CN102933711B - 通过抑制沉默调节蛋白(sirt)的天然反义转录物而治疗沉默调节蛋白(sirt)相关疾病 - Google Patents
通过抑制沉默调节蛋白(sirt)的天然反义转录物而治疗沉默调节蛋白(sirt)相关疾病 Download PDFInfo
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Abstract
本发明涉及调节沉默调节蛋白(SIRT)的表达和/或功能的反义寡核苷酸,尤其是通过靶向沉默调节蛋白(SIRT)的天然反义多核苷酸。本发明还涉及这些反义寡核苷酸的鉴定和它们在治疗沉默调节蛋白(SIRT)表达相关的疾病和病症中的用途。
Description
发明领域
本申请要求2010年5月03日提交的美国临时专利申请No.61/330,427、2010年11月2日提交的美国临时专利申请No.61/409,136、2010年11月10日提交的美国临时专利申请No.61/412,066和2010年11月22日提交的美国临时专利申请No.61/415,891的优先权。
本发明的实施方案包括调节沉默调节蛋白(SIRT)和相关分子的表达和/或功能的寡核苷酸。
背景
DNA-RNA和RNA-RNA杂交对于核酸功能的许多方面是重要的,包括DNA复制、转录和翻译。杂交对于检测特定核酸或改变其表达的多种技术也是关键的。反义核苷酸,例如通过与靶RNA杂交从而干扰RNA剪接、转录、翻译和复制来破坏基因表达。反义DNA具有额外的特性,即DNA-RNA杂交物作被核糖核酸酶H消化的底物,这是在大多数细胞类型中存在的活性。反义分子可被递送到细胞中,如寡脱氧核苷酸(ODN)的情形,或反义分子可从内源基因表达为RNA分子。FDA最近批准了一种反义药物VITRAVENETM(用于治疗巨细胞病毒视网膜炎),反映了反义药物具有治疗效用。
概述
在一个实施方案中,本发明提供通过利用靶向天然反义转录物任何区域的反义寡核苷酸而导致相应有义基因的上调来抑制天然反义转录物作用的方法。本文还预期,天然反义转录物的抑制可由siRNA、核酶和小分子实现,认为这些在本发明的范围中。
一个实施方案提供体内或体外调节患者细胞或组织中沉默调节蛋白(SIRT)多核苷酸的功能和/或表达的方法,包括将所述细胞或组织与长度为5至30个核苷酸的反义寡核苷酸接触,其中所述寡核苷酸与包括SEQ ID NO:9的核苷酸1至1028或SEQ ID NO:10的核苷酸1至429、或SEQ ID NO:11的核苷酸1至508或SEQ ID NO:12的核苷酸1至593、SEQ ID NO:13的1至373、SEQ ID NO:14的1至1713、SEQ ID NO:15的1至660、SEQ ID NO:16的1至589、SEQ ID NO:17的1至726、SEQ ID NO:18的1至320、SEQ ID NO:19的1至616、SEQ ID NO:20的1至492、SEQ ID NO:21的1至428、SEQ ID NO:22的1至4041或SEQ ID NO:23的1至705或SEQID NO:141的1至2714或SEQ ID NO:142的1至1757或SEQ ID NO:143的1至3647中的5至30个连续核苷酸的多核苷酸的反向互补序列具有至少50%序列同一性,从而体内或体外调节患者细胞或组织中沉默调节蛋白(SIRT)多核苷酸的功能和/或表达。
在另一个实施方案中,寡核苷酸靶向沉默调节蛋白(SIRT)多核苷酸的天然反义序列,例如,SEQ ID NO:9至23、141至143所列的核苷酸及其任何变体、等位基因、同系物、突变体、衍生物、片段及其互补序列。用于实施本发明的方法的反义寡核苷酸的实例如SEQIDNO:24至127所列。
另一实施方案提供体内或体外调节患者细胞或组织中沉默调节蛋白(SIRT)多核苷酸的功能和/或表达的方法,包括将所述细胞或组织与长度为5至30个核苷酸的反义寡核苷酸接触,其中所述寡核苷酸与沉默调节蛋白(SIRT)多核苷酸的反义的反向互补序列具有至少50%序列同一性;从而体内或体外调节患者细胞或组织中沉默调节蛋白(SIRT)多核苷酸的功能和/或表达。
另一实施方案提供体内或体外调节患者细胞或组织中沉默调节蛋白(SIRT)多核苷酸的功能和/或表达的方法,包括将所述细胞或组织与长度为5至30个核苷酸的反义寡核苷酸接触,其中所述寡核苷酸与沉默调节蛋白(SIRT)反义多核苷酸的反义寡核苷酸具有至少50%序列同一性;从而体内或体外调节患者细胞或组织中沉默调节蛋白(SIRT)多核苷酸的功能和/或表达。
在一个实施方案中,组合物包括一种或多种结合有义和/或反义沉默调节蛋白(SIRT)多核苷酸的反义寡核苷酸。
在另一个实施方案中,寡核苷酸包括一种或多种修饰或取代的核苷酸。
在另一个实施方案中,寡核苷酸包括一种或多种修饰的键。
在又一实施方案中,修饰的核苷酸包括包含硫代磷酸酯、膦酸甲酯、肽核酸、2’-O-甲基、氟-或碳、亚甲基或其它锁核酸(LNA)分子的修饰的碱基。优选地,修饰的核苷酸是锁核酸分子,包括α-L-LNA。
在另一个实施方案中,将寡核苷酸皮下、肌内、静脉内或腹膜内施用给患者。
在另一个实施方案中,寡核苷酸以药物组合物施用。治疗方案包括向患者施用反义化合物至少一次;然而,可修改该治疗以包括经一段时间的多个剂量。该治疗可与一种或多种其它类型的治疗联合。
在另一个实施方案中,将寡核苷酸封装在脂质体中或连接于载体分子(例如,胆固醇、TAT肽)。
其它方面在以下描述。
附图简述
图1和图2是实验的实时PCR结果,其中HepG2细胞用针对靶SIRT反义CV396200设计的寡核苷酸处理。该结果显示用针对sirtas(sirtas_5,P=0.01)设计的siRNA之一处理后48h,HepG2细胞中SIRT1 mRNA的水平显著增加。在相同的样品中,用sirtas_5处理后,sirtas RNA的水平显著下降,但是用sirtas_6和sirtas_7(它们也对SIRT1 mRNA水平没有影响)处理后,其水平并未变化(图2)。sirtas_5、sirtas_6和sirtas_7分别对应于SEQ IDNO:47、48和49。
图3显示跨SIRT反义的寡核苷酸通道。实时PCR结果显示用针对sirtas的反义寡核苷酸中的三个(CUR-0292、CUR-0307和CUR-0308)处理后48h,HepG2细胞中SIRT1 mRNA的水平显著增加。CUR-0292至CUR-0309分别对应于SEQ ID NO:24至41。
图4和5显示HepG2(图4)和Vero76(图5)细胞中的PS、LNA和2’OMe修饰的寡核苷酸的结果。实时PCR结果显示用针对SIRT1反义设计的PS、LNA、2’O Me和2’O Me混合物反义寡核苷酸处理后48h,HepG2细胞中SIRT1 mRNA的水平显著增加。用针对SIRT1反义的PS和LNA修饰的反义寡核苷酸处理后48h,Vero细胞中SIRT1 mRNA的水平也增加。标为CUR-0245、CUR-0736、CUR 0688、CUR-0740和CUR-0664的条柱分别对应于SEQ ID NO:42至46。
图6显示猴脂肪或组织检查(Monkey Fat Biopsies)的PCR结果。实时PCR结果显示来自用CUR-963(一种针对SIRT1反义CV396200.1设计的寡核苷酸)给药的猴的脂肪活组织检查中SIRT1 mRNA水平的增加。CUR-963对应于SEQ ID NO:43。
图7显示原代猴肝细胞的PCR结果。实时PCR结果显示用抗SIRT1反义的寡核苷酸处理后,SIRT1 mRNA水平的增加。标为CUR-0245的条柱对应于SEQ ID NO:42。
图8显示针对SIRT反义CV396200设计的寡核苷酸的结果。实时PCR结果显示用针对SIRT1反义CV396200设计的寡核苷酸之一处理后,HepG2细胞中SIRT1 mRNA的水平显著增加。标为CUR-1230至CUR-1233的条柱对应于SEQ ID NO:50至53。
图9显示针对SIRT反义CV428275设计的寡核苷酸的结果。实时PCR结果显示用针对SIRT1反义CV428275设计的寡核苷酸中的两个处理后,HepG2细胞中SIRT1 mRNA的水平显著增加。标为CUR-1302、CUR-1304、CUR-1303和CUR-1305的条柱对应于SEQ ID NO:54至57。
图10显示实时PCR结果。结果显示用针对SIRT反义BE717453设计的寡核苷酸之一处理后48小时,HepG2细胞中的SIRT1 mRNA水平显著增加。标为CUR-1264至CUR-1266的条柱分别对应于SEQ IDNO:58至60。
图11显示实时PCR结果。结果显示用针对SIRT反义AV718812设计的寡核苷酸中的三个处理后48小时,HepG2细胞中的SIRT1mRNA水平显著增加。标为CUR-1294、CUR-1297、CUR-1295、CUR-1296和CUR-1298的条柱分别对应于SEQ ID NO:61至65。
图12是实时PCR结果的图,显示利用Lipofectamine 2000引入的硫代磷酸酯寡核苷酸处理HepG2细胞后与对照相比SIRT1 mRNA的倍数变化+标准差。实时PCR结果显示,用针对SIRT1反义AW169958设计的寡核苷酸中的两个处理后48h,HepG2细胞中SIRT1 mRNA的水平显著增加。标为CUR-1381、CUR-1382、CUR-1383和CUR-1384的条柱分别对应于用SEQ IDNO:66至69处理的样品。
图13是实时PCR结果的图,显示利用Lipofectamine 2000引入的硫代磷酸酯寡核苷酸处理3T3细胞后与对照相比SIRT1 mRNA的倍数变化+标准差。实时PCR结果显示,用针对SIRT1小鼠反义AK044604设计的寡核苷酸中的三个处理后48h,3T3细胞中SIRT1mRNA的水平显著增加。标为CUR-0949、CUR-0842、CUR-1098和CUR-1099的条柱分别对应于用SEQ ID NO:76、70、80和81处理的样品。
图14是实时PCR结果的图,显示利用Lipofectamine 2000引入的硫代磷酸酯寡核苷酸处理3T3细胞后与对照相比SIRT1 mRNA的倍数变化+标准差。实时PCR结果显示,用针对SIRT1小鼠反义AK044604设计的寡核苷酸中的五个处理后48h,3T3细胞中SIRT1mRNA的水平显著增加。标为CUR-0948至CUR-0951、CUR-0846和CUR-0844的条柱分别对应于用SEQ IDNO:75至78、74和72处理的样品。
图15是实时PCR结果的图,显示利用Lipofectamine 2000引入的硫代磷酸酯寡核苷酸处理3T3细胞后与对照相比SIRT1 mRNA的倍数变化+标准差。实时PCR结果显示,用针对SIRT1小鼠反义AK044604设计的寡核苷酸中的两个处理后48h,HepG2细胞中SIRT1 mRNA的水平显著增加。标为CUR-0842、CUR-0844和CUR-0845的条柱分别对应于用SEQ ID NO:70、72和73处理的样品。
图16是实时PCR结果的图,显示利用Lipofectamine 2000引入的硫代磷酸酯寡核苷酸处理3T3细胞后与对照相比SIRT1 mRNA的倍数变化+标准差。实时PCR结果显示,用针对SIRT1小鼠反义AK044604设计的寡核苷酸中的两个处理后48h,HepG2细胞中SIRT1 mRNA的水平显著增加。标为CUR-0843和CUR-0846的条柱分别对应于用SEQ ID NO:71和74处理的样品。
图17是实时PCR结果的图,显示利用Lipofectamine 2000引入的硫代磷酸酯寡核苷酸处理HepG2细胞后与对照相比沉默调节蛋白3mRNA的倍数变化+标准差。RT PCR结果显示,用针对sirt3反义Hs.683117设计的寡核苷酸处理后48h,HepG2细胞中的sirt3水平增加。标为CUR-0551、CUR-1552、CUR-1555、CUR-1556、CUR-1553、CUR-1554、CUR-1545、CUR-1546、CUR-1548、CUR-1549、CUR-1550和CUR-1547的条柱分别对应于用SEQ ID NO:82至93处理的样品。
图18是实时PCR结果的图,显示利用Lipofectamine 2000引入的硫代磷酸酯寡核苷酸处理HepG2细胞后与对照相比沉默调节蛋白3mRNA的倍数变化+标准差。RT PCR结果显示,用针对sirt3反义BQ024738和BE164357设计的寡核苷酸处理后48h,HepG2细胞中的sirt3水平增加。标为CUR-1869、CUR-1871和CUR-1873至CUR-1878的条柱分别对应于用SEQID NO:94、95、96和98、99、100、101和102处理的样品。
图19是实时PCR结果的图,显示利用Lipofectamine 2000引入的硫代磷酸酯和siRNA寡核苷酸处理Hek293细胞后与对照相比沉默调节蛋白3mRNA的倍数变化+标准差。标为CUR-1883和CUR-1884的条柱对应于用SEQ ID NO:126和127处理的样品。
图20是实时PCR结果的图,显示利用Lipofectamine 2000引入的硫代磷酸酯和siRNA寡核苷酸处理Vero76细胞后与对照相比SIRT3mRNA的倍数变化+标准差。标为CUR-1883 CUR-1884 CUR-1873、CUR-1875、CUR-1878和CUR-1546的条柱分别对应于用SEQ IDNO:126、127、96、98、100和92处理的样品。
图21是实时PCR结果的图,显示利用Lipofectamine 2000引入的硫代磷酸酯寡核苷酸处理HUVEC细胞后与对照相比SIRT4 mRNA的倍数变化+标准差。标为CUR-1832和CUR-1835的条柱分别对应于用SEQ ID NO:105和107处理的样品。
图22是实时PCR结果的图,显示利用Lipofectamine 2000引入的硫代磷酸酯寡核苷酸处理HepG2细胞后与对照相比SIRT4 mRNA的倍数变化+标准差。标为CUR-1833和CUR-1835的条柱对应于用SEQ ID NO:104至107处理的样品。
图23是实时PCR结果的图,显示利用Lipofectamine 2000引入的硫代磷酸酯寡核苷酸处理HepG2细胞后与对照相比SIRT5 mRNA的倍数变化+标准差。标为CUR-1828、CUR-1829、CUR-1831和CUR-1830的条柱分别对应于用SEQ ID NO:108、109、111和110处理的样品。
图24是实时PCR结果的图,显示利用Lipofectamine 2000引入的硫代磷酸酯寡核苷酸处理HepG2细胞后与对照相比SIRT6 mRNA的倍数变化+标准差。实时PCR结果显示,用针对SIRT6反义序列(登录号NM_133475)设计的寡核苷酸之一处理后48h,HepG2细胞中SIRT6mRNA的水平显著增加。标为CUR-0873、CUR-0869至CUR-0871、CUR-0874和CUR-0872的条柱分别对应于用SEQ ID NO:116、112、113、114、117和115处理的样品。
图25是实时PCR结果的图,显示利用Lipofectamine 2000引入的硫代磷酸酯寡核苷酸处理HepG2细胞后与对照相比SIRT6 mRNA的倍数变化+标准差。实时PCR结果显示,用针对SIRT6反义bf772662设计的寡核苷酸之一处理后48h,HepG2细胞中SIRT6 mRNA的水平显著增加。标为CUR-0878、CUR-0876、CUR-0877和CUR-0875的条柱分别对应于用SEQ ID NO:121、119、120和118处理的样品。
图26是实时PCR结果的图,显示利用Lipofectamine 2000引入的硫代磷酸酯寡核苷酸处理DBS-FCL-1细胞后与对照相比SIRT6mRNA的倍数变化+标准差。实时PCR结果显示,用针对SIRT6反义bf772662设计的寡核苷酸中的两个和针对登录号NM_133475的序列设计的寡核苷酸之一处理后48h,DBS-FCL-1细胞中SIRT6 mRNA的水平显著增加。标为CUR-0876、CUR-0878、CUR-0875和CUR-0874的条柱分别对应于用SEQ ID NO:119、121、118和117处理的样品。
图27是实时PCR结果的图,显示利用Lipofectamine 2000引入的硫代磷酸酯寡核苷酸处理Vero76细胞后与对照相比SIRT7 mRNA的倍数变化+标准差。标为CUR-1824和CUR-1825的条柱分别对应于用SEQ ID NO:122和123处理的样品。
图28是实时PCR结果的图,显示利用Lipofectamine 2000引入的硫代磷酸酯寡核苷酸处理SK-N-AS细胞后与对照相比SIRT7mRNA的倍数变化+标准差。标为CUR-1824和CUR-1825的条柱分别对应于用SEQ ID NO:124和125处理的样品。
图29是实时PCR结果的图,显示利用Lipofectamine 2000引入的硫代磷酸酯寡核苷酸处理HepG2细胞后与对照相比SIRT7 mRNA的倍数变化+标准差。标为CUR-1824和CUR-1825的条柱对应于用SEQ ID NO:122和123处理的样品。
序列表描述-
SEQ ID NO:1:智人沉默调节蛋白(沉默交配型信息调控2同系物)1(酿酒酵母)(SIRT1),mRNA(NCBI登录号:NM_012238.4)
SEQ ID NO:133:智人沉默调节蛋白1(SIRT1),转录变体2,mRNA(NCBI登录号:NM_001142498.1)
SEQ ID NO:2:小家鼠沉默调节蛋白1(沉默交配型信息调控2同系物)1(酿酒酵母)(SIRT1)mRNA(NCBI登录号:NM_001159589)
SEQ ID NO:3:智人沉默调节蛋白2(SIRT2),转录变体1,mRNA(NCBI登录号:NM_012237.3).
SEQ ID NO:134:智人沉默调节蛋白2(SIRT2),转录变体2,mRNA(NCBI登录号:NM_030593.2)
SEQ ID NO:135:智人沉默调节蛋白2(SIRT2),转录变体3,mRNA(NCBI登录号:NM_001193286.1)
SEQ ID NO:136:智人沉默调节蛋白2(SIRT2),转录变体4,非编码RNA(NCBI登录号:NR_034146.1)
SEQ ID NO:4:智人沉默调节蛋白(沉默交配型信息调控2同系物)3(酿酒酵母)(SIRT3),转录变体1,mRNA(NCBI登录号:NM_012239.5).
SEQ ID NO:137:智人沉默调节蛋白3(SIRT3),转录变体2,mRNA(NCBI登录号:NM_001017524.2)
SEQ ID NO:5:智人沉默调节蛋白4(SIRT4),mRNA(NCBI登录号:NM_012240).
SEQ ID NO:138:智人沉默调节蛋白5(SIRT5),转录变体2,mRNA(NCBI登录号:NM_031244.2)
SEQ ID NO:139:智人沉默调节蛋白5(SIRT5),转录变体3,mRNA(NCBI登录号:NM_001193267.1)
SEQ ID NO:6:智人沉默调节蛋白5(SIRT5),转录变体1,mRNA(NCBI登录号:NM_012241).
SEQ ID NO:7:智人沉默调节蛋白6(SIRT6),转录变体1,mRNA(NCBI登录号:NM_016539).
SEQ ID NO:140:智人沉默调节蛋白6(SIRT6),转录变体2,mRNA(NCBI登录号:NM_001193285.1)
SEQ ID NO:8:智人沉默调节蛋白7(SIRT7),mRNA(NCBI登录号:NM_016538).
天然反义序列-SEQ ID NO:9:扩展型天然反义序列(CV396200-扩展型);SEQ IDNO:10:天然反义序列(CV428275);SEQ ID NO:11:天然反义序列(BE717453)
SEQ ID NO:12:天然反义序列(AV718812);SEQ ID NO:13:天然SIRT1反义序列(AW169958);SEQ ID NO:14:小鼠天然SIRT1小鼠反义序列(AK044604);SEQ ID NO:15:天然SIRT3反义序列(Hs.683117);SEQ ID NO:16:天然SIRT3反义序列(DA645474)
SEQ ID NO:17:天然SIRT3反义序列(BQ024738);SEQ ID NO:18:天然SIRT3反义序列(BE164357);天然SIRT3反义序列(RIC8A)SEQ ID NO:141、天然SIRT3反义序列(PMSD13)SEQ ID NO:142、天然SIRT3反义序列(DA246502)SEQ ID NO:143,SEQ ID NO:19:天然SIRT4反义序列(AA156947);SEQ ID NO:20:天然SIRT5反义序列(Hs.671550);SEQ ID NO:21:天然SIRT6反义序列(BF772662);SEQ ID NO:22:天然SIRT6反义序列(ANKRD24);SEQ ID NO:23:天然SIRT7反义序列(Hs.671550)
反义寡核苷酸-SEQ ID NO:24至127.*指示硫代磷酸酯键,+指示LNA且m指示2’OMe,r指示RNA
SEQ ID NO:128至130-SEQ ID NO:128对应于SIRT1天然反义CV396200的外显子4,SEQ ID NO:129、130和131分别对应于正向引物序列、反向引物序列和报告序列。SEQ IDNO:132对应于CUR962,*指示硫代磷酸酯键且+指示LNA。
SEQ ID NO:144和145分别对应于反义寡核苷酸SEQ ID NO:126和127的反向互补序列。
详述
下面参考用于示例的实例应用来描述本发明的多个方面。应理解的是,列出许多具体细节、关联和方法以提供对本发明的完全理解。然而,相关领域普通技术人员将容易认识到,可没有一种或多种具体细节地实践本发明或以其它方法实践本发明。本发明不限于行为或事件的顺序,因为一些行为可以不同顺序进行和/或与其它行为或事件同时进行。而且,并非所有列举的行为或事件都是实施根据本发明的方法所需的。
本文公开的所有基因、基因名称和基因产物预期对应来自本文公开的组合物和方法可适用的任何物种的同系物。因此,这些术语包括但不限于来自人和小鼠的基因和基因产物。应理解的是,当公开来自具体物种的基因或基因产物时,这一公开仅旨在示例,不应解释为限制,除非在其存在的上下文清楚地指明。因此,例如,对于本文公开的基因,其在一些实施方案中涉及哺乳动物核酸和氨基酸序列,预期涵盖来自其它动物的同源和/或直系同源基因和基因产物,所述其它动物包括但不限于其它哺乳动物、鱼、两栖类、爬行动物和鸟类。在实施方案中,基因或核酸序列是人的。
除非另有指出,否则本文命名的登录号识别美国国立卫生研究院数据库,GenBank(参见Nucleic Acids Research,2008年1月36日Database issue:D25-30)中公众可得的序列。由登录号提及的所有序列通过引用并入本文。
定义
本文所用的术语仅是为了描述具体实施方案的目的,并不旨在限制本发明。除非上下文另外清楚地指明,否则本文所用的单数形式"一个/一种(a)"、"一个/一种(an)"和"该(the)"预期包括复数形式。而且,就详述和/或权利要求书中使用术语"包括(including)"、"包括(includes)"、"具有(having)"、"具有(has)"、"带有(with)"或其变化形式来说,这些术语预期以类似于术语"包含(comprising)"的方式被包括。
术语"约"或"大约"是指在由本领域普通技术人员确定的特定数值的可接受误差范围内,其将部分地取决于如何测量或确定该数值,即,测量系统的限度。例如,按照本领域中的实践,"约"可表示在1个或多于1个标准差内。可选地,"约"可表示给定数值的达20%、优选地达10%、更优选地达5%、仍更优选地达1%的范围。可选地,尤其是有关生物系统或方法,术语可表示在数值的数量级内,优选地在5倍内,更优选地在2倍内。当在本申请和权利要求书中描述特定数值时,除非另外指明,否则应假设术语"约"表示在特定数值可接受的误差范围内。
本文所用的术语"mRNA"是指靶基因的目前已知的mRNA转录物和可能说明的任何进一步的转录物。
"反义寡核苷酸"或"反义化合物"是指结合另一RNA或DNA(靶RNA、DNA)的RNA或DNA分子。例如,如果其是RNA寡核苷酸,其借助于RNA-RNA相互作用结合另一RNA靶并且改变靶RNA的活性。反义寡核苷酸可上调或下调特定多核苷酸的表达和/或功能。该定义意为包括从治疗、诊断或其它观点来说有用的任何外来RNA或DNA分子。这种分子包括,例如,反义RNA或DNA分子、干扰RNA(RNAi)、微RNA、诱饵RNA分子、siRNA、酶促RNA、治疗性编辑RNA和激动剂与拮抗剂RNA、反义寡聚化合物、反义寡核苷酸、外部指导序列(EGS)寡核苷酸、可选剪接体、引物、探针以及与靶核酸的至少一部分杂交的其它寡聚化合物。因此,这些化合物可以单链、双链、部分单链或环状寡聚化合物的形式引入。
在本发明的范畴中,术语"寡核苷酸"是指核糖核酸(RNA)或脱氧核糖核酸(DNA)或其模拟物的寡聚物或聚合物。术语"寡核苷酸"还包括天然和/或修饰的单体或键合的线性或环状寡聚物,包括脱氧核糖核苷、核糖核苷、其取代形式和其α-异头形式、肽核酸(PNA)、锁核酸(LNA)、硫代磷酸酯、膦酸甲酯和类似物。寡核苷酸能够经由规则方式的单体与单体间的相互作用,例如Watson-Crick型碱基配对、或逆型碱基配对或类似物特异性结合靶多核苷酸。
寡核苷酸可以是"嵌合的",即,包括不同区域。在本发明的范畴中,"嵌合"化合物是寡核苷酸,其包含两个或更多个化学区域,例如,DNA区域、RNA区域、PNA区域等等。每个化学区域由至少一个单体单位构成,在寡核苷酸化合物的情形中所述单体单位即为核苷酸。这些寡核苷酸通常包括至少一个区域,其中寡核苷酸经修饰以表现一种或多种期望特性。寡核苷酸的期望特性包括但不限于,例如,对核酸酶降解增加的耐受性、增加的细胞摄取和/或对靶核酸增加的结合亲和力。因此,寡核苷酸的不同区域可具有不同特性。如上所述,本发明的嵌合寡核苷酸可形成为两种或更多种寡核苷酸的混合结构、修饰的寡核苷酸、寡核苷和/或寡核苷酸类似物。
寡核苷酸可由可被"成行"地连接(即当单体被连续地连接时,如在天然DNA中)的区域或经由间隔物连接的区域构成。预期间隔物构成区域之间的共价"桥",在情形中具有不超过约100个碳原子的长度。间隔物可携带不同功能性,例如,具有正电荷或负电荷,携带特殊的核酸结合特性(嵌入剂、槽沟结合物、毒素、荧光团等等),为亲脂性的,诱导特殊的二级结构,如例如,诱导α-螺旋的含丙氨酸的肽。
本文所用的"沉默调节蛋白(SIRT)"包括所有家族成员、突变体、等位基因、片段、种类(species)、编码和非编码序列、有义和反义多核苷酸链等等。
本文所用的词语沉默调节蛋白1、SIRT1、沉默调节蛋白、沉默交配型信息调控2同系物1、hSIR2、hSIRT1、NAD-依赖性脱乙酰化酶沉默调节蛋白1、SIR2L1、SIR2样蛋白1被认为在文献中是相同的,且在本申请中可交换地使用。
本文所用的词语沉默调节蛋白2、沉默调节蛋白-2、SIRT2、SIR2L和SIR2L2被认为在文献中是相同的,且在本申请中可交换地使用。
本文所用的词语’沉默调节蛋白3’、沉默调节蛋白3、沉默调节蛋白-3、SIRT3、SIRT-3、hSIRT3、NAD-依赖性脱乙酰化酶沉默调节蛋白-3、线粒体、SIR2L3、SIR2样蛋白3被认为在文献中是相同的,且在本申请中可交换地使用。
本文所用的词语沉默调节蛋白4、SIRT4、MGC130046、MGC130047、MGC57437、NAD-依赖性ADP-核糖基转移酶沉默调节蛋白-4、SIR2L4、SIR2-样蛋白4被认为在文献中是相同的,且在本申请中可交换地使用。
本文所用的词语沉默调节蛋白5、SIRT5、FLJ36950、NAD-依赖性脱乙酰化酶沉默调节蛋白-5、SIR2L5、SIR2-样蛋白5被认为在文献中是相同的,且在本申请中可交换地使用。
本文所用的词语‘沉默调节蛋白6’、沉默调节蛋白6、沉默调节蛋白-6、SIRT6、SIRT-6、NAD-依赖性脱乙酰化酶沉默调节蛋白-6、SIR2L6、SIR2-样蛋白6被认为在文献中是相同的,且在本申请中可交换地使用。
本文所用的词语沉默调节蛋白7、SIRT7、MGC126840、MGC126842、NAD-依赖性脱乙酰化酶沉默调节蛋白-7、SIR2L7、SIR2-样蛋白7被认为在文献中是相同的,且在本申请中可交换地使用。
本文所用的术语"对…有特异性的寡核苷酸"或"靶向…的寡核苷酸"是指具有(i)能够与靶基因的一部分形成稳定复合体,或(ii)能够与靶基因的mRNA转录物的一部分形成稳定双链体的序列的寡核苷酸。复合体和双链体的稳定性可通过理论计算和/或体外测定来确定。用于确定杂交复合体和双链体的稳定性的示例性测定在以下实施例中描述。
本文所用的术语"靶核酸"涵盖DNA、从这种DNA转录的RNA(包括前体mRNA和mRNA)、还有从这种RNA衍生的cDNA、编码序列、非编码序列、有义或反义多核苷酸。寡聚化合物与其靶核酸的特异性杂交干扰核酸的正常功能。特异性地与靶核酸杂交的化合物对靶核酸功能的这一调节通常称为"反义"。待干扰的DNA功能包括,例如复制和转录。待干扰的RNA功能包括所有重要功能,例如,RNA向蛋白翻译位置的移位,从RNA翻译为蛋白,剪接RNA以产生一种或多种mRNA种类以及可能由RNA参与或促进的催化活性。这种干扰靶核酸功能的总效果是调节编码的产物或寡核苷酸的表达。
RNA干扰"RNAi"由对其"靶"核酸序列具有序列特异性的同源性的双链RNA(dsRNA)分子介导。在本发明的某些实施方案中,介导物是5-25个核苷酸的"小干扰"RNA双链体(siRNA)。siRNA来源于称为Dicer的RNA酶对dsRNA的加工。siRNA双链体产物被募集到称为RISC(RNA诱导沉默复合体)的多蛋白siRNA复合体中。不希望受任何特定理论束缚,认为随后RISC被引导至靶核酸(适当地为mRNA),在那里siRNA双链体以序列特异性方式相互作用来以催化方式介导裂解。根据本发明可使用的小干扰RNA可根据本领域公知并且本领域普通技术人员熟悉的方案合成和使用。用于本发明方法的小干扰RNA适当地包括约1至约50个核苷酸(nt)。在非限制性实施方案的实例中,siRNA可包括约5至约40nt、约5至约30nt、约10至约30nt、约15至约25nt或约20-25个核苷酸。
通过利用自动比对核酸序列并指明同一性或同源性的区域的计算机程序来便于选择适当的寡核苷酸。这种程序用来比较获得的核酸序列,例如通过搜寻数据库例如GenBank或通过对PCR产物测序。比较来自一系列物种的核酸序列允许选择在物种之间展示适当的同一性程度的核酸序列。在未被测序的基因的情形中,进行DNA印迹(Southernblots)以允许确定靶物种与其它物种的基因之间的同一性程度。如本领域所熟知的,通过以不同的严格性程度进行DNA印迹,可能获得近似的同一性测量。这些方案允许选择展现与待控制的受治疗者中的靶核酸序列的高程度互补性和与其它物种中的相应核酸序列的较低程度互补性的寡核苷酸。本领域技术人员将认识到,在选择用于本发明的基因的适当区域方面存在相当大的自由。
"酶促RNA"是指具有酶促活性的RNA分子。酶促核酸(核酶)通过首先结合靶RNA来作用。这种结合经由被保持在邻近用于裂解靶RNA的分子的酶促部分处的酶促核酸的靶结合部分来进行。因此,酶促核酸首先识别靶RNA然后经由碱基配对结合靶RNA,结合到正确位置时,酶促地作用以切割靶RNA。
"诱饵RNA"是指模拟配体的天然结合结构域的RNA分子。因此,诱饵RNA与天然结合靶竞争结合特定配体。例如,已经显示HIV反式激活响应(TAR)RNA的过表达可作为"诱饵"起作用并有效地结合HIV tat蛋白,从而阻止其结合HIV RNA中编码的TAR序列。这表示一个特定的实例。本领域技术人员将认识到,这仅是一个实例,利用本领域通常已知的技术可容易地产生其它实施方案。
本文所用的术语"单体"通常是指由磷酸二酯键或其类似物连接以形成大小从数个单体单位例如约3-4个至约数百个单体单位范围的寡核苷酸的单体。磷酸二酯键合的类似物包括:硫代磷酸酯、二硫代磷酸酯、甲基膦酸酯、硒代磷酸酯、氨基磷酸酯和类似物,如以下更充分地描述。
术语“核苷酸”涵盖天然存在的核苷酸以及非天然存在的核苷酸。本领域技术人员应清楚的是,此前被认为是"非天然存在的"各种核苷酸后来已在自然界中发现。因此,"核苷酸"不仅包括已知的含嘌呤和嘧啶杂环的分子,还包括其杂环类似物和互变异构体。其它类型的核苷酸的示例性实例是含腺嘌呤、鸟嘌呤、胸腺嘧啶、胞嘧啶、尿嘧啶、嘌呤、黄嘌呤、二氨基嘌呤、8-氧代-N6-甲基腺嘌呤、7-脱氮杂黄嘌呤、7-脱氮杂鸟嘌呤、N4,N4-桥亚乙基胞嘧啶、N6,N6-桥亚乙基-2,6-二氨基嘌呤、5-甲基胞嘧啶、5-(C3-C6)-炔基胞嘧啶、5-氟尿嘧啶、5-溴尿嘧啶、假异胞嘧啶、2-羟基-5-甲基-4-三唑并吡啶、异胞嘧啶、异鸟嘌呤、肌苷的分子以及美国专利No.5,432,272中描述的"非天然存在的"核苷酸。术语"核苷酸"预期涵盖这些实例的每一种和所有以及其类似物和互变异构体。尤其关注的核苷酸是包含腺嘌呤、鸟嘌呤、胸腺嘧啶、胞嘧啶和尿嘧啶的那些,它们被认为是与在人的治疗和诊断应用有关的天然存在的核苷酸。核苷酸包括天然2'-脱氧糖和2'-羟基糖,例如在Kornberg和Baker,DNA Replication,第2版.(Freeman,San Francisco,1992)中描述的,以及它们的类似物。
提及核苷酸的"类似物"包括具有修饰的碱基部分和/或修饰的糖部分的合成的核苷酸。这种类似物包括经设计以增强结合特性,例如,双链体或三链体稳定性、特异性或类似特性的合成的核苷酸。
本文所用的"杂交"是指寡聚化合物的大致互补链的配对。配对的一种机制包括寡聚化合物的链的互补核苷或核苷酸碱基(核苷酸)之间的氢键合,其可以是Watson-Crick、或逆氢键合。例如,腺嘌呤和胸腺嘧啶是经由氢键形成而配对的互补核苷酸。杂交可在不同情况下发生。
当反义化合物与靶核酸的结合干扰靶核酸的正常功能以导致功能和/或活性的调节时,该化合物是"可特异性杂交的",且在期望特异性结合的条件下(即,在体内测定或治疗性治疗的情形中的生理条件下和在体外测定的情形中进行测定的条件下)存在足够程度的互补性以避免反义化合物与非靶核酸序列的非特异性结合。
本文所用的短语"严格杂交条件"或"严格条件"是指本发明化合物将与其靶序列杂交,但与最小数目的其它序列杂交的条件。严格条件是序列依赖性的且在不同情况中将是不同的,并且在本发明范畴中,寡聚化合物与靶序列杂交的"严格条件"由寡聚化合物的性质和组成以及研究它们的测定决定。通常,严格杂交条件包括低浓度(<0.15M)的带有无机阳离子例如Na++或K++的盐(即,低离子强度)、高于20℃-25℃低于寡聚化合物:靶序列复合体的Tm的温度、和存在变性剂例如甲酰胺、二甲基甲酰胺、二甲亚砜或去垢剂十二烷基硫酸钠(SDS)。例如,对于每种1%甲酰胺,杂交率降低1.1%。高严格杂交条件的实例是在60℃下0.1×氯化钠-柠檬酸钠缓冲液(SSC)/0.1%(w/v)SDS进行30分钟。
本文所用的"互补"是指一条或两条寡聚链上的两个核苷酸之间准确配对的能力。例如,如果在反义化合物某一位置的核碱基能够与在靶核酸某一位置的核碱基氢键结合,所述靶核酸为DNA、RNA或寡核苷酸分子,则认为寡核苷酸与靶核酸之间的氢键结合位置是互补位置。当每个分子的足够数目的互补位置由可彼此成氢键的核苷酸占据时,寡聚化合物和另外的DNA、RNA或寡核苷酸分子是彼此互补的。因此,"可特异性杂交"和"互补"是用来表示经足够数目的核苷酸足够程度的准确配对或互补性,从而在寡聚化合物和靶核酸之间发生稳定和特异性结合的术语。
本领域应理解的是,寡聚化合物的序列不必与待可特异性杂交的其靶核酸的序列100%互补。而且,寡核苷酸可经一个或多个区段杂交,从而其间的或相邻区段不牵涉在杂交事件中(例如,环结构、错配或发夹结构)。本发明的寡聚化合物包括与其所靶向的靶核酸序列中靶区域具有至少约70%、或至少约75%、或至少约80%、或至少约85%、或至少约90%、或至少约95%、或至少约99%序列互补性。例如,其中反义化合物的20个核苷酸中的18个与靶区域互补从而将特异性杂交的反义化合物将表示90%互补性。在这一实例中,其余非互补核苷酸可成串或散布于互补核苷酸,不必彼此连续或与互补核苷酸连续。因此,具有侧翼为与靶核酸具有完全互补性的两个区域的4(四)个非互补核苷酸的长度为18个核苷酸的反义化合物将与靶核酸具有77.8%总互补性,因此属于本发明的范围中。反义化合物与靶核酸的区域的互补性百分比可常规地利用本领域已知的BLAST程序(基本局部比对搜索工具)和PowerBLAST程序来确定。同源性、序列同一性或互补性的百分比可通过(例如)Gap程序确定。
本文所用的术语"热熔点(Tm)"是指在指定的离子强度、pH和核酸浓度下,与靶序列互补的寡核苷酸的50%平衡地与靶序列杂交的温度。通常,严格条件将是其中盐浓度为至少约0.01至1.0M Na离子浓度(或其它盐)、pH 7.0至8.3,且对于短寡核苷酸(例如,10至50个核苷酸)温度为至少约30℃的条件。严格条件还可通过加入去稳定剂例如甲酰胺来实现。
本文所用的"调节"是指基因表达的增加(刺激)或减少(抑制)。
术语"变体"当在多核苷酸序列的上下文中使用时,可涵盖与野生型基因相关的多核苷酸序列。这一定义还可包括,例如,"等位"、"剪接"、"物种"或"多态"变体。剪接变体可与参考分子具有显著的同一性,但由于在mRNA加工期间外显子的可选剪接通常将具有更大数目或更小数目的多核苷酸。相应的多肽可具有另外的功能结构域或缺少结构域。物种变体是在物种之间不同的多核苷酸序列。本发明中特别有用的是野生型基因产物的变体。变体可来源于核酸序列中至少一种突变,并可产生改变的mRNA或产生结构或功能可能改变或可能不改变的多肽。任何给定的天然或重组基因可具有0种、一种或多种等位基因形式。产生变体的常见突变改变通常归因于核苷酸的天然缺失、添加或取代。在给定序列中,这些类型改变的每一种可单独发生,或组合其它类型改变发生一次或多次。
所得的多肽通常将具有相对于彼此显著的氨基酸同一性。多态变体是给定物种的个体之间特定基因的多核苷酸序列的变化。多态变体还可涵盖"单核苷酸多态性"(SNP)或其中多核苷酸序列差异为一个碱基的单碱基突变。SNP的存在可指示,例如,具有疾病状态的倾向的某一群体,所述倾向相比于耐受性为易感性。
衍生的多核苷酸包括经受化学修饰(例如以烷基、酰基或氨基代替氢)的核酸。衍生物例如,衍生物寡核苷酸,可包括非天然存在的部分,例如改变的糖部分或糖间键合。其中示例的有硫代磷酸酯和本领域已知的其它含硫物质。衍生的核酸还可包含标记,包括放射性核苷酸、酶、荧光剂、化学发光剂、显色剂、底物、辅因子、抑制剂、磁性粒子和类似物。
"衍生物"多肽或肽是例如通过糖基化、聚乙二醇化、磷酸化、硫酸化、还原/烷基化、酰化、化学偶合或适度福尔马林处理修饰的多肽或肽。还可修饰衍生物以直接或间接包含可检测的标记,包括但不限于,放射性同位素、荧光和酶标记。
本文所用的术语"动物"或"患者"意为包括,例如人、绵羊、麋鹿、鹿、长耳鹿、貂、哺乳动物、猴、马、牛、猪、山羊、犬、猫、大鼠、小鼠、鸟类、鸡、爬行动物、鱼、昆虫和蛛形纲动物。
"哺乳动物"涵盖通常处于医疗护理下的温血哺乳动物(例如,人和驯养的动物)。实例包括猫科动物、犬科动物、马科动物、牛科动物和人,以及仅仅人。
"治疗(Treating)"或"治疗(treatment)"涵盖治疗哺乳动物的疾病状态,并包括:(a)防止疾病状态在哺乳动物中发生,尤其是当所述哺乳动物倾向于疾病状态但还未被诊断为患有其的时候;(b)抑制疾病状态,例如阻止其发展;和/或(c)缓解疾病状态,例如导致疾病状态消退,直到达到期望端点。治疗还包括疾病症状的改善(例如,减轻疼痛或不适),其中所述改善可或不可直接影响疾病(例如起因、传染、表达等等)。
本文所用的"癌症"是指在哺乳动物中发现的所有类型的癌症或赘生物或恶性肿瘤,包括但不限于:白血病、淋巴瘤、黑素瘤、癌和肉瘤。癌症本身表现为"肿瘤"或包括癌症恶性细胞的组织。肿瘤的实例包括肉瘤和癌,例如但不限于:纤维肉瘤、粘液肉瘤、脂肪肉瘤、软骨肉瘤、成骨肉瘤、脊索瘤、血管肉瘤、内皮肉瘤、淋巴管肉瘤、淋巴管内皮肉瘤、滑膜瘤、间皮瘤、尤因氏瘤、平滑肌肉瘤、横纹肌肉瘤、结肠癌、胰腺癌、乳腺癌、卵巢癌、前列腺癌、鳞状细胞癌、基底细胞癌、腺癌、汗腺癌、皮脂腺癌、乳头状癌、乳头状腺癌、囊腺癌、髓样癌、支气管癌、肾细胞癌、肝细胞瘤、胆管癌、绒毛膜癌、精原细胞瘤、胚胎性癌、肾母细胞瘤、宫颈癌、睾丸肿瘤、肺癌、小细胞肺癌、膀胱癌、上皮癌、神经胶质瘤、星形细胞瘤、髓母细胞瘤、颅咽管瘤、室管膜瘤、松果体瘤、血管母细胞瘤、听神经瘤、少突神经胶质瘤、脑膜瘤、黑素瘤、神经母细胞瘤和视网膜母细胞瘤。可用根据本发明公开的组合物治疗的其它癌症包括但不限于,例如霍奇金病、非霍奇金淋巴瘤、多发性骨髓瘤、神经母细胞瘤、乳腺癌、卵巢癌、肺癌、横纹肌肉瘤、原发性血小板增多症、原发性巨球蛋白血症、小细胞肺肿瘤、原发性脑瘤、胃癌、结肠癌、恶性胰岛肿瘤、恶性类癌瘤、膀胱癌、恶变前皮肤损伤、睾丸癌、淋巴瘤、甲状腺癌、神经母细胞瘤、食管癌、泌尿生殖道癌、恶性高钙血症、宫颈癌、子宫内膜癌、肾上腺皮质癌和前列腺癌。
"神经病学疾病或病症"是指神经系统和/或视觉系统的任何疾病或病症。"神经病学疾病或病症"包括牵涉中枢神经系统(脑、脑干和小脑)、外周神经系统(包括颅神经)和自主神经系统(其部分位于中枢神经系统和外周神经系统两者中)的疾病或病症。神经病学病症的实例包括但不限于,头痛、麻痹和昏迷、痴呆、癫痫、睡眠障碍、外伤、感染、赘生物、神经眼科学、运动障碍、脱髓鞘疾病、脊髓病症以及外周神经、肌肉和神经肌肉接头的病症。成瘾和精神疾病,包括但不限于双相性精神障碍和精神分裂症,也包括在神经病学病症的定义中。以下是可利用根据本发明的组合物和方法治疗的多种神经病学病症、症状、迹象和综合征的列表:获得性癫痫样失语症;急性播散性脑脊髓炎;脑白质肾上腺萎缩症;年龄相关的黄斑变性;胼胝体发育不全;失认症;艾卡迪综合征;亚力山大病;阿尔佩斯病;交替性偏瘫;血管性痴呆;肌萎缩性侧索硬化;无脑;Angelman综合征;血管瘤病;缺氧症;失语症;失用症;蛛网膜囊肿;蛛网膜炎;阿-基氏脑畸形;动静脉畸形;阿斯佩各综合征;共济失调毛细血管扩张;注意力缺乏过动症;孤独症;自主神经失调;背痛;巴藤病;白塞病;贝耳麻痹;良性自发性睑痉挛;良性局灶性肌萎缩;良性颅内高压;宾斯旺格氏病;睑痉挛;BlochSulzberger综合征;臂丛损伤;脑脓肿;脑损伤;脑肿瘤(包括多形性胶质母细胞瘤);脊髓肿瘤;布朗-塞卡尔综合征;卡纳万病;腕管综合症;灼痛;中枢性疼痛综合症;脑桥中部髓鞘溶解;头部障碍;脑动脉瘤;脑动脉硬化;脑萎缩;大脑性巨人症;大脑性麻痹;夏-马-图三氏病;化疗引起的神经病和神经性疼痛;基氏脑畸形;舞蹈症;慢性炎症性脱髓鞘多神经病;慢性痛;慢性局部疼痛综合征;科-勒二氏综合征;昏迷,包括持续性植物人状态;先天性面瘫;皮质基底节变性;颅动脉炎;颅缝早闭;克雅氏病;积累性损伤错乱;柯兴综合征;巨细胞包涵体病;巨细胞病毒感染;眼舞蹈-足舞蹈综合征;丹-沃二氏综合征;Dawson病;德摩西埃氏综合征;下臂丛麻痹;痴呆;皮肌炎;糖尿病性神经病;弥漫性硬化症;家族性自主神经异常;书写困难;阅读困难;张力障碍;早期幼儿癫痫性脑病;空蝶鞍综合征;脑炎;脑膨出;脑三叉神经血管瘤病;癫痫;欧勃氏麻痹;特发性震颤;法布里氏病;法尔氏综合征;昏厥;家族性痉挛麻痹症;热性癫痫发作;菲希尔综合征;弗里德赖希氏共济失调;额颞痴呆和其它"tau病变";高歇病;格斯特曼氏综合征;巨细胞性动脉炎;巨细胞性包涵体病;球样细胞脑白质营养不良;格-巴二氏综合征;HTLV-1相关的骨髓病;哈-斯二氏病;头部损伤;头痛;半面痉挛;遗传性痉挛性截瘫;多神经炎型遗传性共济失调;耳部带状疱疹;带状疱疹;Hirayama综合征;HIV相关的痴呆和神经病(也是AIDS的神经病学表现);前脑无裂畸形;亨延顿氏舞蹈病和其它多谷氨酰胺重复序列病;积水性无脑畸形;脑积水;皮质醇过多症;低氧;免疫介导的脑脊髓炎;包涵体肌炎;色素失调症;婴儿植烷酸贮积病;婴儿雷夫叙姆病;婴儿痉挛;炎性肌病;颅内囊肿;颅内高压;Joubert综合征;卡恩斯-塞尔综合征;Kennedy病;金斯布林纳综合征;克-费二氏综合征;克拉贝病;库-韦二氏病;库鲁病;拉福拉病;Lambert-Eaton肌无力综合征;Landau-Kleffner综合征;侧髓(瓦伦伯格氏)综合征;学习障碍;利氏病;Lennox-Gustaut综合征;莱-萘二氏综合征;脑白质病变;路易体痴呆;无脑回症;闭锁综合征;LouGehrig病(即,运动神经元病或肌萎缩性侧索硬化);椎间盘退变;莱姆病-神经病学后遗症;Machado-Joseph病;巨头;巨脑;梅-罗二氏综合征;美尼尔症;脑膜炎;门克斯病;异染性脑白质营养不良;头小畸形;偏头痛;Miller Fisher综合征;小中风;线粒体肌病;默比厄斯氏综合征;单肢肌萎缩;运动神经元病;Moyamoya病;粘多糖贮积症;多发梗塞性痴呆;多灶性运动神经病;多发性硬化和其它脱髓鞘病症;伴有体位性低血压的多系统萎缩症;肌肉萎缩症;重症肌无力;脑脱髓鞘弥散性硬化;婴儿肌阵挛性脑病;肌阵挛;肌病;先天性肌强直;嗜睡病;神经纤维瘤病;抗精神病药的恶性综合征;AIDS的神经病学表现;狼疮的神经病学后遗症;神经性肌强直;神经元蜡样脂褐质沉积症;神经元移行异常;尼-皮二氏病;O'Sullivan-McLeod综合征;枕神经痛;隐性脊柱神经管闭合不全序列征;大田原综合征;橄榄体脑桥小脑萎缩;眼阵挛-肌阵挛;视神经炎;直立性低血压;过度使用综合征;感觉异常;神经变性疾病或病症(帕金森病、亨延顿氏舞蹈病、阿尔茨海默氏病、肌萎缩性侧索硬化(ALS)、痴呆、多发性硬化和与神经元细胞死亡相关的其它疾病和病症);先天性肌强直病;副肿瘤性疾病;突发性癫痫;帕-罗二氏综合征;佩-梅氏病;周期性麻痹;外周神经病;痛性神经病和神经性疼痛;持续性植物人状态;全身性发育迟缓;光喷嚏反射;植烷酸贮积病;皮克氏病;神经挟捏;垂体肿瘤;多肌炎;孔洞脑;小儿麻痹症后期综合症;带状疱疹后神经痛;感染后脑脊髓炎;体位性低血压;帕-魏二氏综合征;原发性脊髓侧索硬化;朊病毒病;进行性面偏侧萎缩症;进行性多灶性白质脑病;进行性硬化性灰质萎缩;进行性核上性麻痹;假性脑瘤;Ramsay-Hunt综合征(I型和II型);Rasmussen脑炎;反射性交感神经营养不良综合征;雷夫叙姆病;重复性运动损伤;重复性压力损伤;多动腿综合征;逆转录病毒相关的脊髓病;Rett综合征;雷依氏综合征;圣维特斯舞蹈病;桑德霍夫病;谢耳德氏病;脑裂;视隔发育不全;摇晃婴儿综合症;带状疱疹;希-德二氏综合征;斯耶格伦氏综合征;睡眠窒息;Soto综合征;僵直;脊柱裂;脊髓损伤;脊髓肿瘤;脊髓性肌萎缩;僵人综合征;中风;斯特奇-韦伯综合征;亚急性硬化全脑炎;动脉硬化性皮层下脑病;西德纳姆舞蹈;晕厥;脊髓空洞症;迟发性运动障碍;泰-萨二氏病;颞动脉炎;脊髓拴系综合征;肌强直性白内障;胸部出口综合征;三叉神经痛;托德氏麻痹;图雷特综合症;暂时性缺血性发作;传染性海绵状脑病;横贯性脊髓炎;外伤性脑损伤;震颤;三叉神经痛;热带痉挛性轻截瘫;结节性脑硬化;血管性痴呆(多发梗塞性痴呆);血管炎(包括颞动脉炎);希-林二氏病;瓦伦伯格氏综合征;韦-霍二氏病;韦斯特综合征;鞭抽式损伤(whiplash);威廉斯综合征;Wildon病和泽韦格综合征。
‘代谢疾病或病症"是指内分泌系统的各种疾病和病症,包括例如胰岛素抗性、糖尿病、肥胖症、葡萄糖耐量受损、高血胆固醇、高血糖症、高胰岛素血症、血脂障碍和高脂血症。
"炎症"是指系统性炎症病状和局部地伴有单核细胞、粒细胞和/或中性白细胞的迁移和吸引的病状。炎症的实例包括但不限于,病原生物体(包括革兰氏阳性细菌、革兰氏阴性细菌、病毒、真菌和寄生虫诸如原生动物和蠕虫)感染引起的炎症、移植排斥(包括排斥实体器官诸如肾脏、肝脏、心脏、肺或角膜、以及排斥骨髓移植物包括移植物抗宿主病(GVHD))、或局部的慢性或急性自身免疫或变应性反应引起的炎症。自身免疫疾病包括急性肾小球性肾炎;类风湿性关节炎或反应性关节炎;慢性肾小球性肾炎;炎性肠病诸如克罗恩氏病、溃疡性结肠炎和坏死性小肠结肠炎;粒细胞输血相关的综合征;炎症性皮肤病诸如接触性皮炎、特应性皮炎、银屑病;全身性红斑狼疮(SLE)、自身免疫性甲状腺炎、多发性硬化、和一些形式的糖尿病、或其中受治疗者自身免疫系统的攻击导致病理学组织破坏的任何其它自身免疫状态。变应性反应包括变应性哮喘、慢性支气管炎、急性和延迟的过敏症。系统性炎症疾病状态包括外伤、烧伤、缺血事件后再灌注(如,心脏、脑、肠或外周脉管系统中的血栓形成事件,包括心肌梗塞和中风)相关的炎症、败血症、ARDS或多器官功能障碍综合征。炎性细胞募集也发生在动脉粥样硬化斑块中。炎症包括但不限于,非霍奇金淋巴瘤、韦格纳氏肉芽肿、桥本氏甲状腺炎、肝细胞癌、胸腺萎缩、慢性胰腺炎、类风湿性关节炎、反应性淋巴样增生、骨关节炎、溃疡性结肠炎、乳头状癌、克罗恩氏病、溃疡性结肠炎、急性胆囊炎、慢性胆囊炎、肝硬化、慢性涎腺炎、腹膜炎、急性胰腺炎、慢性胰腺炎、慢性胃炎、内在性子宫内膜异位症、子宫内膜异位症、急性宫颈炎、慢性宫颈炎、淋巴样增生、多发性硬化、特发性血小板减少性紫癜继发性的肥大、原发性IgA肾病、全身性红斑狼疮、银屑病、肺气肿、慢性肾盂肾炎和慢性膀胱炎。
心血管疾病或病症包括可导致缺血或由心脏再灌注引起的那些病症。实例包括但不限于,动脉硬化、冠状动脉病、巨细胞性心肌炎、慢性心肌炎(非肉芽肿性)、原发性肥大型心肌病、外周动脉病(PAD)、中风、心绞痛、心肌梗塞、心搏停止造成的心血管组织损伤、心脏旁路造成的心血管组织损伤、心源性休克、和本领域技术人员已知的相关病状或包括心脏或脉管系统的功能障碍或组织损伤的相关病状,尤其是但不限于,沉默调节基因3激活相关的组织损伤。CVS疾病包括但不限于,动脉硬化、肉芽肿性心肌炎、心肌梗塞、瓣膜性心脏病继发性心肌纤维化、无梗塞的心肌纤维化、原发性肥大性心肌病和慢性心肌炎(非肉芽肿性)。
多核苷酸和寡核苷酸组合物和分子
靶:在一个实施方案中,靶包括沉默调节蛋白(SIRT)的核酸序列,包括但不限于沉默调节蛋白(SIRT)相关的有义和/或反义的非编码和/或编码序列。
在一个实施方案中,靶包括SIRT1的核酸序列,包括但不限于与SIRT1基因相关的有义和/或反义的非编码和/或编码序列。
在一个实施方案中,靶包括SIRT2的核酸序列,包括但不限于与SIRT2基因相关的有义和/或反义的非编码和/或编码序列。
在一个实施方案中,靶包括SIRT3的核酸序列,包括但不限于与SIRT3基因相关的有义和/或反义的非编码和/或编码序列。
在一个实施方案中,靶包括SIRT4的核酸序列,包括但不限于与SIRT4基因相关的有义和/或反义的非编码和/或编码序列。
在一个实施方案中,靶包括SIRT5的核酸序列,包括但不限于与SIRT5基因相关的有义和/或反义的非编码和/或编码序列。
在一个实施方案中,靶包括SIRT6的核酸序列,包括但不限于与SIRT6基因相关的有义和/或反义的非编码和/或编码序列。
在一个实施方案中,靶包括SIRT7的核酸序列,包括但不限于与SIRT7基因相关的有义和/或反义的非编码和/或编码序列。
"SIRT1蛋白"是指沉默调节蛋白脱乙酰化酶的sir2家族的成员。在一个实施方案中,SIRT1蛋白包括酵母Sir2(GenBank登录号P53685)、秀丽隐杆线虫(C.elegans)Sir-2.1(GenBank登录号NP.sub.--501912)、人SIRT1(GenBank登录号NM.sub.—012238和NP.sub.--036370(或AF083106))。
SIRT1″沉默调节蛋白"是包括SIR2结构域(一个如在Pfam家族"SIR2"-PF02146(附于附录的)中被评分为命中的氨基酸序列定义的结构域)的蛋白质。该家族在INTERPRO数据库中被引用为INTERPRO说明(条目IPR003000)。为了鉴定"SIR2"结构域在蛋白质序列中的存在和作出目标多肽或蛋白质具有特定特征谱的决定,可使用缺省参数(http://www.sanger.ac.uk/Software/Pfam/HMM_search)针对HMM的Pfam数据库(例如,Pfam数据库,释放9)搜索蛋白质的氨基酸序列。SIR2结构域在Pfam中被索引为PF02146以及在INTERPRO中被索引为INTERPRO说明(条目IPR003000)。Pfam数据库的说明可见于"The PfamProtein Families Database"Bateman A等人(2002)Nucleic Acids Research 30(l):276-280和Sonhammer等人(1997)Proteins 28(3):405-420,并且HMM的详细描述可见于例如Gribskov等人(1990)Meth.Enzymol.183:146-159;Gribskov等人(1987)Proc.Natl.Acad.Sci.USA 84:4355-4358;Krogh等人(1994)J.Mol.Biol.235:1501-1531;和Stultz等人(1993)Protein Sci.2:305-314。
在线粒体沉默调节蛋白当中,SIRT3具有最强劲的脱乙酰化酶活性。事实上,与SIRT4或SIRT5敲除动物的肝中的线粒体蛋白质乙酰化水平相比较,在SIRT3为空值的小鼠的肝中检测到的显著更高的线粒体蛋白质乙酰化水平。然而,关于SIRT3的生理作用知之甚少,尽管已鉴定了许多SIRT3底物和共沉淀蛋白质:乙酰基辅酶A合成酶2、Ku70、FOXO3a、线粒体复合物I的亚基9(NDUFA9)、谷氨酸脱氢酶和异柠檬酸脱氢酶2。
SIRT3为主要的线粒体脱乙酰化酶。线粒体蛋白质在SIRT3敲除小鼠中显示超乙酰化,但在SIRT4或SIRT5敲除小鼠中未显示超乙酰化。乙酰基辅酶A合成酶2(AceCS2)(一种将乙酰盐转化成乙酰基辅酶A的线粒体酶)是第一个鉴定的SIRT3的线粒体底物。SIRT3在赖氨酸642上对AceCS2的脱乙酰基作用激活乙酰基辅酶A合成酶的活性,从而提供了增加的乙酰基辅酶A供给三羧酸循环。谷氨酸脱氢酶(GDH)(另一种参与能量产生的线粒体蛋白质)被SIRT3脱乙酰化。GDH也可被SIRT4 ADP-核糖基化,反过来降低其酶活性。这指示SIRT3可在细胞代谢中起重要作用。也已显示SIRT3参与选择性细胞凋亡途径和细胞生长控制。SIRT3和SIRT4,但非SIRT5,已牵涉与细胞存活相关的调控NAD+水平的补救途径。此外,已将hSIRT3基因的变异性与人长寿相联系。
沉默信息调节蛋白-2基因(Sir2)编码NAD-依赖性组蛋白脱乙酰化酶,该酶与酿酒酵母的染色质、基因组稳定性和寿命的调节相关。Sir2抑制数个基因座上的转录并且抑制核糖体DNA(rDNA)重复上的重组。在Sir2上具有突变的酵母在rDNA重组的背景中具有增强的基因组不稳定性,这反过来缩短复制的寿命–一种该生物体繁殖老化的标志。相反地,抑制rDNA重组的Sir2的额外拷贝增加复制的寿命。Sir2的此类作用促成其中通过染色质调节促进基因组稳定化的基因可以是调节生物体的寿命、衰老和年龄相关性病理学的重要贡献者的范例。
与Sir2因子在寿命调节中的保守作用一致,Sir2蛋白在多细胞生物秀丽隐杆线虫和黑腹果蝇中的增加的活性也增加寿命。然而,此类Sir2因子可通过不依赖于基因组稳定化的机制来起作用,并且它们的生理分子底物仍然不清楚。在哺乳动物中,存在7个Sir2家族成员SIRT1-SIRT7。SIRT一直以来作为哺乳动物寿命和年龄相关过程的候选调节剂而极具吸引力。在本说明书中,几种哺乳动物SIRT具有影响年龄相关分子途径和疾病的功能。然而,哺乳动物SIRT的初步研究使此类酶与与酿酒酵母Sir2的生物化学靶和细胞功能不同的生物化学靶和细胞功能联系起来。
沉默调节蛋白是酵母转录抑制因子Sir2p的同系物并且从细菌至人都是保守的。人SIRT4被定位在线粒体。SIRT4为基质蛋白质并且在输入线粒体后在氨基酸28上被切割。与SIRT4共沉淀的蛋白质的质谱分析鉴定了胰岛素降解酶和ADP/ATP载体蛋白、ANT2和ANT3。SIRT4未显示组蛋白脱乙酰化酶活性,但用作组蛋白和牛血清白蛋白的高效ADP-核糖基转移酶。SIRT4在胰岛中表达并且与表达胰岛素的β细胞共定位。从产生胰岛素的INS-1E细胞耗尽SIRT4导致响应葡萄糖的增加的胰岛素分泌。
沉默调节蛋白(沉默交配型信息调控2同系物)5(酿酒酵母),也称为SIRT5,是在人中由SIRT5基因和在其它物种中由Sirt5基因编码的蛋白质。该基因编码与酵母Sir2蛋白同源的许多蛋白质的沉默调节蛋白家族。沉默调节蛋白家族的成员的特征在于沉默调节蛋白核心结构域并且所述成员被分成4类。现在仍然未确定人沉默调节蛋白的功能;然而,已知酵母沉默调节蛋白调控表观遗传基因沉默和抑制rDNA的重组。研究表明人沉默调节蛋白可用作具有单-ADP-核糖基转移酶活性的细胞内调节蛋白质。由该基因编码的蛋白质包括在沉默调节蛋白家族的种类III中。该基因的选择性剪接导致两种转录变体。
哺乳动物SIRT6基因缺陷型小鼠的产生显示SIRT6在联系寿命、染色质和基因组稳定性的调节中的潜在作用。在本说明书中,小鼠的SIRT6缺乏导致显著缩短的寿命和与过早衰老的病理学重叠的急性变性表型。此外,SIRT6敲除小鼠细胞具有基因组不稳定性和DNA损伤超敏感性。在生物化学分级分离测定中,SIRT6蛋白优先与富含染色质的细胞级分缔合。综合起来,这些观察表明SIRT6可能将染色质调控与DNA修复相偶联。然而,迄今仍未证明SIRT6在这样的过程中的生理学作用。
最近已提出哺乳动物沉默调节蛋白(SIRT1-7)(酵母Sir2的同系物)参与关键代谢途径以及细胞凋亡、应激反应、DNA修复、细胞周期、基因组稳定性和基因表达的控制。沉默调节蛋白(也称为III类组蛋白脱乙酰基酶)为蛋白质脱乙酰基酶/ADP核糖基转移酶。此类酶从原核生物至真核生物高度保守。它们全都共有保守的NAD-依赖性催化核心结构域,并且显示促成它们的独特亚细胞定位的可变N末端和C末端延伸,并且还可调控它们的催化活性。沉默调节蛋白的亚细胞分布、底物特异性和细胞功能是相当多样的。SIRT2是主要的细胞质蛋白,SIRT3-5是线粒体蛋白质,SIRT7、-6和-7定位在细胞核中。SIRT7与酵母Sir2最密切相关并且为最详尽表征的沉默调节蛋白,具有许多底物(包括p53、Ku70、NF-κB和叉头转录因子),所述底物调节细胞氧化和遗传毒性应激。SIRT6牵涉在防止细胞的基因组不稳定性和类早老表型中的重要功能。此外,SIRT6为唯一的显示强劲的自身-ADP-核糖基转移酶活性的沉默调节蛋白。SIRT7为唯一的定位在核仁中的沉默调节蛋白。已显示当对乙酰化组蛋白和RNA Pol I机器的各种乙酰化组分进行测试时,其显示无脱乙酰基酶或ADP-核糖基转移酶活性。关于SIRT7的核仁功能,Ford等人提出SIRT7可以是通过其与RNA Pol I的缔合进行的rDNA转录的正调节剂。其过表面增加rDNA转录,然而其的抑制减少rDNA转录。有趣地,SIRT7的表达与细胞生长正相关:SIRT7在代谢活性组织诸如肝脏、脾脏和睾丸中非常丰富。迄今为止,没有关于SIRT7的细胞周期调控和其在有丝分裂过程中(此时rDNA转录被抑制)的命运的数据。
在一些实施方案中,反义寡核苷酸用来预防或治疗沉默调节蛋白(SIRT)家族成员相关的疾病或病症。可用从利用反义化合物获得的干细胞再生的细胞/组织治疗的示例性沉默调节蛋白(SIRT)介导的疾病和病症包括:与沉默调节蛋白的异常功能和/或表达相关的疾病或病症、癌症(例如,乳腺癌、结直肠癌、CCL、CML、前列腺癌)、神经变性疾病或病症(例如,阿尔茨海默病(AD)、亨廷顿氏病、帕金森病、肌萎缩性侧索硬化症(ALS)、多发性硬化和由聚谷氨酰胺聚集引起的病症)、β-淀粉样蛋白疾病或病症(例如,以β-淀粉样蛋白积聚为特征的病症诸如阿尔茨海默病)、骨骼肌疾病(例如,杜兴肌营养不良、骨骼肌萎缩症、贝克氏肌营养不良、或肌强直性营养不良);代谢性疾病或病症(例如,胰岛素抗性、糖尿病、2型糖尿病、肥胖症、葡萄糖耐量受损、代谢性综合征、成人发病型糖尿病、糖尿病性肾病、高血糖症、糖尿病性肾病、高胆固醇血症、血脂异常高脂血症和年龄相关代谢性疾病等)、与胰岛素调节受损相关的疾病或病症、神经病变(例如,感觉性神经病变、自发性神经病变、运动性神经病变、视网膜病变)、与酮体生成性病状相关的疾病或病症、与能量体内稳态相关的疾病或病症、与乙酰基辅酶A合成酶2活性受损相关的疾病或病症、与代谢性体内稳态相关的疾病或病症、脂质代谢疾病或病症、与产热受损相关的疾病或病症、与细胞分裂调节受损相关的疾病或病症、与线粒体功能障碍相关的疾病或病症、神经病变(例如,感觉性神经病变、自发性神经病变、运动性神经病变、视网膜病变)、纤维变性、炎症性心肌病变、心脏肥大、慢性炎症、动脉粥样硬化、关节炎、痴呆、骨质疏松症和心血管疾病或病症、肝疾病或病症(例如,由于酒精滥用或肝炎、脂肪肝疾病等)、年龄相关性黄斑变性、骨疾病(例如,骨质疏松症)、血液疾病(例如,白血病)、骨质吸收、年龄相关性黄斑变性、AIDS相关性痴呆、ALS、贝尔氏麻痹、动脉粥样硬化、心脏疾病或病症(例如,心脏节律紊乱、慢性充血性心力衰竭、缺血性中风、冠状动脉疾病和心肌病)、慢性退行性疾病(例如,心肌疾病)、慢性肾衰竭、2型糖尿病、溃疡、白内障、远视、肾小球肾炎、吉兰-巴雷综合征(Guillan-Barre syndrome)、出血性中风、类风湿性关节炎、炎性肠病疾病、SLE、克罗恩氏病、骨关节炎、骨质疏松症、慢性阻塞性肺病(COPD)、肺炎、皮肤老化、皮肤疾病或病症、尿失禁、与线粒体功能障碍相关的疾病或病症(例如,线粒体肌病变、脑病、利伯(Leber)疾病、利(Leigh)脑病、皮尔森氏病(Pearson's disease)、乳酸性酸中毒、‘线粒体脑病、乳酸性酸中毒和中风样症状’(MELAS)等)、肝变性、骨骼肌变性、肌肉疾病或病症、炎症、与异位脂质沉积相关的疾病或病症、与氧化性应激相关的疾病或病症、与细胞应激相关的疾病或病症、与神经元细胞死亡相关的疾病或病症、老化或以不必要细胞损耗为特征的其它病状、退行性综合征、与氨解毒相关的病或病症、衰老、与端粒功能障碍相关的疾病或病症、与染色质调节受损相关的疾病或病症、与早熟细胞衰老相关的疾病或病症、与SIRT介导的DNA修复受损相关的疾病或病症和以不必要细胞损耗为特征的病状。
已报道沉默调节蛋白调节TNF-α活性,如描述于例如美国专利申请公布No.2010/0137345,“Prophylactic and therapeutic use of sirtuininhibitors in TNF-alphamediated pathologies”,其通过引用整体并入本文。在实施方案中,本发明的反义寡核苷酸用于调节沉默调节蛋白,例如SIRT 6,以治疗TNF-α-介导的病症或疾病。TNF-α-介导病症或疾病包括,例如强直性脊柱炎、动脉粥样硬化、炎性肠疾病(IBD)(包括克罗恩氏病和溃疡性结肠炎)、银屑病、银屑病性关节炎或类风湿关节炎、恶病质、革兰阴性脓毒症、内毒素诱导的休克、脓毒性休克综合征、全身性炎性反应综合征(SIRS)或多器官功能紊乱综合征(MODS);和/或移植物抗宿主病理学(包括反应移植物抗宿主病(GVHD)和移植的异种或同种异体组织或器官的排斥);和/或急性或慢性感染性或寄生性过程(包括病毒、细菌或真菌感染和原生动物或后生动物寄生虫感染,优选脑疟疾或脑膜炎球菌性脑膜炎);和/或变应性病症(包括变应性鼻炎、变应性结膜炎、哮喘、湿疹、荨麻疹、接触性皮炎、全身性变应性应答(过敏性反应)和过敏性休克、变应性鼻炎或哮喘、急性播散性脑脊髓炎(ADEM));Addison's疾病;强直性脊柱炎;抗磷脂抗体综合征(APS);再生障碍性贫血;动脉粥样硬化;自身免疫性胃炎;自身免疫性肝炎;自身免疫性血小板减少症;Behcet's疾病;腹腔疾病;皮肌炎;I型糖尿病;II型糖尿病;家族性地中海热;家族性冷诱导自身炎症综合征;古德帕斯彻氏综合征(Goodpasture's syndrome);痛风;假痛风;格雷夫斯氏病;吉兰-巴雷巴利综合征(Guillain-Barre syndrome)(GBS);桥本氏疾病;遗传性周期性发热;特发性血小板减少性紫癜;炎性肠病(IBD)(包括克罗恩氏病和溃疡性结肠炎);缺血-再灌注损伤;Kawasaki's疾病;混合结缔组织疾病;穆-韦二氏综合征(Muckle-Wells syndrome);多发性硬化(MS);重症肌无力;夜间肌阵挛综合征(OMS);视神经炎;奥德氏甲状腺炎;骨关节炎;天疱疮;恶性贫血;结节性多发性动脉炎;多肌炎;术后或创伤性炎症;原发性胆汁性肝硬变;primarymyoxedema;银屑病;银屑病性关节炎;风湿热;类风湿性关节炎;莱特尔综合征;硬皮病;干燥综合征(Sjogren's syndrome);中风-缺血(stroke-ischemia);系统性红斑狼疮(SLE);全身型幼年特发性关节炎;高安氏动脉炎;颞动脉炎;白癫风;温热自身免疫性溶血性贫血;和韦格纳氏肉芽肿。
在另一个实施方案中,反义寡核苷酸调节遭受与沉默调节蛋白(SIRT)相关的疾病或病症或处于形成所述疾病或病症的危险的患者中沉默调节蛋白(SIRT)的正常表达和/或正常功能。
在本发明的实施方案中,给需要皮肤治疗或存在他们为此需要皮肤治疗的发展中病状的风险的受治疗者提供治疗和/或美容方法和相关的特定治疗。可例如基于受治疗者SIRT状态进行诊断。患者给定组织例如皮肤中的SIRT表达水平可通过本领域技术人员已知的方法和本文别处所述的方法来确定,例如通过使用PCR或基于抗体的检测方法来分析组织。
本发明的优选实施方案提供一种用于皮肤治疗和/或美容应用的组合物,所述组合物包含SIRT反义寡核苷酸例如以上调SIRT在皮肤中的表达。反义寡核苷酸的实例如SEQID NOS:24至127所列。通过引用并入本文的美国专利No.7,544,497“Compositionsformanipulating the lifespan and stress response of cells and organisms”描述了通过降低沉默调节蛋白对其底物的Km而调节沉默调节蛋白活性的试剂的潜在美容用途。在实施方案中,通过本发明的寡核苷酸体内处理细胞来增加细胞寿命、预防细胞凋亡。例如,如本文所述,通过处理皮肤(例如上皮细胞)可以保护皮肤避免衰老,例如起皱纹。在一个示例性实施方案中,使皮肤与包含本文所述的SIRT反义化合物的药物组合物或美容组合物相接触。示例性皮肤折磨或皮肤状况包括与炎症、晒伤或自然衰老有关的病症或疾病或者由炎症、晒伤或自然衰老所导致的病症或疾病。例如,所述组合物在预防和治疗接触性皮炎(包括刺激性接触性皮炎和过敏性接触性皮炎)、遗传过敏性皮炎(也称作过敏性湿疹)、光化性角化病、角质化病症(包括湿疹)、大疱性表皮松解症(包括天疱疮)、剥脱性皮炎、脂溢性皮炎、红斑(包括多形性红斑和结节性红斑)、由于太阳或其他光源所导致的损伤、盘状红斑狼疮、皮肌炎、皮肤癌以及自然衰老效应中有效。
已报道沉默调节蛋白干扰双氢睾酮诱导的雄激素受体信号传导。(参见,例如,Fu等人,2006,“Hormonal Control of Androgen ReceptorFunction through SIRT1,”Molecular and Cellular Biology 26(21):8122–8135,其通过引用并入本文)。在本发明的实施方案中,包含SIRT反义寡核苷酸的组合物例如上调SIRT在头皮中的表达并且抑制雄激素受体发信号,由此防止雄激素性脱发(头发脱落)。在实施方案中,以局部制剂或全身制剂施用给患有脱发的患者。在实施方案中,将本文所述的反义寡核苷酸掺合至包含通常适于局部药物施用的局部载体以及包括本领域内公知的任何此类物质的局部制剂中。所述局部载体可以如此选择以便以所需形式(例如以软膏剂、洗剂、乳膏剂、微乳剂、凝胶剂、油剂、溶液等形式)提供组合物,并且可以由天然存在或合成来源的物质组成。优选的是所选载体不会对局部制剂中的有效剂或其他组份造成不利影响。适于本文使用的局部载体的例子包括水、醇、其他的无毒有机溶剂、甘油、矿物油、硅酮、石油膏、羊毛脂、脂肪酸、植物油、尼泊金类、蜡类等。制剂可以是无色无味的软膏剂、洗剂、乳膏剂、微乳剂和凝胶剂。
本发明的反义寡核苷酸可以掺入到软膏剂中,所述软膏剂通常为代表性地基于凡士林和其他凡士林衍生物的半固体制剂。如那些本领域技术人员所领会到的,所使用的特定的软膏剂基质用于提供最适宜的药物递送,优选是提供其他所需要的特性(例如柔润性等)。如同其他载体或媒介物那样,软膏剂基质应该是惰性的、稳定的、无刺激性的和非致敏性的。如Remington's Pharmaceutical Sciences(Mack Pub.Co.)中解释的那样,软膏剂基质可分为四类:油性基质;可乳化基质;乳剂基质;和水溶性基质。油性软膏剂基质包括例如植物油、源自动物的脂肪和源自石油的半固体烃类。可乳化软膏剂基质也称作可吸收的软膏剂基质,包含很少的水或者不含水,并且包括例如硫酸羟基硬脂精、无水羊毛脂和吸水性凡士林。乳剂软膏剂基质是油包水(W/O)乳剂或水包油(O/W)乳剂中的任一种,并且包括例如鲸蜡醇、单硬脂酸甘油酯、羊毛脂和硬脂酸。示例性水溶性软膏剂基质由不同分子量(例如参见Remington's,同上)的聚乙二醇(PEG)制备。
本发明的反义寡核苷酸可以掺合到洗剂中,所述洗剂通常是没有摩擦地应用于皮肤表面的制剂,并且典型地为液体或半液体制剂,其中包括活性剂的固体颗粒存在于水或醇基质中。洗剂经常是固体的混悬剂,可以包括水包油型的液体-油状乳剂。由于易于应用更多液体的组合物,因而洗剂优选是用于治疗大身体面积的制剂。通常需要洗剂中的不溶物质被很好地分开。洗剂典型地包含用于产生良好分散的助悬剂以及对于局部化活性剂并保持其与皮肤接触有用的化合物,例如甲基纤维素、羧甲基纤维素钠等。与目前方法结合使用的示例性洗剂制剂包含混合有吸水性凡士林的丙二醇,其可以以商标AquaphorRTM由拜尔斯道夫公司(Beiersdorf,Inc.)(Norwalk,Conn.)获得。
本发明的反义寡核苷酸可以掺合到乳膏剂中,所述乳膏剂通常为粘性的液体或者半固体乳剂,可以是水包油或油包水乳剂的任一种。乳膏剂基质是可水洗的,并且包含油相、乳化剂和水相。该油相通常由凡士林和脂肪醇如鲸蜡醇或硬脂醇构成;该水相经常但并非必须在体积上超过油相,并且通常包含润湿剂。如Remington's,同上所解释的那样,乳膏剂制剂中的乳化剂通常是非离子型、阴离子型、阳离子型或两性表面活性剂。
本发明的反义寡核苷酸可以掺合到微乳剂中,所述微乳剂通常是热力学上稳定的、两种不混溶液体(如油和水)的各向同性地透明的分散体,通过表面活性剂分子的界面膜得以稳定(Encyclopedia ofPharmaceutical Technology(New York:Marcel Dekker,1992),卷9)。对于微乳剂的制备,需要表面活性剂(乳化剂)、共表面活性剂(共乳化剂)、油相和水相。适合的表面活性剂包括任何在制备乳剂中有用的表面活性剂,例如典型地用于制备乳膏剂的乳化剂。所述共表面活性剂(或"共乳化剂")通常选自聚甘油衍生物、丙三醇衍生物和脂肪醇。优选的乳化剂/共乳化剂组合通常但并非必须选自:单硬脂酸甘油酯和聚氧乙烯硬脂酸酯;聚乙二醇和硬脂酸棕榈酸乙二醇酯;辛酸甘油三酯和癸酸甘油三酯以及油酰基聚乙二醇甘油酯。水相不仅包括水,还典型地包括缓冲液、葡萄糖、丙二醇、聚乙二醇,优选低分子量聚乙二醇(例如PEG 300和PEG 400)和/或丙三醇等,而油相通常包括如脂肪酸酯、改性植物油、硅酮油、甘油单酯和甘油二酯和甘油三酯的混合物、PEG的单酯和二酯(例如油酰基聚乙二醇甘油酯)等。
本发明的反义寡核苷酸可以掺合到凝胶制剂中,所述凝胶制剂通常是包含由小的无机颗粒构成的悬浮液(双相系统)或基本上均匀地分布在载体溶液中的大的有机分子(单相凝胶)的半固体系统。单相凝胶可如下制作:例如通过将所述活性剂、载体液体、适合的胶凝剂,如黄蓍胶(2-5%)、藻酸钠(2-10%)、明胶(2-15%)、甲基纤维素(3-5%)、羧甲基纤维素钠(2-5%)、卡波姆(0.3-5%)或聚乙烯醇(10-20%)组合在一起并且混合直至产生特征性半固体产物。其他适合的胶凝剂包括羟甲基纤维素、聚氧乙烯-聚氧丙烯、羟乙基纤维素和明胶。尽管凝胶通常采用水性载体液体,但醇和油也可用作载体液体。
本领域技术人员所熟知的各种添加剂也可包括在制剂中,例如局部制剂。添加剂的例子包括但不限于增溶剂、透皮促渗剂、遮光剂、防腐剂(例如抗氧化剂)、胶凝剂、缓冲剂、表面活性剂(特别是非离子型和两性表面活性剂)、乳化剂、软化剂、增稠剂、稳定剂、润湿剂、着色剂、芳香剂(fragrance)等。特别优选与乳化剂、软化剂和防腐剂一起,含有增溶剂和/或透皮促渗剂。最佳的局部制剂主要包括:约2wt.%~60wt.%、优选2wt.%~50wt.%的增溶剂和/或透皮促渗剂;2wt.%~50wt.%、优选2wt.%~20wt.%的乳化剂;2wt.%~20wt.%的软化剂;和0.01~0.2wt.%防腐剂,以及制备所述制剂剩余部分的活性剂和载体(例如水)。
透皮促渗剂对促进治疗水平的活性剂通过合理大小面积的完整皮肤有用。适合的促进剂在本领域是熟知的,包括例如链烷醇(如甲醇、乙醇和2-丙醇);烷基甲基亚砜(如二甲基亚砜(DMSO)、癸基甲基亚砜(C10MSO)和十四烷基甲基亚砜);吡咯烷酮(如2-吡咯烷酮,N-甲基-2-吡咯烷酮和N-(-羟基乙基)吡咯烷酮);脲;N,N-二乙基-间甲苯酰胺;C2-C6链烷二醇;混溶性溶剂(如二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺(DMA)和四氢呋喃甲醇);1-取代的氮杂环庚烷-2-酮,特别是1-正十二烷基环氮杂环庚烷-2-酮(月桂氮酮);以商标AzoneRTM可由Whitby Research股份有限公司(Richmond,Va)获得。
增溶剂的例子包括但不限于以下物质:亲水性醚,如二乙二醇单乙醚(乙氧基二甘醇,可以TranscutolRTM市售可得)和二乙二醇单乙醚油酸酯(可以SoficutolRTM市售可得);聚乙烯蓖麻油衍生物,如聚氧乙烯(35)蓖麻油、聚氧乙烯(40)氢化蓖麻油等;聚乙二醇,特别是低分子量聚乙二醇,如PEG 300和PEG 400,以及聚乙二醇衍生物,如PEG-8辛酸/癸酸甘油酯(可以LabrasolRTM市售可得);烷基甲基亚砜,如DMSO;吡咯烷酮,如2-吡咯烷酮、N-甲基-2-吡咯烷酮;和DMA。很多增溶剂还可作为吸收促进剂发挥作用。可将单独的增溶剂掺合至制剂中,或者可以将增溶剂的混合物掺合至制剂中。
合适的乳化剂和共乳化剂包括但不限于那些关于微乳剂制剂所描述的乳化剂和共乳化剂。软化剂包括例如丙二醇、丙三醇、肉豆蔻酸异丙酯、聚丙二醇-2(PPG-2)肉豆蔻基醚丙酸酯等。
其他的活性剂也可包含在制剂中,例如其它抗炎药、止痛药、抗菌剂、抗真菌剂、抗生素、维生素、抗氧化剂、以及通常在防晒制剂中发现的防晒剂,所述防晒剂包括但不限于邻氨基苯甲酸盐、二苯甲酮(特别是二苯甲酮-3)、樟脑衍生物、肉桂酸酯(例如甲氧基肉桂酸辛酯)、二苯甲酰甲烷(例如丁基甲氧基二苯甲酰甲烷)、对氨基苯甲酸(PABA)及其衍生物、以及水杨酸盐(例如水杨酸辛酯)。
在实施方案中,寡核苷酸是对沉默调节基因(SIRT)多核苷酸有特异性,该多核苷酸包括但不限于非编码区。沉默调节基因(SIRT)靶包括沉默调节基因(SIRT)的变体;沉默调节基因(SIRT)的突变体,包括SNP;沉默调节基因(SIRT)的非编码序列;等位基因、片段和类似物。优选地寡核苷酸是反义RNA分子。
根据本发明的实施方案,靶核酸分子不限于仅沉默调节基因(SIRT)多核苷酸,还延伸到沉默调节基因(SIRT)的任何同种型、受体、同系物、非编码区和类似物。
在另一个实施方案中,寡核苷酸靶向沉默调节基因(SIRT)靶的天然反义序列(与编码区和非编码区天然反义),包括但不限于,其变体、等位基因、同系物、突变体、衍生物、片段及其互补序列。优选地寡核苷酸是反义RNA或DNA分子。
在另一个实施方案中,本发明的寡聚化合物还包括变体,其中在化合物中一个或多个核苷酸位置存在不同碱基。例如,如果第一个核苷酸是腺嘌呤,可产生在这一位置包含胸苷、鸟苷、胞苷或其它天然或非天然核苷酸的变体。这可在反义化合物的任何位置进行。
在一些实施方案中,反义化合物与靶之间的同源性、序列同一性或互补性是从约50%至约60%。在一些实施方案中,同源性、序列同一性或互补性是从约60%至约70%。在一些实施方案中,同源性、序列同一性或互补性是从约70%至约80%。在一些实施方案中,同源性、序列同一性或互补性是从约80%至约90%。在一些实施方案中,同源性、序列同一性或互补性是约90%、约92%、约94%、约95%、约96%、约97%、约98%、约99%或约100%。
当反义化合物与靶核酸的结合干扰靶核酸的正常功能以导致活性的丧失时,该化合物是可特异性杂交的,且在期望特异性结合的条件下存在足够程度的互补性以避免反义化合物与非靶核酸序列的非特异性结合。这种条件包括,即,在体内测定或治疗性治疗的情形中的生理条件以及在体外测定的情形中进行测定的条件。
当反义化合物(无论是DNA、RNA、嵌合、取代的等等)与靶DNA或RNA分子的结合干扰靶DNA或RNA的正常功能以导致效用的丧失时,该化合物是可特异性杂交的,且在期望特异性结合的条件下(即,在体内测定或治疗性治疗的情形中的生理条件下以及在体外测定的情形中进行测定的条件下)存在足够程度的互补性以避免反义化合物与非靶序列的非特异性结合。
在另一个实施方案中,沉默调节基因(SIRT)的靶向包括但不限于,利用例如PCR、杂交等鉴定和扩展的反义序列、一种或多种如SEQ ID NO:9至23、141至143所列的序列和调节沉默调节基因(SIRT)表达或功能的类似物。在一个实施方案中,与对照相比表达或功能被上调。在另一个实施方案中,与对照相比表达或功能被下调。
在另一个实施方案中,寡核苷酸包括如SEQ ID NO:24至127所列的核酸序列,包括利用例如PCR、杂交等鉴定和扩展的反义序列。这些寡核苷酸可包括一种或多种修饰的核苷酸、更短或更长的片段、修饰的键和类似物。修饰的键或核苷酸间键合的实例包括硫代磷酸酯、二硫代磷酸酯或类似物。在另一个实施方案中,核苷酸包括磷衍生物。可附加于本发明的修饰的寡核苷酸中的糖或糖类似物部分的磷衍生物(或修饰的磷酸酯基团)可以是单磷酸酯、二磷酸酯、三磷酸酯、磷酸烷基酯、磷酸烷烃酯、硫代磷酸酯和类似物。上述磷酸酯类似物的制备和将其向核苷酸、修饰的核苷酸和寡核苷酸的并入本身是已知的,不必在此描述。
反义的特异性和灵敏性还由本领域技术人员利用以用于治疗用途。反义寡核苷酸已在动物和人的疾病状态的治疗中用作治疗部分。反义寡核苷酸已经安全且有效地施用于人,目前正在进行许多临床试验。因此已经确定,寡核苷酸可以是有用的治疗形态,可被配置以用于治疗细胞、组织和动物(尤其是人)的治疗方案。
在本发明的实施方案中,寡聚反义化合物,尤其是寡核苷酸,结合靶核酸分子并调节靶基因编码的分子的表达和/或功能。待干扰的DNA的功能包括,例如复制和转录。待干扰的RNA功能包括所有重要功能,例如RNA向蛋白翻译位置的移位,从RNA翻译为蛋白,剪接RNA以产生一种或多种mRNA种类以及可由RNA参与或促进的催化活性。取决于期望的功能,功能可被上调或抑制。
反义化合物包括反义寡聚化合物、反义寡核苷酸、外部指导序列(EGS)寡核苷酸、可选剪接体、引物、探针以及与靶核酸的至少一部分杂交的其它寡聚化合物。因此,这些化合物可以单链、双链、部分单链或环状寡聚化合物的形式引入。
在本发明范畴中,将反义化合物靶向特定核酸分子可以是多步骤的过程。该过程通常开始于鉴定待调节其功能的靶核酸。这一靶核酸可以是,例如,其表达与特定病症或疾病状态相关的细胞基因(或从基因转录的mRNA)或来自感染物的核酸分子。在本发明中,靶核酸编码性激素集合球蛋白沉默调节蛋白(SIRT)。
靶向过程通常还包括确定靶核酸中发生反义相互作用从而产生期望作用例如调节表达的至少一个靶区域、区段或位置。在本发明范畴中,术语"区域"定义为具有至少一种可鉴定结构、功能或特征的靶核酸的一部分。靶核酸区域中是区段。"区段"定义为靶核酸中较小区域或区域的亚部分。本发明中使用的"位置"定义为靶核酸中的位置。
在一个实施方案中,反义寡核苷酸结合沉默调节蛋白(SIRT)的天然反义序列并调节沉默调节蛋白(SIRT)(SEQ ID NO:1至23和133至143)的表达和/或功能。反义序列的实例包括SEQ ID NO:24至127。
在另一个实施方案中,反义寡核苷酸结合沉默调节蛋白(SIRT)多核苷酸的一个或多个区并调节沉默调节蛋白(SIRT)的表达和/或功能。区段包括沉默调节蛋白(SIRT)的有义或反义多核苷酸的至少五个连续核苷酸。
在另一个实施方案中,反义寡核苷酸是对沉默调节蛋白(SIRT)的天然反义序列有特异性,其中寡核苷酸对沉默调节蛋白(SIRT)的天然反义序列的结合调节沉默调节蛋白(SIRT)的表达和/或功能。
在另一个实施方案中,寡核苷酸化合物包括如SEQ ID NO:24至127所列的序列、利用例如PCR、杂交等鉴定和扩展的反义序列。这些寡核苷酸可包括一种或多种修饰的核苷酸、更短或更长的片段、修饰的键和类似物。修饰的键或核苷酸间键合的实例包括硫代磷酸酯、二硫代磷酸酯或类似物。在另一个实施方案中,核苷酸包括磷衍生物。可附加于本发明的修饰的寡核苷酸中的糖或糖类似物部分的磷衍生物(或修饰的磷酸酯基团)可以是单磷酸酯、二磷酸酯、三磷酸酯、磷酸烷基酯、磷酸烷烃酯、硫代磷酸酯和类似物。上述磷酸酯类似物的制备和将其向核苷酸、修饰的核苷酸和寡核苷酸的并入本身是已知的,不必在此描述。
如本领域已知的,因为翻译起始密码子通常是5'-AUG(在转录的mRNA分子中;在相应DNA分子中是5'-ATG),翻译起始密码子也称为"AUG密码子"、"起始密码子"或"AUG起始密码子"。少数基因具有具有RNA序列5'-GUG、5'-UUG或5'-CUG的翻译起始密码子;且5'-AUA、5'-ACG和5'-CUG已显示在体内起作用。因此,术语"翻译起始密码子"和"起始密码子"可涵盖许多密码子序列,尽管每种情形中的起始氨基酸通常是甲硫氨酸(真核细胞中)或甲酰甲硫氨酸(原核细胞中)。真核基因和原核基因可具有两个或更多个替代性起始密码子,其中的任何一个可在特定细胞类型或组织中或在特定条件设置下优先地用于翻译起始。在本发明范畴中,"起始密码子"和"翻译起始密码子"是指体内用于起始从编码沉默调节蛋白(SIRT)的基因转录的mRNA的翻译的一种或多种密码子,而不论这种密码子的序列。基因的翻译终止密码子(或"终止密码子")可具有三种序列即5'-UAA、5'-UAG和5'-UGA之一(相应的DNA序列分别是5'-TAA、5'-TAG和5'-TGA)。
术语"起始密码子区"和"翻译起始密码子区"是指这种mRNA或基因的一部分,涵盖以任一方向(即,5'或3')从翻译起始密码子的约25至约50个连续核苷酸。类似地,术语"终止密码子区"和"翻译终止密码子区"是指这种mRNA或基因的一部分,涵盖以任一方向(即,5'或3')从翻译终止密码子的约25至约50个连续核苷酸。因此,"起始密码子区"(或"翻译起始密码子区")和"终止密码子区"(或"翻译终止密码子区")都是可用本发明的反义化合物有效地靶向的区域。
本领域已知开放读码框(ORF)或"编码区"是指翻译起始密码子与翻译终止密码子之间的区域,也是可被有效地靶向的区域。在本发明范畴中,靶向的区域是涵盖基因开放读码框(ORF)的翻译起始或终止密码子的基因内区域。
另一靶区域包括5′非翻译区(5'UTR),本领域已知是指mRNA以5'方向从翻译起始密码子的部分,因此包括mRNA的5'帽位置与翻译起始密码子之间的核苷酸(或基因上相应的核苷酸)。又一靶区域包括3′非翻译区(3'UTR),本领域已知是指mRNA以3'方向从翻译终止密码子的部分,因此包括mRNA的翻译终止密码子与3'端之间的核苷酸(或基因上相应的核苷酸)。mRNA的5'帽位置包括经由5'-5'三磷酸酯键合与mRNA的最5'残基连接的N7-甲基化鸟苷残基。认为mRNA的5'帽区域包括5'帽结构本身以及与帽位置相邻的前50个核苷酸。本发明的另一靶区域是5'帽区域。
SIRT1的其它靶区域包括反义转录物CV396200的核苷酸65至85,和221至253。在实施方案中,调节SIRT1多核苷酸的功能和/或表达的方法包括将细胞或组织与靶向这些区域中的一个或多个的至少一种反义寡核苷酸,部分或整体地接触。在某些实施方案中,使用靶向这些区域中的一个或多个的反义寡核苷酸和靶向其它沉默调节蛋白的一个或多个反义转录物的组合。在实施方案中,组合使用靶向SIRT不同区域的多种反义寡核苷酸,或组合施用靶向一个或多个不同SIRT区域的多种反义寡核苷酸。
尽管一些真核mRNA转录物被直接翻译,但是许多包含一个或多个称为"内含子"的区域,在翻译前从转录物切除。其余(因此被翻译的)区域称为"外显子",被剪接在一起以形成连续的mRNA序列。在一个实施方案中,靶向剪接位置,即,内含子-外显子结点或外显子-内含子结点在其中疾病中牵涉异常剪接的情形或其中疾病中牵涉特定剪接产物的过度产生的情形尤其有用。由于重排或缺失的异常融合结点是靶位置的另一形式。由剪接来自不同基因来源的两个(或更多个)mRNA的过程产生的mRNA转录物称为"融合转录物"。利用靶向例如DNA或前体mRNA的反义化合物可有效地靶向内含子。
在另一个实施方案中,反义寡核苷酸结合靶多核苷酸的编码区和/或非编码区并调节靶分子的表达和/或功能。
在另一个实施方案中,反义寡核苷酸结合天然反义多核苷酸并调节靶分子的表达和/或功能。
在另一个实施方案中,反义寡核苷酸结合有义多核苷酸并调节靶分子的表达和/或功能。
可从DNA的相同基因组区域产生可选RNA转录物。这些可选转录物通常称为"变体"。更具体地,"前体mRNA变体"是从相同基因组DNA产生的转录物,在其起始或终止位置与从相同基因组DNA产生的其它转录物不同,并包含内含子序列和外显子序列两者。
在剪接期间切除一个或多个外显子或内含子区域或其部分后,前体mRNA变体产生更小的"mRNA变体"。因此,mRNA变体是加工的前体mRNA变体,且每个独特的前体mRNA变体必定因为剪接而产生独特的mRNA变体。这些mRNA变体还称为"可选剪接变体"。如果不进行前体mRNA变体的剪接,则前体mRNA变体与mRNA变体相同。
变体可经由使用可选信号产生以起始或终止转录。前体mRNA和mRNA可具有多于一个起始密码子或终止密码子。来源于使用可选起始密码子的前体mRNA或mRNA的变体称为该前体mRNA或mRNA的"可选起始变体"。使用可选终止密码子的那些转录物称为该前体mRNA或mRNA的"可选终止变体"。一种特定类型的可选终止变体是"聚腺苷酸变体",其中产生的多个转录物由"聚腺苷酸终止信号"之一被转录机制可选选择所致,从而产生在独特聚腺苷酸位点终止的转录物。在本发明范畴中,本文所述的变体类型也是靶核酸的实施方案。
靶核酸上与反义化合物杂交的位置定义为活性反义化合物靶向的靶区域的至少5-核苷酸长的部分。
尽管本文列出了某些示例性靶区段的具体序列,但是本领域技术人员将理解这些用于阐释和描述于本发明范围中的具体实施方案。本领域普通技术人员考虑到本公开内容可容易地鉴定另外的靶区段。
认为包括选自示例性优选的靶区段中的至少五(5)个连续核苷酸的段的长度为5-100个核苷酸的靶区段也适合于靶向。
靶区段可包括包括从示例性的靶区段之一的5'-末端的至少5个连续核苷酸的DNA或RNA序列(其余核苷酸为从靶区段5'-末端的紧邻上游开始的相同DNA或RNA的连续段并延伸直到DNA或RNA包含约5至约100个核苷酸)。类似地,靶区段由包括从示例性的靶区段之一的3'-末端的至少5个连续核苷酸的DNA或RNA序列代表(其余核苷酸为从靶区段3'-末端的紧邻下游开始的相同DNA或RNA的连续段并延伸直到DNA或RNA包含约5至约100个核苷酸)。借助本文所示例的靶区段的本领域技术人员将能够鉴定另外的靶区段而不需过度试验。
已经鉴定出一种或多种靶区域、区段或位置后,选择与靶足够地互补,即,充分良好并以足够特异性杂交的反义化合物以获得期望作用。
在本发明的实施方案中,寡核苷酸结合特定靶的反义链。寡核苷酸长度为至少5个核苷酸并可合成以使每个寡核苷酸靶向重叠序列,从而寡核苷酸被合成以覆盖靶多核苷酸的整个长度。靶还包括编码区以及非编码区。
在一个实施方案中,反义寡核苷酸靶向特定核酸。将反义化合物靶向特定核酸是多步骤的过程。该过程通常开始于鉴定待调节其功能的核酸序列。这一核酸序列可以是,例如,其表达与特定病症或疾病状态相关的细胞基因(或从基因转录的mRNA)、或非编码多核苷酸,例如非编码RNA(ncRNA)。
RNA可分为(1)信使RNA(mRNA),其被翻译为蛋白,和(2)非蛋白编码RNA(ncRNA)。ncRNA包括微RNA、反义转录物和包含高密度终止密码子和缺少任何广泛的"开放读码框"的其它转录单位(TU)。许多ncRNA表现为从蛋白-编码基因座的3′非翻译区(3'UTR)中的起始位点开始。ncRNA通常是罕见的,已被FANTOM财团测序的ncRNA的至少一半似乎不是多腺苷酸化的。出于明显的原因,大多数研究者集中于被加工并输出到细胞质的多腺苷酸化mRNA。最近,显示非多腺苷酸化的核RNA的组可能是非常大的,且许多这样的转录物来源于所谓的基因间区。ncRNA可调节基因表达的机制是通过与靶转录物的碱基配对。通过碱基配对起作用的RNA可分为(1)顺式编码的RNA,其在它们所作用的RNA的相同遗传位置但在相对链上被编码,因此与其靶展示极佳的互补性,和(2)反式编码的RNA,其在不同于它们所作用的RNA的染色体位置被编码,通常不与其靶展示极佳的碱基-配对可能。
不希望受限于理论,反义多核苷酸被本文所述的反义寡核苷酸的扰动可改变相应有义信使RNA的表达。然而,这一调节可以是不一致的(反义敲低导致信使RNA升高)或一致的(反义敲低导致相伴的信使RNA减少)。在这些情形中,反义寡核苷酸可靶向于反义转录物的重叠或非重叠部分,导致其敲低或隔离。编码以及非编码反义可以相同方式靶向,任一种类能够调节相应的有义转录物-以一致的或不一致的方式。鉴定针对靶使用的新寡核苷酸中采用的策略可基于反义RNA转录物被反义寡核苷酸的敲低或调节期望靶的任何其它手段。
策略1:在不一致调节的情形下,敲低反义转录物升高常规(有义)基因的表达。如果后者基因编码已知或推测的药物靶,则其反义对应物的敲低能够可设想地模拟受体激动剂或酶刺激剂的作用。
策略2:在一致调节的情形下,人们可以协同地敲低反义转录物和有义转录物两者,从而实现常规(有义)基因表达的协同减少。例如,如果反义寡核苷酸用来实现敲低,则这一策略可用来施加靶向有义转录物的一种反义寡核苷酸和靶向相应反义转录物的另一反义寡核苷酸,或同时靶向重叠的有义转录物和反义转录物的单个有力地对称的反义寡核苷酸。
根据本发明,反义化合物包括反义寡核苷酸、核酶、外部指导序列(EGS)寡核苷酸、siRNA化合物、单链或双链RNA干扰(RNAi)化合物例如siRNA化合物以及杂交于靶核酸的至少一部分并调节其功能的其它寡聚化合物。因此,它们可以是DNA、RNA、DNA-样、RNA-样或其混合物,或可以是一种或多种这些的模拟物。这些化合物可以是单链、双链、环状或发夹寡聚化合物,并可包含结构元件,例如内部凸出或末端凸出、错配或环。常规线性地制备反义化合物,但可被连接或以其它方式制备为环状和/或分支的。反义化合物可包括构建体,例如,两条链杂交以形成完全或部分双链的化合物或者具有足够自互补性的单链以允许杂交和形成完全或部分双链的化合物。两条链可在内部被连接,留下游离的3'或5'末端,或可被连接以形成连续的发夹结构或环。发夹结构可包含在5'或3'末端的突出,产生单链特征的延伸段。双链化合物任选地可包括在末端的突出。进一步的修饰可包括附加于末端之一、所选的核苷酸位置、糖位置或核苷间键合之一的缀合物基团。可选地,两条链可经由非核酸部分或接头基团连接。当仅由一条链形成时,dsRNA可采取自互补发夹型分子的形式,其与自身对折以形成双链体。因此,dsRNA可以是完全或部分双链的。基因表达的特异性调节可通过在转基因细胞系中稳定表达dsRNA发夹来实现,然而,在一些实施方案中,基因表达或功能被上调。当由两条链或采取与自身对折以形成双链体的自互补发夹型分子形式的单链形成时,两条链(或单链的双链体形成区)是以Watson-Crick方式碱基配对的互补RNA链。
被引入系统中后,本发明的化合物可引发一种或多种酶或结构蛋白的作用以实现靶核酸的裂解或其它修饰,或可经由基于占位性的机制作用。通常,核酸(包括寡核苷酸)可描述为"DNA-样"(即,通常具有一个或多个2'-脱氧糖,且通常具有T而不是U碱基)或"RNA-样"(即,通常具有一个或多个2'-羟基或2'-修饰的糖,且通常具有U而不是T碱基)。核酸螺旋可采用多于一种类型的结构,最通常是A-和B-形式。通常认为,具有B-形式-样结构的寡核苷酸是"DNA-样",且具有A-形式样结构的是"RNA-样"。在一些(嵌合)实施方案中,反义化合物可包含A-形式区域和B-形式区域两者。
在另一个实施方案中,期望寡核苷酸或反义化合物包括以下至少一种:反义RNA、反义DNA、嵌合反义寡核苷酸、包括修饰的键合的反义寡核苷酸、干扰RNA(RNAi)、短干扰RNA(siRNA)、微干扰RNA(miRNA)、时序调节小RNA(stRNA)或短发夹RNA(shRNA)、小RNA-诱导的基因活化(RNAa)、小活化RNA(saRNA)或其组合。
dsRNA还可活化基因表达,这是已被称为″小RNA-诱导的基因活化"或RNAa的机制。dsRNA靶向基因启动子诱导相关基因的有效的转录活化。RNAa在人细胞中利用合成的dsRNA证实,称为″小活化RNA"(saRNA)。
已发现小双链RNA(dsRNA),例如小干扰RNA(siRNA)和微RNA(miRNA)是称为RNA干扰(RNAi)的进化保守机制的触发物。RNAi不变性导致基因沉默。然而在以下实施例部分详细描述的情况中,寡核苷酸显示增加沉默调节蛋白(SIRT)多核苷酸和其编码的产物的表达和/或功能。dsRNA还可作为小活化RNA(saRNA)作用。不希望受理论束缚,通过靶向基因启动子中的序列,saRNA将以称为dsRNA-诱导的转录活化(RNAa)的现象诱导靶基因表达。
在进一步的实施方案中,本文鉴定的"靶区段"可用于筛选调节沉默调节蛋白(SIRT)多核苷酸表达的另外的化合物。"调节剂"是减少或增加编码沉默调节蛋白(SIRT)的核酸分子表达的那些化合物,且包括与靶区段互补的至少5-核苷酸部分。筛选方法包括以下步骤:将编码沉默调节蛋白(SIRT)的有义或天然反义多核苷酸的核酸分子的靶区段与一种或多种候选调节剂接触,并选择减少或增加编码沉默调节蛋白(SIRT)多核苷酸的核酸分子(例如SEQ ID NO:24至127)的表达的一种或多种候选调节剂。显示一种或多种候选调节剂能够调节(例如,减少或增加)编码沉默调节蛋白(SIRT)多核苷酸的核酸分子的表达后,随后调节剂可用于沉默调节蛋白(SIRT)多核苷酸功能的进一步研究性研究,或用作根据本发明的研究剂、诊断剂或治疗剂。
靶向天然反义序列调节靶基因的功能。例如,沉默调节蛋白(SIRT)(例如登录号M_012238.4、NM_001159589、NM_012237.3、NM_012239、NM_012240、NM_012241、NM_016539、NM_016538、NM_001142498.1、NM_030593.2、NM_001193286.1,NR_034146.1、NM_001017524.2、NM_031244.2、NM_001193267.1、NM_001193285.1)。在实施方案中,靶是沉默调节蛋白(SIRT)的反义多核苷酸。在实施方案中,反义寡核苷酸靶向沉默调节蛋白(SIRT)多核苷酸(例如,登录号NM_012238.4、NM_001159589、NM_012237.3、NM_012239、NM_012240、NM_012241、NM_016539、NM_016538、NM_001142498.1、NM_030593.2、NM_001193286.1,NR_034146.1、NM_001017524.2、NM_031244.2、NM_001193267.1、NM_001193285.1)的有义和/或天然反义序列、变体、等位基因、同种型、同系物、突变体、衍生物、片段及其互补序列。优选地寡核苷酸是反义分子且靶包括反义和/或有义沉默调节蛋白(SIRT)多核苷酸的编码区和非编码区。
本发明的靶区段还可与本发明的其各自的互补反义化合物组合以形成稳定的双链(双链体)寡核苷酸。
在本领域中,这种双链寡核苷酸部分已显示经由反义机制调节靶表达和调节翻译以及RNA加工。而且,可对双链部分进行化学修饰。例如,这种双链部分已经显示通过双链体的反义链与靶经典杂交,从而触发靶的酶促降解来抑制靶。
在实施方案中,反义寡核苷酸靶向沉默调节蛋白(SIRT)多核苷酸(例如,登录号NM_012238.4、NM_001159589、NM_012237.3、NM_012239、NM_012240、NM_012241、NM_016539、NM_016538、NM_001142498.1、NM_030593.2、NM_001193286.1,NR_034146.1、NM_001017524.2、NM_031244.2、NM_001193267.1、NM_001193285.1)、变体、等位基因、同种型、同系物、突变体、衍生物、片段及其互补序列。优选地寡核苷酸是反义分子。
根据本发明的实施方案,靶核酸分子不限于仅沉默调节蛋白(SIRT),还延伸到沉默调节蛋白(SIRT)分子的同种型、受体、同系物和类似物的任一种。
在另一个实施方案中,寡核苷酸靶向沉默调节蛋白(SIRT)多核苷酸的天然反义序列,例如,如SEQ ID NO:9至23、141至143所列的多核苷酸,和任何变体、等位基因、同系物、突变体、衍生物、片段及其互补序列。反义寡核苷酸的实例列在SEQ ID NO:24至127。
在一个实施方案中,寡核苷酸与沉默调节蛋白(SIRT)反义的核酸序列互补或结合,包括但不限于沉默调节蛋白(SIRT)多核苷酸相关的非编码有义和/或反义序列,并调节沉默调节蛋白(SIRT)分子的表达和/或功能。
在另一个实施方案中,寡核苷酸与如SEQ ID NO:9至23、141至143所列的沉默调节蛋白(SIRT)天然反义的核酸序列互补或结合,并调节沉默调节蛋白(SIRT)分子的表达和/或功能。
在另一个实施方案中,寡核苷酸包括SEQ ID NO:24至127的至少5个连续核苷酸的序列,并调节沉默调节蛋白(SIRT)分子的表达和/或功能。
多核苷酸靶包括沉默调节蛋白(SIRT),包括其家族成员、沉默调节蛋白(SIRT)的变体;沉默调节蛋白(SIRT)的突变体,包括SNP;沉默调节蛋白(SIRT)的非编码序列;沉默调节蛋白(SIRT)的等位基因;物种变体、片段和类似物。优选地寡核苷酸是反义分子。
在另一个实施方案中,靶向沉默调节蛋白(SIRT)多核苷酸的寡核苷酸包括:反义RNA、干扰RNA(RNAi)、短干扰RNA(siRNA);微干扰RNA(miRNA);时序调节小RNA(stRNA);或短发夹RNA(shRNA);小RNA诱导的基因活化(RNAa);或小活化RNA(saRNA)。
在另一个实施方案中,靶向沉默调节蛋白(SIRT)多核苷酸(例如SEQ ID NO:9至23、141至143)调节这些靶的表达或功能。在一个实施方案中,与对照相比表达或功能被上调。在另一个实施方案中,与对照相比表达或功能被下调。
在另一个实施方案中,反义化合物包括如SEQ ID NO:24至127所列的序列。这些寡核苷酸可包括一种或多种修饰的核苷酸、更短或更长片段、修饰的键和类似物。
在另一个实施方案中,SEQ ID NO:24至127包括一种或多种LNA核苷酸。
期望靶核酸的调节可以本领域已知的多种方式进行。例如,反义寡核苷酸、siRNA等。酶促核酸分子(例如,核酶)是能够催化多种反应的一种或多种的核酸分子,包括以核苷酸碱基序列特异性方式重复地裂解其它单独核酸分子的能力。这种酶促核酸分子可用于例如靶向几乎任何RNA转录物。
由于其序列特异性,反式裂解酶促核酸分子显示用作人疾病的治疗剂的希望。可设计酶促核酸分子以裂解细胞RNA背景中的特定RNA靶。这种裂解事件使得mRNA无功能并消除从该RNA的蛋白表达。以这种方式,可选择性地抑制疾病状态相关的蛋白的合成。
通常,具有RNA裂解活性的酶促核酸通过首先结合靶RNA来作用。这种结合经由被保持在邻近用于裂解靶RNA的分子的酶促部分的酶促核酸的靶结合部分来进行。因此,酶促核酸首先识别靶RNA然后经由互补碱基配对结合靶RNA,结合到正确位置时,酶促地作用以切割靶RNA。对这种靶RNA的关键裂解将破坏其指导编码蛋白合成的能力。在酶促核酸已结合和裂解其RNA靶后,其从该RNA释放以搜寻另一靶并可重复地结合和裂解新的靶。
多种方法例如体外选择(进化)策略已经用于进化能够催化多种反应(例如磷酸二酯键合和酰胺键合的裂解和连接)的新核酸催化剂。
催化活性最佳的核酶的开发将显著有助于为了调节基因表达的目的采用RNA-裂解核酶的任何策略。例如,锤头状核酶在饱和(10mM)浓度的Mg2+辅因子存在下以约1min-1的催化速率(kcat)作用。人工的"RNA连接酶"核酶已经显示以约100min-1的速率催化相应的自修饰反应。此外,已知具有DNA制成的底物结合臂的某些修饰的锤头状核酶以接近100min-1的多倍周转率催化RNA裂解。最后,用某些核苷酸类似物代替锤头的催化核心中的特定残基获得显示催化速率改进多达10倍的修饰的核酶。这些发现证明,核酶可促进化学转化,伴随催化速率显著大于大多数天然自裂解核酶体外展示的催化速率。那么可能可优化某些自裂解核酶的结构以获得最大催化活性,或可能可制备对于RNA磷酸二酯裂解展示显著更快速率的完全新的RNA基序。
符合"锤头"模型的RNA催化剂对RNA底物的分子间裂解首次在1987年显示。回收RNA催化剂并与多种RNA分子反应,证实其真正是催化性的。
通过在催化性RNA中进行适当的碱基改变以保持与靶序列必需的碱基配对,基于"锤头"基序设计的催化性RNA已用于裂解特定靶序列。这已经允许使用催化性RNA来裂解特定靶序列并指示,按照"锤头"模型设计的催化性RNA可能可体内裂解特定底物RNA。
RNA干扰(RNAi)已经变成在哺乳动物和哺乳动物细胞中调节基因表达的强有力工具。这一方法要求利用表达质粒或病毒和被加工为siRNA的小发夹RNA的编码序列递送作为RNA本身或作为DNA的小干扰RNA(siRNA)。这一系统使得能够有效地运输前体siRNA到细胞质,在那里它们是活性的,并允许使用用于基因表达的受控型启动子和组织特异性启动子。
在一个实施方案中,寡核苷酸或反义化合物包括核糖核酸(RNA)和/或脱氧核糖核酸(DNA)的寡聚物或聚合物或其模拟物、嵌合体、类似物或同系物。这一术语包括包括天然存在的核苷酸、糖和共价核苷间(主链)键的寡核苷酸以及具有类似地起作用的非天然存在的部分的寡核苷酸。因为期望的特性,例如对增加的细胞摄取、对靶核酸增加的亲和力和在核酸酶存在下增加的稳定性,这种修饰的或取代的寡核苷酸通常相比于天然形式是期望的。
根据本发明,寡核苷酸或"反义化合物"包括反义寡核苷酸(例如,RNA、DNA、其模拟物、嵌合体、类似物或同系物)、核酶、外部指导序列(EGS)寡核苷酸、siRNA化合物、单链或双链RNA干扰(RNAi)化合物例如siRNA化合物、saRNA、aRNA和与靶核酸的至少一部分杂交并调节其功能的其它寡聚化合物。因此,它们可以是DNA、RNA、DNA-样、RNA-样或其混合物,或可以是一种或多种这些的模拟物。这些化合物可以是单链、双链、环状或发夹寡聚化合物,并可包含结构元件,例如内部凸出或末端凸出、错配或环。常规线性地制备反义化合物,但可被连接或以其它方式制备为环状和/或分支的。反义化合物可包括构建体,例如,两条链杂交以形成完全或部分双链的化合物,或具有足够自互补性的单链以允许杂交和形成完全或部分双链的化合物。两条链可在内部被连接,留下游离的3'或5'末端,或可被连接以形成连续的发夹结构或环。发夹结构可包含在5'或3'末端的突出,产生单链特征的延伸段。双链化合物任选地可包括在末端的突出。进一步的修饰可包括附加于末端之一、所选的核苷酸位置、糖位置或核苷间键合之一的缀合物基团。可选地,两条链可经由非核酸部分或接头基团连接。当仅由一条链形成时,dsRNA可采取自互补发夹型分子的形式,其与自身对折以形成双链体。因此,dsRNA可以是完全或部分双链的。基因表达的特异性调节可通过在转基因细胞系中稳定表达dsRNA发夹来实现。当由两条链或采取与自身对折以形成双链体的自互补发夹型分子形式的单链形成时,两条链(或单链的双链体形成区)是以Watson-Crick方式碱基配对的互补RNA链。
被引入系统中后,本发明的化合物可引发一种或多种酶或结构蛋白的作用以实现靶核酸的裂解或其它修饰,或可经由基于占位性的机制作用。通常,核酸(包括寡核苷酸)可描述为"DNA-样"(即,通常具有一个或多个2'-脱氧糖,且通常具有T而不是U碱基)或"RNA-样"(即,通常具有一个或多个2'-羟基或2'-修饰的糖,且通常具有U而不是T碱基)。核酸螺旋可采用多于一种类型的结构,最通常是A-和B-形式。通常认为,具有B-形式-样结构的寡核苷酸是"DNA-样",且具有A-形式样结构的是"RNA-样"。在一些(嵌合)实施方案中,反义化合物可包含A-形式区域和B-形式区域两者。
根据本发明的反义化合物可包括长度为从约5至约80个核苷酸(即,从约5至约80个连接的核苷)的反义部分。这是指反义化合物的反义链或部分的长度。换言之,本发明的单链反义化合物包括从5至约80个核苷酸,且本发明的双链反义化合物(例如dsRNA)包括长度为5至约80个核苷酸的有义和反义链或部分。本领域普通技术人员将理解,这包括长度为5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50、51、52、53、54、55、56、57、58、59、60、61、62、63、64、65、66、67、68、69、70、71、72、73、74、75、76、77、78、79或80个核苷酸或其中的任何范围的反义部分。
在一个实施方案中,本发明的反义化合物具有长度为10至50个核苷酸的反义部分。本领域普通技术人员将理解,这包括具有长度为10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49或50个核苷酸或其中的任何范围的反义部分的寡核苷酸。在一些实施方案中,寡核苷酸长度为15个核苷酸。
在一个实施方案中,本发明的反义或寡核苷酸化合物具有长度为12或13至30个核苷酸的反义部分。本领域普通技术人员将理解,这包括具有长度为12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29或30个核苷酸或其中的任何范围的反义部分的反义化合物。
在另一个实施方案中,本发明的寡聚化合物还包括变体,其中在化合物中一个或多个核苷酸位置存在不同碱基。例如,如果第一个核苷酸是腺嘌呤,可产生在这一位置包含胸苷、鸟苷或胞苷的变体。这可在反义或dsRNA化合物的任何位置进行。随后利用本文所述的方法测定这些化合物以确定它们抑制靶核酸表达的能力。
在一些实施方案中,反义化合物与靶之间的同源性、序列同一性或互补性是从约40%至约60%。在一些实施方案中,同源性、序列同一性或互补性是从约60%至约70%。在一些实施方案中,同源性、序列同一性或互补性是从约70%至约80%。在一些实施方案中,同源性、序列同一性或互补性是从约80%至约90%。在一些实施方案中,同源性、序列同一性或互补性是约90%、约92%、约94%、约95%、约96%、约97%、约98%、约99%或约100%。
在另一个实施方案中,反义寡核苷酸,例如SEQ ID NO:24至127所列的核酸分子,包括一种或多种取代或修饰。在一个实施方案中,核苷酸是用锁核酸(LNA)取代的。
在另一个实施方案中,寡核苷酸靶向与SIRT和如SEQ ID NO:1至23和133至143所列的序列相关的编码和/或非编码序列的有义和/或反义的核酸分子的一个或多个区域。寡核苷酸还靶向于SEQ IDNO:1至23和133至143的重叠区域。
本发明某些寡核苷酸是嵌合寡核苷酸。在本发明范畴中,"嵌合寡核苷酸"或"嵌合体"是包含两个或更多个化学不同区域的寡核苷酸,每个区域由至少一个核苷酸组成。这些寡核苷酸通常包含赋予一种或多种有益特性(例如,增加的核酸酶耐受性、增加的摄取入细胞、增加的对靶的结合亲和力)的修饰的核苷酸的至少一个区域和为能够裂解RNA:DNA或RNA:RNA杂交物的酶的底物的区域。例如,RNA酶H是裂解RNA:DNA双链体的RNA链的细胞核酸内切酶。因此,RNA酶H的活化导致RNA靶的裂解,从而大大增强基因表达的反义调节的效力。因此,与杂交于相同靶区域的硫代磷酸酯脱氧寡核苷酸相比,当使用嵌合寡核苷酸时以较短寡核苷酸通常可获得可比较的结果。RNA靶的裂解可常规地通过凝胶电泳来检测,如果需要,通过本领域已知的相关核酸杂交技术来检测。在一个实施方案中,嵌合寡核苷酸包括经修饰以增加靶结合亲和性的至少一个区域和通常作为RNA酶H底物作用的区域。寡核苷酸对其靶(在这一情形中是编码ras的核酸)的亲和性常规地通过测量寡核苷酸/靶配对的Tm来确定,Tm是寡核苷酸与靶解离的温度;分光光度地检测解离。Tm越高,寡核苷酸对靶的亲和性越大。
本发明的嵌合反义化合物可形成为两种或更多种寡核苷酸、如上所述的修饰的寡核苷酸、寡核苷和/或寡核苷酸模拟物的复合结构。这种化合物在本领域中也已称为杂交物或间隙体(gapmer)。教导这种杂交物结构的制备的代表性美国专利包括但不限于,美国专利No.5,013,830、5,149,797、5,220,007、5,256,775、5,366,878、5,403,711、5,491,133、5,565,350、5,623,065、5,652,355、5,652,356和5,700,922,其每一个通过引用并入本文。
在另一个实施方案中,经修饰的寡核苷酸的区域包括在糖的2'位置修饰的至少一个核苷酸,最优选地2'-O烷基、2'-O-烷基-O-烷基或2'-氟代-修饰的核苷酸。在其它实施方案中,RNA修饰包括在RNA3'端的嘧啶、脱碱基残基或反向碱基的核糖上的2'-氟代、2'-氨基和2'O-甲基修饰。这种修饰常规地并入寡核苷酸,且这些寡核苷酸已经显示对给定靶具有比2'-脱氧寡核苷酸更高的Tm(即,更高的靶结合亲和性)。这种增加的亲和性的作用是大大增强基因表达的RNAi寡核苷酸抑制。RNA酶H是裂解RNA:DNA双链体的RNA链的细胞核酸内切酶;因此该酶的活化导致RNA靶的裂解,从而可大大增强RNAi抑制的效力。RNA靶的裂解可常规地通过凝胶电泳来证实。在另一个实施方案中,还修饰嵌合寡核苷酸以增强核酸酶的耐受性。细胞包含多种可降解核酸的核酸外切酶和核酸内切酶。多种核苷酸和核苷修饰已经显示使得它们并入的寡核苷酸比天然寡脱氧核苷酸对核酸酶消化更耐受。核酸酶耐受性常规地通过如下测量:培养寡核苷酸与细胞提取物或分离的核酸酶溶液,并随着时间测量剩余的完整寡核苷酸的程度,通常通过凝胶电泳测量。经修饰以增强其核酸酶耐受性的寡核苷酸比未修饰的寡核苷酸保持完整更长时间。多种寡核苷酸修饰已证实增强或赋予核酸酶耐受性。包含至少一种硫代磷酸酯修饰的寡核苷酸目前是更优选的。在一些情形中,增强靶结合亲和性的寡核苷酸修饰也独立地能够增强核酸酶耐受性。一些期望的修饰可在DeMesmaeker等人(1995)Acc.Chem.Res.,28:366-374中发现。
本发明预期的一些寡核苷酸的具体实例包括包括修饰的主链的那些,例如,硫代磷酸酯、磷酸三酯、膦酸甲基酯、短链烷基或环烷基糖间键合或短链杂原子或杂环糖间键合。大多数是具有硫代磷酸酯主链的寡核苷酸和具有杂原子主链的那些,尤其是CH2--NH--O--CH2、CH、--N(CH3)--O--CH2[称为亚甲基(甲基亚氨基)或MMI主链]、CH2--O--N(CH3)--CH2、CH2-N(CH3)--N(CH3)--CH2和O--N(CH3)--CH2--CH2主链,其中天然磷酸二酯主链表示为O--P--O--CH。由De Mesmaeker等(1995)Acc.Chem.Res.28:366-374公开的酰胺主链也是优选的。还有具有吗啉代主链结构的寡核苷酸(Summerton和Weller,美国专利No.5,034,506)。在其它实施方案中,例如肽核酸(PNA)主链,寡核苷酸的磷酸二酯主链被聚酰胺主链代替,核苷酸被直接或间接地结合于聚酰胺主链的氮杂氮原子。寡核苷酸还可包括一种或多种取代的糖部分。寡核苷酸在2'位置包括以下之一:OH、SH、SCH3、F、OCN、OCH3 OCH3、OCH3O(CH2)n CH3、O(CH2)n NH2或O(CH2)n CH3,其中n是1至约10;C1至C10低级烷基、烷氧基烷氧基、取代的低级烷基、烷芳基或芳烷基;Cl;Br;CN;CF3;OCF3;O--、S--或N-烷基;O--、S--或N-烯基;SOCH3;SO2 CH3;ONO2;NO2;N3;NH2;杂环烷基;杂环烷芳基;氨基烷基氨基;聚烷基氨基;取代的甲硅烷基;RNA裂解基团;报告基团;嵌入剂;用于改善寡核苷酸药代动力学特性的基团;或用于改善寡核苷酸药效学特性的基团和具有类似特性的其它取代基。修饰包括2'-甲氧基乙氧基[2'-O-CH2 CH2 OCH3,还称为'-O-(2-甲氧基乙基)]。其它修饰包括2'-甲氧基(2'-O--CH3)、2'-丙氧基(2'-OCH2 CH2CH3)和2'-氟代(2'-F)。还可在寡核苷酸上的其它位置进行类似修饰,尤其是3'末端核苷酸上糖的3'位置和5'末端核苷酸的5'位置。寡核苷酸还可具有糖模拟物例如环丁基来代替戊呋喃糖基。
另外或可选地,寡核苷酸还可包括核碱基(本领域中通常简称为"碱基")修饰或取代。本文所用的"未修饰"或"天然"核苷酸包括腺嘌呤(A)、鸟嘌呤(G)、胸腺嘧啶(T)、胞嘧啶(C)和尿嘧啶(U)。修饰的核苷酸包括天然核酸中仅仅罕见或短暂出现的核苷酸,例如,次黄嘌呤、6-甲基腺嘌呤、5-Me嘧啶、尤其是5-甲基胞嘧啶(也称为5-甲基-2'脱氧胞嘧啶,本领域中通常称为5-Me-C)、5-羟基甲基胞嘧啶(HMC)、糖基HMC和龙胆二糖基HMC以及合成的核苷酸,例如,2-氨基腺嘌呤、2-(甲基氨基)腺嘌呤、2-(咪唑基烷基)腺嘌呤、2-(氨基烷基氨基)腺嘌呤或其它杂取代的烷基腺嘌呤、2-硫代尿嘧啶、2-硫代胸腺嘧啶、5-溴尿嘧啶、5-羟基甲基尿嘧啶、8-氮杂鸟嘌呤、7-脱氮杂鸟嘌呤、N6(6-氨基己基)腺嘌呤和2,6-二氨基嘌呤。可包括本领域中已知的"通用"碱基,例如肌苷。5-Me-C取代已显示增加核酸双链体的稳定性0.6-1.2℃,是目前优选的碱基取代。(Sanghvi,Y.S.,参见Crooke,S.T.和Lebleu,B.编辑,Antisense Research and Applications,CRC Press,BocaRaton,1993,第276-278页)
本发明寡核苷酸的另一修饰包括与该寡核苷酸化学连接增强寡核苷酸的活性或细胞摄取的一个或多个部分或缀合物。这种部分包括但不限于脂质部分例如胆固醇部分、胆固醇基部分、硫醚例如己基-S-三苯甲基硫醇、硫代胆固醇、脂肪族链如十二烷二醇或十一烷基残基、磷脂例如二-十六烷基-rac-甘油或1,2-二-O-十六烷基-rac-甘油基-3-H-磷酸三乙基铵、聚胺或聚乙二醇链或金刚烷乙酸。包括亲脂部分的寡核苷酸和制备这种寡核苷酸的方法是本领域已知的,例如,美国专利No.5,138,045、5,218,105和5,459,255。
给定的寡核苷酸中的所有位置不必一致地被修饰,事实上多于一个上述修饰可并入单个寡核苷酸中或甚至在寡核苷酸中的单个核苷中。本发明还包括为上文定义的嵌合寡核苷酸的寡核苷酸。
在另一实施方案中,本发明的核酸分子缀合于另一部分,该另一部分包括但不限于脱碱基核苷酸、聚醚、聚胺、聚酰胺、肽、碳水化合物、脂质或聚烃化合物。本领域技术人员将认识到,这些分子可在糖、碱基或磷酸酯基团上的多个位置连接于一种或多种任何核苷酸(包括核酸分子)。
根据本发明使用的寡核苷酸可方便和常规地通过公知的固相合成技术制备。用于这种合成的设备由包括Applied Biosystems的多个供应商出售。还可采用用于这种合成的任何其它手段;寡核苷酸的实际合成完全在本领域普通技术人员的才能范围内。还公知的是使用类似技术来制备其它寡核苷酸例如硫代磷酸酯和烷基化衍生物。还公知的是使用类似技术和市售可获得的修饰的亚酰胺化物(amidite)和可控孔度玻璃(CPG)产物例如生物素、荧光素、吖啶或补骨脂素-修饰的亚酰胺化物和/或CPG(可从Glen Research,SterlingVA获得)来合成荧光标记的、生物素化的或其它修饰的寡核苷酸,例如胆固醇-修饰的寡核苷酸。
根据本发明,使用修饰例如使用LNA单体来增强包括本发明化学性质例如MOE、ANA、FANA、PS等的寡核苷酸的效力、特异性和作用持续时间并增宽所述寡核苷酸施用途径。这可通过以LNA单体取代本发明寡核苷酸中的一些单体来实现。LNA修饰的寡核苷酸可具有与亲本化合物相似的大小或可更大或优选地更小。这种LNA-修饰的寡核苷酸包含少于约70%、更优选地少于约60%、最优选地少于约50%的LNA单体,且其大小为约5至25个核苷酸,更优选地约12至20个核苷酸。
修饰的寡核苷酸主链包括但不限于,硫代磷酸酯、手性硫代磷酸酯、二硫代磷酸酯、磷酸三酯、氨烷基磷酸三酯、膦酸甲基酯和其它膦酸烷基酯(包括膦酸3'亚烷基酯和手性膦酸酯)、亚膦酸酯、氨基磷酸酯(包括3'-氨基氨基磷酸酯和氨基烷基氨基磷酸酯)、硫羰氨基磷酸酯、硫羰磷酸烷基酯、硫羰烷基磷酸三酯和具有正常3'-5'键合的硼磷酸酯、这些的2'-5'连接的类似物和具有倒转极性的那些,其中相邻的核苷单元对是3'-5'至5'-3'或2'-5'至5'-2'连接的。还包括多种盐、混合盐和游离酸形式。
教导以上含磷键合的制备的代表性美国专利包括但不限于,美国专利No.3,687,808、4,469,863、4,476,301、5,023,243、5,177,196、5,188,897、5,264,423、5,276,019、5,278,302、5,286,717、5,321,131、5,399,676、5,405,939、5,453,496、5,455,233、5,466,677、5,476,925、5,519,126、5,536,821、5,541,306、5,550,111、5,563,253、5,571,799、5,587,361和5,625,050,其每一个通过引用并入本文。
其中不包含磷原子的修饰的寡核苷酸主链具有由短链烷基或环烷基核苷间键合、混合的杂原子和烷基或环烷基核苷间键合或者一种或多种短链杂原子或杂环核苷间键合形成的主链。这些包括具有吗啉代键合(部分地从核苷的糖部分形成)的那些;硅氧烷主链;硫化物、亚砜和砜主链;甲酰基(formacetyl)和硫代甲酰基主链;亚甲基甲酰基和硫代甲酰基主链;含链烯的主链;氨基磺酸酯主链;亚甲基亚胺基和亚甲基肼基主链;磺酸酯和磺胺主链;酰胺主链;和具有混合的N、O、S和CH2组成部分的其它主链。
教导以上寡核苷的制备的代表性美国专利包括但不限于,美国专利No.5,034,506、5,166,315、5,185,444、5,214,134、5,216,141、5,235,033、5,264,562、5,264,564、5,405,938、5,434,257、5,466,677、5,470,967、5,489,677、5,541,307、5,561,225、5,596,086、5,602,240、5,610,289、5,602,240、5,608,046、5,610,289、5,618,704、5,623,070、5,663,312、5,633,360、5,677,437和5,677,439,其每一个通过引用并入本文。
在其它寡核苷酸模拟物中,核苷酸单元的糖和核苷间键合两者即主链被新的基团代替。碱基单元被保留用于与适当的核酸靶化合物杂交。一种这样的寡聚化合物,即已显示具有极佳的杂交特性的寡核苷酸模拟物称为肽核酸(PNA)。在PNA化合物中,寡核苷酸的糖-主链被包含酰胺的主链,特别是氨基乙基甘氨酸主链代替。核碱基被保留,并直接或间接与主链的酰胺部分的氮杂氮原子结合。教导PNA化合物的制备的代表性美国专利包括但不限于,美国专利No.5,539,082、5,714,331和5,719,262,其每一个通过引用并入本文。PNA化合物的进一步教导可见于Nielsen等(1991)Science 254,1497-1500。
在本发明的另一个实施方案中,具有硫代磷酸酯主链的寡核苷酸和具有杂原子主链的寡核苷,尤其是-CH2-NH-O-CH2、称为亚甲基(甲基亚氨基)或MMI主链的-CH2-N(CH3)-O-CH2-、-CH2-O-N(CH3)-CH2、-CH2N(CH3)-N(CH3)CH2和-O-N(CH3)-CH2-CH2,其中天然磷酸二酯主链表示为以上引用的美国专利No.5,489,677的-O-P-O-CH2-和以上引用的美国专利No.5,602,240的酰胺主链。还有具有以上引用的美国专利No.5,034,506的吗啉代主链结构的寡核苷酸。
修饰的寡核苷酸还可包含一种或多种取代的糖部分。寡核苷酸在2'位置包括以下之一:OH;F;O-、S-或N-烷基;O-、S-或N-烯基;O-、S-或N-炔基;或O烷基-O-烷基,其中烷基、烯基和炔基可以是取代或未取代的C至CO烷基或C2至CO烯基和炔基。尤其是O(CH2)nOmCH3、O(CH2)n、OCH3、O(CH2)nNH2、O(CH2)nCH3、O(CH2)nONH2和O(CH2nON(CH2)nCH3)2,其中n和m可以为1至约10。其它寡核苷酸包括在2'位置包括以下之一:C至CO低级烷基、取代的低级烷基、烷芳基、芳烷基、O-烷芳基或O-芳烷基、SH、SCH3、OCN、Cl、Br、CN、CF3、OCF3、SOCH3、SO2CH3、ONO2、NO2、N3、NH2、杂环烷基、杂环烷芳基、氨基烷基氨基、聚烷基氨基、取代的甲硅烷基、RNA裂解基团、报告基团、嵌入剂、用于改善寡核苷酸药代动力学特性的基团或用于改善寡核苷酸药效学特性的基团和具有类似特性的其它取代基。修饰包括2'-甲氧基乙氧基(2'-O-CH2CH2OCH3,还称为2'-O-(2-甲氧基乙基)或2'-MOE)即,烷氧基烷氧基基团。另外修饰包括如在本文以下实施例中描述的2'-二甲基氨基氧基乙氧基,即O(CH2)2ON(CH3)2基团,还称为2'-DMAOE,和2'-二甲基氨基乙氧基乙氧基(本领域还称为2'-O-二甲基氨基乙氧基乙基或2'-DMAEOE),即,2'-O-CH2-O-CH2-N(CH2)2。
其它修饰包括2'-甲氧基(2'-O--CH3)、2'-氨基丙氧基(2'-OCH2CH2CH2NH2)和2'-氟代(2'-F)。还可在寡核苷酸上的其它位置进行类似修饰,尤其是3'末端核苷酸或2'-5'连接的寡核苷酸上糖的3'位置和5'末端核苷酸的5'位置。寡核苷酸还可具有糖模拟物例如环丁基部分来代替戊呋喃糖基糖。教导这种修饰的糖结构的制备的代表性美国专利包括但不限于,美国专利No.4,981,957、5,118,800、5,319,080、5,359,044、5,393,878、5,446,137、5,466,786、5,514,785、5,519,134、5,567,811、5,576,427、5,591,722、5,597,909、5,610,300、5,627,053、5,639,873、5,646,265、5,658,873、5,670,633和5,700,920,其每一个通过引用并入本文。
寡核苷酸还可包括核碱基(本领域中通常简称为"碱基")修饰或取代。本文所用的"未修饰"或"天然"核苷酸包括嘌呤碱基腺嘌呤(A)和鸟嘌呤(G)、和嘧啶碱基胸腺嘧啶(T)、胞嘧啶(C)和尿嘧啶(U)。修饰的核苷酸包括其它合成的和天然核苷酸例如5-甲基胞嘧啶(5-me-C)、5-羟甲基胞嘧啶、黄嘌呤、次黄嘌呤、2-氨基腺嘌呤、腺嘌呤和鸟嘌呤的6-甲基和其它烷基衍生物、腺嘌呤和鸟嘌呤的2-丙基和其它烷基衍生物、2-硫尿嘧啶、2-硫胸腺嘧啶和2-硫胞嘧啶、5-卤尿嘧啶和胞嘧啶、5-丙炔基尿嘧啶和胞嘧啶、6-偶氮尿嘧啶、胞嘧啶和胸腺嘧啶、5-尿嘧啶(假-尿嘧啶)、4-硫尿嘧啶、8-卤代、8-氨基、8-硫氢基、8-硫烷基、8-羟基和其它8-取代的腺嘌呤和鸟嘌呤、5-卤代尤其是5-溴、5-三氟甲基和其它5-取代的尿嘧啶和胞嘧啶、7-甲基鸟嘌呤和7-甲基腺嘌呤、8-氮杂鸟嘌呤和8-氮杂腺嘌呤、7-脱氮杂鸟嘌呤和7-脱氮杂腺嘌呤和3-脱氮杂鸟嘌呤和3-脱氮杂腺嘌呤。
此外,核苷酸包括美国专利No.3,687,808中公开的那些、'TheConciseEncyclopedia of Polymer Science And Engineering',第858-859页,Kroschwitz,J.I.编著.John Wiley & Sons,1990中公开的那些、Englisch等,'Angewandle Chemie,International Edition',1991,30,第613页中公开的那些以及Sanghvi,Y.S.,第15章,'Antisense Researchand Applications',第289-302页,Crooke,S.T.和Lebleu,B.编著,CRCPress,1993中公开的那些。这些核苷酸的某些尤其有用于增加本发明寡聚化合物的结合亲和性。这些包括5-取代的嘧啶、6-氮杂嘧啶、N-2、N-6和0-6取代的嘌呤,包括2-氨丙基腺嘌呤、5-丙炔基尿嘧啶和5-丙炔基胞嘧啶。5-甲基胞嘧啶取代已显示增加核酸双链体稳定性0.6-1.2℃(Sanghvi,Y.S.,Crooke,S.T.和Lebleu,B.编著,'AntisenseResearch andApplications',CRC Press,Boca Raton,1993,pp.276-278),并且目前是碱基取代,甚至更尤其是当与2'-O甲氧基乙基糖修饰组合时。
教导上述修饰的核苷酸以及其它修饰的核苷酸的制备的代表性美国专利包括但不限于,美国专利No.3,687,808以及4,845,205、5,130,302、5,134,066、5,175,273、5,367,066、5,432,272、5,457,187、5,459,255、5,484,908、5,502,177、5,525,711、5,552,540、5,587,469、5,596,091、5,614,617、5,750,692和5,681,941,其每一个通过引用并入本文。
本发明寡核苷酸的另一修饰包括将寡核苷酸化学连接于增强寡核苷酸的活性、细胞分布或细胞摄取的一个或多个部分或缀合物。
这种部分包括但不限于,脂质部分例如胆固醇部分、胆酸、硫醚例如己基-S-三苯甲基硫醇、硫胆固醇、脂肪族链例如十二烷二醇或十一烷基残基、磷脂例如二-十六烷基-rac-甘油或1,2-二-O-十六烷基-rac-甘油-3-H-膦酸三乙基铵、聚胺或聚乙二醇链、或金刚烷乙酸、棕榈酰基部分、或十八胺或己基氨基-羰基-t羟胆固醇部分。
教导这种寡核苷酸缀合物的制备的代表性美国专利包括但不限于,美国专利No.4,828,979、4,948,882、5,218,105、5,525,465、5,541,313、5,545,730、5,552,538、5,578,717、5,580,731、5,580,731、5,591,584、5,109,124、5,118,802、5,138,045、5,414,077、5,486,603、5,512,439、5,578,718、5,608,046、4,587,044、4,605,735、4,667,025、4,762,779、4,789,737、4,824,941、4,835,263、4,876,335、4,904,582、4,958,013、5,082,830、5,112,963、5,214,136、5,082,830、5,112,963、5,214,136、5,245,022、5,254,469、5,258,506、5,262,536、5,272,250、5,292,873、5,317,098、5,371,241、5,391,723、5,416,203、5,451,463、5,510,475、5,512,667、5,514,785、5,565,552、5,567,810、5,574,142、5,585,481、5,587,371、5,595,726、5,597,696、5,599,923、5,599,928和5,688,941,其每一个通过引用并入本文。
药物发现:本发明的化合物还可应用于药物发现和靶确认的领域。本发明涵盖本文鉴定的化合物和靶区段在药物发现尝试中使用以阐明沉默调节蛋白(SIRT)多核苷酸与疾病状态、表型或病状之间存在的关联。这些方法包括检测或调节沉默调节蛋白(SIRT)多核苷酸,包括将样品、组织、细胞或生物体与本发明化合物接触,在处理后某一时间测量沉默调节蛋白(SIRT)多核苷酸的核酸或蛋白水平和/或相关的表型或化学端点,和任选地将测量值与未处理样品或用本发明另外化合物处理的样品比较。这些方法还可与其它试验平行或组合进行,以为靶确认方法确定未知基因的功能,或确定特定基因产物作为治疗或预防特定疾病、病状或表型的靶的有效性。
评价基因表达的上调或抑制:
外源核酸向宿主细胞或生物体中的转移可通过直接检测细胞或生物体中该核酸的存在来评价。这种检测可通过本领域公知的多种方法来实现。例如,外源核酸的存在可通过DNA印迹或利用特异性地扩增与该核酸相关的核苷酸序列的引物通过聚合酶链式反应(PCR)技术来检测。外源核酸的表达还可利用包括基因表达分析的常规方法测量。例如,从外源核酸产生的mRNA可利用RNA印迹(Northern blot)和逆转录PCR(RT-PCR)来检测和定量。
RNA从外源核酸的表达还可通过测量酶促活性或报告蛋白活性来检测。例如,反义调节活性可间接地作为靶核酸表达的减少或增加来测量,靶核酸表达的减少或增加作为外源核酸在产生效应RNA的指示。基于序列保守性,可设计引物并用于扩增靶基因的编码区域。最初,来自每个基因的最高度表达的编码区域可用于构建模式对照基因,尽管可使用任何编码或非编码区域。通过在报告基因编码区域和其poly(A)信号之间插入每个编码区域来组装每个对照基因。这些质粒将产生报告基因在基因的上游部分且可能的RNAi靶在3′非编码区域的mRNA。单独反义寡核苷酸的效果将通过报告基因的调节来测定。可用于本发明方法的报告基因包括乙酰羟酸合酶(AHAS)、碱性磷酸酶(AP)、β半乳糖苷酶(LacZ)、β葡糖醛酸酶(GUS)、氯霉素乙酰转移酶(CAT)、绿色荧光蛋白(GFP)、红色荧光蛋白(RFP)、黄色荧光蛋白(YFP)、青色荧光蛋白(CFP)、辣根过氧化物酶(HRP)、荧光素酶(Luc)、胭脂碱合酶(NOS)、章鱼碱合酶(OCS)及其衍生物。赋予对氨苄西林、博来霉素、氯霉素、庆大霉素、潮霉素、卡那霉素、林可霉素、甲氨蝶呤、草丁膦、嘌呤霉素和四环素抗性的多种选择标记是可得的。确定报告基因的调节的方法是本领域公知的,包括但不限于,荧光方法(例如,荧光光谱学、荧光激活细胞分选术(FACS)、荧光显微镜检术)、抗生素抗性确定。
SIRT1、SIRT3和SIRT6蛋白和mRNA表达可利用本领域技术人员已知和在本文别处描述的方法来测定。例如,免疫测定例如ELISA可用于测量蛋白水平。ELISA的沉默调节蛋白(SIRT)抗体是市售可获得的,如,得自R&D Systems(Minneapolis,MN),Abcam,Cambridge,MA。
在实施方案中,利用本发明反义寡核苷酸处理的样品(例如,体内或体外的细胞或组织)中的SIRT1、SIRT3和SIRT6表达(例如,mRNA或蛋白)通过与对照样品中的沉默调节蛋白(SIRT)表达比较来评价。例如,蛋白或核酸的表达可利用本领域技术人员已知的方法与模拟处理或未处理样品中的比较。可选地,取决于期望的信息,可与以对照反义寡核苷酸(例如,具有改变的或不同序列的反义寡核苷酸)处理的样品进行比较。在另一实施方案中,处理样品与未处理样品中沉默调节蛋白(SIRT)蛋白或核酸的表达差异可与处理样品与未处理样品中不同核酸(包括研究者认为适当的任何标准,例如,看家基因)的表达差异比较。
观察到的差异可如期望地表示,例如,以比率或分数的形式,用于与对照比较。在实施方案中,以本发明反义寡核苷酸处理的样品中沉默调节蛋白(SIRT)mRNA或蛋白的水平相对于未处理样品或以对照核酸处理的样品增加或减少约1.25倍至约10倍或更多。在实施方案中,沉默调节蛋白(SIRT)mRNA或蛋白的水平增加或减少至少约1.25倍、至少约1.3倍、至少约1.4倍、至少约1.5倍、至少约1.6倍、至少约1.7倍、至少约1.8倍、至少约2倍、至少约2.5倍、至少约3倍、至少约3.5倍、至少约4倍、至少约4.5倍、至少约5倍、至少约5.5倍、至少约6倍、至少约6.5倍、至少约7倍、至少约7.5倍、至少约8倍、至少约8.5倍、至少约9倍、至少约9.5倍、或至少约10倍或更多。
试剂盒、研究试剂、诊断和治疗
本发明的化合物可用于诊断、治疗和预防,及作为研究试剂和试剂盒的成分。而且,能够以强烈特异性抑制基因表达的反义寡核苷酸通常被本领域技术人员用来阐明特定基因的功能或区分生物途径的不同成员的功能。
对于在试剂盒和诊断和不同生物系统中使用,本发明的化合物,单独地或与其它化合物或治疗组合地用作差异和/或组合分析中的工具来阐明细胞和组织中表达的基因的一部分或完全互补序列的表达模式。
本文所用的术语"生物系统"或"系统"定义为表达或使成为感受态以表达沉默调节蛋白(SIRT)基因产物的任何生物体、细胞、细胞培养物或组织。这些包括但不限于,人、转基因动物、细胞、细胞培养物、组织、异种移植物、移植物及其组合。
作为一个非限制性实例,将以一种或多种反义化合物处理的细胞或组织中的表达模式与未被反义化合物处理的对照细胞或组织比较,并按照其属于所检查的基因的例如疾病关联、信号传导途径、细胞定位、表达水平、大小、结构或功能分析所产生的模式的基因表达差异水平。这些分析可对刺激或未刺激的细胞进行,并在影响表达模式的其它化合物存在或不存在下。
本领域已知的基因表达分析方法的实例包括DNA阵列或微阵列、SAGE(基因表达系列分析)、READS(消化的cDNA的限制性酶扩增)、TOGA(总基因表达分析)、蛋白阵列和蛋白质组学、表达的序列标签(EST)测序、消减RNA指纹技术(SuRF)、消减克隆、差异展示(DD)、比较基因组杂交、FISH(荧光原位杂交)技术和质谱方法。
本发明的化合物可用于研究和诊断,因为这些化合物杂交于编码沉默调节蛋白(SIRT)的核酸。例如,在本文公开的这种条件下以这种效力杂交的为有效的沉默调节蛋白(SIRT)调节剂的寡核苷酸,在有利基因扩增或检测的条件下分别是有效的引物或探针。这些引物和探针可用于需要特异性检测编码沉默调节蛋白(SIRT)的核酸分子的方法和可用于扩增用于检测或用于进一步研究沉默调节蛋白(SIRT)的所述核酸分子。本发明的反义寡核苷酸,尤其是引物和探针与编码沉默调节蛋白(SIRT)的核酸的杂交可通过本领域已知的手段检测。这种手段可包括将酶缀合于寡核苷酸、放射性标记寡核苷酸或任何其它适当的检测手段。还可制备利用这种检测手段来检测样品中沉默调节蛋白(SIRT)水平的试剂盒。
本领域技术人员还利用反义的特异性和灵敏性用于治疗用途。反义化合物已经在动物(包括人)的疾病状态的治疗中用作治疗部分。反义寡核苷酸药物已经安全且有效地施用于人,目前正在进行许多临床试验。因此已经确定,反义化合物可以是有用的治疗形态,可被配置以用于治疗细胞、组织和动物(尤其是人)的治疗方案。
对于治疗,通过施用根据本发明的反义化合物来治疗怀疑患有可通过调节沉默调节蛋白(SIRT)多核苷酸的表达来治疗的疾病或病症的动物,优选地人。例如,在一个非限制性实施方案中,方法包括向需要治疗的动物施用治疗有效量的沉默调节蛋白(SIRT)调节剂的步骤。本发明的沉默调节蛋白(SIRT)调节剂有效地调节沉默调节蛋白(SIRT)的活性或调节沉默调节蛋白(SIRT)蛋白的表达。在一个实施方案中,与对照相比,动物中沉默调节蛋白(SIRT)的活性或表达被抑制约10%。优选地,动物中沉默调节蛋白(SIRT)的活性或表达被抑制约30%。更优选地,动物中沉默调节蛋白(SIRT)的活性或表达被抑制50%或更多。因此,与对照相比,寡聚化合物调节沉默调节蛋白(SIRT)mRNA的表达至少10%、至少50%、至少25%、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95%、至少98%、至少99%或100%。
在一个实施方案中,与对照相比,动物中沉默调节蛋白(SIRT)的活性或表达增加约10%。优选地,动物中沉默调节蛋白(SIRT)的活性或表达增加约30%。更优选地,动物中沉默调节蛋白(SIRT)的活性或表达增加50%或更多。因此,与对照相比,寡聚化合物调节沉默调节蛋白(SIRT)mRNA的表达至少10%、至少50%、至少25%、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95%、至少98%、至少99%或100%。
在实施方案中,通过测量生物样品中的沉默调节蛋白mRNA、反义RNA、蛋白质、沉默调节蛋白生物标记物或其组合的水平观察到沉默调节蛋白调节。沉默调节蛋白生物标记物包括例如MCP-1、BMP受体1A、Smpd13a、CD14、ApoE、FAS、转甲状腺素蛋白、FABP1、酰基辅酶A硫酯酶1、酰基辅酶A硫酯酶2、水通道蛋白4、Rrad、CXCL9、CCL8、Ppp1r3g、ApoA-I、ApoA-II和ApoB。沉默调节蛋白的生物标记物和其在监控沉默调节蛋白表达中的用途已描述于例如美国专利申请公布No.2010/0215632,“Biomarkers of Sirtuin Activity and MethodsofUse Thereof”中,其通过引用整体并入本文。
沉默调节蛋白活性的测定包括乙酰基转移酶/脱乙酰化酶活性的测定。此类测定已描述于文献例如美国专利申请公布No.2009/0221020,“Mass Spectrometry Assays forAcetyltransferase/Deacetylase Activity”中,其通过引用整体并入本文。设想本领域技术人员已知的沉默调节蛋白活性的任何测定与本发明的方法结合,用于测量沉默调节蛋白活性。
在某些实施方案中,通过与对照例如未处理的或模拟物处理的样品相比,增加(上调)或减少(下调)沉默调节蛋白mRNA拷贝数、mRNA浓度或生物标记物mRNA或蛋白质表达或活性至少约10%、至少约15%、至少约20%、至少约25%、至少约30%、至少约40%、至少约50%、至少约60%、至少约70%、至少约75%、至少约80%、至少约90%、至少约100%、至少约125%、至少约150%、至少约200%、至少约250%、至少约300%、至少约3500%、至少约400%、至少约450%、或至少约500%、至少约600%、至少约700%、至少约800%、至少约900%、或至少约1000%,而鉴定沉默调节蛋白表达的调节。在实施方案中,沉默调节蛋白mRNA拷贝数、mRNA浓度或生物标记物mRNA或蛋白质表达或活性增加或减少约10%至约500%。在实施方案中,沉默调节蛋白mRNA拷贝数、mRNA浓度或生物标记物mRNA或蛋白质表达或活性增加或减少约10%至约50%、约10%至约100%、约10%至约150%、约10%至约200%、约10%至约250%、约10%至约300%、约10%至约350%、约10%至约400%、约10%至约450%、约10%至约500%、约10%至约600%、约10%至约700%、约10%至约800%、约10%至约900%、约10%至约1000%、约50%至约100%、约50%至约150%、约50%至约200%、约50%至约250%、约50%至约300%、约50%至约350%、约50%至约400%、约50%至约450%、约50%至约500%、约50%至约600%、约50%至约700%、约50%至约800%、约50%至约900%、约50%至约1000%、约100%至约150%、约100%至约200%、约100%至约250%、约100%至约300%、约100%至约350%、约100%至约400%、约100%至约450%、约100%至约500%、约100%至约600%、约100%至约700%、约100%至约800%、约100%至约900%、约100%至约1000%、约150%至约200%、约150%至约250%、约150%至约300%、约150%至约350%、约150%至约400%、约150%至约450%、约150%至约500%、约150%至约600%、约150%至约700%、约150%至约800%、约150%至约900%、约150%至约1000%、约200%至约250%、约200%至约300%、约200%至约350%、约200%至约400%、约200%至约450%、约200%至约500%、约200%至约600%、约200%至约700%、约200%至约800%、约200%至约900%、或约200%至约1000%。
例如,可测量动物的血清、血液、脂肪组织、肝脏或任何其它体液、组织或器官中沉默调节蛋白(SIRT)表达的减少。优选地,待分析的所述体液、组织或器官中包含的细胞包含编码沉默调节蛋白(SIRT)肽和/或沉默调节蛋白(SIRT)蛋白本身的核酸分子。
本发明的化合物可用于药物组合物,通过向适当的药学上可接受的稀释剂或载体加入有效量的本发明化合物。本发明的化合物和方法的用途还可以是预防上有用的。
缀合物
本发明寡核苷酸的另一修饰包括将该寡核苷酸化学连接至增强寡核苷酸的活性、细胞分布或细胞摄取的一个或多个部分或缀合物。这些部分或缀合物可包括共价结合官能团例如伯羟基或仲羟基基团的缀合物基团。本发明的缀合物基团包括嵌入剂、报告分子、聚胺、聚酰胺、聚乙二醇、聚醚、增强寡聚物药代动力学特性的基团、增强寡聚物药效学特性的基团。典型缀合物基团包括胆固醇、脂质、磷脂、生物素、吩嗪、叶酸、菲啶、蒽醌、吖啶、荧光素、罗丹明、香豆素和染料。在本发明范畴中,增强药效学特性的基团包括改进摄取、增强对降解的耐受性和/或加强与靶核酸序列特异性杂交的基团。在本发明范畴中,增强药代动力学特性的基团包括改进本发明化合物的摄取、分布、代谢或排泄的基团。代表性缀合物基团公开在1992年10月23日提交的国际专利申请No.PCT/US92/09196和美国专利No.6,287,860中,其通过引用并入本文。缀合物部分包括但不限于,脂质部分例如胆固醇部分、胆酸、硫醚例如己基-5-三苯甲基硫醇、硫胆固醇、脂肪族链例如十二烷二醇或十一烷基残基、磷脂例如二-十六烷基-rac-甘油或1,2-二-O-十六烷基-rac-甘油-3-H膦酸三乙基铵、聚胺或聚乙二醇链、或金刚烷乙酸、棕榈酰基部分或十八胺或己基氨基-羰基-羟胆固醇部分。本发明的寡核苷酸还可缀合于活性药物物质,例如,阿斯匹林、华法林、苯基丁氮酮、布洛芬、舒洛芬、芬布芬、酮洛芬、(S)-(+)-普拉洛芬、卡洛芬、丹肌氨酸、2,3,5-三碘苯甲酸、氟灭酸、亚叶酸、苯并噻二嗪、氯噻嗪、二氮杂环庚三烯、吲哚美辛、巴比妥酸盐、头孢菌素、磺胺药物、抗糖尿病药、抗菌药或抗生素。
教导这种寡核苷酸缀合物的制备的代表性美国专利包括但不限于,美国专利No.4,828,979、4,948,882、5,218,105、5,525,465、5,541,313、5,545,730、5,552,538、5,578,717、5,580,731、5,580,731、5,591,584、5,109,124、5,118,802、5,138,045、5,414,077、5,486,603、5,512,439、5,578,718、5,608,046、4,587,044、4,605,735、4,667,025、4,762,779、4,789,737、4,824,941、4,835,263、4,876,335、4,904,582、4,958,013、5,082,830、5,112,963、5,214,136、5,082,830、5,112,963、5,214,136、5,245,022、5,254,469、5,258,506、5,262,536、5,272,250、5,292,873、5,317,098、5,371,241、5,391,723、5,416,203、5,451,463、5,510,475、5,512,667、5,514,785、5,565,552、5,567,810、5,574,142、5,585,481、5,587,371、5,595,726、5,597,696、5,599,923、5,599,928和5,688,941。
制剂
为了辅助摄取、分布和/或吸收,本发明的化合物还可与其它分子、分子结构或化合物的混合物混合、包封、缀合或以其它方式关联,例如脂质体、受体靶向分子、口服、直肠、局部或其它制剂。教导这种摄取、分布和/或吸收辅助制剂的制备的代表性美国专利包括但不限于,美国专利No.5,108,921、5,354,844、5,416,016、5,459,127、5,521,291、5,543,165、5,547,932、5,583,020、5,591,721、4,426,330、4,534,899、5,013,556、5,108,921、5,213,804、5,227,170、5,264,221、5,356,633、5,395,619、5,416,016、5,417,978、5,462,854、5,469,854、5,512,295、5,527,528、5,534,259、5,543,152、5,556,948、5,580,575和5,595,756,其每一个通过引用并入本文。
尽管反义寡核苷酸不必以载体的背景施用以便调节靶表达和/或功能,但是本发明的实施方案涉及用于表达反义寡核苷酸的表达载体构建体,包括启动子、杂合体启动子基因序列,并具备强的组成型启动子活性或在期望情形中可被诱导的启动子活性。
在实施方案中,发明实践包括以适当的核酸递送系统施用至少一种上述反义寡核苷酸。在一个实施方案中,该系统包括可操作地连接于多核苷酸的非病毒载体。这种非病毒载体的实例包括单独寡核苷酸(例如,SEQ ID NO:24至127的任何一种或多种)或寡核苷酸与适当的蛋白、多糖或脂质制剂的组合。
另外适当的核酸递送系统包括病毒载体,通常序列来自以下的至少一种:腺病毒、腺病毒相关病毒(AAV)、辅助病毒依赖型腺病毒、逆转录病毒或日本血凝病毒-脂质体(HVJ)复合体。优选地,病毒载体包括可操作地连接于多核苷酸的强的真核启动子,例如巨细胞病毒(CMV)启动子。
另外优选的载体包括病毒载体、融合蛋白和化学缀合物。逆转录病毒载体包括莫洛尼氏鼠白血病病毒和基于HIV的病毒。一种基于HIV的病毒载体包括至少两种载体,其中gag和pol基因来自HIV基因组且env基因来自另一病毒。DNA病毒载体是优选的。这些载体包括痘病毒载体例如正痘病毒或禽痘病毒载体、疱疹病毒载体例如I型单纯疱疹病毒(HSV)载体、腺病毒载体和腺相关病毒载体。
本发明的反义化合物涵盖任何药学上可接受的盐、酯或这种酯的盐、或当施用于动物(包括人)时能够提供(直接或间接)生物活性代谢物的任何其它化合物或其残留物。
术语"药学上可接受的盐"是指本发明化合物的生理上和药学上可接受的盐:即,保留亲本化合物的期望生物活性且不对其赋予不期望的毒物学作用的盐。对于寡核苷酸,药学上可接受的盐及其用途的实例进一步描述于美国专利No.6,287,860,其通过引用并入本文。
本发明还包括包含本发明反义化合物的药物组合物和制剂。取决于期望局部还是系统治疗和待治疗的区域,本发明的药物组合物可以多种方式施用。施用可以是局部的(包括眼睛和向粘膜,包括阴道和直肠递送)、肺部,例如通过吸入或喷入粉末或气雾剂,包括通过喷雾器;气管内、鼻内、表皮和经皮)、口服或肠胃外。肠胃外施用包括静脉内、动脉内、皮下、腹膜内或肌内注射或输注;或颅内,例如鞘内或心室内的施用。
对于治疗中枢神经系统中的组织,施用可通过例如注射或输注到脑脊液中来进行。反义RNA向脑脊液的施用描述于例如美国专利申请公布No.2007/0117772“Methods forslowing familial ALS diseaseprogression”中,通过引用整体并入本文。
当预期本发明的反义寡核苷酸被施用于中枢神经系统中的细胞时,可以能够促进本发明反义寡核苷酸跨越血脑屏障的渗透的一种或多种试剂施用。注射可在例如内嗅皮质或海马中进行。通过向肌肉组织中的运动神经元施用腺病毒载体来递送神经营养因子描述于例如美国专利No.6,632,427“Adenoviral-vector-mediated gene transferintomedullary motor neurons”中,其通过引用并入本文。向脑例如纹状体、丘脑、海马或黑质直接递送载体是本领域已知的,描述于例如美国专利No.6,756,523“Adenovirusvectors for the transfer of foreign genesinto cells of the central nervoussystem particularly in brain”中,其通过引用并入本文。施用可以是快速的,如通过注射,或经一段时间进行,如通过缓慢输注或施用缓释制剂。
本发明反义寡核苷酸可还连接或缀合于提供期望的药物或药效学特性的试剂。例如,反义寡核苷酸可偶联于本领域已知的促进跨血脑屏障渗透或运输的任何物质,例如转铁蛋白受体的抗体,并通过静脉内注射施用。反义化合物可连接于病毒载体,例如,使得反义化合物更有效和/或增加反义化合物跨血脑屏障的运输的病毒载体。渗透血脑屏障破坏还可通过例如输注以下物质来实现:糖包括但不限于,赤藓糖醇、木糖醇、D(+)半乳糖、D(+)乳糖、D(+)木糖、卫矛醇、肌醇、L(-)果糖、D(-)甘露醇、D(+)葡萄糖、D(+)阿拉伯糖、D(-)阿拉伯糖、纤维二糖、D(+)麦芽糖、D(+)棉子糖、L(+)鼠李糖、D(+)蜜二糖、D(-)核糖、侧金盏花醇、D(+)阿拉伯糖醇、L(-)阿拉伯糖醇、D(+)岩藻糖、L(-)岩藻糖、D(-)来苏糖、L(+)来苏糖和L(-)来苏糖,或氨基酸包括但不限于,谷氨酰胺、赖氨酸、精氨酸、天冬酰胺、天冬氨酸、半胱氨酸、谷氨酸、甘氨酸、组氨酸、亮氨酸、甲硫氨酸、苯丙氨酸、脯氨酸、丝氨酸、苏氨酸、酪氨酸、缬氨酸和牛磺酸。用于增强血脑屏障渗透的方法和材料描述于,例如,美国专利No.4,866,042“Methodfor the delivery of genetic material across the blood brainbarier”,美国专利No.6,294,520“Material for passage through the blood-brainbarrier”和美国专利No.6,936,589“Parenteral delivery systems”,其每一个通过引用整体并入本文。
为了帮助摄取、分布和/或吸收,本发明反义化合物可与其它分子、分子结构或化合物混合物,例如,脂质体、受体靶向分子、口服、直肠、局部或其它制剂混合、包封、缀合或以其它方式关联。例如,阳离子脂质可被包括在制剂中以促进寡核苷酸摄取。显示促进摄取的一种这样的组合物是LIPOFECTIN(可从GIBCO-BRL,Bethesda,MD获得)。
认为具有至少一种2'-O-甲氧基乙基修饰的寡核苷酸尤其可用于口服施用。用于局部施用的药物组合物和制剂可包括经皮贴片、软膏、洗剂、乳膏、凝胶、滴剂、栓剂、喷雾剂、液体和粉末。常规药物载体、水性、粉状或油性基质、增稠剂和类似物可以是必需或期望的。涂覆的避孕套、手套和类似物也是可用的。
可方便地以单位剂型呈现的本发明的药物制剂可按照制药工业中公知的常规技术制备。这种技术包括将活性成分与药物载体或赋形剂关联的步骤。通常,制剂通过以下制备:均匀且密切地将活性成分与液态载体或磨碎的固态载体或两者关联,然后,如果需要,将产品成型。
本发明的组合物可配制为任何的许多可能剂型,例如但不限于,片剂、胶囊、凝胶胶囊、液体糖浆剂、软凝胶、栓剂和灌肠剂。本发明的组合物还可配制为在含水、不含水或混合介质中的悬浮剂。含水悬浮剂可进一步包含增加悬浮剂粘度的物质,包括例如,羧甲基纤维素钠、山梨醇和/或葡聚糖。悬浮剂还可包含稳定剂。
本发明的药物组合物包括但不限于,溶液、乳液、泡沫剂和含脂质体制剂。本发明的药物组合物和制剂可包括一种或多种渗透促进剂、载体、赋形剂或其它活性或无活性配料。
乳剂通常是一种液体以直径通常超过0.1μm的液滴形式分散在另一液体中的异质系统。除了分散相和可作为以水相、油相或本身作为单独相的溶液存在的活性药物以外,乳剂可包含另外的成分。包括微乳剂作为本发明的实施方案。乳剂及其用途是本领域公知的,进一步描述于美国专利No.6,287,860。
本发明的制剂包括脂质体制剂。本发明所用的术语"脂质体"是指包括以一个或多个球形双层排列的两亲性脂质的囊泡。脂质体是单层或多层囊泡,具有从亲脂性材料形成的膜和包含待递送的组合物的含水内部。阳离子脂质体是带正电荷的脂质体,认为其与带负电荷的DNA分子相互作用形成稳定复合体。认为pH-敏感或带负电荷的脂质体捕获DNA而不是与其复合。阳离子和非阳离子脂质体两者已经用于向细胞递送DNA。
脂质体还包括"空间上稳定的"脂质体,本文所用的该术语是指包括一种或多种特化的脂质的脂质体。当被并入脂质体时,这些特化的脂质产生相对于松散这种特化脂质的脂质体具有增强的循环生命周期的脂质体。空间上稳定的脂质体的实例是其中脂质体的形成囊泡的脂质部分的部分包括一种或多种糖脂或以一种或多种亲水性聚合物例如聚乙二醇(PEG)部分衍生化的脂质体。脂质体及其用途进一步描述于美国专利No.6,287,860中。
本发明的药物制剂和组合物还可包括表面活性剂。表面活性剂在药物产品、制剂和乳剂中的使用是本领域公知的。表面活性剂及其用途进一步描述于美国专利No.6,287,860中,其通过引用并入本文。
在一个实施方案中,本发明采用多种渗透促进剂来实现核酸尤其是寡核苷酸的有效递送。除了帮助非亲脂性药物跨细胞膜的扩散,渗透促进剂还增强亲脂性药物的渗透性。渗透促进剂可分为属于五个大类之一,即,表面活性剂、脂肪酸、胆酸、螯合剂和非螯合非表面活性剂。渗透促进剂及其用途进一步描述于美国专利No.6,287,860中,其通过引用并入本文。
本领域技术人员将认识到,制剂常规地根据其预期用途即施用途径来设计。
用于局部施用的制剂包括其中本发明的寡核苷酸与局部递送剂例如脂质、脂质体、脂肪酸、脂肪酸酯、类固醇、螯合剂和表面活性剂混合的制剂。脂质和脂质体包括中性(例如,二油酰基-磷脂酰DOPE乙醇胺、二肉豆蔻酰磷脂酰胆碱DMPC、二硬脂酰磷脂酰胆碱)、阴性(例如,二肉豆蔻酰磷脂酰甘油DMPG)和阳离子(例如,二油酰基四甲基氨基丙基DOTAP和二油酰基-磷脂酰乙醇胺DOTMA)。
对于局部或其它施用,可将本发明的寡核苷酸封装于脂质体中或可与其形成复合体,尤其是阳离子脂质体。可选地,寡核苷酸可与脂质,尤其是阳离子脂质复合。脂肪酸和酯、其药学上可接受的盐及其用途进一步描述于美国专利No.6,287,860中。
用于口服施用的组合物和制剂包括粉末剂或颗粒剂、微颗粒、纳米颗粒、水或非水介质中的悬浮剂或溶液、胶囊、凝胶胶囊、囊剂、片剂或小片剂。增稠剂、芳香剂、稀释剂、乳化剂、分散助剂或粘合剂可以是期望的。口服制剂是其中本发明的寡核苷酸连同一种或多种渗透促进剂、表面活性剂和螯合剂一起施用的那些。表面活性剂包括脂肪酸和/或其酯或盐、胆酸和/或其盐。胆酸/盐和脂肪酸及其用途进一步描述于美国专利No.6,287,860中,其通过引用并入本文。还有渗透促进剂的组合,例如,脂肪酸/盐与胆酸/盐的组合。尤其是月桂酸、癸酸和UDCA的钠盐。进一步的渗透促进剂包括聚氧乙烯-9-月桂基醚、聚氧乙烯-20-十六烷基醚。本发明的寡核苷酸可口服递送,以包括喷雾干燥颗粒的粒状形式或复合以形成微颗粒或纳米颗粒。寡核苷酸络合剂及其用途进一步描述于美国专利No.6,287,860中,其通过引用并入本文。
用于肠胃外、鞘内或心室内施用的组合物和制剂可包括还可包含缓冲剂、稀释剂和其它适当的添加剂(例如但不限于渗透促进剂、载体化合物和其它药学上可接受的载体或赋形剂)的无菌水溶液。
本发明的某些实施方案提供包含与一种或多种其它试剂组合的一种或多种寡聚化合物的药物组合物。其它试剂可通过非反义机制起作用。第二试剂是例如目前用于治疗沉默调节蛋白相关疾病或病症的试剂。第二试剂可选择性地是非-沉默调节蛋白调节剂,例如化疗剂。例如,在治疗癌症中,一种或多种用于治疗特定癌症的化疗剂可与本发明的至少一种反义寡核苷酸组合施用。组合治疗方案包括这样的治疗方案,其中在用第二试剂治疗之前、期间或之后引发SIRT反义寡核苷酸的施用,并且继续这种施用直到用第二试剂的治疗期间的任何时间或用第二试剂的治疗终止后。这也包括这样的治疗,其中在治疗期过程中,同时或在不同时间和/或以递减或递增的间隔施用组合使用的试剂。组合治疗包括在不同时间开始并停止以协助患者的临床管理的周期性治疗。例如,组合的试剂可在治疗开始时每周施用一次,递减至每两周施用一次,并且酌情进一步递减。
可与本发明的反义寡核苷酸组合向患者施用的其它调节沉默调节蛋白的试剂已描述于文献例如美国专利申请公布No.2009/0163476,“N-Phenyl Benzamide Derivativesas Sirtuin Modulators”中,其通过引用整体并入本文。该公布报道了某些沉默调节蛋白调节化合物用于治疗神经变性疾病、和中枢神经系统(CNS)、脊髓或周围神经系统(PNS)的创伤性或机械性损伤的用途。其还列出了可与沉默调节蛋白调节剂组合使用的其它治疗剂。设想与本发明的反义寡核苷酸组合向患者施用的其它沉默调节蛋白调节剂描述于:美国专利No.7,855,289,“Sirtuinmodulating compounds”和美国专利No.7,829,556,“Sirtuin modulatingcompounds”;美国专利申请公布No.2009/0143376,“FusedHeterocyclicCompounds and Their Use as Sirtuin Modulators”;美国专利申请公布No.2009/0069301,“Acridine and Quinoline Derivatives as SirtuinModulators”;美国专利申请公布No.2007/0037865,“Sirtuin modulatingcompounds”;美国专利申请公布No.2007/0149466,“Methods andrelated compositions for treating or preventingobesity,insulin resistancedisorders,and mitochondrial-associated disorders”,其每一个通过引用整体并入本文。
这种化疗剂的实例包括但不限于,癌症化疗药物例如柔红霉素、道诺霉素、放线菌素、多柔比星、表柔比星、伊达比星、依索比星、博来霉素、马磷酰胺、异环磷酰胺、阿糖胞苷、双氯乙亚硝基脲、白消安、丝裂霉素C、放线菌素D、光神霉素、泼尼松、羟孕酮、睾酮、他莫昔芬、达卡巴嗪、丙卡巴肼、六甲蜜胺、五甲蜜胺、米托蒽醌、安吖啶、苯丁酸氮芥、甲基环己亚硝基脲、氮芥、美法仑、环磷酰胺、6-巯嘌呤、6-硫鸟嘌呤、阿糖胞苷、5-氮杂胞苷、羟基脲、脱氧柯福霉素、4-羟基过氧环磷酰胺、5-氟尿嘧啶(5-FU)、5-氟脱氧尿苷(5-FUdR)、甲氨蝶呤(MTX)、秋水仙碱、泰素、长春新碱、长春碱、依托泊苷(VP-16)、三甲曲沙、伊立替康、托泊替康、吉西他滨、替尼泊苷、顺铂和己烯雌酚(DES)。当与本发明的化合物一起使用时,这种化疗剂可单独地使用(例如,5-FU和寡核苷酸),顺序地使用(例如,5-FU和寡核苷酸持续一段时间,随后是MTX和寡核苷酸)或与一种或多种其它这种化疗剂组合使用(例如,5-FU、MTX和寡核苷酸,或5-FU、放疗和寡核苷酸)。包括但不限于非类固醇抗炎药物和皮质激素的抗炎药物及包括但不限于利巴韦林、阿糖腺苷、无环鸟苷和更昔洛韦的抗病毒药物也可组合在本发明的组合物中。反义化合物与其它非反义药物的组合也在本发明的范围中。两种或更多种组合的化合物可一起或顺序地使用。
在另一相关实施方案中,本发明的组合物可包含靶向第一核酸的一种或多种反义化合物,尤其是寡核苷酸,和靶向第二核酸靶的一种或多种另外的反义化合物。例如,第一靶可以是沉默调节蛋白(SIRT)的特定反义序列,第二靶可以是来自另一核苷酸序列的区域。可选地,本发明的组合物可包含靶向同一沉默调节蛋白(SIRT)核酸靶的不同区域的两种或更多种反义化合物。本文阐述了反义化合物的许多实例,其它的可选自本领域已知的适当的化合物。两种或更多种组合的化合物可一起或顺序地使用。
给药:
认为治疗性组合物的配制及其随后的施用(给药)在本领域技术人员的能力范围内。给药依赖于待治疗的疾病状态的严重度和响应性,治疗的时期持续数天到数月,或直到实现治愈或实现疾病状态的减轻。最佳给药计划可从患者体内药物积累的测量来计算。本领域普通技术人员可容易地确定最佳剂量、给药方法和重复率。最佳剂量可根据单独寡核苷酸的相对效力而变化,通常可基于在有效的体外和体内动物模型中有效的EC50来估算。通常,剂量是每kg体重从0.01μg至100g,可每天、每周、每月或每年一次或多次,或甚至每2至20年一次地提供。本领域普通技术人员可基于测量的药物在体液或组织中的停留时间和浓度容易地估算重复率。在成功治疗之后,可能期望对患者进行维持疗法以阻止疾病状态复发,其中寡核苷酸以维持剂量施用,范围从每kg体重0.01μg至100g,每天一次或多次,至每20年一次。
在实施方案中,患者以至少约1、至少约2、至少约3、至少约4、至少约5、至少约6、至少约7、至少约8、至少约9、至少约10、至少约15、至少约20、至少约25、至少约30、至少约35、至少约40、至少约45、至少约50、至少约60、至少约70、至少约80、至少约90或至少约100mg/kg体重的药物剂量治疗。反义寡核苷酸的某些注射剂量描述于,例如,美国专利No.7,563,884“Antisense modulation ofPTP1B expression”,其通过引用整体并入本文。
尽管以上已经描述了本发明多种实施方案,应理解的是,它们仅以示例而非限制的方式呈现。可根据本公开内容对公开的实施方案进行多种改变而不偏离本发明的主旨或范围。因此,本发明的宽度和范围不应限于任何上述的实施方案。
本文提及的所有文件通过引用并入本文。本申请中提及的所有出版物和专利文件为了所有目的通过引用并入本文,其程度如同每个单独出版物或专利文件被单独地提及。通过在本文件中提及多个参考文献,申请人不承认任何特定参考文献是本发明的"现有技术"。本发明组合物和方法的实施方案在以下实施例中阐述。
实施例
以下非限制性实施例用于阐述本发明的选定实施方案。应理解的是,所示组分的成分的比例和其它选择方面的改变对于本领域技术人员是明显的,并且在本发明实施方案范围中。
实施例1:对与沉默调节蛋白(SIRT)反义的核酸分子和/或沉默调节蛋白(SIRT)多核苷酸的有义链有特异性的反义寡核苷酸的设计
如上所述,术语"对…有特异性的寡核苷酸"或"寡核苷酸靶"是指具有(i)能够与靶向基因的一部分形成稳定双链体,或(ii)能够与靶基因的mRNA转录物的一部分形成稳定双链体的序列的寡核苷酸。
进一步通过利用自动比对核酸序列并指明同一性或同源性的区域的计算机程序来便于选择适当的寡核苷酸。这种程序用来比较获得的核酸序列,例如通过搜寻数据库例如GenBank或通过对PCR产物测序。比较来自一系列物种的核酸序列允许选择在物种之间展示适当的同一性程度的核酸序列。在未被测序的基因的情形中,进行DNA印迹以允许确定靶物种与其它物种的基因之间的同一性程度。如本领域所熟知的,通过以不同的严格性程度进行DNA印迹,可能获得近似的同一性测量。这些方案允许选择展现与待控制的受治疗者中靶核酸序列的高程度互补性和与其它物种中的相应核酸序列的较低程度互补性的寡核苷酸。本领域技术人员将认识到,在选择用于本发明的基因的适当区域方面存在相当大的自由。
当反义化合物与靶核酸的结合干扰靶核酸的正常功能以导致功能和/或活性的调节时,该化合物是"可特异性杂交的",且在期望特异性结合的条件下(即,在体内测定或治疗性治疗的情形中的生理条件下,和在体外测定的情形中进行测定的条件下)存在足够程度的互补性以避免反义化合物与非靶核酸序列的非特异性结合。
本文所述寡核苷酸的杂交特性可通过本领域已知的一种或多种体外测定来确定。例如,本文所述寡核苷酸的特性可利用解链曲线测定确定靶天然反义与可能的药物分子之间的结合强度来获得。
靶天然反义与可能的药物分子(分子)之间的结合强度可利用测量分子间相互作用强度的任何已建立的方法例如解链曲线测定来估算。
对于天然反义/分子复合体,解链曲线测定确定双链向单链构象的快速转变发生时的温度。这一温度被广泛接受作为两种分子之间相互作用强度的可靠量度。
解链曲线测定可利用对应分子结合位置的实际天然反义RNA分子或合成的DNA或RNA核苷酸的cDNA拷贝进行。多种包含所有进行这一测定所必需的试剂的试剂盒是可获得的(例如,AppliedBiosystems Inc.MeltDoctor试剂盒)。这些试剂盒包括包含双链DNA(dsDNA)结合染料之一(例如ABI HRM染料、SYBR Green、SYTO等等)的适当的缓冲溶液。dsDNA染料的特性是使得它们在游离形式几乎不发出荧光,但当结合dsDNA时是高度荧光的。
为了进行测定,将cDNA或相应的寡核苷酸与由具体制造商的方案规定的浓度的分子混合。将混合物加热到95℃以使所有预形成的dsDNA复合体解离,然后缓慢冷却到室温或试剂盒制造商规定的其它较低温度以允许DNA分子退火。然后将新形成的复合体缓慢加热到95℃,同时连续收集反应产生的荧光的量的数据。荧光强度与反应中存在的dsDNA的量成反比。数据可利用与试剂盒相容的实时PCR仪器(例如ABI’s StepOne Plus实时PCR系统或LightTyperinstrument,Roche Diagnostics,Lewes,UK)来收集。
利用适当的软件(例如LightTyper(Roche)或SDS DissociationCurve,ABI)将荧光相对于温度的负导函数(y轴上的-d(荧光)/dT))对温度(x轴)绘图来构建熔融峰。分析数据以鉴定dsDNA复合体向单链分子快速转变的温度。这一温度称为Tm,与两种分子之间相互作用的强度成正比。通常,Tm将超过40℃。
实施例2:SIRT多核苷酸的调节
以反义寡核苷酸处理HepG2细胞
在37℃和5%CO2下将来自ATCC的HepG2细胞(cat#HB-8065)生长在生长培养基(MEM/EBSS(Hyclone cat#SH30024或Mediatechcat#MT-10-010-CV)+10%FBS(Mediatechcat#MT35-011-CV)+青霉素/链霉素(Mediatech cat#MT30-002-CI))中。实验前一天,将细胞以1.5×105/ml的密度重新铺板到6孔板中并且在37℃和5%CO2下孵育。在实验当天将6孔板中培养基改变为新鲜生长培养基。将所有反义寡核苷酸稀释到20μM的浓度。将此溶液的2μl与400μl Opti-MEM培养基(Gibco cat#31985-070)和4μl Lipofectamine 2000(Invitrogen cat#11668019)在室温一起孵育20min,然后施加到带有HepG2细胞的6孔板的每一孔。代替寡核苷酸溶液的包括2μl水的类似混合物用于模拟转染的对照。在37℃和5%CO2培养3-18h后,将培养基改变为新鲜生长培养基。加入反义寡核苷酸48h后,去除培养基且利用来自Promega的SV总RNA分离系统(cat#Z3105)或来自Qiagen的RNeasy总RNA分离试剂盒(cat#74181)按照制造商的说明书从细胞提取RNA。将600ng RNA加入到利用来自Thermo Scientific的VersocDNA试剂盒(cat#AB1453B)或高容量cDNA逆转录试剂盒(cat#4368813)如制造商的方案所述地进行的逆转录反应中。来自这一逆转录反应的cDNA用于利用ABI Taqman基因表达混合物(cat#4369510)和由ABI(Applied Biosystems Taqman基因表达测定:Hs00202021_m1、Hs00202030_m1、Hs00953479_m1、Hs00202033_m1,Hs00978329_m1、Hs00213036_m1和Hs00213029_m1,由AppliedBiosystems Inc.,Foster City CA)设计的引物/探针通过实时PCR监测基因表达。利用StepOne Plus Real Time PCR Machine(AppliedBiosystems)使用以下PCR循环:50℃持续2min、95℃持续10min、40个循环的(95℃持续15秒、60℃持续1min)。以反义寡核苷酸处理后的基因表达倍数变化基于处理样品和模拟转染样品之间18S-标准化的dCt值的差异来计算。
结果:
实时PCR结果显示,用针对SIRT1反义CV396200的一些反义寡核苷酸处理后48h,HepG2细胞中SIRT1 mRNA的水平显著增加(图3,4)。
实时PCR结果显示,利用针对SIRT1反义CV396200设计的寡核苷酸之一,HepG2细胞中SIRT1 mRNA的水平显著增加(图8)。
实时PCR结果显示,利用针对SIRT1反义CV428275设计的寡核苷酸中的两个,HepG2细胞中SIRT1 mRNA的水平显著增加(图9)。
结果显示,分别用针对SIRT反义BE717453设计的寡核苷酸中的三个处理后48h,HepG2细胞中SIRT1 mRNA的水平显著增加(图10)。
结果显示,用针对SIRT反义AV718812设计的寡核苷酸之一处理后48h,HepG2细胞中SIRT1 mRNA的水平显著增加(图11)。
实时PCR结果显示,用针对SIRT1反义AW169958设计的寡核苷酸中的两个处理后48h,HepG2细胞中SIRT1 mRNA的水平显著增加(图12)。
RT PCR结果显示,用针对sirt3反义Hs.683117设计的硫代磷酸酯反义寡核苷酸(CUR-1545-1550)处理后48h,HepG2细胞中sirt3的水平增加(图17)。
RT PCR结果显示,用针对sirt3反义BQ024738和BE164357设计的硫代磷酸酯反义寡核苷酸处理后48h,HepG2细胞中sirt3的水平增加(图18)。
RT PCR结果显示,用针对sirt3反义RIC8A和PMSD13设计的siRNA寡核苷酸处理后48h,HepG2细胞中sirt3的水平增加(图19)
实时PCR结果显示,用针对SIRT4反义设计的反义寡核苷酸之一处理后48h,HepG2细胞中SIRT4 mRNA的水平显著增加(图22)。
实时PCR结果显示,用针对SIRT5反义Hs.671550设计的反义寡核苷酸之一处理后48h,HepG2细胞中SIRT5 mRNA的水平显著增加(图23)。
实时PCR结果显示,用针对SIRT6反义NM_133475设计的寡核苷酸之一处理后48h,HepG2细胞中SIRT6 mRNA的水平显著增加(图24)。
实时PCR结果显示,用针对SIRT6反义bf772662设计的寡核苷酸之一处理后48h,HepG2细胞中SIRT6 mRNA的水平显著增加(图25)。
实时PCR结果显示,用针对SIRT7反义设计的寡核苷酸之一处理后48h,HepG2细胞中SIRT7 mRNA的水平显著增加(图29)。
以反义寡核苷酸处理3T3细胞
在37℃和5%CO2下将来自ATCC的3T3细胞(cat#CRL-1658)生长在生长培养基(MEM/EBSS(Hyclone cat#SH30024或Mediatechcat#MT-10-010-CV)+10%FBS(Mediatech cat#MT35-011-CV)+青霉素/链霉素(Mediatech cat#MT30-002-CI))中。实验前一天,将细胞以1.5×105/ml的密度重新铺板到6孔板中并且在37℃和5%CO2下孵育。在实验当天将6孔板中培养基改变为新鲜生长培养基。将所有反义寡核苷酸稀释到20μM的浓度。将此溶液的2μl与400μl Opti-MEM培养基(Gibco cat#31985-070)和4μl Lipofectamine 2000(Invitrogencat#11668019)在室温一起孵育20min,然后施加到带有3T3细胞的6孔板的每一孔。代替寡核苷酸溶液的包括2μl水的类似混合物用于模拟转染的对照。在37℃和5%CO2培养3-18h后,将培养基改变为新鲜生长培养基。加入反义寡核苷酸48h后,去除培养基且利用来自Promega的SV总RNA分离系统(cat#Z3105)或来自Qiagen的RNeasy总RNA分离试剂盒(cat#74181)按照制造商的说明书从细胞提取RNA。将600ng RNA加入到利用来自ThermoScientific的VersocDNA试剂盒(cat#AB1453B)或高容量cDNA逆转录试剂盒(cat#4368813)如制造商的方案所述地进行的逆转录反应中。来自这一逆转录反应的cDNA用于利用ABITaqman基因表达混合物(cat#4369510)和由ABI(Applied Biosystems Taqman基因表达测定:Hs00202021_m1,由Applied Biosystems Inc.,Foster City CA)设计的引物/探针通过实时PCR监测基因表达。利用StepOne Plus Real Time PCRMachine(Applied Biosystems)使用以下PCR循环:50℃持续2min、95℃持续10min、40个循环的(95℃持续15秒、60℃持续1min)。以反义寡核苷酸处理后的基因表达倍数变化基于处理样品和模拟转染样品之间18S-标准化的dCt值的差异来计算。
结果:
实时PCR结果显示,用针对SIRT1小鼠反义AK044604设计的寡核苷酸中的三个处理后48h,3T3细胞中SIRT1 mRNA的水平显著增加(图13)。
实时PCR结果显示,用针对SIRT1小鼠反义AK044604设计的寡核苷酸中的五个处理后48h,3T3细胞中SIRT1 mRNA的水平显著增加(图14)。
实时PCR结果显示,用针对SIRT1小鼠反义AK044604设计的寡核苷酸中的两个处理后48h,3T3细胞中SIRT1 mRNA的水平显著增加(图15)。
实时PCR结果显示,用针对SIRT1小鼠反义AK044604设计的寡核苷酸中的两个处理后48h,3T3细胞中SIRT1 mRNA的水平显著增加(图16)。
以反义寡核苷酸处理Vero76细胞
在37℃和5%CO2下将来自ATCC的Vero76细胞(cat#CRL-1587)生长在生长培养基(MEM/EBSS(Hyclone cat#SH30024或Mediatechcat#MT-10-010-CV)+10%FBS(Mediatechcat#MT35-011-CV)+青霉素/链霉素(Mediatech cat#MT30-002-CI))中。实验前一天,将细胞以1.5×105/ml的密度重新铺板到6孔板中并且在37℃和5%CO2下孵育。在实验当天将6孔板中培养基改变为新鲜生长培养基。将所有反义寡核苷酸在水中稀释到20μM的浓度。将此溶液的2μl与400μlOpti-MEM培养基(Gibco cat#31985-070)和4μl Lipofectamine2000(Invitrogen cat#11668019)在室温一起孵育20min,然后施加到带有Vero76细胞的6孔板的每一孔。代替寡核苷酸溶液的包括2μl水的类似混合物用于模拟转染的对照。在37℃和5%CO2培养3-18h后,将培养基改变为新鲜生长培养基。加入反义寡核苷酸48h后,去除培养基且利用来自Promega的SV总RNA分离系统(cat#Z3105)或来自Qiagen的RNeasy总RNA分离试剂盒(cat#74181)按照制造商的说明书从细胞提取RNA。将600ng RNA加入到利用来自ThermoScientific的Verso cDNA试剂盒(cat#AB1453B)如制造商的方案所述地进行的逆转录反应中。来自这一逆转录反应的cDNA用于利用ABITaqman基因表达混合物(cat#4369510)和由ABI(Applied BiosystemsTaqman基因表达测定:Hs00202021_m1,由AppliedBiosystems Inc.,Foster City CA)设计的引物/探针通过实时PCR监测基因表达。利用StepOne Plus Real Time PCR Machine(Applied Biosystems)使用以下PCR循环:50℃持续2min、95℃持续10min、40个循环的(95℃持续15秒、60℃持续1min)。以反义寡核苷酸处理后的基因表达倍数变化基于处理样品和模拟转染样品之间18S-标准化的dCt值的差异来计算。
结果:
实时PCR结果显示,用针对SIRT1反义CV396200的反义寡核苷酸处理后48h,Vero细胞中SIRT1 mRNA的水平显著增加(图5)。
实时PCR结果显示,用针对SIRT3反义PSMD13的反义寡核苷酸之一处理后48h,Vero细胞中SIRT3 mRNA的水平显著增加(图20)。
实时PCR结果显示,用针对SIRT7反义CV308253设计的反义寡核苷酸之一处理后48h,Vero76细胞中SIRT7 mRNA的水平显著增加(图27)。
以反义寡核苷酸处理HUVEC细胞
在37℃和5%CO2下将来自ATCC的HUVEC细胞(Promo Cellcat#C-12253)生长在上皮细胞生长培养基(Promo Cell cat#C-22010)中。实验前一天,使用Promo Cell Detach Kit(cat#C-41200)将细胞以1.5×105/ml的密度重新铺板到6孔板中并且在37℃和5%CO2下孵育。在实验当天将6孔板中培养基改变为新鲜上皮细胞生长培养基。将所有反义寡核苷酸稀释到20μM的浓度。将此溶液的2μl与400μlOpti-MEM培养基(Gibco cat#31985-070)和4μlLipofectamine2000(Invitrogen cat#11668019)在室温一起孵育20min,然后施加到带有HUVEC细胞的6孔板的每一孔。代替寡核苷酸溶液的包括2μl水的类似混合物用于模拟转染的对照。在37℃和5%CO2培养3-18h后,将培养基改变为新鲜生长培养基。加入反义寡核苷酸48h后,去除培养基且利用来自Promega的SV总RNA分离系统(cat#Z3105)或来自Qiagen的RNeasy总RNA分离试剂盒(cat#74181)按照制造商的说明书从细胞提取RNA。将600ng RNA加入到利用来自ThermoScientific的Verso cDNA试剂盒(cat#AB1453B)如制造商的方案所述地进行的逆转录反应中。来自这一逆转录反应的cDNA用于利用ABITaqman基因表达混合物(cat#4369510)和由ABI(Applied BiosystemsTaqman基因表达测定:Hs00202033_m1,由Applied Biosystems Inc.,Foster City CA)设计的引物/探针通过实时PCR监测基因表达。利用StepOne Plus Real Time PCR Machine(Applied Biosystems Inc.)或Mx4000热循环仪(Stratagene)使用以下PCR循环:50℃持续2min、95℃持续10min、40个循环的(95℃持续15秒、60℃持续1min)。以反义寡核苷酸处理后的基因表达倍数变化基于处理样品和模拟转染样品之间18S-标准化的dCt值的差异来计算。
结果:
实时PCR结果显示,用针对SIRT4反义AA156947设计的反义寡核苷酸之一处理后48h,HUVEC细胞中SIRT4 mRNA的水平显著增加(图21)。
以反义寡核苷酸处理DBS细胞
在37℃和5%CO2下将来自ATCC的DBS细胞(cat#CCL-161)生长在生长培养基(MEM/EBSS(Hyclone cat#SH30024或Mediatech cat#MT-10-010-CV)+10%FBS(Mediatech cat#MT35-011-CV)+青霉素/链霉素(Mediatech cat#MT30-002-CI))中。实验前一天,将细胞以1.5×105/ml的密度重新铺板到6孔板中并且在37℃和5%CO2下孵育。在实验当天将6孔板中培养基改变为新鲜生长培养基。将所有反义寡核苷酸稀释到20μM的浓度。将此溶液的2μl与400μl Opti-MEM培养基(Gibco cat#31985-070)和4μl Lipofectamine 2000(Invitrogencat#11668019)在室温一起孵育20min,然后施加到带有3T3细胞的6孔板的每一孔。代替寡核苷酸溶液的包括2μl水的类似混合物用于模拟转染的对照。在37℃和5%CO2培养3-18h后,将培养基改变为新鲜生长培养基。加入反义寡核苷酸48h后,去除培养基且利用来自Promega的SV总RNA分离系统(cat#Z3105)或来自Qiagen的RNeasy总RNA分离试剂盒(cat#74181)按照制造商的说明书从细胞提取RNA。将600ng RNA加入到利用来自ThermoScientific的VersocDNA试剂盒(cat#AB1453B)或高容量cDNA逆转录试剂盒(cat#4368813)如制造商的方案所述地进行的逆转录反应中。来自这一逆转录反应的cDNA用于利用ABITaqman基因表达混合物(cat#4369510)和由ABI(Applied Biosystems Taqman基因表达测定:Hs00202021_m1、Hs00202030_m1、Hs00202033_m1、Hs00978329_m1、Hs00213036_m1和Hs00213029_m1,由Applied Biosystems Inc.,FosterCity CA)设计的引物/探针通过实时PCR监测基因表达。利用StepOnePlus Real Time PCR Machine(Applied Biosystems)使用以下PCR循环:50℃持续2min、95℃持续10min、40个循环的(95℃持续15秒、60℃持续1min)。以反义寡核苷酸处理后的基因表达倍数变化基于处理样品和模拟转染样品之间18S-标准化的dCt值的差异来计算。
结果:
实时PCR结果显示,用针对SIRT6反义bf772662设计的寡核苷酸中的两个和针对NM_133475设计的一个寡核苷酸处理后48h,DBS细胞中SIRT6 mRNA的水平显著增加(图26)。
以反义寡核苷酸处理SK-N-AS细脆
在37℃和5%CO2下将SK-N-AS细胞(成神经细胞瘤ATCC#CRL-2137)生长在DMEM(Mediatech cat#10-013-CV)+10%FBS(Mediatech cat#MT35-011-CV)+青霉素/链霉素(Mediatech cat#MT30-002-CI))中。实验前一天,将细胞以约3×105/孔的密度重新铺板到6孔板中并且在37℃和5%CO2下孵育过夜。在给药时,细胞为约75%汇合。为了给药,将6孔板中培养基改变为新鲜DMEM+10%FBS+青霉素+链霉素(1.5ml/孔)。将所有反义寡核苷酸在不含DNA酶/RNA酶的无菌水(工作储备液)中稀释到20μM的浓度。为了向一个孔给药,将此溶液的2μl与400μl Opti-MEM培养基(Gibco cat#31985-070)和4μl Lipofectamine 2000(Invitrogen cat#11668019)在室温一起孵育20min,然后滴加到带有SK-N-AS细胞的6孔板的一个孔(最终寡核苷酸浓度=20nM)。相同浓度的失活寡核苷酸用作控制。另外向每个板上的一个孔给药400ul Opti-MEM培养基的混合物,4ul Lipofectamine 2000和2ul不含DNA酶/RNA酶的无菌水用于模拟转染的控制。在37℃和5%CO2培养约18h后,将培养基改变为新鲜DMEM+10%FBS+青霉素+链霉素。加入反义寡核苷酸约48h后,去除培养基且利用来自Promega的SV总RNA分离系统(cat#Z3105)按照制造商的说明书从细胞提取RNA。将600ngRNA加入到利用来自Applied Biosystems的高容量cDNA试剂盒(cat#4368813)如制造商的方案所述地进行的逆转录反应中。来自这一逆转录反应的cDNA用于利用ABI Taqman基因表达混合物(cat#4369510)和由ABI(对于SIRT7,测定ID#Hs00213029_m1)设计的引物/探针通过实时PCR监测基因表达。利用StepOne Plus Real Time PCR系统(AppliedBiosystems)使用以下PCR循环:50℃持续2min、95℃持续10min、40个循环的(95℃持续15秒、60℃持续1min)。用ABI(cat#4319413E)制造18S的测定。以反义寡核苷酸处理后的基因表达倍数变化基于处理样品和模拟转染样品之间18S-标准化的dCt值的差异来计算。
结果:实时PCR结果显示,用针对SIRT7反义设计的寡核苷酸处理后48h,SK-N-AS细胞中SIRT7 mRNA的水平显著增加(图28)。
实施例3:SIRT基因表达的调节
材料和方法
以反义寡核苷酸处理裸露的HepG2细胞
在37℃和5%CO2下将来自ATCC的HepG2细胞(cat#HB-8065)生长在生长培养基(MEM/EBSS(Hyclone cat#SH30024或Mediatechcat#MT-10-010-CV)+10%FBS(Mediatechcat#MT35-011-CV)+青霉素/链霉素(Mediatech cat#MT30-002-CI))中。实验前一天,将细胞以0.5×105/ml的密度重新铺板到6孔板中并且在37℃和5%CO2下孵育。在实验当天将6孔板中培养基替换为1.5ml/孔的新鲜生长培养基。将所有反义寡核苷酸在水中稀释到20μM的浓度。将此溶液的2μl与400μl Opti-MEM培养基(Gibco cat#31985-070)和4μlLipofectamine 2000(Invitrogen cat#11668019)在室温一起孵育20min,然后施加到带有HepG2细胞的6孔板的每一孔。代替寡核苷酸溶液的包括2μl水的类似混合物用于模拟转染的对照。在37℃和5%CO2培养3-18h后,将培养基改变为新鲜生长培养基。加入反义寡核苷酸72h后,如上所述地重新给药细胞。第二次给药反义寡核苷酸48h后,去除培养基且利用来自Promega的SV总RNA分离系统(cat#Z3105)或来自Qiagen的RNeasy总RNA分离试剂盒(cat#74181)按照制造商的说明书从细胞提取RNA。将600ng RNA加入到利用来自ThermoScientific的Verso cDNA试剂盒(cat#AB1453B)如制造商的方案所述地进行的逆转录反应中。来自这一逆转录反应的cDNA用于利用ABI Taqman基因表达混合物(cat#4369510)和由ABI(AppliedBiosystems Taqman基因表达测定:Hs00202021_m1、Hs00202030_m1、Hs00202033_m1、Hs00978329_m1、Hs00213036_m1和Hs00213029_m1,由Applied BiosystemsInc.,Foster City CA)设计的引物/探针通过实时PCR监测基因表达。利用StepOne PlusReal Time PCR Machine(AppliedBiosystems)使用以下PCR循环:50℃持续2min、95℃持续10min、40个循环的(95℃持续15秒、60℃持续1min)。以反义寡核苷酸处理后的基因表达倍数变化基于处理样品和模拟转染样品之间18S-标准化的dCt值的差异来计算。
对于定制设计的Taqman测定的外显子4的引物和探针:AACTGGAGCTGGGGTGTCTGTTTCA(SEQ ID NO:128)和SIRT1天然反义CV396200。
正向引物序列CCATCAGACGACATCCCTTAACAAA(SEQ IDNO:129)
反向引物序列ACATTATATCATAGCTCCTAAAGGAGATGCA(SEQ ID NO:130)
报告序列CAGAGTTTCAATTCCC(SEQ ID NO:131)
结果:结果显示,用针对sirtas(sirtas_5,P=0.01)设计的siRNA之一处理后48h,HepG2细胞中SIRT mRNA的水平显著增加。在相同的样品中,用sirtas_5处理后,sirtas RNA的水平显著下降,但是用sirtas_6和sirtas_7(它们也对SIRT1 mRNA水平没有影响)处理后,其水平并未变化(图2)。sirtas_5、sirtas_6和sirtas_7分别对应于SEQ IDNO:47、48和49。
处理原代猴肝细胞
原代猴肝细胞由RxGen Inc.引入到培养物中并在6孔板中铺板。它们用寡核苷酸如下处理。6孔板中的培养基改变为新鲜生长培养基,所述新鲜生长培养基由补充有5%FBS、50U/ml青霉素和50ug/ml链霉素、4ug/ml胰岛素、1uM地塞米松、10ug/ml菌纤维素(InVivogen,San Diego CA)的William’s Medium E(Sigma cat#W4128)组成。将所有反义寡核苷酸稀释至20μM的浓度。在室温下用400μl Opti-MEM培养基(Gibco cat#31985-070)和4μl Lipofectamine 2000(Invitrogen cat#11668019)孵育2μl该溶液20min,然后施加到带有该细胞的6孔板的每一孔。代替寡核苷酸溶液的包括2μl水的类似混合物用于模拟转染的对照。在37℃和5%CO2培养3-18h后,将培养基改变为新鲜生长培养基。加入反义寡核苷酸48h后,去除培养基且利用来自Promega的SV总RNA分离系统(cat#Z3105)或来自Qiagen的RNeasy总RNA分离试剂盒(cat#74181)按照制造商的说明书从细胞提取RNA。将600ng RNA加入到利用来自Thermo Scientific的VersocDNA试剂盒(cat#AB1453B)如制造商的方案所述地进行的逆转录反应中。来自这一逆转录反应的cDNA用于利用ABI Taqman基因表达混合物(cat#4369510)和由ABI(Applied Biosystems Taqman基因表达测定:Hs00202021_m1、Hs00202030_m1、Hs00202033_m1、Hs00978329_m1、Hs00213036_m1和Hs00213029_m1,由AppliedBiosystems Inc.,Foster City CA)设计的引物/探针通过实时PCR监测基因表达。利用Mx4000热循环仪(Stratagene)使用以下PCR循环:50℃持续2min、95℃持续10min、40个循环的(95℃持续15秒、60℃持续1min)。以反义寡核苷酸处理后的基因表达倍数变化基于处理样品和模拟转染样品之间18S-标准化的dCt值的差异来计算。
结果:结果示于图7。实时PCR结果显示用针对SIRT1反义的寡核苷酸处理后,SIRT1mRNA水平的增加。
实施例4:CUR 963在非洲绿猴中的作用功效和持续时间的研究
本研究的目的是在非人灵长类动物模型中评估和比较在静脉内施用后调控SIRT1基因的不协调的非编码反义序列的反义敲低的作用。被设计来抑制SIRT1调控序列的反义寡核苷酸测试品称为CUR963。
CUR 963:+G*+T*C*T*G*A*T*G*G*+A*+G*+A(SEQ ID NO:43).
CUR 962(对照):+G*+C*T*A*G*T*C*T*G*+T*+T*+G(SEQ IDNO:132).
管理测试指导方针
本研究按照可接受的毒理学原理和遵从国际协调会议(ICH)统一的三方指导方针(药物ICH M3(m)的用于实施人临床试验的非临床安全研究),2000年11月9日)来进行设计,并且通常接受用于测试治疗剂的方法。
测试品和对照品
测试品身份和制备
测试品CUR-963为化学上稳定的反义寡核苷酸。用于静脉内递送的媒介物为磷酸缓冲盐水(PBS)。
媒介物的表征
对于PBS媒介物,组成、批号、药品有效期和贮存条件(温度和光/暗)从提供商获得。
测试品贮存和处理
相应地按照由资助者和制造商提供的接受的贮存条件贮存测试物质和媒介物。
测试品制剂的分析
冷冻保存测试品制剂的样品以用于分析测试物质制剂的浓度、稳定性和均匀性。
测试系统原理
灵长类动物是监管机构可接受为潜在危害的指示者并且关于其的详尽背景资料是可获得的适当的非啮齿类动物物种。非洲绿猴特别地为多种人生理和疾病状态的高度临床相关模型。
静脉内施用途径对应于可能的人治疗途径。测试品的剂量基于先前在非洲绿猴中进行的类似化合物的剂量调查研究的结果。
非洲绿猴被选择作为选择的灵长类动物,因为测试物质的靶序列在物种间是保守的,在灵长类动物中具有100%的同源性。此外,测试物质为合成寡核苷酸。因此,灵长类动物的给药允许进行此类化合物的功效的优良评估,与在任何其它物种中相比,所述评估更能反映可能在人中看到的摄取。
动物
物种:Chlorocebus sabaeus,非人灵长类动物
品种:St.Kitts土生土长的非洲绿猴
来源:RxGen,Lower Bourryeau,St.Kitts,West Indies.
预期年龄:测试动物为成年。
预期生物体重:猴体重约3-4kg。实际范围可变化但记录在资料中。
性别:测试动物为成年雌性。
动物的数目:筛选10只动物以确保鉴定8只动物适合于本研究的招募。
关于研究的数目:雌性:8只
关于研究的数目的论证:本研究被设计来尽可能使用最少数目的动物,与目的在于评价测试品在非洲绿猴中的治疗功效和该类型的寡核苷酸在该物种中的全身性施用的先前研究的灵长类动物一致。
动物说明:将体重在3至4kg范围内的10只成年非洲绿猴用于研究。猴为从栖息在岛上的野生群体人道地捕获的首次接触药物的成年动物。利用驱肠虫剂处理捕获的猴以消除任何可能的肠寄生虫负荷,在研究招募筛选之前隔离观察其最少4周。通过大小和齿状突起估计捕获的猴的年龄,将较老的动物从研究排除。在研究招募之前,对每一只猴进行临床检查,包括运动和灵巧的估计。采集血液样品,将其送至Antech Diagnostics(Memphis,TN)以获得全面的临床化学和完全血细胞计数以及脂质特征谱(关于说明参见部分9.2和319567928)。将具有异常实验值(如通过与St.Kitts聚居地的猴的确定的正常范围相比较测定的)的猴从研究排除。为了鉴定满足该标准的8只猴,对10只猴进行筛选,必要时筛选额外的动物。在研究开始前,将选择的猴转移至单个笼子中以使其适应个别关养,进行1周的时期。仅将被认为适合于实验的动物招募用于研究。研究开始时的实际(或估计的)年龄和体重范围将被详细记录在原始数据和最终的报告中。
动物健康与福利:使动物福利的最高标准遵照和坚持由圣基茨岛农业部(St.Kitts Department of Agriculture)和美国卫生与人类服务部(U.S.Department ofHealth and Human Services)规定的指导方针。所有研究将按照这些要求和所有可适用的实验室动物的护理和居住的实施规程来进行。兽医护理、操作和检查的所有可适用标准如动物的护理和使用的NIH指南中包括的。St.Kitts设施维持检查方案和考察如指南所要求的设施的动物研究委员会。基金会具有由实验动物福利办公室(Office of LaboratoryAnimal Welfare)提交的批准的保险,如Guide,#A4384-01(Axion Research Foundation/St.Kitts Biomedical Foundation)所要求的。不存在由本研究中指定的研究产生的特定非人灵长类动物兽医护理问题和生物危害问题。
居住和环境:为了使得能够检测任何处理相关临床症状,在手术之前和手术后直至处死将动物单独地关养。其中放置个体笼子的灵长类动物建筑物完全按照处于北纬17度接近U.S.D.H.H.S指导方针中推荐的12hr:12hr光-暗周期的环境光照明。RxGen灵长类动物建筑物完全对外通风。通过吊扇确保另外的空气流动以维持23-35°C的恒定目标温度,这是St.Kitts一年中的典型气候条件。每天测量24小时的温度和相对湿度的极限值(这也不受控制)。在研究过程中,定期清洁笼子。
钦食和水:每天给每只动物提供约90克的标准猴饲料(chowdiet)(TekLad,Madison,WI)。记录饮食的具体营养组成。定期分析水的微生物学纯度。常规饲料(stockdiet)和水供给的污染物的可接受水平的标准分别在由食物制造商和定期设施水评价建立的分析规范内。水满足证明为对于人消费可接受的所必需的所有标准。
实验设计
动物鉴定和随机化:通过基于体重和血浆胆固醇特性的分层随机化程序进行分配。在分配至组之前和之后,通过腹部上的纹身鉴定每一只动物。将纹身置于所有聚居动物上作为常规健康检查过程中的鉴定的工具。笼计划(cage plan)被制定来鉴定关养在笼内的个体,还可通过系在它们各自笼上的标记标签来鉴定个别猴。
组大小、剂量和标识号:将动物分配至2个处理组,每组由4只猴组成。按照设施编号系统给每一只猴提供特定的动物标识号。该系统通过一个字母后跟3个数字的号码例如Y032来唯一地标识每一只猴。
施用的途径和频率:在第1、3和5天通过持续约10分钟的手工输注进行的静脉内递送每天给动物给药一次。输注速率将为24mL/kg/h。在给药过程之前和期间利用氯胺酮和赛拉嗪使动物镇静。将静脉导管(Terumo迷你静脉输液装置,20号针或类似的适当的输液装置)插入隐静脉。每一只猴的给药在早上8:00至10:00点之间在动物醒来后不久并且在喂食之前进行。在即将进行每一次输注之前收集血液样品以估量血浆胆固醇和其它脂质水平,如下面血液化学部分中所描述的。在两次取样间隔在喂食之前收集血液以使对胆固醇测量的饮食影响降至最低。
临床观察:在给药的每一天记录对处理的反应的所有可见症状。此外,每周检查动物的身体属性诸如外表和一般状况至少一次。
体重:在处理期间和处理后时期以每周一次的间隔记录体重。
食物消耗:不定量个体的食物消耗。然而监控喂食模式并且记录任何较大的变化。
死亡率和发病率:记录死亡率和发病率。如果可能的话,在与实验负责人和资助者的监测科学家商量之后作出关于过早处死(premature sacrifice)的任何决定。将被发现过早死亡或杀死的动物经历尸体剖检以收集肝、肾、心和脾肺组织以进行组织病理学。倘若过早处死,也可获取血液样品(如果可能的话),测定参数。将被发现在正常工作时间后死亡的动物冷藏过夜,在接下来的工作日开始时进行尸体剖检。如果动物的状况需要过早处死,则通过戊巴比妥钠的静脉内过量给药来将其无痛致死。所有研究遵照动物使用原则(Principlesfor Use of Animals)。RxGen按法律规定遵从关于灵长类动物设施的美国卫生与人类服务部(U.S.Department of Health and Human Services)标准,所述标准表示指定为温和的本研究内的过程必须遵守的严重性的水平。
临床实验室研究
脂肪活组织检查:在第26个研究日通过经脐下1cm正中切口提取组织对所有研究猴(除Y775外)进行皮下脂肪活组织检查。立即将活检组织浸没在装有2ml RNAlater(Qiagen)的标记冷冻管中,于4℃下温育过夜,之后吸出RNAlater,将样品管快速冷冻在液氮中。在于氮中运输后,分离总RNA以进行靶基因的实时qPCR。
结果:实时PCR结果显示与用CUR-962(SEQ ID NO.:132)(一种对SIRT1的体外表达没有影响的寡核苷酸(针对ApoA1反义DA327409设计的,数据未显示))给药的猴相比较来自用CUR-963(一种针对SIRT1反义CV396200.1设计的寡核苷酸)给药的猴的脂肪活组织检查中SIRT1 mRNA水平的增加。通过实时PCR测量mRNA水平(图6)。
实施例5:反义DNA寡核苷酸对沉默调节蛋白(SIRT)的体内调节
利用反义DNA寡核苷酸(ASO)的处理:给被喂食高脂肪饮食12周以诱导肥胖症和糖尿病的C57Bl/6J小鼠施用对于SIRT1 AS是特异性的反义寡核苷酸(ASO)。利用ASO对小鼠的处理始于执行高脂肪饮食时。每周一次用浓度为5mg/kg的在生理盐水中制备的ASO对小鼠进行IP注射。
体重和食物摄入的测量:在IP注射ASO之前,每周两次测量小鼠的体重和食物摄入。
血糖测量:通过从尾静脉采集血液样品每周测量进食和空腹血糖浓度。
葡萄糖耐量测试(GTT):每只小鼠总共进行2次GTT,在高脂肪饮食进行至一半时(在第4周)和高脂肪饮食快结束时(在第10周)。GTT将告诉我们关于小鼠的作为从血液快速清除葡萄糖推注(glucosebolus)的能力的葡萄糖耐量。这为糖尿病的量度。将小鼠禁食过夜,进行16小时。给小鼠IP注射葡萄糖2g/kg。对于30g重的小鼠,这转化为终体积0.2ml的30%(w/v)葡萄糖溶液。在葡萄糖注射前和在注射后5、15、30、60、90和120分钟测量葡萄糖。在IP葡萄糖注射前,通过在异氟烷麻醉下从尾巴末端切取1mm的尾尖来测量葡萄糖。将血滴抽吸至测试条(strip),并利用血糖测计仪测量葡萄糖浓度。每只小鼠总共进行2次GTT,在高脂肪饮食进行至一半时(在第4周)和高脂肪饮食快结束时(在第10周)。GTT将告诉我们关于小鼠的作为从血液快速清除葡萄糖推注的能力的葡萄糖耐量。这为糖尿病的量度。
胰岛素耐量测试(ITT):将小鼠从早上9点至下午3点禁食6小时。随后给小鼠IP注射0.5-1U胰岛素/kg。调整胰岛素浓度以便终注射体积为0.1-0.15ml。在注射之前和在注射后5、15、30、45和60分钟进行血糖测量。完全如GTT下所述收集血液。除了监控葡萄水平外,还在ITT期间不断观察小鼠的行为。低血糖症可表现为动物变得非常安静并且显示不适的行为的改变。为了预防低血糖症,血糖浓度一降至低于50mg/ml或观察到不适的症状就立即IP注射终体积为0.1-0.15ml的葡萄糖(1g/kg)。
通过面静脉穿刺进行血液收集:通过颈背和尾基部控制小鼠,通过紧握颈部皮肤上的夹子轻度压紧颈部血管。取样位置在下颌角稍前方的颌上。利用18G针或柳叶刀以90°的角度刺穿取样位置上的皮肤直至针/柳叶刀的尖端刚好通过皮肤。使用微量血细胞比容管收集血液样品。在已收集血液后,松开颈上的夹子,用纱布海绵压住插入位置以确保止血。通过该方法收集0.05-0.2ml血液。该方法在高脂肪饮食的第5周中仅进行一次,如果心内穿刺效果不好(参见下文)最终在第12周进行该方法。使用商购可得的ELISA试剂盒(例如,R&DSystems,Minneapolis,MN,Assay Pro St.Charles,MO,Mabtech,Mariemont,OH)测量调节葡萄和脂质代谢的血液激素(诸如胰岛素、脂连素(adiponectin)和瘦素)。
心内穿刺:在12周的高脂肪饮食结束时,通过连续异氟烷吸入麻醉小鼠。通过将小鼠置于提供有异氟烷和氧气的吸气盒(inductionbox)中来诱导麻醉。将小鼠仰卧控制。利用27G针对心脏进行穿刺。在放血后,切断头以确保死亡。收集组织(肝、胰、白色和棕色脂肪组织以及骨骼肌)以进一步调查(RNA和蛋白质测量以及组织学)。获取约0.5–1ml血液,将其用于测定葡萄糖和脂质代谢的几个临床参数(葡萄糖、胰岛素、胆固醇、甘油三酯、游离脂肪酸、瘦素、脂肪因子、皮质类固醇、甲状腺激素)。如果该方法存在困难,我们就改由在异氟烷麻醉下通过面静脉穿刺收集血液(参见上文)。
尽管已经参照一种或多种实现来说明和描述了本发明,本领域技术人员在阅读和理解说明书和附图后将进行等价的改变和修饰。此外,尽管仅关于多种实现之一公开了本发明的特定特征,这种特征可如所需地与其它实现的一种或多种其它特征组合,如对于任何给定或特定应用可能是期望和有利的。
本公开内容的摘要将允许阅读者快速地确定技术公开内容的性质。应理解的是,提交其并不用于解释或限制所附权利要求书的范围或含义。
Claims (11)
1.一种筛选长度为10至30个核苷酸的用于体内或体外上调患者细胞或组织中沉默调节蛋白(SIRT)多核苷酸的功能和/或表达的至少一种反义寡核苷酸的方法,其中所述沉默调节蛋白(SIRT)选自SIRT3,所述方法包括:提供沉默调节蛋白(SIRT)多核苷酸的天然反义转录物,所述天然反义转录物选自如SEQ ID NOs:17-18和141-142的序列;基于所述沉默调节蛋白(SIRT)多核苷酸的天然反义转录物设计长度为10至30个核苷酸的反义寡核苷酸;和筛选能够体内或体外上调患者细胞或组织中沉默调节蛋白(SIRT)多核苷酸的功能和/或表达的反义寡核苷酸,其中所述至少一种反义寡核苷酸的序列选自:SEQ ID NOs:96、100、102和126-127。
2.如权利要求1中所述的方法,其中所述方法进一步包括修饰筛选得到的反义寡核苷酸。
3.如权利要求2所述的方法,其中所述修饰包括2'-O-甲氧基乙基修饰、硫代磷酸酯修饰、或锁核酸(LNA)修饰。
4.一种筛选长度为10至30个核苷酸的用于体内或体外上调哺乳动物细胞或组织中沉默调节蛋白(SIRT)的功能和/或表达的至少一种短干扰RNA(siRNA)寡核苷酸的方法,其中所述沉默调节蛋白(SIRT)选自SIRT3,所述方法包括:提供沉默调节蛋白(SIRT)多核苷酸的天然反义转录物,其中所述天然反义转录物选自如SEQ ID NOs:17-18和141-142的序列;基于所述沉默调节蛋白(SIRT)多核苷酸的天然反义转录物设计长度为10至30个核苷酸的短干扰RNA(siRNA)寡核苷酸;和筛选能够体内或体外上调哺乳动物细胞或组织中沉默调节蛋白(SIRT)的功能和/或表达的短干扰RNA(siRNA)寡核苷酸,其中所述至少一种短干扰RNA(siRNA)寡核苷酸的序列选自:SEQ ID NOs:96、100、102和126-127。
5.如权利要求4所述的方法,其中所述寡核苷酸与至少一种沉默调节蛋白(SIRT)多核苷酸的天然反义转录物杂交并与正常对照相比体内或体外上调其表达和/或功能。
6.如权利要求1-5任一项所述的方法,其中通过测定所述沉默调节蛋白或沉默调节蛋白生物标记物而确定沉默调节蛋白的上调。
7.如权利要求6所述的方法,其中所述沉默调节蛋白生物标记物选自由MCP-1、BMP受体1A、Smpd13a、CD14、ApoE、FAS、转甲状腺素蛋白、FABP1、酰基辅酶A硫酯酶1、酰基辅酶A硫酯酶2、水通道蛋白4、Rrad、CXCL9、CCL8、Ppp1r3g、ApoA-I、ApoA-II和ApoB组成的组。
8.一种合成的、修饰的寡核苷酸,其中所述寡核苷酸的长度为10至30个核苷酸,其中所述寡核苷酸是与沉默调节蛋白(SIRT)基因的天然反义转录物杂交并与正常对照相比体内或体外上调其功能和/或表达的反义化合物,其中所述沉默调节蛋白(SIRT)选自SIRT3,所述天然反义转录物的序列选自SEQ ID NOs:17-18和141-142的序列,并且所述合成的、修饰的寡核苷酸的序列选自SEQ ID NOS:96、100、102和126-127。
9.由权利要求1-7任一项所述的方法获得的寡核苷酸。
10.一种组合物,所述组合物包含权利要求9所述的一种或多种寡核苷酸、或权利要求8所述的合成的、修饰的寡核苷酸或其组合。
11.权利要求10所述的组合物在制备用于体内或体外上调患者细胞或组织中沉默调节蛋白(SIRT)多核苷酸功能和/或表达的药物中的用途。
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JP6100839B2 (ja) | 2017-03-22 |
RU2018110641A3 (zh) | 2021-12-27 |
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CN102933711A (zh) | 2013-02-13 |
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RU2693462C2 (ru) | 2019-07-03 |
KR101915115B1 (ko) | 2018-11-05 |
KR101992076B1 (ko) | 2019-06-21 |
US20150284724A1 (en) | 2015-10-08 |
EP2957636A3 (en) | 2016-06-15 |
JP2013525483A (ja) | 2013-06-20 |
RU2018110641A (ru) | 2019-02-27 |
HK1217031A1 (zh) | 2016-12-16 |
JP2016013125A (ja) | 2016-01-28 |
KR101936011B1 (ko) | 2019-01-07 |
EP2957636B1 (en) | 2020-04-01 |
CN107988228B (zh) | 2022-01-25 |
CN107988228A (zh) | 2018-05-04 |
US9089588B2 (en) | 2015-07-28 |
KR101892888B1 (ko) | 2018-08-28 |
WO2011139387A1 (en) | 2011-11-10 |
KR20170117202A (ko) | 2017-10-20 |
CA2798218A1 (en) | 2011-11-10 |
EP2566966A1 (en) | 2013-03-13 |
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