The present invention relates to oligonucleotides capable of inducing ubiquitin protein ligase E3A (UBE3A) expressed by male parent alleles in animal or human neurons. Oligonucleotides target UBE3A male parent alleles by hybridized with SNHG14 long non coding RNA downstream of SNORD109B. The invention also relates to pharmaceutical compositions and methods for the treatment of Angelman's syndrome (Angelman syndrome).
【技术实现步骤摘要】
【国外来华专利技术】用于诱导父本UBE3A表达的寡核苷酸专利
本专利技术涉及与SNORD109B下游的SNHG14互补并杂交的寡核苷酸(寡聚物),其导致诱导动物或人中泛素-蛋白连接酶E3A(UBE3A)的父本表达。本专利技术还涉及用于治疗安吉尔曼综合征(Angelmansyndrome)的药物组合物和方法。
技术介绍
安吉尔曼综合征是由母本遗传染色体15q11.2上的UBE3A基因的缺失或失活引起的神经遗传病。UBE3A基因的父本拷贝通过称为SNHG14(也称为UBE3A-ATS)的UBE3A内源性反义转录物在神经元中经受基因组印记和沉默(Meng等人2012HumMolGenet.Vol.21pp.3001-12)。除神经元之外的其它细胞类型似乎表达来自母本和父本等位基因的UBE3A基因。安吉尔曼综合征的特征在于严重的智力和发育障碍、睡眠障碍、发作(seizures)、急动性运动、脑电图(EEG)异常、频繁的笑声或微笑、以及深度的语言障碍。WO2012/064806公开了通过使用拓扑异构酶抑制剂在细胞中诱导UBE3A表达的方法。该方法可以用于治疗安吉尔曼综合征。其并未公开反义寡核苷酸。WO2014/004572公开了具有靶向小鼠UBE3A-ATS的2’-O-甲氧基乙基-RNA(MOE)修饰的寡核苷酸。所述寡核苷酸仅在小鼠相关测定中进行测试。在MBII-52snoRNA(也称为SNORD115)下游和UBE3A前-mRNA上游的区域,小鼠和人之间不存在保守性。因此,靶向小鼠UBE3A-ATS的寡核苷酸不能转换成将在人中起作用的寡核苷酸。其并未公开靶向人UBE3A-ATS的寡核 ...
【技术保护点】
1.一种反义寡核苷酸,所述反义寡核苷酸包含长度为10至30个核苷酸的连续核苷酸序列,所述连续核苷酸序列与人15号染色体上的位置25278410至25419462具有至少98%的互补性。
【技术特征摘要】
【国外来华专利技术】2015.11.12 EP 15194367.7;2016.09.19 EP 16189502.41.一种反义寡核苷酸,所述反义寡核苷酸包含长度为10至30个核苷酸的连续核苷酸序列,所述连续核苷酸序列与人15号染色体上的位置25278410至25419462具有至少98%的互补性。2.根据权利要求1所述的寡核苷酸,其中所述连续核苷酸序列与SEQIDNO:1和/或2的靶核酸的区域互补。3.根据权利要求1或2所述的寡核苷酸,其中所述连续核苷酸序列与靶核酸的子序列互补,其中所述子序列选自由表1或2所示的区域组成的组。4.根据权利要求1-3所述的寡核苷酸,其中所述寡核苷酸包含选自由以下组成的组的序列:SEQIDNO:4,5,6,7,8,9,10,11,12,13,14,15,16,17,1819,20,21,22,23,23,24,25,26,26,27,28,29,30,31,31,32,33,34,35,36,37,38,39,40,41,42,43,44,44,45,45,46,47,48,49,50,51,52,53,53,54,54,55,56,57,58,59,60,61,62,63,64,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,79,80,81,8283,84,85,86,87,88,89,90,91,92,93,94,95,95,96,96,96,97,98,99,100,101,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138,139,140,141,142,143,144,145,146,147,148,149,150,151,152,153,154,155,156,157,158,159,160,161,162,163,164,165,166,167,168,169,170,171,172,173,174,175,176,177,178,179,180,181,182,183,184,185,186,187,188,189,190,191,192,193,194,195,196,197,198,199,200,201,202,203,204,205,206,207,208,209,210,211,212,213,214,215,216,217,218,219,220,221,222,223,224,225,226,227,228,229,230,231,232,233,234,235,236,237,238,239,240,241,242,243,244,245,246,247,248,249,250,251,252,253,254,255,256,257,258,259,260,261,262,263,264,265,266,267,268,269,270,271,272,273,274,275,276,277,278,279,280,281,282,283,284,285,286,287,288,289,290,291,292,293,294,295,296,297,298,299,300,301,302,303,304,304,305,306,307,308,309,310,311,312,313,314,315,316,317,318,319,320,321,322,323,324,325,326,327,328,329,330,331,332,333,334,335,336,337,338,339,340,341,342,343,344,345,346,347,348,349,350,351,352,353,354,355,356,357,358,359,360,361,362,363,364,365,366,367,368,369,370,371,372,373,374,375,376,377,378,379,380,381,382,383,384,385,386,387,388,389,390,391,392,393,394,395,396,397,398,399,400,401,402,403,404,405,406,407,408,409,410,411,412,413,414,415,416,417,418,419,420,421,422,423,424,425,426,427,428,429,430,431,432,433,434,435,436,437,438,439,440,441,442,443,444,445,446,447,448,449,450,451,452,453,454,455,456,457,458,459,460,461,462,463,464,465,466,467,468,469,470,471,472,473,474,475,476,477,478,479,480,481,482,483,484,485,486,487,488,489,490,491,492,493,494,495,496,497,498,499,500,501,502,503,504,505,506,507,508,509,510,511,512,513,514,515,516,517,518,519,520,521,522,523,524,525,526,527,528,529,530,531,532,533,534,535,536,537,538,539,540,541,542,543,544,545,546,547,548,549,550,551,552,553,554,555,556,557,558,559,560,561,562,563,564,565,566,567,568,569,570,571,572,573,574,575,576,577,578,579,580,581,582,583,584,585,586,587,588,589,590,591,592,593,594,595,596,596,597,598,599,600,601,602,603,604,605,606,607,608,609,610,611,612,613,614,615,616,617,618,619,620,621,622,623,624,625,626,627,628,629,630,631,632,633,634,635,636,637,638,639,640,641,642,643,644,645,646,647,648,649,650,651,652,653,654,655,656,657,658,659,660,661,662,663,664,665,666,667,668,669,670,671,672,673,674,675,676,677,678,679,680,681,682,683,684,685,686,687,688,689,690,691,692,693,694,695,696,697,698,699,700,702,703,704,705,706,707,708,709,710,711,712,713,714,715,716,717,718,719,719,720,721,722,723,724,725,726,727,728,729,730,731,732,733,734,735,736,737,738,739,740,741,742,743,744,745,746,747,748,749,750,751,752,754,755,756,757,758,759,760,761,762,763,764,765,766,767,768,769,770,772,773,774,775,776,777,778,779,780,781,782,783,784,785,786,787,788,789,790,791,792,793,794,795,796,797,798,799,800,801,802,803,804,805,806,807,808,809,810,811,812,813,814,815,816,817和818。5.根据权利要求1-4所述的寡核苷酸,所述寡核苷酸包含一个或多个修饰的核苷。6.根据权利要求5所述的寡核苷酸,其中所述一个或多个修饰的核苷是2’糖修饰的核苷。7.根据权利要求6所述的寡核苷酸,其中一个或多个所述2’糖修饰的核苷独立地选自由以下组成的组:2’-O-烷基-RNA、2’-O-甲基-RNA、2’-烷氧基-RNA、2’-O-甲氧基乙基-RNA、2’-氨基-DNA、2’-氟-DNA、阿糖基核酸(ANA)、2’-氟-ANA和LNA核苷。8.根据权利要求5至7中任一项所述的寡核苷酸,其中所述一个或多个修饰的核苷是LNA核苷。9.根据权利要求1-8中任一项所述的寡核苷酸,其中所述寡核苷酸包含至少一个修饰的核苷间连接。10.根据权利要求9所述的寡核苷酸,其中所述连续核苷酸序列内的所述核苷间连接是硫代磷酸酯核苷间连接。11.根据权利要求1-10所述的寡核苷酸,其中所述寡核苷酸能够募集RNA酶H。12.根据权利要求11所述的寡核苷酸,其中所述寡核苷酸是间隔聚体。13.根据权利要求11或12所述的寡核苷酸,其中所述寡核苷酸是式5’-F-G-F’-3’的间隔聚体,其中区域F和F’独立地包含1-7个修饰的核苷,并且G是能够募集RNA酶H的6至16个核苷的区域。14.根据权利要求1-13中任一项所述的寡核苷酸,其中所述寡核苷酸选自由以下组成的组:CMPIDNO:4_1,4_2,5_1,5_2,6_1,6_2,7_1,7_2,8_1,9_1,10_1,11_1,11_2,12_1,12_2,13_1,13_2,14_1,15_1,16_1,17_1,17_2,18_1,18_2,19_1,19_2,20_1,21_1,22_1,23_1,23_2,24_1,25_1,26_1,26_2,27_1,28_1,28_2,29_1,29_2,30_1,31_1,31_2,32_1,33_1,34_1,34_2,34_3,34_4,34_5,34_6,34_7,35_1,35_2,36_1,37_1,38_1,38_2,38_3,38_4,38_5,38_6,39_1,39_2,39_3,39_4,39_5,40_1,40_2,40_3,40_4,40_5,40_6,40_7,40_8,41_1,42_1,43_1,44_1,44_2,45_1,45_2,46_1,47_1,48_1,48_2,48_3,48_4,48_5,48_6,48_7,49_1,50_1,51_1,52_1,53_1,53_2,54_1,54_2,54_3,55_1,55_2,56_1,57_1,58_1,58_2,58_3,59_1,59_2,60_1,60_2,60_3,61_1,62_1,63_1,64_1,64_2,65_1,66_1,67_1,68_1,69_1,69_2,69_3,70_1,70_2,70_3,71_1,72_1,72_2,73_1,73_2,73_3,74_1,74_2,75_1,75_2,76_1,77_1,77_2,77_3,78_1,79_1,79_2,79_3,80_1,80_2,80_3,81_1,82_1,82_2,83_1,83_2,84_1,84_2,85_1,85_2,86_1,87_1,88_1,88_2,89_1,90_1,91_1,92_1,93_1,94_1,95_1,95_2,96_1,96_2,96_3,97_1,97_2,97_3,97_4,98_1,98_2,98_3,99_1,99_2,99_3,99_4,100_1,100_2,100_3,101_1,101_2,101_3,101_4,102_1,102_2,102_3,102_4,103_1,103_2,103_3,103_4,104_1,104_2,104_3,105_1,105_2,105_3,105_4,106_1,106_2,106_3,106_4,107_1,107_2,107_3,107_4,108_1,108_2,108_3,108_4,109_1,109_2,109_3,109_4,110_1,110_2,111_1,111_2,111_3,112_1,112_2,113_1,114_1,115_1,116_1,117_1,118_1,119_1,120_1,120_2,121_1,122_1,123_1,124_1,125_1,126_1,126_2,127_1,128_1,128_2,128_3,128_4,129_1,129_2,130_1,131_1,132_1,132_2,132_3,133_1,133_2,133_3,133_4,134_1,134_2,135_1,135_2,136_1,137_1,138_1,139_1,140_1,141_1,142_1,143_1,144_1,145_1,145_2,146_1,146_2,147_1,148_1,149_1,150_1,150_2,151_1,152_1,153_1,154_1,155_1,156_1,157_1,158_1,159_1,160_1,161_1,162_1,163_1,164_1,165_1,166_1,167_1,168_1,169_1,169_10,169_11,169_12,169_13,169_14,169_15,169_16,169_17,169_18,169_19,169_2,169_20,169_21,169_22,169_23,169_24,169_25,169_26,169_27,169_28,169_29,169_3,169_30,169_31,169_32,169_33,169_34,169_35,169_36,169_37,169_38,169_39,169_4,169_40,169_41,169_42,169_43,169_44,169_45,169_46,169_47,169_48,169_49,169_5,169_50,169_51,169_52,169_53,169_54,169_55,169_56,169_57,169_6,169_7,169_8,169_9,169_58,169_59,169_60,169_61,169_62,170_1,171_1,172_1,173_1,174_1,175_1,176_1,177_1,178_1,179_1,180_1,181_1,182_1,183_1,184_1,185_1,186_1,187_1,188_1,189_1,190_1,191_1,192_1,193_1,194_1,195_1,196_1,197_1,198_1,199_1,200_1,201_1,202_1,203_1,204_1,205_1,206_1,207_1,208_1,208_2,208_3,208_4,208_5,208_6,208_7,209_1,209_10,209_2,209_3,209_4,209_5,209_6,209_7,209_8,209_9,210_1,211_1,212_1,213_1,214_1,215_1,216_1,217_1,218_1,219_1,220_1,221_1,222_1,223_1,224_1,225_1,226_1,227_1,228_1,229_1,230_1,231_1,232_1,233_1,234_1,235_1,236_1,236_10,236_11,236_12,236_13,236_14,236_15,236_16,236_2,236_3,236_4,236_5,236_6,236_7,236_8,236_9,236_17,236_18,236_19,236_20,236_21,237_1,237_10,237_11,237_12,237_13,237_14,237_15,237_16,237_2,237_3,237_4,237_5,237_6,237_7,237_8,237_9,237_17,237_18,237_19,237_20,237_21,238_1,239_1,239_10,239_11,239_12,239_13,239_14,239_15,239_16,239_2,239_3,239_4,239_5,239_6,239_7,239_8,239_9,239_17,239_18,239_19,239_20,239_21,240_1,241_1,241_10,241_2,241_3,241_4,241_5,241_6,241_7,241_8,241_9,241_11,241_12,241_13,241_14,241_15,242_1,243_1,244_1,244_2,244_3,244_4,244_5,245_1,246_1,247_1,248_1,249_1,250_1,251_1,252_1,253_1,254_1,255_1,256_1,257_1,258_1,259_1,260_1,261_1,262_1,263_1,264_1,265_1,266_1,267_1,268_1,269_1,270_1,271_1,272_1,273_1,274_1,275_1,276_1,277_1,278_1,279_1,280_1,281_1,282_1,283_1,284_1,285_1,285_2,285_3,285_4,285_5,285_6,285_7,285_8,285_9,285_10,285_11,286_1,287_1,288_1,289_1,290_1,291_1,292_1,293_1,294_1,295_1,296_1,297_1,298_1,299_1,300_1,301_1,302_1,303_1,304_1,304_10,304_2,304_3,304_4,304_5,304_6,304_7,304_8,304_9,304_11,304_12,304_13,304_14,304_15,305_1,306_1,307_1,308_1,309_1,310_1,311_1,312_1,313_1,314_1,315_1,316_1,317_1,318_1,319_1,320_1,321_1,322_1,323_1,324_1,325_1,326_1,327_1,328_1,329_1,330_1,331_1,332_1,333_1,334_1,335_1,336_1,337_1,338_1,339_1,340_1,341_1,342_1,343_1,344_1,345_1,346_1,347_1,348_1,349_1,350_1,351_1,352_1,353_1,354_1,355_1,356_1,357_1,358_1,359_1,360_1,361_1,361_10,361_2,361_3,361_4,361_5,361_6,361_7,361_8,361_9,362_1,362_10,362_2,362_3,362_4,362_5,362_6,362_7,362_8,362_9,363_1,364_1,365_1,366_1,367_1,368_1,369_1,370_1,371_1,372_1,373_1,374_1,375_1,376_1,377_1,378_1,379_1,380_1,381_1,382_1,383_1,384_1,385_1,386_1,387_1,388_1,389_1,390_1,391_1,392_1,393_1,394_1,395_1,396_1,397_1,398_1,399_1,400_1,401_1,402_1,403_1,404_1,405_1,406_1,407_1,408_1,409_1,410_1,411_1,412_1,413_1,414_1,415_1,416_1,417_1,418_1,419_1,420_1,421_1,422_1,423_1,424_1,425_1,425_10,425_2,425_3,425_4,425_5,425_6,425_7,425_8,425_9,426_1,427_1,428_1,429_1,430_1,431_1,432_1,433_1,434_1,435_1,436_1,437_1,438_1,439_1,440_1,441_1,442_1,443_1,444_1,445_1,446_1,447_1,448_1,449_1,450_1,451_1,452_1,453_1,454_1,455_1,456_1,457_1,458_1,459_1,460_1,461_1,462_1,463_1,464_1,465_1,466_1,467_1,468_1,469_1,470_1,471_1,472_1,473_1,474_1,475_1,476_1,477_1,478_1,479_1,480_1,481_1,482_1,483_1,484_1,485_1,486_1,487_1,488_1,489_1,490_1,491_1,492_1,493_1,494_1,495_1,496_1,497_1,498_1,499_1,500_1,501_1,502_1,503_1,504_1,505_1,506_1,507_1,508_1,509_1,510_1,511_1,512_1,513_1,514_1,515_1,516_1,517_1,518_1,519_1,520_1,521_1,522_1,523_1,524_1,525_1,526_1,527_1,528_1,529_1,530_1,531_1,532_1,533_1,534_1,535_1,536_1,537_1,538_1,539_1,540_1,541_1,542_1,543_1,544_1,545_1,546_1,547_1,548_1,549_1,550_1,551_1,552_1,553_1,554_1,555_1,556_1,557_1,558_1,559_1,560_1,561_1,562_1,563_1,564_1,565_1,566_1,567_1,568_1,569_1,570_1,570_2,570_3,570_4,570_5,570_6,570_7,570_8,570_9,570_10,570_11,570_12,570_13,570_14,571_1,571_2,571_3,571_4,571_5,571...
【专利技术属性】
技术研发人员:韦罗妮卡·科斯塔,马伊·黑特耶恩,马里乌斯·赫纳,拉维·姚高希亚,马斯·奥波尔·詹森,克里斯托弗·帕奇,吕克·彼泽森,索伦·韦斯特高·拉斯穆森,
申请(专利权)人:豪夫迈·罗氏有限公司,
类型:发明
国别省市:瑞士,CH
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