降低、肥胖症、性腺功能减退、肾上腺素机能减退、生长激素产生减少、肌张力低下、睡眠障碍、肠胃失调、耐力减少、专注力降低、认知功能受损、行为障碍、焦虑、生长不足、不成熟激素转化为成熟活性形式减少以及糖尿病和尿崩症。
在某些实施方案中,所述方法还包括施用一种或多种有效治疗或缓解一种或多种PWS症状的其它治疗剂。
在某些实施方案中,所述不成熟激素包含以下中的一种或多种:胰岛素、胃饥饿素、GHRH、α-MSH、催产素、食欲素、BDNF、血管加压素、NPY、AGRP以及促性腺激素、ACTH。
在某些实施方案中,所述一种或多种有效治疗或缓解PWS的其它治疗剂包括胰岛素、胰岛素受体激动剂、胃饥饿素、胃饥饿素受体激动剂、GHRH、GHRH受体激动剂、α-MSH、α-MSH受体激动剂、催产素、催产素受体激动剂、食欲素、食欲素受体激动剂、BDNF、BDNF受体激动剂、血管加压素、血管加压素受体激动剂、NPY、NPY受体激动剂、AGRP、AGRP受体激动剂、促性腺激素、促性腺激素受体激动剂或它们的组合。
附图说明
图1是显示Nhlh2和PC1缺乏如何驱动PWS的主要神经内分泌表型的模型。由于PC1和Nhlh2产量缺乏导致激素原加工缺陷可解释PWS的许多主要神经内分泌表型。假设父系损失SNORD116可足以引起Nhlh2和PC1缺乏,反过来又导致激素原加工的功能缺陷。虚线的箭头/线表示理论联系。实线的箭头/线表示已研究的路径。
图2是显示使用增加细胞cAMP水平从而增加细胞PC1的水平和/或活性以及增加激素原加工的药剂来治疗PWS的基本原理的示意图。
图3A-P是显示PWS模型中的PC1下调与激素原加工受损相关;由佛司可林治疗的未受影响对照物中的PCSK1转录水平可增加的图表。
图4是显示在患有PWS和可能患有其它类型肥胖症(包括常见肥胖症)的个体中与佛司可林和/或茶碱组合共同施用MC4R激动剂和/或AgRP抑制剂的治疗原理的示意图。
图5A-H是显示应用佛司可林(一种AC激动剂)使原代小鼠神经元、源自iPSC的神经元以及原代小鼠胰岛中的PCSK1/Pcsk1转录水平增加的图表。
图6A-F是显示向源自iPSC的神经元应用磷酸二酯酶抑制剂来增加PCSK1转录水平和激素原加工的图表。图6A:茶碱以10mM浓度增加源自D34iPSC的下丘脑ARC神经元中的PCSK1转录水平(1023A线)。图6B-C:罗氟司特1mM浓度在分化第40天时增加源自iPSC的神经元中的PCSK1转录水平(1043D3线)。图6D-E:罗氟司特(100nM)与佛司可林(1μM)组合治疗以比单独任一药剂更低的浓度增加PCSK1转录水平以及增加POMC加工为ACTH,表明一种加合作用或可能为协同作用。图6F:以10μM与1μM佛司可林组合应用的MK0952使源自iPSC的神经元中的PCSK1转录水平增加约2倍(1043D3线)。
图7A-B是显示以MK0952单独治疗增加野生型小鼠中的下丘脑Pcsk1的图表。图7A是显示使用的所有小鼠的体重相当的图表。图7B是显示在10%甲基纤维素中以10mg/kg体重的剂量通过经口灌胃施用的MK0952使下丘脑Pcsk1水平增加约25%的图表。用佛司可林以25mg/kg治疗并未导致下丘脑Pcsk1水平增加。MK0952(10mg/kg)与佛司可林(25mg/kg)组合治疗也导致下丘脑Pcsk1转录水平增加25%,可能主要是由于MK0952的作用。
图8A-C是显示临床试验设计各方面的示意图、表格和图表。
具体实施方式
本公开提供用于体外或体内调节PC1(激素原转化酶1)水平的方法。所述方法可用于上调(增加表达)或增加PC1水平和/或活性。本公开还涵盖用于治疗普拉德-威利综合症(PWS)和其它形式肥胖症的方法。所述方法可包括施用治疗有效量的PDE4抑制剂和/或腺苷酸环化酶活化剂的步骤。还预期这些方法将适用于治疗患有Schaaf-Yang综合症和自闭症谱系障碍的患者(Fabienne Schaller Watrin Rachel Sturny AnnickMassacrier Pierre Szepetowski Francoise Muscatelli;Hum Mol Genet(2010)19(24):4895-4905。DOI:https://doi.org/10.1093/hmg/ddq424;Green L,Fein D,Modahl C,Feinstein C,Waterhouse L,Morris M.Oxytocin and autistic disorder:alterationsin peptide forms.Biol Psychiatry.2001年10月15日;50(8):609-13。
增加细胞激素原转化酶1水平/活性的理论机制包括(但不限于):(1)通过接合内源性启动子上调转录水平,(2)直接增加PC1的酶活性,(3)增加PCSK1翻译成PC1的比率,(4)减少PC1酶/蛋白质的降解,通过减少PC1的内源性抑制剂ProSAAS的水平(通过反义寡”基因敲低”、传统的小分子抑制或其它方式)的一种可能的方法,(5)减少PCSK1转录物的降解(miRNA靶向,无义介导的衰变,假定的mRNA甲基化水平),由此增加翻译,(6)PC1本身由92kDa酶原加工成66kDa成熟酶,因此增加preproPC1加工的水平也可具有治疗用途,以及(7)通过基因治疗方法将其它PCSK1cDNA传递至细胞,(8)通过基因治疗方法传递SNORD116RNA,以及(9)通过酶替代治疗直接将PC1酶传递至循环和/或组织中。
本发明的发现表明,PWS的主要神经内分泌特征可能是由于功能性的PC1缺陷。参考图1。由于编码PC1的基因PCSK1在PWS中是完整的,因此增加PWS患者体内的PC1表达和/或活性水平将纠正此功能性的PC1缺陷。PC1水平的这种增加在药理学上可以通过施用增加环磷酸腺苷(cAMP)水平或阻止cAMP降解的药剂来实现。
环核苷酸磷酸二酯酶(PDE)催化环状AMP和环状GMP的水解,由此调节这些环核苷酸的胞内浓度、其信号通路并且因此调节健康体和患病体中的大量生物反应。Maurice等人Advances in targeting cyclic nucleotide phosphodiesterases.Nat.Rev.Drug.Disc ov.13(4):290-314(2014)。PDE4同种型在调节免疫炎症反应和组织重塑的细胞中高度表达。同上。抑制PDE4导致细胞中的cAMP水平增加。可获得多种PDE4抑制剂。PDE4抑制剂的的非限制性实例包括:茶碱、罗弗司特、阿普司特、异丁司特、GSK356278、MK0952、IBMX(3-异丁基-1-甲基黄嘌呤)、松叶菊酮碱、咯利普兰、吡拉米司特、木犀草素、曲他维林(Drotaverine)、AN2728、西洛司特、地西泮、木犀草素和E6005。其它磷酸二酯酶抑制剂包括甲基化黄嘌呤和衍生物(诸如咖啡因、氨茶碱、副黄嘌呤、已酮可可碱、可可碱和茶碱)。
也可使用活化腺苷酸环化酶的药剂来增加cAMP的水平。腺苷酸环化酶活化剂的非限制性实例包括:佛司可林、FD1、FD2、FD3、FD4、FD5(NKH477)和FD6。
PDE4抑制剂和腺苷酸环化酶活化剂可单独或组合称为治疗剂。
表1A:选定的PDE4抑制剂
表2:选定的腺苷酸环化酶活化剂
缩写
ACTH:促肾上腺皮质激素。
AgRP:Agouti相关蛋白;一种也在弓状核中产生的蛋白质并且是MC4R的一种反向激动剂。ProAgRP由PC1加工成AgRP。
cAMP:环磷酸腺苷
GH:胃饥饿素(“饥饿激素”,也称为lenomorelin(INN))是由胃底部的内分泌细胞产生的一种在中枢神经系统中充当神经肽的肽激素。
proGHRH:促生长激素-释放激素。
GHRH:生长激素-释放激素(GHRH),其内源性形式也称为促生长素释放素或几种其它名称,并且其药物形式称为生长释素(INN),是一种生长激素(GH)的释放激素。它是在下丘脑的弓状核中产生的一种44-氨基酸肽激素。
PC1:前蛋白转化酶1,也称为激素原转化酶1、激素原转化酶3、前蛋白转化酶3、神经内分泌转化酶1或神经内分泌转化酶3,并且常缩写为PC1/3,是在人体内由PCSK1基因编码的一种酶。PC1和PC2(PCSK1和PCSK2基因的蛋白质产物)以不同方式裂解多种神经内分泌或内分泌激素,包括阿黑皮素原、胰岛素原和胰高血糖素原。
PC2:前蛋白转化酶2(PC2),也称为激素原转化酶2或神经内分泌转化酶2(NEC2),是一种丝氨酸蛋白酶,并且前蛋白转化酶PC2如同前蛋白转化酶1(PC1),是一种在许多神经内分泌肽自其前体成熟中负责第一步骤的酶,诸如胰岛素原转化为胰岛素中间体。为产生生物活性形式的胰岛素(以及许多其它肽),需要涉及去除C末端碱性残基的第二步骤;此步骤由羧肽酶E和/或D来介导。与PC1相比,PC2在胰岛素生物合成的第一步骤中只起到很小的作用,但在胰高血糖素生物合成的第一步骤中起更大的作用。PC2与命名为7B2的神经内分泌蛋白质结合,并且如果这种蛋白质不存在,proPC2则无法具有酶活性。7B2通过阻止proPC2聚集成可灭活形式来实现此目的。7B2的C-末端结构域也抑制PC2活性,直到其被裂解为更小的非活性形式。因此,7B2是PC2的活化剂和抑制剂。在人体内,前蛋白转化酶2由PCSK2基因来编码。它与细菌酶枯草杆菌蛋白酶相关,并且在哺乳动物中总计有9种不同的类似枯草杆菌蛋白酶的基因:弗林蛋白酶、PACE4、PC4、PC5/6、PC7/8、PCSK9和SKI1/S1P。
PCSK1:编码PC1的基因。
PCSK2:编码PC2的基因。
POMC:阿黑皮素原(POMC)是一种具有241个氨基酸残基的前体多肽。POMC在脑垂体中由285-氨基酸长多肽前体前阿黑皮素原(pre-POMC)通过在翻译期间去除44-氨基酸-长信号肽序列来合成。
PDE4:磷酸二酯酶4。
PWS:普拉德-威利综合症。
SNORD 116:SNORD116(也称为HBII-85)是一种非编码RNA(ncRNA)分子,用于修饰其它小核RNA(snRNA)。这种类型的修饰RNA通常位于真核细胞的核仁中,这是snRNA生物发生的主要位点。称为小核仁RNA(snoRNA),而且也常称为向导RNA。SNORD 116属于snoRNA的C/D框类,其含有称为C框(UGAUGA)和D框(CUGA)的保守序列基序。框C/D家族的大多数成员用于引导底物RNA的位点特异性2’-O-甲基化。在人类基因组中,在染色体15的PWS区中有29个SNORD 116串联重复拷贝。另外,其它非编码RNA物种由SNORD 116基因座编码,包括长的非编码RNA、116HG、五个sno-lncRNA和两个spa-lncRNA。SNORD 116是一种缺少明确定义标靶的罕见非编码RNA基因座。缺少父系Snord116的小鼠模型显示与人类PWS类似的症状,包括摄食过量和生长缺陷。
DPI装置/吸入器:干粉吸入器;通常为手持式的。
MDI装置:定量吸入器;通常为手持式的。
αMSH:是黑皮质素4受体的一种内源性配体。
MC2R:黑皮质素2受体。
MC4R:黑皮质素4受体。
WT:野生型。
定义
如本文中所用,术语“药学上可接受的载体”意思是药学上可接受的材料、组合物或媒介物,诸如液体或固体填充剂、稀释剂、赋形剂、溶剂或封装材料,涉及到运载或输送化学药剂。稀释剂或载体成分不应如此而减小活性化合物的治疗作用。
如本文中所用,术语“组合物”意思是由一种以上要素或成分混合或合并得到的产物。
“治疗(treating/treatment)”疾病状态、病症或病况包括:
(1)预防或延迟在罹患或有疾病状态、病症或病况倾向,但尚未经历或呈现出所述疾病状态、病症或病况的临床症状的人体中发展的疾病状态、病症或病况出现临床症状;或
(2)抑制疾病状态、病症或病况,即阻止、减少或延迟疾病发展或它们的复发(在维持治疗的情况下)或它们的至少一种临床症状、征象或测试;或
(3)缓解疾病,即致使疾病状态、病症或病况或它们的至少一种临床或亚临床症状或征象衰退。
对于待治疗受试者的益处对于患者或医生而言在统计学上是显著的或至少是可感知的。
“患者”或“受试者”指的是哺乳动物,且包括人类和兽医受试者。
“抑制剂”和“拮抗剂”或“活化剂”和“激动剂”分别指的是例如对于例如配体、受体、辅因子、基因、细胞、组织或器官的活化而言的抑制或活化分子。例如基因、受体、配体或细胞的调节剂是改变基因、受体、配体或细胞的活性的分子,其中活性可受到活化、抑制或改变其调节性质。调节剂可单独作用,或可使用辅因子,例如蛋白质、金属离子或小分子。抑制剂为减小、阻断、阻止、延迟例如基因、蛋白质、配体、受体或细胞的活化,使其灭活、脱敏或下调的化合物。活化剂为增加、活化、促进、增强例如基因、蛋白质、配体、受体或细胞的活化,使其敏感或上调的化合物。抑制剂也可定义为减小、阻断或灭活组成性活性的化合物。“激动剂”为与标靶相互作用以致使或促进标靶活化增加的化合物。“拮抗剂”为对抗激动剂的作用的化合物。拮抗剂阻止、减小、抑制或中和激动剂的活性。拮抗剂也可阻止、抑制或减小标靶(例如,标靶受体)的组成性活性,即使在无确定的激动剂时。
为检查抑制程度,例如用可能的活化剂或抑制剂处理包含给定的例如蛋白质、基因、细胞或生物体的样本或分析用试样,并与不含抑制剂的对照样本进行比较。对照样本(即,未经拮抗剂处理的样本)指定相对活性值为100%。当相对于对照物的活性值为约90%或90%以下、通常为85%或85%以下、更通常为80%或80%以下、最通常为75%或75%以下、通常为70%或70%以下、更通常为65%或65%以下、最通常为60%或60%以下、通常为55%或55%以下、通常为50%或50%以下、更通常为45%或45%以下、最通常为40%或40%以下、优选为35%或35%以下、更优选为30%或30%以下、又更优选为25%或25%以下且最优选为小于25%时,实现抑制。当相对于对照物的活性值为约110%、通常为至少120%、更通常为至少140%、更通常为至少160%、通常为至少180%、更通常为至少2倍、最通常为至少2.5倍、通常为至少5倍、更通常为至少10倍、优选为至少20倍、更优选为至少40倍且最优选超过40倍以上时,实现活化。
治疗制剂的剂量将视疾病的性质、患者的病史、施药频率、施药方式、宿主的药剂清除率等而广泛变化。初始剂量可较大,接着为较小的维持剂量。剂量可按每周或每两周的频率施用,或分成更小的剂量并每天、每半周等来施用以维持有效的剂量水平。在某些情况下,口服将需要比静脉内施药时更高的剂量。在某些情况下,局部施药将包括每天视需要施用数次,持续多日或数周来提供有效的局部剂量。
术语“载体”指的是与化合物一起施用的稀释剂、佐剂、赋形剂或媒介物。所述药物载体可为无菌液体,诸如水和油,包括石油、动物、植物或合成来源的那些油,诸如花生油、大豆油、矿物油、橄榄油、芝麻油等。优选采用水或水溶液性的生理盐水溶液以及葡萄糖和甘油水溶液作为载体,尤其对于可注射溶液而言。或者,载体可为固体剂型的载体,包括(但不限于)粘合剂(对于压缩药丸而言)、助流剂、封装剂、食用香料和着色剂中的一种或多种。E.W.Martin的“Remington's Pharmaceutical Sciences”中描述合适的药物载体。
本文所述的治疗性组合物可通过本领域中已知的任何方法来施用,包括(不限于)鼻内、口服、经皮、经眼、腹膜内、吸入、静脉内、ICV、脑池内注射或输注、皮下、植入体、阴道、舌下、尿道(例如,尿道栓剂)、皮下、肌肉内、静脉内、直肠、舌下、粘膜、眼睛、脊髓、鞘内、关节内、动脉内、蛛网膜下、支气管或淋巴施药。局部制剂可为凝胶、软膏、乳霜、气雾剂等形式;鼻内制剂可以喷雾或滴剂的形式传递;经皮制剂可经由经皮贴剂或离子电渗疗法施用;或吸入制剂可使用雾化器或类似装置来传递。组合物也可采用药片、药丸、胶囊、半固体、粉末、缓释制剂、溶液、悬浮液、酏剂、气雾剂或任何其它适当组合物的形式。
为制备所述药物组合物,可根据传统的药物混配技术将一种或多种PDE4抑制剂和/或一种或多种腺苷酸环化酶活化剂和/或一种或多种MC4R激动剂与药学上可接受的载体、佐剂和/或赋形剂混合在一起。在本发明的组合物中可使用的药学上可接受的载体涵盖任何标准的药物制剂,诸如磷酸盐缓冲生理盐水溶液、水和乳液(诸如,水包油或油包水乳液)以及各种类型的湿润剂。组合物可另外含有固体药物赋形剂,诸如淀粉、纤维素、滑石粉、葡萄糖、乳糖、蔗糖、明胶、麦芽、大米、面粉、白垩、硅胶、硬脂酸镁、硬脂酸钠、单硬脂酸甘油酯、氯化钠、干燥脱脂奶粉等。液体和半固体赋形剂可选自甘油、丙二醇、水、乙醇和各种油,包括石油、动物、植物或合成来源的那些油,例如花生油、大豆油、矿物油、橄榄油、芝麻油等。尤其用于可注射溶液的液体载体包括水、生理盐水、葡萄糖水溶液和乙二醇。关于载体、稳定剂和佐剂的实例,参考Remington's Pharmaceutical Sciences,由E.W.Martin编辑(Mack Publishing Company,第18版,1990)。组合物还可包括稳定剂和防腐剂。
如本文所用,术语“治疗有效量”是在诸如人类或非人类患者的哺乳动物中,经体外或体内足以治疗指定病症或疾病,或者足以获得治疗病症或疾病的药理学反应的量。确定最有效施药方式和剂量的方法可根据用于治疗的组合物、治疗目的、治疗的靶细胞以及治疗的受试者而变化。治疗剂量通常可通过滴定法测量来优化安全性和功效。可由治疗医师选择的剂量水平和方案进行单次或多次施药。本领域技术人员可易于确定施用药剂的合适剂型制剂和方法。例如,以约0.01mg/kg至约200mg/kg、约0.1mg/kg至约100mg/kg或约0.5mg/kg至约50mg/kg施用组合物。当本文所述的化合物与另一种药剂或疗法共同施用时,有效量可小于、等于或大于单独使用任一药剂时。
经皮制剂可通过将活性剂并入触变性或凝胶状载体中来制备,所述触变性或凝胶状载体诸如纤维素介质,例如甲基纤维素或羟乙基纤维素,得到的制剂随后包装在经皮装置中以适于与佩戴者皮肤真皮接触来固定。如果组合物为凝胶形式,可将组合物擦在患者的膜上,例如肩部或上臂和/或上部躯体的皮肤,优选为完整、清洁且干燥的皮肤,并且在上面保持足够长时间段以将PDE4抑制剂和/或腺苷酸环化酶活化剂传递至患者的血流。本发明的凝胶形式的组合物可包含在管、小袋或计量泵中。所述管或小袋可含有一单位剂量或一单位剂量以上的组合物。计量泵能够分配一计量剂量的组合物。
本发明还提供如上文所述的用于鼻内施药的组合物。因此,所述组合物还可包含渗透促进剂。Southall等人Developments in Nasal Drug Delivery,2000。PDE4抑制剂和/或腺苷酸环化酶活化剂可以诸如溶液、乳液、悬浮液、滴剂的液体形式或以诸如粉末、凝胶或软膏的固体形式经鼻内施用。本领域中熟知用于传递鼻内药物的装置。鼻腔药物传递可使用包括(但不限于)以下的装置来进行:鼻内吸入器、鼻内喷雾装置、喷雾器、鼻腔喷雾瓶、单位剂量容器、泵、点滴器、塑料挤瓶、雾化器、定量吸入器(MDI)、压力定量吸入器、吹入器以及双向装置。鼻腔传递装置可向鼻腔定量施用准确有效的剂量。鼻腔传递装置可用于单一单位传递或多单位传递。在一个特定实施例中,在本发明中可使用来自KurveTechnology(Bethell,Washington)的ViaNase电子喷雾器(http://www.kurvetech.com)。本发明的化合物也可通过管、导管、注射器、包尾(packtail)、纱布、鼻塞或通过粘膜下输注来传递。美国专利公布No.20090326275、20090291894、20090281522和20090317377。
PDE4抑制剂和/或腺苷酸环化酶活化剂可使用标准程序配制成气雾剂。PDE4抑制剂和/或腺苷酸环化酶活化剂可在有溶剂或无溶剂的情况下配制,以及在有载体或无载体的情况下配制。制剂可为溶液,或可为具有一种或多种表面活性剂的水性乳液。例如,气雾剂喷雾可由具有合适推进剂的加压容器产生,所述推进剂诸如二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷、烃类、压缩空气、氮气、二氧化碳或其它合适的气体。剂量单位可通过提供阀来传递定量的量来确定。泵喷雾分配器可分配定量剂量或具有特定粒度或液滴大小的剂量。如本文所用,术语“气雾剂”指的是精细固体粒子或液体溶液液滴在气体中的悬浮液。具体来说,气雾剂包括如可由诸如MDI、雾化器或弥雾机的任何合适装置产生的PDE4抑制剂和/或腺苷酸环化酶活化剂液滴的含气悬浮液。气雾剂还包括本发明的组合物悬浮在空气或其它载体气体中的干粉组合物。Gonda(1990)Critical Reviews in Therapeutic Drug Carrier Systems 6:273-313。Raeburn等人,(1992)Pharmacol.Toxicol.Methods 27:143-159。
PDE4抑制剂和/或腺苷酸环化酶活化剂可以诸如由鼻腔吹入器传递的微球体形式的粉末传递至鼻腔。PDE4抑制剂和/或腺苷酸环化酶活化剂可吸附至固体表面,例如载体。粉末或微球体可以干燥的空气可分配形式来施用。粉末或微球体可储存在吹入器的容器中。或者,可将粉末或微球体填充至胶囊(诸如,明胶胶囊)或其它适合经鼻施药的单一剂量单位中。
可通过将药物组合物例如以凝胶、软膏、鼻用乳液、洗液、乳霜、鼻塞、点滴器或生物粘附带的形式直接置于鼻腔中来将所述组合物传递至鼻腔。在某些实施方案中,可能有利的是延长药物组合物在鼻腔中的停留时间,例如用以增强吸附。因此,药物组合物可任选地与生物粘附聚合物、胶(例如,黄原胶)、壳聚糖(例如,高度纯化的阳离子多糖)、果胶(或在涂敷至鼻粘膜时如同凝胶或乳化剂一样增稠的任何碳水化合物)、微球体(例如,淀粉、白蛋白、葡聚糖、环糊精)、明胶、脂质体、卡波姆(carbamer)、聚乙烯醇、藻酸盐、阿拉伯树胶(acacia)、壳聚糖和/或纤维素(例如,甲基或丙基;羟基或羧基;羧甲基或羟丙基)一起来配制。
含有PDE4抑制剂和/或腺苷酸环化酶活化剂的组合物可通过经口吸入施用于呼吸道,即肺。
用于可吸入剂的典型传递系统包括雾化器吸入器、干粉吸入器(DPI)和定量吸入器(MDI)。
雾化器装置产生高速气流,致使液体形式的治疗剂喷射成雾状。治疗剂配制成诸如具有合适尺寸粒子的溶液或悬浮液的液体形式。在一种实施方案中,粒子是微粉化的。术语“微粉化”定义为具有约90%或90%以上直径小于约10μm的粒子。合适的雾化器装置例如由PARIGmbH(Starnberg,Germany)商业提供。其它雾化器装置包括Respimat(BoehringerIngelheim)和例如在美国专利No.7,568,480和6,123,068以及WO 97/12687中公开的那些雾化器装置。PDE4抑制剂和/或腺苷酸环化酶活化剂可配制成水溶液或液体悬浮液形式用于雾化器装置中。
DPI装置通常以可分散在患者吸气时的气流中的自由流动粉末的形式施用治疗剂。使用外部能源的DPI装置也可用在本发明中。为了实现自由流动粉末,治疗剂可与合适的赋形剂(例如,乳糖)一起配制。干粉制剂例如可通过将具有约1μm与100μm之间粒度的干乳糖与本发明化合物的微粉化粒子合并,并且进行干混合而制得。或者,本发明的化合物可不加赋形剂来配制。将制剂负载在干粉分配器中,或负载在吸入套筒或胶囊中以用于干粉传递装置。商业上提供的DPI装置的实例包括Diskhaler(GlaxoSmithKline,ResearchTriangle Park,N.C.)(例如参考,美国专利No.5,035,237);Diskus(GlaxoSmithKline)(例如参考,美国专利No.6,378,519;Turbuhaler(AstraZeneca,Wilmington,Del.)(例如参考,美国专利No.4,524,769);以及Rotahaler(GlaxoSmithKline)(例如参考,美国专利No.4,353,365)。合适DPI装置的其它实例在美国专利No.5,415,162、5,239,993和5,715,810以及其中的参考文献中描述。
MDI装置通常使用压缩推进气体来排放计量的治疗剂。用于MDI施药的制剂包括活性成分在液化推进剂中的溶液或悬浮液。推进剂的实例包括氢氟烷烃(HFA),诸如1,1,1,2-四氟乙烷(HFA 134a)和1,1,1,2,3,3,3-七氟正丙烷(HFA 227)和氯氟烃诸如CCl3F。用于MDI施药的HFA制剂的其它组分包括助溶剂,诸如乙醇、戊烷、水;以及表面活性剂,诸如脱水山梨糖醇三油酸酯、油酸、卵磷脂和甘油。(例如参考美国专利No.5,225,183、EP 0717987和WO 92/22286)。将制剂负载于气雾剂罐中,所述气雾剂罐构成MDI装置的一部分。美国专利No.6,006,745和6,143,227中提供专门为用于HFA推进剂所研发的MDI装置的实例。关于制备合适制剂的方法以及适合吸入计量的装置的实例,参考美国专利No.6,268,533、5,983,956、5,874,063和6,221,398以及WO 99/53901、WO 00/61108、WO 99/55319和WO00/30614。
PDE4抑制剂可囊封在脂质体或微胶囊中用于通过吸入来传递。脂质体是由脂质双层膜和水性内部组成的囊泡。脂质膜可由磷脂组成,所述磷脂的实例包括磷脂酰胆碱,诸如卵磷脂和溶血卵磷脂;酸性磷脂,诸如磷脂酰丝氨酸和磷脂酰甘油;以及鞘磷脂,诸如磷脂酰乙醇胺和神经鞘髓磷脂。或者,可加入胆固醇。微胶囊是涂有涂层材料的粒子。例如,涂层材料可由成膜聚合物、疏水性增塑剂、表面活性剂或/和润滑剂含氮聚合物的混合物组成。美国专利No.6,313,176和7,563,768。
PDE4抑制剂和/或腺苷酸环化酶活化剂可单独或与其它药物组合给与以用于短时间或长时间治疗以上疾病,例如1、2、3、4、5、6、7、8、9、10、20、30、40、50或60天或1、2、4、5、6、7、8、9、10、11或12个月或在患者终生连续给与。本发明的组合物可施用于哺乳动物,优选为人类患者。哺乳动物包括(但不限于)小鼠、大鼠、兔、类人猿、牛、绵羊、猪、犬、猫、农场动物、运动型动物、宠物、马和灵长类动物。
以下为非限制性实施例。
实施例1
在源自iPSC的下丘脑神经元和β-细胞中操纵PC1表达和活性
佛司可林的环化酶活化作用和/或通过磷酸二酯酶(茶碱、IBMX)的抑制作用抑制cAMP的分解代谢将增加PWS体外模型中的PC1水平,随之增加激素原加工。在PWS体内和体外模型中识别PCSK1的明显多组织缺陷使得可确定合理的治疗目标,可减轻PWS的主要神经内分泌症状(图1)。
PCSK1基因的启动子区域含有两个环磷酸腺苷(cAMP)-反应元件(Conkright等人2003;Udupi等人1998)。增加cAMP细胞水平的药剂增加PCSK1mRNA并且增加由PC1加工的激素原的分泌(图2)(Udupi 1998)。佛司可林和茶碱是两种获得FDA核准的药物,通常在儿科群体中具有安全治疗概况。佛司可林与接近其催化结构域的腺苷酸环化酶通过疏水性相互作用和氢键结结合(Tang和Hurley 1998,Tesmer等人1999)。佛司可林结合导致腺苷酸环化酶构象变为其活性形式,因此增加AC活性以及增加细胞cAMP水平(Onda等人2001)。茶碱和其它磷酸二酯酶4(PDE4)抑制剂(诸如MK0952)通过阻断细胞cAMP降解来增加其水平。
PDE4抑制剂的非限制性实例包括茶碱、MK0952以及表1A-B中的其它PDE抑制剂。腺苷酸环化酶(AC)活化剂的非限制性实例包括佛司可林和表2中的活化剂。
本发明方法中可用的药剂还包括可修饰G蛋白活性的药剂,诸如G蛋白活化剂或抑制剂以及G蛋白偶合的受体激动剂。
如RNA测序所示,在源自PWS微缺失症和大缺失iPSC的神经元中,NHLH2和PCSK1下调(图3A、3C)。图3A:与未受影响的对照物相比,源自PWS微缺失症和大缺失iPSC的神经元中的NHLH2下调。图3B:与未受影响的对照物相比,源自PWS微缺失症和大缺失iPSC的神经元中的NHLH2蛋白下调>90%。图3C-D:与未受影响的对照物相比,源自PWS微缺失症和大缺失iPSC的神经元中的PCSK1转录物和其蛋白产物PC1分别下调>55%和>80%。图3E-F:仅缺失Snord116父系拷贝(剩余PWS区域是完整的)的小鼠在分离胰岛中显示PC1和PC2蛋白>40%下调。图3G:胰岛素原依赖于PC1进行其适当加工。在葡萄糖注射后30分钟时,Snord116p-/m+小鼠体内的胰岛素原加工与WT同窝出生仔畜相比存在功能缺损。图3H:与禁食的年老且BMI匹配的对照物相比,患有PWS的个体血浆中的胰岛素原与胰岛素的比率增加60%,表明在胰岛素原加工成胰岛素中存在缺陷。作用小于在具有PC1突变的患者中所见的作用与PWS模型中PC1减少约50%相一致。图3I:胃饥饿素原也由PC1来加工;与WT同窝出生仔畜相比,在来自Snord116p-/m+小鼠的胃溶解物中的胃饥饿素原加工受损。包括来自PC1空白小鼠胃溶解物作为用于受损胃饥饿素原加工的阳性对照。图3J:与WT同窝出生仔畜相比,来自Snord116p -/m+小鼠的下丘脑溶解物中的ProGHRH加工也受损,p=0.06。proGHRH加工受损与PC1空白小鼠的低循环GH和侏儒症相关。Snord116p-/m+也显示出低GH和严重发育不全。图3K:初始数据表明用佛司可林(FSK)处理源自未受影响的对照物下丘脑iPSC的神经元可以剂量依赖性方式增加PCSK1的转录水平。POMC转录水平可不受影响。图3L:用佛司可林处理源自未受影响的对照物iPSC的β-细胞增加PCSK1转录水平。SNORD116和INS转录水平可受到最小程度的影响。图3M:在禁食的Snord116p-/m+下丘脑中,Pcsk1的转录水平下降41%;再投喂时,Pcsk1水平无差异。图3N:与WT同窝出生仔畜相比,Snord116p-/m+下丘脑中的Nhlh2转录水平在禁食时和再投喂后均下降。图3O-P:与WT相比,Snord116p-/m+下丘脑中的Agrp和Npy转录水平在再投喂时增加。追踪的独立实验通过QPCR(基因表达)和西方墨点法(蛋白质水平)证实这些变化(图3B、3D)。患有PWS的个体与年老且BMI匹配的对照物相比展现出禁食胰岛素水平下降。假定这可能是由于胰岛素原加工受损。本发明的数据说明,在只缺失Snord116的父系拷贝的PWS小鼠模型中,分离胰岛中的PC1和PC2蛋白质水平下降,并且与胰岛素原加工成胰岛素中的功能缺损有关(图3E-3G)。与禁食的年老且BMI匹配的对照物相比,来自人类PWS患者的血浆中的胰岛素原加工也受损(p=0.089)(图3H)。包括来自具有PC1图表的禁食患者的血浆作为用于受损胰岛素原加工的阳性对照。
PWS患者的胃饥饿素增多(hyperghrelinemia)是与胃饥饿素原加工为成熟胃饥饿素受损相关的一种独特的表型。实际上,本发明的结果说明与WT同窝出生仔畜相比,胃饥饿素原加工为成熟胃饥饿素在Snord116p-/m+小鼠的胃溶解物中受损(图3I)。包括来自PC1空白小鼠的胃溶解物作为用于受损胃饥饿素原加工的阳性对照。
如同PWS个体,具有PC1突变的患者具有降低的循环GH水平。PC1空白的小鼠具有与proGHRH加工为GHRH受损相关的严重发育不全和降低的循环GH。我们发现,同样发育不全并且具有低循环GH的Snord116p-/m+小鼠的下丘脑溶解物中也倾向于proGHRH加工为GHRH受损(图3J)。
如图2中概述,在PWS确定PC1减少和激素原加工受损表明一种统一的分子理论,这可以解释所述疾病的多种神经内分泌特征。因此,增加PC1活性并且因此增加激素原加工的药剂代表了对于PWS的主要神经内分泌特征的一种合理的靶向治疗。
已知佛司可林增加细胞Pcsk1水平并且可增加激素原加工。将佛司可林应用于源自非PWS iPSC的神经元和β-细胞,并且结果表明PCSK1转录水平与未经处理的细胞相比增加(图3K-L)。将在源自PWS的神经元和β-细胞中进行研究。
将在体外和体内模型系统中测试PCSK1转录水平、PC1蛋白水平和相关激素原加工水平的反应。我们将用分级水平的佛司可林、茶碱以及佛司可林+茶碱来处理未受影响的对照物和源自下丘脑iPSC的神经元,并测量PC1转录物和蛋白质、POMC转录物和蛋白质以及POMC的加工产物的蛋白质水平,所述加工产物包括:αMSH、β-脑内啡和ACTH。将在全细胞溶解物中定量这些肽,以及所述水平分泌到细胞培养基中。将用不同浓度的佛司可林和茶碱来处理细胞以确定PC1水平是否可以剂量依赖性的方式增加并识别增加PC1水平和POMC加工的最佳剂量范围。其它PDE4和腺苷酸环化酶抑制剂也将通过这些分析来测试(参考表1A-B和2)。
将进行分批RNA测序和/或单细胞RNA测序来识别最受药物治疗影响的其它转录物。预期这种方法将预测对体内治疗的脱靶效应。单细胞RNA测序将尤其提供关于在表达POMC的神经元中进行处理后PCSK1转录物增加的信息。其它腺苷酸环化酶活化剂和PDE4抑制剂(表1A-B,2)将根据如上文所述的相同研究方案,在源自iPSC的下丘脑神经元中进行测试。
我们将从未受影响的对照物和PWS(大和最小程度的缺失)到源自iPSC的β-细胞来区分iPSC。我们将用佛司可林、茶碱和佛司可林+茶碱处理源自iPSC的β-细胞并在转录和蛋白质水平上测量PC1的水平。我们还将测量INS转录水平以及来自全细胞溶解物的胰岛素原、胰岛素和c-肽的蛋白质水平以及由β-细胞分泌到培养基中的蛋白质的浓度。这些细胞可移植到裸小鼠体内以使其成熟;可体内测试这些细胞的胰岛素加工;如所述对切除的细胞进行测试。我们还将使用来自非糖尿病、非肥胖症个体的人类分离胰岛(可通过国家胰腺捐赠者登记处为我们所用)来测试佛司可林、茶碱和佛司可林+茶碱对完全成熟人类胰岛中的PC1水平的影响。
实施例2
Snord116p-/m+、Pc1-/-和Pc1+/-小鼠中的PC1代谢的验证性分子生理学
通过腺苷酸环化酶(AC)活化以及同时的PDE抑制来增加cAMP水平将增加PWS离体和体内模型中的PC1水平,并且可因此增加PWS的Snord116p-/m+小鼠模型中的激素原加工。由于存在Snord116父系缺失的小鼠(PWS的小鼠模型)与PC1转录物和蛋白质减少相关而在胰岛素原加工为胰岛素中存在受损,因此将从野生型(WT)和Snord116p-/m+小鼠分离胰岛,并分析这些细胞对佛司可林、茶碱和佛司可林+茶碱的反应。将对源自iPSC的β-细胞进行同样的操纵和测量。如果与WT同窝出生仔畜相比可在来自Snord116p-/m+小鼠的分离胰岛中救援胰岛素原加工,则将对在经佛司可林、茶碱和佛司可林+茶碱体内处理的Snord116p-/m+小鼠中的胰岛素原加工救援进行研究。
本发明的结果说明,与胰岛中的PC1和PC2含量减少相关,Snord116p-/m+小鼠的胰岛素原加工为胰岛素减少(图3E-G)。此外,与WT同窝出生仔畜相比,Snord116p-/m+小鼠胃中的胃饥饿素原加工也受损,以及Snord116p-/m+小鼠下丘脑中的proGHRH加工为GHRH(图3I-J)。此外,与年老且BMI匹配的对照物相比,在患有PWS的禁食个体中,胰岛素原与胰岛素的比率升高,表明胰岛素原加工为胰岛素时受损(图3H)。
将包括来自Pc1空白且杂合小鼠的分离胰岛作为受损胰岛素原加工以及对药物治疗的预测负性反应的对照物。将在禁食时以及在腹膜内葡萄糖注射后15、30、60和120分钟时测量葡萄糖、胰岛素原、胰岛素和c-肽的外周水平。在外周测量胰岛素原加工之前,对Snord116p-/m+和WT小鼠药物治疗的最佳持续时间将通过经验来确定。也将包括Pc1空白且杂合小鼠作为对体内实验中受损胰岛素原加工的对照。测试的最初时间将为3天、1周以及1个月。还将测试几种药物传递方法。
将对于人类和小鼠研发可区分胃饥饿素原与成熟胃饥饿素,并且因此可用来测量循环中的胃饥饿素原加工的分析。将对上文所述对Snord116p-/m+、PC1空白、PC1杂合和WT动物进行体内药物治疗后的胃饥饿素原加工进行测量。
将分析经佛司可林、茶碱和佛司可林+茶碱处理的Snord116p-/m+、WT以及Pc1空白和Pc1杂合小鼠的下丘脑并测量PC1、POMC、αMSH、β-脑内啡和ACTH的蛋白质水平来评估体内治疗是否可影响PC1和POMC加工的水平。
由于Snord116p-/m+动物为侏儒且不发生肥胖症,因此将评估POMC加工的主要模型为源自iPSC的人类神经元,其中观察到对NHLH2和PC1更极端的下调。然而,也在来自年幼WTPOMC-GFP小鼠的原代神经元中分析PC1和POMC对这些药理剂的反应。可特别地使用其中POMC神经元表达GFP的小鼠来分离POMC表达神经元。我们将敲低Pcsk1作为用于受损POMC加工的对照物。我们也可尝试使用siRNA-或2-O-甲基-修饰反义寡基方法体外敲低Snord116的特异性同种型;siRNA为通常用于敲低细胞质RNA的小的双链干扰RNA,而2-O-甲基-修饰反义寡核苷酸用来敲低通常可见于核仁中的snoRNA(Liang等人2011)。然后我们将测量PC1水平和POMC加工水平,并研究药物治疗在相对于WT而言已敲低Snord116的原代小鼠神经元中是否可增加PC1的水平以及增加POMC加工。
另外,将获得或产生具有SNORD116的有条件亚效等位基因的小鼠。具有所述等位基因的成年动物在特定下丘脑核(例如,弓状核)中的Snord116将通过引入合适的cre表达构筑体,包括由特异性启动子驱动的那些构筑体(例如,对于POMC而言)而急剧减少。这种方法将避免Snord116次形态对小鼠中的体细胞发育影响(矮化)。
环化酶活化剂和/或磷酸二酯酶抑制剂的作用=50%或50%以上在测试的至少一种模型中的相关激素原加工中增加:源自PWS iPSC的神经元、源自PWS iPSC的β-细胞、Snord116p-/m+分离胰岛、Snord116p-/m+循环激素原或Snord116-敲低原代神经元。这些表型将伴随有受影响细胞中的相关转录物和/或蛋白质增加。
环化酶活化
将佛司可林应用于各种细胞模型且结果说明其稳健地并且可靠地增加PCSK1转录水平、PC1蛋白质水平以及功能性地增加激素原加工。在暴露于10μM佛司可林的源自iPSC的神经元和原代小鼠神经元中,PCSK1/Pcsk1转录水平增加2-3倍之间(图5A、C、D)。
在暴露于10μM佛司可林的源自iPSC的下丘脑ARC神经元中,环状AMP浓度增加约8.5倍,证明以下推理,即应用佛司可林通过提高细胞cAMP水平增加PCSK1转录水平,这又使PCSK1的cAMP-反应元件启动子活化。图5A是显示从野生型小鼠的妊娠日19.5(E19.5)胚胎中分离并培养72小时的原代前脑神经元的图表。接着将细胞暴露于10μM佛司可林或它的媒介物二甲亚砜(DMSO)持续20小时。在暴露于佛司可林的原代神经元中,Pcsk1转录物增加约2.5倍。图5B是显示将在分化37天(D37)的未受影响对照下丘脑类弓状(ARC)神经元(HesNkx2-1hESC系)用10μM佛司可林或媒介物处理三十分钟的图表。在暴露于佛司可林的细胞中,环磷酸腺苷(cAMP)水平增加约8.5倍。图5C是显示将在分化30天的源自未受影响对照下丘脑iPSC的神经元(1023A系)暴露于分级浓度的佛司可林引发PCSK1转录水平的剂量依赖性反应的图表。图5D是显示将源自iPSC的神经元(1043D3系)以多个时间间隔暴露于10μM佛司可林发现在仅暴露1小时后,PCSK1并未显著上调,而在暴露4和18小时时显著上调的图表。暴露四小时导致测试时间点的上调最大增加约2.5倍。图5E-F是显示在分化30天时用分级浓度的佛司可林处理源自未受影响的对照(1023A)iPSC的下丘脑ARC神经元确定POMC加工为β-脑内啡(βEP)和α-促黑素细胞激素(αMSH)两者均剂量依赖性增加的图表。图5G-H是显示用多种浓度的佛司可林处理从成年(8-12周大)WT小鼠分离的胰岛在25和50μM佛司可林浓度下分别显示PC1蛋白质水平上调,而PC2蛋白质水平未上调的图表。
用佛司可林处理不仅增加转录水平,而且具有增加POMC加工为β-脑内啡和αMSH的功能性后果(图5E-F)。此外,对由野生型小鼠分离的胰岛应用佛司可林导致PC1蛋白质水平增加约3倍(图5G)。PC2蛋白质水平未受影响(图5H)。总而言之,这些结果表明,在以下三种独立的模型系统中,PC1水平因佛司可林而增加:源自iPSC的神经元、原代神经元和分离胰岛。此外,佛司可林诱发PC1升高是功能性后果,导致激素原加工的水平增加。
磷酸二酯酶抑制
也已在源自iPSC的神经元中测试PDE抑制剂,并且发现磷酸二酯酶的抑制作用也可增加PCSK1的转录。然而,PDE抑制作用对PCSK1转录水平的影响大小小于由佛司可林的AC激动作用引起的影响。茶碱(10mM)和罗氟司特(1mM)两者都以单独药剂形式增加PCSK1转录,而MK0952至今仅发现与佛司可林体外组合来增加PCSK1转录(图6A-C、F)。以佛司可林和罗氟司特组合处理表明,这些药剂可以加合、可能协同的方式诱发而共同作用,并且以比单独给与任一药剂时更低的浓度(1μM佛司可林、100nM罗氟司特)增加PCSK1转录(图6D)。而且,由于佛司可林与罗氟司特组合处理而增加PCSK1转录也增加了POMC激素原加工为ACTH(图6E)。具体来说,用分级浓度的佛司可林在分离的小鼠胰岛中测试表明在25μM和50μM的浓度下,PC1蛋白上调3倍。对应于应用佛司可林,未观察到PC2蛋白质水平的变化。我们还发现,对由E19.5小鼠分离的原代小鼠神经元应用10μM佛司可林使Pcsk1转录水平增加约2倍。
MK0952
最局限于PWS患者的表型为最可能受发生在中枢神经系统,尤其是下丘脑中的过程所介导的摄食过量。因此,旨在改善摄食过量的药剂必须能够渗透血脑屏障。MK0952是具有有限全血活性(IC50=555nM)的本质上有效的(IC50=0.6nM)脑渗透性PDE4抑制剂(M.Gallant等人2010)。如本文所述,MK0952目前是领先的PDE抑制候选物。
在野生型小鼠中进行MK0952的初步体内测试。以10mg/kg体重单次施用MK0952导致下丘脑Pcsk1转录水平增加25%(图7A)。以25mg/kg施用佛司可林未导致下丘脑Pcsk1转录水平增加。共同施用10mg/kg MK0952和25mg/kg佛司可林再次诱发下丘脑Pcsk1水平增加约25%,表明此增加主要是由于MK0952的作用(图7B)。我们还将分析循环cAMP水平、皮层proBDNF/BDNF、小脑Pcsk1、胃部Pcsk1和胃部胃饥饿素原/胃饥饿素、循环胰岛素原和胰岛素浓度(及它们的比率)以及最后也分析来自这些动物的肺部Pcsk1转录和cAMP水平。
完成向禁食约4小时的野生型小鼠经口灌胃施用MK0952、同时通过腹膜内一次性施用佛司可林的首次体内研究。在以单独药剂形式施用10mg/kg MK0952或同时施用10mg/kg MK0952和25mg/kg佛司可林后,Pcsk1的下丘脑转录水平上调约25%。然而,仅施用25mg/kg佛司可林并未导致下丘脑Pcsk1上调,表明此剂量的佛司可林无法以足够影响Pcsk1转录的量到达下丘脑。这也表明在同时施用25mg/kg佛司可林和10mg/kg MK0952后,下丘脑Pcsk1的增加主要是由于MK0952在下丘脑中的作用。这种差异可能反映出MK0952的更大CNS渗透性,而非环化酶活化剂与PWS治疗的一般相关性。在施用MK0952或佛司可林后,未检测到循环胰岛素原:胰岛素的比率变化。由于胰岛素原加工为胰岛素在WT动物中已相当有效,因此事后分析不可能在禁食时进一步增加。然而,这些‘基线’数据对于在WT和Snord116p-/m+小鼠中3mg/kg葡萄糖的腹膜内葡萄糖耐性测试条件下评估胰岛素原加工为胰岛素仍具有价值。另外,收集样本以供测量循环cAMP水平、皮层proBDNF/BDNF、小脑Pcsk1、胃部Pcsk1和胃部胃饥饿素原/胃饥饿素以及最终测量肺部Pcsk1转录和cAMP水平。
实施例3
化合物在普拉德-威利综合症(PWS)患者中的临床研究
对PWS个体建议的临床研究的初步设计是基于假设PWS个体神经元中的转化酶原1(PC1)的表达减少(Burnett等人2017)。实验中体外和体内暴露于腺苷酸环化酶激动剂和PDE4抑制剂导致源自人类干细胞的神经元和啮齿前脑神经元以及人类成纤维细胞中的PC1表达和活性上调。预期施用这些药物将增加所牵涉的激素原转化为活性激素。
临床研究将解决并如下说明药物对于增强PC1活性的功效:
1.说明候选治疗剂PWS的行为和内分泌表型的影响。
2.监控所述药剂的临床安全概况。
研究设计:
临床研究将使用交叉研究设计(Cleophas等人2006,Wellek and Blettner 2012以及Louis等人1984)。此设计为评估解释小群受试者之间的可变性的治疗作用提供支持(图8A)。两个治疗臂之间的清除期将减轻延滞效应;研究持续时间短将使“时间效应”(随着时间推移对于疾病过程变化的影响)最小化。
纳入标准*:
1.PWS的基因诊断证明
2.年龄>18岁
*可允许重组生长激素治疗。
排除标准:
1.严重精神障碍
2.不配合服药
3.系统性疾病,例如严重胃肠道疾病,如发炎性肠病,心脏疾病,尤其为节律紊乱,诊断为糖尿病、肝病或肾病或肾衰竭。
4.贫血症,定义为血红蛋白<10gm/dL
5.依赖于可能与标靶药物相互作用的药物的患者,例如PDE4抑制剂与抗癫痫发作药物、西咪替丁(cimetidine)、奥美拉唑(omeprazole)、抗生素等相互作用。许多这些药物改变肝酶活性并且可干扰PDE4抑制剂的代谢。排除药物的完整清单将基于确认治疗剂的药代动力学和药效学性质。
招募:将通过与关心PWS患儿的PWS基金会(FPWR和PWSA)、患者支援团以及临床医师的合作关系来促使对受试者的招募。电话筛查将确定将被邀进行筛查访问的潜在合格受试者。
研究将持续4-6周并由以下访问组成:
1.筛查访问:在此访问中,将连同筛查实验室测量一起进行对医疗记录、药物治疗和身体检查的全面评估(来自图8B,与除药物水平以外的安全性概况相同)。将为受试者提供一周安慰剂用于磨合期来评估依从性。这将是一个短期的门诊访问(约3小时)。所有其它研究访问将为6-8小时长的短期入院停留。
2.基线访问(图8A的t1和t3):成功完成磨合期的受试者将被邀参与研究。将合格受试者随机分为AP组或PA组(图8A)。将建议受试者禁食>8小时以进行访问。身体概况分析将包括身高、体重、体脂测量、生命体征、静息能量消耗以及全面的身体检查。将进行全面的垂体概况分析,包括ACTH、皮质醇、FSH/LH、雌激素/睾丸素、TSH/游离T4、GH、IGF-1、IGFBP3。受试者将经历标准餐的混合餐耐量试验(MMTT),并在第0、30、60、90、120和180分钟由留置的IV导管获得血液测量值(图8B)。
原代监护人将完成与摄食过量相关的问卷调查(Dykens或修改的Dykens)并将使用催产素研究问卷调查(25-28)进行行为评估。除此之外,他们将独立的3天完成食物频率问卷调查,包括至少一个周末。此访问预期持续6-8小时。1周的研究药物将根据照护者说明来分配。
3.追踪访问(图1的t2和t4):在药物治疗研究开始后一周内,受试者将回到追踪访问。上文提到的测量将在此次访问中重复,并将获得药物计数以及用于评估毒性的结构式调查问卷。这些访问每个将持续6-8小时。在研究的第二阶段之前,将允许1-2周的清除期。
结果测量指标:
1.对应于标准餐的激素水平:基于PC1对激素原转化(诸如胰岛素原转化为胰岛素等)的影响,预期施用所述药物将导致激素原:激素的比率(例如,胰岛素原:胰岛素)增加(Burnett等人2017)。这将由对标准MMTT的激素反应来测试。通过施用流体餐(6cc/kg的强化量(Boost)或等效于360cc的最大值),接着定期测量胰岛素、胰岛素原、POMC激素原、ACTH、AgRP、胰高血糖素原、胰高血糖素、GLP1、催产素(和前肽)、胃饥饿素、胃饥饿素原、游离脂肪酸和葡萄糖来进行MMTT。MMTT已在PWS受试者的临床研究中得以证实(P.GumusBalikcioglu等人2015)。
相对于在施药之前获得的值,预期将存在胰岛素释放的绝对增加、胰岛素原释放的减少以及胰岛素/胰岛素原比率的增加。全部在25%范围内。还预期葡萄糖浓度将减少15-20,并且ffa也将减少。在MMT之前获得的血浆中,预期POMC将增加且AgRP将减少约25%。催产素也应增加15-20%。还预期胃饥饿素原/胃饥饿素比率将减少。也可检查/研究这些受试者体内的脊髓液,但并未评估与膳食的关系。可分析以下组分:pomc激素原、β脑内啡、αmsh、AgRP和催产素,预期所述药物与未经治疗的受试者相比将减少pomc激素原并增加β脑内啡、αmsh和催产素,以及减少AgRP。
2.药物代谢概况:代谢概况分析提供另一种机会来理解药物对代谢表型的作用。将在药物治疗之前和之后对研究受试者进行代谢概况分析来识别用于以下的生物标记:a)对所关注路径(即,胰岛素代谢路径及其它路径)的治疗反应,b)通过识别在不同个体中选择性上调或下调的路径来识别治疗的个体差异,以及c)使用已确定的更大分子概况分析的标准研究并不显而易见的基于路径的分析来识别副作用或毒性的概况(R.Kaddurah-Daouk,R.Weinshilboum,N.2015;R.D.Beger等人2016)。
3.摄食过量相关行为的改变:Dykens(和修改的Dykens)调查问卷评估行为、严重性和饥饿驱动力。除了这些结果以外,催产素行为调查问卷将评估与进食有关的社交行为和情绪化行为。这些结果将由食物频率调查问卷分析进行补充。预期治疗还将改善行为和/或情绪状态。
样本量:将招募6个受试者的初始模拟样本量进行此研究。此样本量检测所关注结果的动力将取决于由动物模型中的体内激素或药物代谢概况分析所确定的效应量。如图8C中所反映,需要约1.47的效应量来检测6个受试者群体中的显著变化。以通过安慰剂观察的结果与活性药物相比的差异除以变化的标准偏差来计算效应量。由于每个受试者都充当其自身的对照物,因此交叉研究设计限制了可变性且对于类似的平行臂研究设计而言允许在3/4的受试者中达到效力。
其它研究信息:
1.基于在PWS患儿中的先行研究以及需要达成高效应量,为所述研究选择标准的混合餐。
2.研究将在欧文临床和转化研究所(Irving Institute for Clinical andTranslational Research)的门诊设施中进行。
3.将针对适当的PDE抑制剂和/或环化酶活化剂来准备用于此研究的IRB实验方案。
4.代谢概况分析–如果在此初步研究中获得–将在糖尿病与内分泌学研究中心的激素和代谢物核心进行。
实施例4
治疗普拉德-威利综合症的方法–内源性和外源性MC4R激动作用的组合疗法
将使用借助于通过提高细胞cAMP产量水平和/或阻断其降解增加PC1产量来增加所加工激素的内源性水平的药剂来治疗患有PWS的个体。
在弓状核中,POMC由转化酶原1(PC1)加工成αMSH(S.L.Wardlaw 2011)。αMSH是黑皮质素4受体(MC4R)的一种内源性配体。在POMC、PCSK1(PCSK1的基因产物为PC1)或MC4R中具有失活性突变的人类和小鼠食欲过盛而且肥胖(C.Vaisse等人1998)。MC4R突变是人类肥胖症的最常见单基因原因(R.J.Loos等人2008)。AgRP也在弓状核中产生,并且是MC4R的一种逆向激动剂。ProAgRP由PC1加工成AgRP(S.L.Wardlaw 2011)。
可能的是,PC1产量增加可使αMSH和AgRP的产量增加,这对MC4R具有相反的作用(图4)。使用小分子或肽基MC4R激动剂可有助于确保使MC4R激动的胞外药剂池超过拮抗MC4R的胞外药剂池(图4,表3)。这预期将MC4R处的信号传递推向使食欲减退的反应(图4)。结合AgRP并且阻断其对MC4R的作用的药剂在此情形下也可为一种适用的策略(表3)(E.C.Lee和P.A Carpino 2016)。表3中未提及的具有类似作用的化合物也可适用。此策略不仅对于治疗PWS有效,而且对于其它形式的单基因/综合肥胖症以及常见肥胖症也有效。
表3:可与FSK和PDE抑制剂共同施药的实例化合物
概要/总结
尽管编码PC1的基因PCSK1在PWS的细胞基和动物模型中下调,但基因本身是完整的且因此可进行药理学操纵。本发明的数据提供进行中的临床前研究的结果以在药理学上操纵PCSK1/PC1的细胞水平。体外实验表明,应用佛司可林(一种腺苷环化酶激动剂)稳健地且可靠地上调源自人类干细胞的神经元、小鼠原代神经元中的PCSK1表达,并且增加小鼠分离胰岛中的PC1蛋白质水平。此外,佛司可林治疗还增加源自干细胞的下丘脑神经元中的POMC激素原加工。向干细胞神经元应用PDE抑制剂茶碱和罗氟司特以单一药剂的形式以及与佛司可林组合来增加PCSK1的转录水平。罗氟司特与佛司可林组合治疗也加合性地增加干细胞下丘脑神经元中的POMC激素原加工(加工成食欲减退肽)。用佛司可林和MK0952(一类4PDE抑制剂)两者处理源自干细胞的神经元使PCSK1mRNA增加。最后,在野生型小鼠中,10mg/kg MK0952的单次口服剂量使下丘脑Pcsk1转录水平增加25%。接下来将测试在野生型和对父系Snord116而言为低效等位基因的小鼠体内更长时间应用MK0952。另外,我们将与Andrea Haqq及他们的同事合作来测量患有PWS的个体以及匹配对照物中的循环激素原和加工激素的水平(例如,胰岛素原、POMC、催产素原、proBDNF)。
还提供一种在患有PWS的个体中对MK0952和其它候选化合物进行初步临床研究的实验方案。此临床研究的主要目的将在于监控这些药剂在PWS受试者中的临床安全概况以及测量行为和神经内分泌终点来评估初步功效。
参考文献:
Conkright,M.D.et al.Genome-Wide Analysis of CREB Target Short ArticIeGenes Reveals A Core Promoter Requirement for cAMP Responsiveness.MolecularCell 11,1101-1108(2003).
Udupi,V.,Townsend,C.M.&Greeley,G.H,Stimulation of ProhormoneConvertase-1mRNA Expression by Second Messenger SignalingSystems.BIOCHEMICALANI)BIOPHYSICAL RESEARCHCOMMUNICATIONS 246,463-465(1998).
Tang,W.J.&Hurley,J.Catalytic Mechanism and Regulation of MammalianAdenylyl Cyclases,Molecular pharmacology 54,231-240(1998),
Tesmer,J.J.G.et al.Two-Metal-Ion Catalysis in AdenylylCyclase.Science 285,756-760(1999).
Onda,T.et al.Type-specific regulation of adenylyl cyclase.Selectiyepharmacological stimulation and inhibition of adenylyl cyclase isoforms.JBiol Chem276,47785-47793.doi;10.1074/jbc.M107233200(2001).
Liang,X.H.,Vickers,T.A.,Guo,S.&Crooke,S.T.Efficient and specificknockdown of small non-coding RNAs in mammalian cells and in mice.NucleicAcids Res39,e13,doi;10.1093/nar/gkq1121(2011).
Sunahara,R.K.&Taussig,R.Isoforms of Mammalian Adenylyl Cyclase:Multiplicities of SignaIing.Molecular Interventiongs 2,168-184(2002),
S.L,Wardlaw,Hypothalamic proopiomelanocortin processing and theregulation of energy balance.European journal of pharmacology660,213-219(2011).
C.Vaisse,K.Clement,B.Guy-Grand,P.Froguel,A frameshift mutation inhuman MC4R is associated with a dominant form of obesity.Nalure Geneiics 20,113-114(1998).
R.J.Loos et al.,Common variants near MC4R are associated with fatmass,weight and risk of obesity.Nat Genet 40,768-775(2008).
E.C.Lee,P.A.Carpino,Melanocortin-4receptor modulators for thetreatment of obesity:a patent analysis(2008-2014),pharmaceutical PatentAnalyst4,95-107(2016).
Fimia GM,Sassone-Corsi P,2001.Cyclic AMP signaling.J Cell Sci 114:1971-1972.
L.C.Burnett et al、,Deficiency in prohormone convertase PCl impairsprohormone processing in prader-Willi syndrome.J Clin Invest 127,293-305(2017).
F.D.P.Deborah J.Good,Kathleen A.Mahon,Albert F.Parlow,HeinerWestpbal,Ilan R.Kirsch,Hypogonadism and obesity in mice with a targeteddeletion of the Nhlh2gene.Naiure Genetics 15,397-1401(1997).
D.L.Fox,Dissertation,University of Massachusets Amherst,Ann Arbor,MI(2007).
P.Stijnen,B.Ramos-Molina,S,ORahily,J.W.M.Creemers,PCSKl mutations andhuman endocrinopathies:from obesity to gastrointestinal disorders.EndocrineReviews 17,(2016).
M.D.Conkright et al.,Genome-Wide Analysis of CREB Target ShortArnicle Genes Reveals A Core Promoter Requirement for cAMP Responsiveness,Molecular Cell11,1101-1108(2003).
V.Udupi,C.M.Townsend,G.H.Greeley,Stimulation of ProhormoneConvertase-1 mRNA Expression by Second Messenger Signaling Systems,Biochemical and Biophysical Research Communications 246,463-465(1998).
W.-J.Tang,J.Hurley,Catalytic Mechanism and Regulation of MammalianAdenylyl Cyclases.Molecular Pharmacology54,231-240(1998).
J.J.G.Tesmer et al.,Two-Metal-Ion Catalysis in AdenylylCyclase.Science 285,756-760(1999).
T.Onda el al.,Type-specific regulation of adenylyl cyclase.Selectivepharmacological stimulation and inhibition of adenylyl cyclase isoforms,JBiol Chem276,47785-47793(2001).
M.Gallant el al.,Discovery of MK-0952,a selective PDE4 inhibitor forthe treatment of long-term memory loss and mild cognitiveimpairment.Bioorgamic &Medicinal Chemistry Letters20,6387-6393(2010).
QZhang,G.J.Bouma,K.McClellan,S.Tobet,Hypothalamic expression ofsnoRNA Snord 116is consistent with a link to the hyperphagia and obesitysymptoms of Prader-Willi syndrome.Inl J Dev Neurosci30,479-485(2012).
Y.Qi et al.,Snord116is critical in the regulation of food intake andbody weight.Sci Rep6,18614(2016).
L.Wang el al.,Differentiation of hypothalamic-like neurons from humanpluripotent stem cells.J Clin Invest125,796-808(2015).
V.Grinevich,M.G.Desarmenien,B.Chini,M.Tauber,F,Muscatelli,Ontogenesisof oxytocin pathways in the mammaalian brain:late mataration and psychosocialdisorders.Front Neuroanat 8.164(2014).
M.Tauber et al.,The Use of Oxytocin to Improve Feeding and SocialSkills in Infants With Prader-Willi Syndrome.Pedialrics 139,(2017).
R.J.Kuppens,S.H.Donze,A.C.Hokken-Koelega,Promising effects ofoxytocin on social and food-related behaviour in young children with Prader-WiHi syndrome:a randomized,double-blind,controlled crossover trial.ClinEndocrinol(Oxf)85,979-987(2016).
G.Alvarez-Bolado,F.A.Paul,S.Blaess,Sonic hedgehog lineage in themouse hypothalamus:from progenitor domains to hypothalamic regions.Neuraldevelopmenl7,4(2012).
S.Blaess,N.Szabo,R.Haddad-Tovolli,X.Zhou.G.Alvarez-Bolado,Sonichedgehog signaling in the development of the mouse hypothalamus.FrontNeuroanal 8,156(2014).
E.O.Mazzoni et al.,Synergistic binding of transcription factors tocell-specific enhancers programs motor neuron identity.Nal Nearosci 16,1219-1227(2013).
P.Arlotta,O.Hobert,Homeotic Transformations of Neuronal CellIdentities.Trends Nearosci38,751-762(2015).
E.S.Deneris,O.Hobert,Maintenance of postmitotic neuronal cellidentity.Nat Neurosci 17,899-907(2014).
T.J.Cleophas,A.H.Zwinderman.T.F.Cleophas,in Statistics Applied toClinical Triais.(Springer Netherlands,Dordrecht,2006),pp.219-228.
S.Wellek,M.Blettner,On the Proper Use of the Crossover Design inClinical Trials.Part 18of a Series on Evaluation of Scientific Publications.DeutschesArztehlall International 109,276-281(2012).
T.A.Louis,P.W.Lavori,J.C.I.Bailar,M.Polansky Crossover and Self-Controlled Designs in Clinical Research.New England Journal of Medicine310,24-31(1984)
E.M.Dykens,M.A.Maxwell,E.Pantino,R.Kossler,E.Roof,Assessment ofHyperphagia in Prader-Willi Syndrome.Obesity 15,1816-1826(2007).
S.R.Crawford et al.,The International Development of The ModifiedHyperphagia Qoestionnaire.Value in Health 18,A761.
J.M.MD,D,D.MD,A.Chen,T.E.Hughes,D.D.Kim,paper presented at theObesity Week2014,Boston,MA,2014.
R.J.Kuppens,S.H.Donze,A.C.S.Hokken-Koelega,Promising effects ofoxytocin on social and food-related behaviour in young children with Prader-Willi syndrome:a randomized,double-blind,controlled crossover trial.ClinicalEndocrinology 85,979-987(2016).
p.Gumus Balikcioglu el al,Macronutrient Regulation of Ghrelin andPeptide YY in Pediatric Obesity and Prader-Willi Symdrome.The Journal ofClinical Endocrinology &Metabolism 100,3822-3831(2015).
R.Kaddurah-Daouk,R.Weinshilboum,N.on behalf of thePharmacometabolomics Research,Metabolomic Signatures for Drug ResponsePhenotypes:Pharmacometabolomics Enables Precision Medicine ClinicalPharmacology&Therapeutics98,71-75(2015).
R.D.Beger et al.,Metabolomics enables precision medicine:“A WhitePaper,Community Perspective”.Metabolomics 12,149(2016).
本发明的范畴不局限于上文已特定显示和描述的内容。在本发明的具体实施方式中引用和论述多个参考文献,包括专利和各种公布。仅提供所述参考文献的引用和论述来阐明本发明的具体实施方式,而并非承认任何参考文献为本文所述发明的现有技术。本说明书中引用和论述的所有参考文献均以全文引用的方式并入本文中。在不偏离本发明的精神和范畴下,本领域一般技术人员将了解对本文所述内容的改变、修改和其它实施方式。尽管已显示和描述本发明的某些实施方案,但本领域技术人员显而易见,在不偏离本发明的精神和范畴下,可进行改变和修改。以上描述和附图中列举的情形仅以说明方式提供且并不作为限制。本发明的实际范畴欲在以下权利要求书中定义。
Claims (53)
1.一种用于调节激素原转化酶的方法,所述方法包括施用治疗有效量的磷酸二酯酶4抑制剂(PDE4抑制剂或PDE4i)。
2.一种用于上调激素原转化酶的表达的方法,所述方法包括施用治疗有效量的PDE4抑制剂。
3.如权利要求2所述的方法,其中所述PDE4抑制剂经体外施用于细胞。
4.如权利要求1所述的方法,其中所述PDE4抑制剂施用于普拉德-威利综合症患者。
5.如权利要求4所述的方法,其中所述PDE4抑制剂经口服施用。
6.如权利要求4所述的方法,其中所述PDE4抑制剂通过静脉内或皮下施用。
7.如权利要求4所述的方法,其中所述PDE4抑制剂通过鞘内施用。
8.如权利要求4所述的方法,其中所述PDE4抑制剂通过局部施用。
9.如权利要求4所述的方法,其中所述PDE4抑制剂通过鼻内施用。
10.如权利要求4所述的方法,其中所述PDE4抑制剂在肺中施用。
11.如权利要求1所述的方法,其中所述PDE4抑制剂是选自由以下组成的组:茶碱、罗弗司特、阿普司特、异丁司特、GSK356278、MK0952、IBMX及它们的组合。
12.一种用于调节激素原转化酶的方法,所述方法包括施用治疗有效量的腺苷酸环化酶活化剂。
13.如权利要求13所述的方法,其中所述腺苷酸环化酶活化剂经体外施用于细胞。
14.如权利要求13所述的方法,其中所述腺苷酸环化酶活化剂施用于普拉德-威利综合症患者。
15.如权利要求13所述的方法,其中所述腺苷酸环化酶活化剂经口、静脉内、皮下、鞘内或鼻内施用。
16.如权利要求13所述的方法,其中所述腺苷酸环化酶活化剂通过局部施用。
17.如权利要求13所述的方法,其中所述腺苷酸环化酶活化剂在肺中施用。
18.如权利要求13所述的方法,其中所述腺苷酸环化酶活化剂是选自由以下组成的组:佛司可林、FD1、FD2、FD3、FD4、FD5(NKH477)、FD6及它们的组合。
19.一种用于调节激素原转化酶的方法,所述方法包括施用治疗有效量的PDE4抑制剂和腺苷酸环化酶活化剂。
20.如权利要求20所述的方法,其中所述PDE4抑制剂和所述腺苷酸环化酶活化剂施用于普拉德-威利综合症患者。
21.如权利要求1所述的方法,其中所述PDE4抑制剂施用于肥胖症受试者。
22.如权利要求13所述的方法,其中所述腺苷酸环化酶活化剂施用于肥胖症受试者。
23.如权利要求20所述的方法,其中所述PDE4抑制剂和所述腺苷酸环化酶活化剂施用于肥胖症受试者。
24.一种用于上调激素原转化酶的表达的方法,所述方法包括施用治疗有效量的MC4R激动剂。
25.如权利要求25所述的方法,其中所述MC4R激动剂经体外施用于细胞。
26.如权利要求25所述的方法,其中所述MC4R激动剂施用于普拉德-威利综合症患者。
27.如权利要求25所述的方法,其中所述MC4R激动剂施用于肥胖症受试者。
28.如权利要求25所述的方法,其中所述MC4R激动剂经口服施用。
29.如权利要求25所述的方法,其中所述MC4R激动剂通过静脉内或皮下施用。
30.如权利要求25所述的方法,其中所述MC4R激动剂通过鞘内施用。
31.如权利要求25所述的方法,其中所述MC4R激动剂通过局部施用。
32.如权利要求25所述的方法,其中所述MC4R激动剂通过鼻内施用。
33.如权利要求25所述的方法,其中所述MC4R激动剂在肺中施用。
34.如权利要求25所述的方法,其中所述MC4R激动剂是选自由以下组成的组:RM-493(赛特糖苷)、TTP2515、2-氨基噻唑衍生物、MK-0493及它们的组合。
35.如权利要求1、2、13或20中任一项所述的方法,所述方法还包括施用治疗有效量的MC4R激动剂。
36.如权利要求36所述的方法,其中所述MC4R激动剂经体外施用于细胞。
37.如权利要求36所述的方法,其中所述MC4R激动剂施用于普拉德-威利综合症患者。
38.如权利要求36所述的方法,其中所述MC4R激动剂施用于肥胖症受试者。
39.如权利要求36所述的方法,其中所述MC4R激动剂是选自由以下组成的组:RM-493(赛特糖苷)、TTP2515、2-氨基噻唑衍生物、MK-0493及它们的组合。
40.如权利要求4、15、21、27或28中任一项所述的方法,其中所述施用导致所述患者的一种或多种以下改进:减少或改善摄食过量;增加Pcsk1水平;增加PC1水平和/或活性;减少循环胰岛素原与胰岛素的比率;减少循环胃饥饿素原与胃饥饿素的比率;减少循环POMC与ACTH的比率;改善甲状腺功能减退、减少催产素原与催产素的循环比率;减少bdnf原与bdnf的循环比率;以及增加激素原:激素的比率;其中所述症状、所述水平或所述比率是关于所述患者的疾病症状、水平或比率而言。
41.一种用于治疗普拉德-威利综合症(PWS)的方法,所述方法包括向有需要的受试者施用磷酸二酯酶4抑制剂(PDE4i),由此缓解、消除或预防PWS的一种或多种症状。
42.如权利要求42所述的方法,其中施用所述PDE4i使所述受试者的环磷酸腺苷(cAMP)浓度或活性上调。
43.如权利要求43所述的方法,其中PWS的特征在于Nhlh2的表达减少。
44.如权利要求44所述的方法,其中Nhlh2的表达减少导致Pcsk1的表达减少。
45.如权利要求43所述的方法,其中增加cAMP的浓度或活性使Pcsk1的表达上调。
46.如权利要求43所述的方法,其中所述PDE4i为选择性PDE4i。
47.如权利要求43所述的方法,其中所述PDE4i为非选择性PDE4i。
48.如权利要求47所述的方法,其中所述选择性PDE4i是选自AN2728、阿普司特、西洛司特、地西泮、异丁司特、木犀草素、松叶菊酮碱、吡拉米司特、罗氟司特、咯利普兰、E6005、GSK356278和MK0952。
49.如权利要求48所述的方法,其中所述非选择性PDE4i是选自甲基化黄嘌呤及它的衍生物、咖啡因、氨茶碱、3-异丁基-1-甲基黄嘌呤、副黄嘌呤、已酮可可碱、可可碱和茶碱。
50.如权利要求42所述的方法,其中所述一种或多种症状包括摄食过量、代谢率降低、肥胖症、性腺功能减退、生长激素产生减少、肌张力低下、睡眠障碍、肠胃失调、耐力减少、专注力降低、认知功能受损、行为障碍、焦虑、生长不足、不成熟激素转化为成熟活性形式减少以及糖尿病。
51.如权利要求42所述的方法,其中所述方法还包括施用一种或多种有效治疗或缓解PWS的一种或多种症状的其它治疗剂。
52.如权利要求51所述的方法,其中所述不成熟激素包括以下中的一种或多种:胰岛素、胃饥饿素、GHRH、α-MSH、催产素、食欲素、BDNF、血管加压素、NPY、AGRP以及促性腺激素。
53.如权利要求52所述的方法,其中所述一种或多种有效治疗或缓解PWS的其它治疗剂包括胰岛素、胰岛素受体激动剂、胃饥饿素、胃饥饿素受体激动剂、GHRH、GHRH受体激动剂、α-MSH、α-MSH受体激动剂、催产素、催产素受体激动剂、食欲素、食欲素受体激动剂、BDNF、BDNF受体激动剂、血管加压素、血管加压素受体激动剂、NPY、NPY受体激动剂、AGRP、AGRP受体激动剂、促性腺激素、促性腺激素受体激动剂或它们的组合。
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111264851A (zh) * | 2020-03-03 | 2020-06-12 | 河南省儿童医院郑州儿童医院 | Pws综合征靶向替代保健食品及其制备方法 |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IL263412B (en) * | 2016-06-03 | 2022-08-01 | Univ Columbia | Treatment methods for Freder Willi syndrome |
AU2018243749A1 (en) * | 2017-03-31 | 2019-11-21 | Epizyme, Inc. | Methods of using EHMT2 inhibitors |
CN118021814A (zh) | 2017-04-21 | 2024-05-14 | Epizyme股份有限公司 | 用ehmt2抑制剂进行的组合疗法 |
WO2019161179A1 (en) * | 2018-02-15 | 2019-08-22 | Ovid Therapeutics Inc. | Methods of treating developmental syndromes with pde10a inhibitors |
KR20210062638A (ko) * | 2018-09-20 | 2021-05-31 | 레보 테라퓨틱스 인코포레이티드 | 카르베토신의 안정한 비강내 제형 |
US20240238237A1 (en) * | 2021-05-04 | 2024-07-18 | Virginia Tech Intellectual Properties, Inc. | Conjugated linoleic acid supplementation for disease treatment |
Family Cites Families (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU3270301A (en) * | 1999-11-13 | 2001-05-30 | Icos Corporation | Combined pde3 and pde4 inhibitor therapy for the treatment of obesity |
US6365593B2 (en) * | 2000-04-12 | 2002-04-02 | Repligen Corporation | Methylxanthines in the diagnosis and treatment of autistic disorder |
US8853266B2 (en) | 2001-12-06 | 2014-10-07 | University Of Tennessee Research Foundation | Selective androgen receptor modulators for treating diabetes |
US20030181461A1 (en) * | 2002-01-25 | 2003-09-25 | Lautt Wilfred Wayne | Use of phosphodiesterase antagonists to treat insulin resistance |
WO2004096222A1 (en) * | 2003-04-30 | 2004-11-11 | Switch Biotech Ag | Use of 1-(5-isoquinolinesulfonyl)homopiperazine, its active metabolites, isomers and salts for treating and preventing hypopigmentary disorders |
TW200530246A (en) * | 2003-12-19 | 2005-09-16 | Bristol Myers Squibb Co | Azabicyclic heterocycles as cannabinoid receptor modulators |
WO2005086750A2 (en) | 2004-03-06 | 2005-09-22 | Irm Llc | Prohormone convertase 1 mutation associated with obesity |
US20060062859A1 (en) | 2004-08-05 | 2006-03-23 | Kenneth Blum | Composition and method to optimize and customize nutritional supplement formulations by measuring genetic and metabolomic contributing factors to disease diagnosis, stratification, prognosis, metabolism, and therapeutic outcomes |
CN101361754B (zh) | 2007-08-09 | 2013-04-17 | 李凌松 | 稀土元素盐或其药物组合物在制备治疗或预防糖尿病和肥胖症药物中的用途 |
WO2010062681A2 (en) * | 2008-10-30 | 2010-06-03 | University Of South Florida | Luteolin and diosmin/diosmetin as novel stat3 inhibitors for treating autism |
EP2322163A1 (en) * | 2009-11-03 | 2011-05-18 | Pharnext | New therapeutics approaches for treating alzheimer disease |
WO2011083718A1 (ja) * | 2010-01-05 | 2011-07-14 | 学校法人慶應義塾 | 肺再生促進剤 |
EP3081568B1 (en) | 2011-05-09 | 2019-11-13 | Eip Pharma, LLC | Compositions and methods for treating alzheimer's disease |
US20140364367A1 (en) * | 2013-06-08 | 2014-12-11 | Sedogen, Llc | Methods of treating prader willi syndrome and conditions associated with low basal metabolic rate or hyperphagia using a katp channel opener |
EP3096749B1 (en) * | 2014-01-24 | 2019-05-15 | Celgene Corporation | Methods for the treatment of obesity using apremilast |
CN113599386A (zh) * | 2014-11-14 | 2021-11-05 | 伊森舍丽斯有限公司 | 用于治疗患有普拉德-威利综合征或史密斯-马吉利综合征的受试者的方法 |
IL263412B (en) * | 2016-06-03 | 2022-08-01 | Univ Columbia | Treatment methods for Freder Willi syndrome |
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CN111264851A (zh) * | 2020-03-03 | 2020-06-12 | 河南省儿童医院郑州儿童医院 | Pws综合征靶向替代保健食品及其制备方法 |
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