TW202405173A - 用於增強aav療法及降低aav向肝臟之趨性的組合物及方法 - Google Patents
用於增強aav療法及降低aav向肝臟之趨性的組合物及方法 Download PDFInfo
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Abstract
本發明提供用於增強AAV療法之組合物及方法,其藉由阻斷AAV與肝臟中之AAV受體結合及隨後投與靶向非肝臟組織之AAV療法,以增加個體中遞送至非肝臟標靶之AAV的百分比來實現。
Description
遺傳藥物、寡核苷酸(諸如小干擾RNA (siRNA)、信使RNA (mRNA)、反義寡核苷酸(ASO)及質體DNA)提供調節及編輯基因表現之潛力。ASO可藉由下調分子標靶而發揮作用,此通常藉由誘導核糖核酸酶H核酸內切酶活性來達成,該核酸內切酶裂解RNA-DNA異雙螺旋且顯著減少標靶基因轉譯。其他ASO所驅動之機制可包括抑制5'帽形成、剪接轉換或核糖體活性之位阻。特定言之,siRNA為短(19至21個核苷酸)的雙股RNA,其使用天然RNA干擾(RNAi)機制且經由使用複雜之蛋白質機制來降解互補mRNA。因此,siRNA會引起所關注之蛋白質在活體內可逆地減弱。然而,裸RNA或DNA分子面臨活體內快速降解、複雜免疫反應及不允許之細胞攝取。因此,此等藥物之遞送需要複雜之遞送系統。
腺相關病毒(AAV)載體傳統上為用於基於病毒之活體內基因療法的主要候選物,因為其具有廣泛之組織趨性、非病原性質及低免疫原性。目前已在人類及非人類靈長類動物群體中鑑別12種AAV血清型及超過100種變異體。在活體內使用AAV之基因療法載體可感染分裂細胞及靜止細胞兩者,並在不整合至宿主細胞之基因體中的情況下保持染色體外狀態,儘管在天然病毒中的確出現一些攜帶病毒之基因整合至宿主基因體中之情況。此等特徵使得AAV成為產生用於基因療法之病毒載體及創建同基因型人類疾病模式的極具吸引力之候選物。參見S. Pillay,
Nature, 530(7588): 108-112 (2016)。
AAV變異體具有或已經工程改造而具有特定趨性,以允許使用靶向基因療法遞送進行有效之局部或全身性投與。AAV變異體之初級及二級受體相互作用之細微變化形式可產生具有特定趨性之變異體或血清型,其中與其他組織或細胞類型相比,AAV優先感染一種組織或細胞類型。參見Naso等人, BioDrugs, 31:317-334 (2017)。作為一非限制性實例,據展示,骨骼肌為經許多AAV血清型及變異體有效轉導之標靶組織。靶向遞送基因療法以復原缺陷型肌肉結構蛋白或酶可用於治療許多使全身肌纖維失效之疾病。另外,一經轉導,肌肉便充當蛋白質產物之產生部位。肌肉可經靶向作為生物工廠以合成及分泌治療劑或分泌蛋白,例如因子VIII及IX以及紅血球生成素,該等治療劑或分泌蛋白可局部或全身性地起作用以治療例如糖尿病、動脈粥樣硬化、血友病、癌症及其他傳染病。參見Wang,
Expert Opin Drug Deliv ., 11(3): 345-364 (2014)。直接中樞神經系統遞送、AAV向心肌之局部遞送及吸入之經肺遞送為其他非限制性例示性AAV基因療法應用。
然而,AAV載體受若干因素(包括其小包裝尺寸)限制。此外,目前使用AAV用於基因轉移之限制包括潛在安全問題,其包括脫靶毒性。在投與之後,除局部及靶向遞送之外,AAV之大部分血清型亦可達成脫靶基因轉移,其可引起所關注之基因在非所需之細胞或組織中轉導及表現。當AAV載體到達血流時,循環系統將載體攜載至全身,包括攜載至肝臟、骨骼及心肌、胰臟及腎上腺。雖然不同AAV血清型在投與之後可具有不同之組織分佈模式,但肝臟為含有大量錯誤靶向之AAV載體的最常見器官。新近生物分佈動物研究發現,儘管直接經腦脊髓液投與,但載體DNA及綠色螢光蛋白(GFP)表現之生物分佈仍為廣泛的。參見Meseck等人, doi.org/10.1101/2021.11.28.470258, BioRxiv.org (發佈於2021年11月28日)。在該研究之一部分中,評估在單次鞘內輸注至腦脊髓液之後,scAAV9-CB-GFP在CNS及周邊組織中之轉導及表現。在該研究中,發現載體DNA及GFP表現在脊髓、背根節及全身組織(例如肝臟)中最高,而在許多大腦區域中具有較低濃度。最近,在2020年至2021年,使用AAV基因療法之基因療法臨床試驗被暫停,此部分歸因於罹患來自肝臟衰竭之併發症之個體的死亡。參見NCT03199469 (使用AAV血清型8載體)。迫切需要解決AAV-基因療法中之繼發性肝毒性問題。
目前解決繼發性肝毒性問題之方法包括嘗試藉由修飾AAV以促進向預期標靶之趨性來減少肝趨性。此包括使用重組技術來工程改造AAV之組成以增強向預期標靶之特定趨性,諸如殼體改組、定向演化及隨機肽庫插入,以及將較大結合蛋白插入AAV殼蛋白之不同區域中以衍生變異體並賦予選擇性。參見Naso等人, BioDrugs, 31:317-334 (2017)。一種其他此類方法為使用組織特異性啟動子來驅動預期標靶中而非錯誤靶向之組織中的轉錄。另一此類方法為設計轉殖基因以使其攜帶在標靶組織或細胞類型中特異性表現之微小RNA (miRNA)的靶標序列,例如將標靶序列併入3'-UTR中以減少非所需組織中之轉殖基因表現,同時維持標靶中之轉殖基因表現。Wang,
Expert Opin Drug Deliv ., 11(3): 345-364 (2014)。然而,值得注意的是,此等方法中之各者針對特定療法進行個別化。即,其涉及設計特定AAV血清型或變異體及/或轉殖基因之態樣,及/或使用啟動子以增強向特定標靶之趨性。對特定載體、轉殖基因及/或啟動子之此等修飾往往為治療特異性的,且未必適用於用以降低繼發性肝毒性之所有AAV-基因療法系統。
因此,此項技術中存在對降低來自AAV之肝毒性的需求,此可應用於所有AAV及所有轉殖基因之投與,無論預期標靶及遞送類型如何。
本發明部分尋求藉由減弱或阻斷肝臟中之AAV之受體而非增強向預期非肝臟標靶之趨性,例如在接受針對非肝臟標靶之AAV-基因療法之前作為預處理療法來去靶向肝臟。舉例而言,在投與AAV之前,投與基於RNA干擾(RNAi)之治療劑,包括使用小干擾RNA (siRNA)或結合GalNAc之RNAi或輔助LNP之RNAi,或反義寡核苷酸(ASO)可有效且暫時阻斷AAV殼體與肝臟中之AAVR的後續結合。已知在活體內使用ASO或siRNA一般為短暫的。因為基於RNAi之預處理可在AAV之前投與,且可稍後自身體清除,所以其可有效且暫時阻斷與肝臟中之AAVR的結合,由此在無長期作用之情況下增強AAV向預期非肝臟標靶之趨性。本發明組合物及方法可用作增強趨性且因此增強非肝臟AAV介導之基因療法之功效及安全性的平台。
因此,提供以下非限制性實施例:
實施例1為 一種組合物,其包含阻斷AAV結合至AAV受體(AAVR)之藥劑及將藥劑遞送至肝臟之遞送分子。
實施例2為 如實施例1之組合物,其中藥劑包含小干擾RNA (siRNA)。
實施例3為 如實施例2之組合物,其中siRNA包含SEQ ID No: 4300至9527中之任一者的至少19個鄰接核苷酸。
實施例4為 如實施例3之組合物,其中siRNA包含SEQ ID No: 4300至9527之序列中之任一者。
實施例5為 如實施例4之組合物,其中siRNA之長度不超過21、25或31個核苷酸。
實施例6為 如實施例1之組合物,其中藥劑包含抗AAVR抗體。
實施例7為 如實施例1之組合物,其中藥劑包含小分子。
實施例8為 如實施例1之組合物,其中藥劑包含反義寡核苷酸(ASO)。
實施例9為 如實施例8之組合物,其中ASO包含SEQ ID No: 9600至9623之序列中之任一者,或包含SEQ ID No: 9600至9623中之任一者的至少14個連續核苷酸。
實施例10為 如實施例1至9中任一項之組合物,其中遞送分子包含以下中之一或多者:乳糖、半乳糖、N-乙醯基半乳胺糖(GalNAc)、半乳胺糖、N-甲醯基半乳胺糖、N-乙醯基半乳胺糖、N-丙醯基半乳胺糖、N-丁醯基半乳胺糖、N-異丁醯基-半乳胺糖及膽固醇或其衍生物。
實施例11為 如實施例10之組合物,其中遞送分子包含N-乙醯基半乳胺糖(GalNAc)。
實施例12為 如實施例1至9中任一項之組合物,其中遞送分子包含脂質奈米粒子(LNP)。
實施例13為 如實施例1至9中任一項之組合物,其中遞送分子包含AAV。
實施例14為 一種方法,其包含:(a)向個體投與阻斷AAV結合至肝臟中之AAV受體(AAVR)之藥劑,及隨後(b)向個體投與AAV載體。
實施例15為 如實施例14之方法,其中AAV載體進一步包含有效負載。
實施例16為 如實施例15之方法,其中有效負載包含用以預防或治療疾病之治療劑。
實施例17為 如實施例15之方法,其中有效負載包含嚮導RNA、核酸內切酶、tRNA、小分子、ASO、抗體、siRNA或RNAi藥劑。
實施例18為 一種增加個體中遞送至非肝臟標靶之AAV之百分比的方法,其包含(a)包含向個體投與組合物之預處理步驟,該組合物包含阻斷AAV結合至肝臟中之AAV受體(AAVR)之藥劑,及隨後(b)投與靶向非肝臟組織之AAV載體。
實施例19為 如實施例14至18中任一項之方法,其中步驟(a)包含向個體投與如實施例1至13中任一項之組合物。
實施例20為 一種降低個體中AAV向肝臟之趨性的方法,其包含(a)向個體投與如實施例1至13中任一項之組合物,及隨後(b)投與靶向非肝臟組織之AAV載體。
實施例21為 如實施例14至20中任一項之方法,其中向個體投與阻斷AAV結合至肝臟中之AAV受體(AAVR)的組合物及/或藥劑暫時阻斷AAV結合至肝臟中之AAV受體。
實施例22為 如實施例14至20中任一項之方法,其中向個體投與阻斷AAV結合至肝臟中之AAV受體(AAVR)的組合物及/或藥劑為預處理步驟之部分。
實施例23為 如實施例14至20中任一項之方法,其中向個體投與阻斷AAV結合至肝臟中之AAV受體(AAVR)的組合物及/或藥劑發生在投與AAV載體之前約2天、約3天、約4天、約5天、約6天、約7天、約8天、約9天、約10天、約11天、約12天、約13天、約14天、約15天、約16天、約17天、約18天、約19天、約20天或約21天。
實施例24為 如實施例14至20中任一項之方法,其中向個體投與阻斷AAV結合至肝臟中之AAV受體(AAVR)的組合物及/或藥劑發生在投與AAV載體之前約1天、約2天、約3天、約4天、約5天、約6天、約7天。
實施例25為 如實施例14至20中任一項之方法,其中向個體投與阻斷AAV結合至肝臟中之AAV受體(AAVR)的組合物及/或藥劑發生在投與AAV載體之前約7天、約8天、約9天、約10天、約11天、約12天、約13天或約14天。
實施例26為 如實施例14至20中任一項之方法,其中向個體投與如實施例1至13中任一項之組合物緊接在投與AAV載體之前。
實施例27為 如實施例14至20中任一項之方法,其中共同投與如實施例1至10中任一項之組合物及AAV載體。
實施例28為 如實施例14至20中任一項之方法,其中步驟(a)包含向個體投與包含小干擾RNA (siRNA)或反義寡核苷酸(ASO)之組合物。
實施例29為 如實施例28之方法,其中組合物包含與肝臟靶向部分結合之小干擾RNA (siRNA)。
實施例30為 如實施例29之方法,其中組合物包含結合N-乙醯基半乳胺糖(GalNAc)之siRNA。
實施例31為 如實施例28之方法,其中組合物包含囊封於脂質奈米粒子(LNP)中之小干擾RNA (siRNA)。
實施例32為 如實施例28之方法,其中組合物包含ASO。
實施例33為 如實施例14至32中任一項之方法,其中組合物包含醫藥學上可接受之載劑。
實施例34為 如實施例33之方法,其中方法包含藉由腹膜內注射進行投與。
實施例35為 如實施例34之方法,其中在投與AAV載體之前約1天、約2天、約3天、約4天、約5天、約6天、約7天投與ASO。
實施例36為 如實施例34之方法,其中在投與AAV載體之前約24小時與約48小時之間投與ASO。
實施例37為 如實施例34之方法,其中在投與AAV載體之前約24小時投與ASO。
實施例38為 如實施例34之方法,其中在投與AAV載體之前約48小時投與ASO。
實施例39為 如實施例31至38中任一項之方法,其中方法包含共同投與在肝臟中促進siRNA或ASO之吸收增加的其他藥物。
實施例40為 如實施例14至39中任一項之方法,其中步驟(a)中對AAV結合至肝臟中之AAV受體的阻斷並非暫時的。
實施例41為 如實施例39之方法,其中組合物包含阻斷AAV結合至AAV受體之抗AAV抗體。
實施例42為 如實施例14至41中任一項之方法,其中AAV載體意欲用於大腦;中樞神經系統;脊髓;眼;視網膜;骨;心肌、骨骼肌及/或平滑肌;肺;胰臟;心臟;及/或腎臟。
實施例43為 如實施例14至42中任一項之方法,其中AAV載體意欲用於心肌、骨骼肌及/或平滑肌。
實施例44為 如實施例14至43中任一項之方法,其中在步驟(a)中投與組合物增加遞送至非肝臟標靶之AAV之百分比。
實施例45為 如實施例14至44中任一項之方法,其中與接受AAV但未接受阻斷AAV結合至肝臟中之AAV受體(AAVR)之藥劑的對照個體之相應組織中的AAV相比,該方法引起大腦;中樞神經系統;脊髓;眼;視網膜;骨;心肌、骨骼肌及/或平滑肌;肺;胰臟;心臟;及/或腎臟中之AAV增加至少10%、30%、50%、75%、100%、125%、150%、200%、250%、300%、350%、400%、450%、500%、600%、700%、800%、900%或1000%。
實施例46為 如實施例45之方法,與接受AAV但未接受藥劑之對照個體之相應肌肉中的AAV相比,該方法引起骨骼肌中之AAV增加至少10%、30%、50%、75%、100%、125%、150%、200%、250%、300%、350%、400%、450%、500%、600%、700%、800%、900%或1000%。
實施例47為 如實施例14至46中任一項之方法,其中AAV載體進一步包含用於增強針對標靶宿主細胞或組織之趨性的分子。
實施例48為 如實施例14至47中任一項之方法,其中個體為人類個體。
實施例49為 如實施例14至48中任一項之方法,其中AAV載體包含編碼一或多個嚮導RNA及Cas9之單一核酸分子,其中單一核酸分子包含:
a. 編碼選自SEQ ID NO: 1至35、1000至1078或3000至3069中之任一者的一或多個間隔子序列之第一核酸,及編碼金黃色葡萄球菌Cas9 (
Staphylococcus aureusCas9;SaCas9)之第二核酸;或
b. 編碼選自SEQ ID NO: 100至225、2000至2116或4000至4251中之任一者的一或多個間隔子序列之第一核酸,及編碼路鄧葡萄球菌(
Staphylococcus lugdunensis;SluCas9)之第二核酸;或
c. 編碼一或多個間隔子序列之第一核酸,該一或多個間隔子序列包含選自SEQ ID NO: 1至35、1000至1078或3000至3069中之任一者之間隔子序列的至少20個鄰接核苷酸,及編碼金黃色葡萄球菌Cas9 (SaCas9)之第二核酸;或
d. 編碼一或多個間隔子序列之第一核酸,該一或多個間隔子序列包含選自SEQ ID NO: 100至225、2000至2116或4000至4251中之任一者之間隔子序列的至少20個鄰接核苷酸,及編碼路鄧葡萄球菌(SluCas9)之第二核酸;或
e. 編碼一或多個間隔子序列之第一核酸,該一或多個間隔子序列與SEQ ID NO: 1至35、1000至1078或3000至3069中之任一者至少90%一致,及編碼金黃色葡萄球菌Cas9 (SaCas9)之第二核酸;或
f. 編碼一或多個間隔子序列之第一核酸,該一或多個間隔子序列與SEQ ID NO: 100至225、2000至2116或4000至4251中之任一者至少90%一致,及編碼路鄧葡萄球菌(SluCas9)之第二核酸;或
g. 編碼嚮導RNA對之第一核酸,該嚮導RNA對包含選自以下間隔子序列對中之任一者的第一及第二間隔子序列:SEQ ID NO: 10及15;10及16;12及16;1001及1005;1001及15;1001及16;1003及1005;16及1003;12及1010;12及1012;12及1013;10及1016;1017及1005;1017及16;1018及16;15及10;16及10;16及12;1005及1001;15及1001;16及1001;1005及1003;1003及16;1010及12;1012及12;1013及12;1016及10;1005及1017;16及1017;以及16及1018;及編碼金黃色葡萄球菌Cas9 (SaCas9)之第二核酸;或
h. 編碼嚮導RNA對之第一核酸,該嚮導RNA對包含選自以下間隔子序列對中之任一者的第一及第二間隔子序列之至少17、18、19、20或21個鄰接核苷酸:SEQ ID NO: 10及15;10及16;12及16;1001及1005;1001及15;1001及16;1003及1005;16及1003;12及1010;12及1012;12及1013;10及1016;1017及1005;1017及16;1018及16;15及10;16及10;16及12;1005及1001;15及1001;16及1001;1005及1003;1003及16;1010及12;1012及12;1013及12;1016及10;1005及1017;16及1017;以及16及1018;及編碼金黃色葡萄球菌Cas9 (SaCas9)之第二核酸;或
i. 編碼嚮導RNA對之第一核酸,該嚮導RNA對與選自以下間隔子序列對中之任一者的第一及第二間隔子序列至少90%一致:SEQ ID NO: 10及15;10及16;12及16;1001及1005;1001及15;1001及16;1003及1005;16及1003;12及1010;12及1012;12及1013;10及1016;1017及1005;1017及16;1018及16;15及10;16及10;16及12;1005及1001;15及1001;16及1001;1005及1003;1003及16;1010及12;1012及12;1013及12;1016及10;1005及1017;16及1017;以及16及1018;及編碼金黃色葡萄球菌Cas9 (SaCas9)之第二核酸;或
j. 編碼嚮導RNA對之第一核酸,該嚮導RNA對包含選自以下間隔子序列對中之任一者的第一及第二間隔子序列:SEQ ID NO: 148及134;149及135;150及135;131及136;151及136;139及131;139及151;140及131;140及151;141及148;144及149;144及150;145及131;145及151;146及148;134及148;135及149;135及150;136及131;136及151;131及139;151及139;131及140;151及140;148及141;149及144;150及144;131及145;151及145;以及148及146;及編碼路鄧葡萄球菌(SluCas9)之第二核酸;或
k. 編碼嚮導RNA對之第一核酸,該嚮導RNA對包含選自以下間隔子序列對中之任一者的第一及第二間隔子序列之至少17、18、19、20或21個鄰接核苷酸:SEQ ID NO: 148及134;149及135;150及135;131及136;151及136;139及131;139及151;140及131;140及151;141及148;144及149;144及150;145及131;145及151;146及148;134及148;135及149;135及150;136及131;136及151;131及139;151及139;131及140;151及140;148及141;149及144;150及144;131及145;151及145;以及148及146;及編碼路鄧葡萄球菌(SluCas9)之第二核酸;或
l. 編碼嚮導RNA對之第一核酸,該嚮導RNA對與選自以下間隔子序列對中之任一者的第一及第二間隔子序列至少90%一致:SEQ ID NO: 148及134;149及135;150及135;131及136;151及136;139及131;139及151;140及131;140及151;141及148;144及149;144及150;145及131;145及151;146及148;134及148;135及149;135及150;136及131;136及151;131及139;151及139;131及140;151及140;148及141;149及144;150及144;131及145;151及145;以及148及146;及編碼路鄧葡萄球菌(SluCas9)之第二核酸;或
m. 編碼嚮導RNA對之第一核酸,該嚮導RNA對與選自以下間隔子序列對中之任一者的第一及第二間隔子序列至少90%一致:
i. SEQ ID NO: 148及134,
ii. SEQ ID No: 145及131,
iii. SEQ ID No: 144及149;
iv. SEQ ID No: 144及150;
v. SEQ ID No: 146及148;
及編碼路鄧葡萄球菌(SluCas9)之第二核酸;或
n. 編碼嚮導RNA對之第一核酸,該嚮導RNA對與選自以下間隔子序列對中之任一者的第一及第二間隔子序列至少90%一致:
i. SEQ ID NO: 12及1013;以及
ii. SEQ ID No: 12及1016;
及編碼SaCas9-KKH之第二核酸。
實施例50為 如實施例14至49中任一項之方法,其中AAV載體自ITR至ITR (包括兩個ITR)之尺寸在3.9至5 kb、4至5 kb、4.2至5 kb、4.4至5 kb、4.6至5 kb、4.7至5 kb、3.9至4.9 kb、4.2至4.9 kb、4.4至4.9 kb、4.7至4.9 kb、3.9至4.85 kb、4.2至4.85 kb、4.4至4.85 kb、4.6至4.85 kb、4.7至4.85 kb、4.7至4.9 kb、3.9至4.8 kb、4.2至4.8 kb、4.4至4.8 kb或4.6至4.8 kb之間。
實施例51為 如實施例14至50中任一項之方法,其中AAV載體為AAV9載體。
實施例52為 如實施例14至51中任一項之方法,其中藥劑為siRNA。
實施例53為 如實施例52之方法,其中siRNA包含SEQ ID No: 4300至9527中之任一者的至少19個鄰接核苷酸。
實施例54為 如實施例52之方法,其中siRNA包含SEQ ID No: 4300至9527之序列中之任一者。
實施例55為 如實施例52之方法,其中siRNA包含SEQ ID No: 9508至9531中之任一者的至少19個鄰接核苷酸。
實施例56為 如實施例52之方法,其中siRNA包含SEQ ID No: 9508至9531之序列中之任一者。
實施例57為 如實施例52至56中任一項之方法,其中siRNA之長度不超過21、25或31個核苷酸。
實施例58為 如實施例14至51中任一項之方法,其中藥劑包含抗AAVR抗體。
實施例59為 如實施例14至51中任一項之方法,其中藥劑包含小分子。
實施例60為 如實施例14至51中任一項之方法,其中藥劑包含反義寡核苷酸(ASO)。
實施例61為 如實施例60之方法,其中ASO包含SEQ ID No: 9600至9623之序列中之任一者,或包含SEQ ID No: 9600至9623中之任一者的至少14個連續核苷酸。
實施例62為 如實施例60之方法,其中ASO之長度在14至35、15至30或15至25個核苷酸之間。
本申請案主張2022年4月18日申請之美國臨時申請案第63/331,968號之優先權的權利,該臨時申請案以全文引用之方式併入本文中。
現將詳細參考本發明之某些實施例。儘管結合所說明之實施例來描述本發明,但應理解其並不意欲將本發明限於此等實施例。相反,本發明意欲涵蓋所有替代方案、修改及等效物,其可如所附申請專利範圍及包括之實施例所定義包括於本發明內。
在詳細描述本發明教示內容之前,應理解,本發明不限於特定組合物或方法步驟,因此可改變。應注意,除非上下文另外明確規定,否則如本說明書及隨附申請專利範圍中所使用,單數形式「一(a)」、「一(an)」及「該(the)」包括複數個參考物。因此,舉例而言,提及「一嚮導」包括複數個嚮導,且提及「一細胞」包括複數個細胞及其類似物。
數值範圍包括定義該範圍之數字。考慮到有效數位及與量測相關之誤差,所量測值及可量測值應理解為近似值。此外,「包含(comprise)」、「包含(comprises)」、「包含(comprising)」、「含有(contain)」、「含有(contains)」、「含有(containing)」、「包括(include)」、「包括(includes)」及「包括(including)」之使用並不意欲為限制性的。應理解,前述一般描述及詳細描述兩者僅為例示性及解釋性的且並不限制教示內容。
除非在本說明書中特定指出,否則在本說明書中敍述「包含」各種組分之實施例亦涵蓋為「由所敍述之組分組成」或「基本上由所敍述之組分組成」;在本說明書中敍述「由各種組分組成」之實施例亦涵蓋為「包含」所敍述之組分或「基本上由所敍述之組分組成」;且在本說明書中敍述「基本上由各種組分組成」之實施例亦涵蓋為「由所敍述之組分組成」或「包含」所敍述之組分(此互換性並不適用於此等術語在申請專利範圍中之使用)。除非上下文另外明確指示,否則術語「或(or)」係以包括性意義使用,亦即等效於「及/或(and/or)」。
本文中所使用之章節標題僅出於組織目的且不應理解為以任何方式限制所描述之標的物。在以引用之方式併入之任何材料與本說明書中所定義之任何術語或本說明書之任何其他表述內容相矛盾之情況下,以本說明書為準。雖然結合各種實施例來描述本發明教示內容,但並不意欲使本發明教示內容限於此類實施例。相反,如熟習此項技術者將瞭解,本發明教示內容涵蓋各種替代方案、修改及等效物。
I. 定義
除非另外說明,否則如本文所使用之以下術語及片語意欲具有以下含義:
「聚核苷酸」、「核酸」及「核酸分子」在本文中用於指包含核苷或核苷類似物之多聚體化合物,該等核苷或核苷類似物具有沿著主鏈連接在一起的含氮雜環鹼基或鹼基類似物,包括習知RNA、DNA、混合型RNA-DNA,及作為其類似物之聚合物。核酸「主鏈」可由各種鍵構成,該等鍵包括糖-磷酸二酯鍵、肽-核酸鍵(「肽核酸」或PNA;PCT第WO 95/32305號)、硫代磷酸酯鍵、甲基磷酸酯鍵或其組合中之一或多者。核酸之糖部分可為核糖、去氧核糖或具有取代(例如2'甲氧基或2'鹵基取代)之類似化合物。含氮鹼基可為習知鹼基(A、G、C、T、U)、其類似物(例如經修飾之尿苷,諸如5-甲氧基尿苷、假尿苷或N1-甲基假尿苷或其他);肌苷;嘌呤或嘧啶之衍生物(例如N
4-甲基去氧鳥苷、去氮嘌呤或氮雜嘌呤、去氮嘧啶或氮雜嘧啶、在5或6位置處具有取代基之嘧啶鹼基(例如5-甲基胞嘧啶)、在2、6或8位置處具有取代基之嘌呤鹼基、2-胺基-6-甲胺基嘌呤、O
6-甲基鳥嘌呤、4-硫基-嘧啶、4-胺基-嘧啶、4-二甲基肼-嘧啶,及O
4-烷基-嘧啶;美國專利第5,378,825號及PCT第WO 93/13121號)。對於一般論述,參見
The Biochemistry of the Nucleic Acids5-36, Adams等人編,第11版, 1992。核酸可包括一或多個「無鹼基」殘基,其中主鏈不包括針對聚合物位置之含氮鹼基(美國專利第5,585,481號)。核酸可僅包含習知RNA或DNA糖、鹼基及鍵,或可包括習知組分及取代(例如具有2'甲氧基鍵之習知鹼基,或含有習知鹼基及一或多個鹼基類似物兩者的聚合物)兩者。核酸包括「鎖核酸」(LNA),其為含有一或多個LNA核苷酸單體之類似物,其中雙環呋喃醣單元經鎖定於模擬糖構形之RNA中,由此增強針對互補RNA及DNA序列之雜交親和力(Vester及Wengel, 2004,
Biochemistry43(42):13233-41)。RNA及DNA具有不同糖部分且不同之處可為RNA中存在尿嘧啶或其類似物及DNA中存在胸腺嘧啶或其類似物。本發明在本文中提供許多例示性核苷酸序列,且涵蓋此等核苷酸序列之反向互補序列,以及此等序列中之任一者的RNA及/或DNA等效物。舉例而言,本文中所揭示之DNA序列中之任一者的RNA等效物將包含在序列中替代胸腺嘧啶之尿嘧啶,而本文中所揭示之RNA序列中之任一者的DNA等效物將包含替代尿嘧啶之胸腺嘧啶。
如本文中所使用,「CRISPR」系統及「靶向RNA之核酸內切酶」或「Cas-核酸酶」包括化膿性葡萄球菌(
S . pyogenes)、金黃色葡萄球菌(
S . aureus)以及其他原核生物(參見例如下一段中之清單)及其經修飾(例如經工程改造或突變)之形式的II型CRISPR系統。參見例如US2016/0312198 A1;US 2016/0312199 A1。在特定實施例中,靶向RNA之核酸內切酶為II型CRISPR Cas酶。Cas核酸酶之其他實例包括III型CRISPR系統之Csm或Cmr複合物或其Cas10、Csm1或Cmr2次單元;及I型CRISPR系統之級聯複合物或其Cas3次單元。在一些實施例中,Cas核酸酶可來自IIA型、IIB型或IIC型系統。關於各種CRISPR系統及Cas核酸酶之論述,參見例如Makarova等人,
Nat. Rev. Microbiol. 9:467-477 (2011);Makarova等人,
Nat. Rev. Microbiol, 13: 722-36 (2015);Shmakov等人,
Molecular Cell, 60:385-397 (2015)。
可衍生Cas核酸酶之非限制性例示性物種包括釀膿鏈球菌(
Streptococcus pyogenes)、嗜熱鏈球菌(
Streptococcus thermophilus)、鏈球菌屬(
Streptococcus sp.)、金黃色葡萄球菌(
Staphylococcus aureus)、無害李氏菌(
Listeria innocua)、加氏乳桿菌(
Lactobacillus gasseri)、新兇手弗朗西斯氏菌(
Francisella novicida)、產琥珀酸沃廉菌(
Wolinella succinogenes)、華德薩特菌(
Sutterella wadsworthensis)、伽馬變形菌(
Gammaproteobacterium)、腦膜炎雙球菌(
Neisseria meningitidis)、空腸彎曲桿菌(
Campylobacter jejuni)、多殺性巴氏桿菌(
Pasteurella multocida)、產琥珀酸纖維桿菌(
Fibrobacter succinogene)、深紅紅螺菌(
Rhodospirillum rubrum)、達松維爾擬諾卡氏菌(
Nocardiopsis dassonvillei)、始旋鏈黴菌(
Streptomyces pristinaespiralis)、產綠色鏈黴菌(
Streptomyces viridochromogenes)、產綠色鏈黴菌、粉紅鏈孢囊菌(
Streptosporangium roseum)、粉紅鏈孢囊菌、嗜酸熱脂環桿菌(
Alicyclobacillus acidocaldarius)、假蕈狀芽孢桿菌(
Bacillus pseudomycoides)、砷還原芽孢桿菌(
Bacillus selenitireducens)、西伯利亞微小桿菌(
Exiguobacterium sibiricum)、德氏乳桿菌(
Lactobacillus delbrueckii)、唾液乳桿菌(
Lactobacillus salivarius)、布氏乳桿菌(
Lactobacillus buchneri)、齒垢密螺旋體(
Treponema denticola)、海洋微顫藍菌(
Microscilla marina)、伯克氏細菌(
Burkholderiales bacterium)、食萘極地單胞菌(
Polaromonas naphthalenivorans)、極地單胞菌屬(
Polaromonas sp .)、瓦氏鱷球藻(
Crocosphaera watsonii)、藍桿菌屬(
Cyanothece sp .)、銅綠微囊藻(
Microcystis aeruginosa)、聚球藻屬(
Synechococcus sp .)、阿拉伯糖醋桿菌(
Acetohalobium arabaticum)、根制胺菌(
Ammonifex degensii)、熱解纖維素菌(
Caldicelulosiruptor becscii)、金礦菌(
Candidatus Desulforudis)、肉毒桿菌(
Clostridium botulinum)、艱難梭菌(
Clostridium difficile)、大芬戈爾德菌(
Finegoldia magna)、嗜熱鹽鹼厭氧菌(
Natranaerobius thermophilus)、熱丙酸消化腸狀菌(
Pelotomaculum thermopropionicum)、嗜酸喜溫硫桿菌(
Acidithiobacillus caldus)、嗜酸氧化亞鐵硫桿菌(
Acidithiobacillus ferrooxidans)、酒色異著色菌(
Allochromatium vinosum)、海桿菌屬(
Marinobacter sp .)、嗜鹽亞硝化球菌(
Nitrosococcus halophilus)、瓦氏亞硝化球菌(
Nitrosococcus watsoni)、遊海假交替單胞菌(
Pseudoalteromonas haloplanktis)、消旋纖線桿菌(
Ktedonobacter racemifer)、甲烷鹽菌(
Methanohalobium evestigatum)、變異念珠藻(
Anabaena variabilis)、泡沫節球藻(
Nodularia spumigena)、念珠藻屬(
Nostoc sp .)、極大節旋藻(
Arthrospira maxima)、鈍頂節旋藻(
Arthrospira platensis)、節旋藻屬(
Arthrospira sp .)、螺旋藻屬(
Lyngbya sp .)、原型微鞘藻(
Microcoleus chthonoplastes)、顫藻屬(
Oscillatoria sp .)、運動石袍菌(
Petrotoga mobilis)、非洲高熱桿菌(
Thermosipho africanus)、巴氏鏈球菌(
Streptococcus pasteurianus)、灰色奈瑟球菌(
Neisseria cinerea)、紅嘴鷗彎曲桿菌(
Campylobacter lari)、食清潔劑細小棒菌(
Parvibaculum lavamentivorans)、白喉棒狀桿菌(
Corynebacterium diphtheria)、胺基酸球菌屬(
Acidaminococcus sp .)、毛螺科菌(
Lachnospiraceae bacterium) ND2006及海洋無核氯菌(
Acaryochloris marina)。
「嚮導RNA (Guide RNA)」、「嚮導RNA (guide RNA)」及簡稱「嚮導(guide)」在本文中可互換地使用且係指crRNA (亦稱為CRISPR RNA),或crRNA與trRNA之組合(亦稱為tracrRNA)。crRNA及trRNA可以單一RNA分子(單嚮導RNA,sgRNA)或以兩個獨立RNA分子(雙嚮導RNA,dgRNA)形式締合。「嚮導RNA (Guide RNA)」或「嚮導RNA (guide RNA)」係指各種類型。trRNA可為天然存在之序列或與天然存在之序列相比具有修飾或變化形式之trRNA序列。為了清楚起見,除非另外特別說明,否則如本文中所使用,術語「嚮導RNA」或「嚮導」可指RNA分子(包含A、C、G及U核苷酸)或編碼此類RNA分子的DNA分子(包含A、C、G及T核苷酸)或其互補序列。一般而言,在DNA核酸構築體編碼嚮導RNA之情況下,本文中所描述之RNA序列中之任一者的U殘基可經T殘基置換,且在嚮導RNA構築體由本文中所描述之DNA序列中之任一者編碼之情況下,T殘基可經U殘基置換。
如本文中所使用,「間隔子序列」在本文中及文獻中有時亦稱為「間隔子」、「原間隔子」、「嚮導序列」或「標靶序列」,且係指在嚮導RNA內與標靶序列互補且用於將嚮導RNA引導至標靶序列以用於Cas9之裂解的序列。嚮導序列之長度可為24、23、22、21、20個或更少個鹼基對,例如在路鄧葡萄球菌(亦即,SluCas9)或金黃色葡萄球菌(亦即,SaCas9)及相關Cas9同源物/異種同源物之情況下。在較佳實施例中,在SluCas9或SaCas9之情況下,嚮導/間隔子序列之長度為至少20個鹼基對,或更特定言之,長度在20至25個鹼基對內(參見例如Schmidt等人, 2021, Nature Communications,「Improved CRISPR genome editing using small highly active and specific engineered RNA-guided nucleases」)。亦可使用更短或更長之序列作為嚮導,例如長度為15、16、17、18、19、20、21、22、23、24或25個核苷酸。舉例而言,在一些實施例中,嚮導序列包含選自SEQ ID NO: 1至35 (對於SaCas9)及100至225 (對於SluCas9)之序列的至少17、18、19、20、21、22、23、24或25個鄰接核苷酸。在一些實施例中,標靶序列處於例如基因中或染色體上,且與嚮導序列互補。在一些實施例中,嚮導序列與其相應標靶序列之間的互補性或一致性之程度可為約75%、80%、85%、90%、95%、96%、97%、98%、99%或100%。在一些實施例中,嚮導序列與標靶區可為100%互補或一致的。在其他實施例中,嚮導序列及標靶區可含有至少一個錯配。舉例而言,嚮導序列及標靶序列可含有1、2、3或4個錯配,其中標靶序列之總長度為至少17、18、19、20或更多個鹼基對。在一些實施例中,嚮導序列及標靶區可含有1至4個錯配,其中嚮導序列包含至少17、18、19、20或更多個核苷酸。在一些實施例中,嚮導序列及標靶區可含有1、2、3或4個錯配,其中嚮導序列包含20個核苷酸。在一些實施例中,嚮導序列及標靶區不含有任何錯配。
如本文中所使用,術語「約(about)」或「大致(approximately)」」意謂經由一般熟習此項技術者所測定之特定值的可接受誤差,其部分取決於如何量測或測定該值。
如本文中所使用,「AAV」係指腺相關病毒載體。如本文中所使用,「AAV」係指任何AAV血清型及變異體,包括(但不限於)AAV1、AAV2、AAV3、AAV4、AAV5、AAV6、AAV7、AAV8、AAVrh10 (參見例如US 9,790,472之SEQ ID NO: 81,該申請案以全文引用之方式併入本文中)、AAVrh74 (參見例如US 2015/0111955之SEQ ID NO: 1,該申請案以全文引用之方式併入本文中)、AAV9載體、亦稱為AAVMYO之AAV9P載體(參見例如Weinmann等人, 2020, Nature Communications, 11:5432),及Tabebordbar等人, 2021, Cell, 184:1-20中所描述之Myo-AAV載體(參見例如MyoAAV 1A、2A、3A、4A、4C或4E),其中AAV後的數字指示AAV血清型。術語「AAV」亦可指任何已知AAV (載體)系統。在一些實施例中,AAV載體為單股AAV (ssAAV)。在一些實施例中,AAV載體為雙股AAV (dsAAV)。通用術語AAV載體、AAV1載體等涵蓋AAV載體或其血清型之任何變異體,諸如自我互補AAV (scAAV)載體。關於各種AAV載體之詳述論述,參見例如McCarty等人,
Gene Ther. 2001;8:1248-54,Naso等人,
BioDrugs2017; 31:317-334,及其中所引用之參考文獻。在結構上,AAV為具有二十面體殼體之小(25 nm)的單DNA股無包膜病毒。如本文中所使用,「AAV」可指天然存在或經工程改造之AAV血清型及重組AAV (rAAV),且可在其殼蛋白之組合物及結構方面不同之變異體具有不同趨性,亦即轉導不同細胞類型之能力。當與活性啟動子組合時,此趨性定義基因表現之部位。
如本文中所使用,「基於AAV之基因療法」係指投與AAV載體及使用包含組織特異性啟動子之任何AAV或AAV(載體)系統來促進基因療法之投與,該基因療法可包括此項技術中任何已知的基因編輯系統。經本文所描述之啟動子亦可為「細胞特異性的」,意謂選擇用於AAV之特定啟動子可引導所選擇之轉殖基因/所關注之核苷酸序列在特定細胞或細胞類型中表現。舉例而言,在一些實施例中,啟動子為肌肉特異性啟動子,包括肌肉肌酸激酶啟動子、肌間線蛋白啟動子、MHCK7啟動子或SPc5-12啟動子。在一些實施例中,肌肉特異性啟動子為CK8啟動子。在一些實施例中,肌肉特異性啟動子為CK8e啟動子。肌肉特異性啟動子詳細描述於例如,US2004/0175727 A1;Wang等人, Expert Opin Drug Deliv. (2014) 11, 345-364;Wang等人, Gene Therapy (2008) 15, 1489-1499中。在一些實施例中,組織特異性啟動子為神經元特異性啟動子,諸如烯醇酶啟動子。關於組織特異性啟動子(包括神經元特異性啟動子)之詳細論述,參見例如Naso等人,
BioDrugs2017; 31:317-334;Dashkoff等人,
Mol Ther Methods Clin Dev. 2016;3:16081,及其中所引用之參考文獻。任何已知啟動子均可與AAV結合使用以向預期標靶組織或細胞投與基因療法。如本文中所使用,「基於非肝臟AAV之基因療法」包括使用基於AAV之基因療法來治療或預防不為肝臟疾病或病症之疾病或病症。
如本文中所使用,「AAVR」或「AAV-R」或「AAV受體」可互換地用於指AAV受體蛋白。AAVR之同義詞亦包括FLJ44532、KIAA0319L、KIAA0319樣蛋白、KIAA1837、KIAA1837失讀症相關蛋白、KIAA0319樣蛋白及多囊性腎病1相關蛋白。AAVR為一種醣基化膜蛋白,其能夠使用細胞胞內體網路自質膜再循環至經高基氏體(Golgi)網路。已知AAVR為介導一組AAV血清型之進入的關鍵受體。參見例如,Pillay, Nature, 530(7588): 108-112 (2016);Meyer 等人, eLife 8:e44707. DOI: doi.org/10.7554/eLife.44707 (2019)。發現AAVR基因剔除使得細胞對AAV2之感染具有高度抵抗性;且其中AAVR在細胞中過度表現,細胞對AAV2感染愈來愈敏感。在Pillay (2016)中,CRISPR/Cas9基因體工程改造係用於在一組表示人類及鼠類組織之細胞類型中產生同基因型AAVR基因剔除細胞株。用一組各種AAV血清型(包括AAV1、AAV2、AAV3B、AAV5、AAV6、AAV8及AAV9)感染AAVR基因剔除細胞,其中基因剔除細胞似乎對所有AAV血清型具有抗性。因此,包括AAV1、AAV2、AAV3B、AAV5、AAV6、AAV8及AAV9之多種血清型需要AAVR用於轉導。在一些實施例中,「AAV」係指任何AAV血清型及變異體。
如本文中所使用,「阻斷AAV結合至AAVR」或其類似物意謂暫時或持久地降低、抑制或阻斷AAV結合至AAVR之能力。在一些實施例中,「阻斷」意謂下調AAVR之基因表現,以使得與未用「阻斷」劑處理之相同細胞類型的對照細胞相比,用「阻斷」劑(例如,AAV特異性siRNA或ASO)處理之細胞上表現較少AAVR。在一些實施例中,「阻斷」意謂使AAVR與阻止AAV與AAVR之結合的藥劑(例如抗體或小分子)接觸。
如本文中所使用,「RNAi化合物」、「RNAi分子」或「RNAi」可互換地使用且係指抑制性RNA。RNAi係指用以調節標靶核酸及/或由標靶核酸編碼之蛋白質的反義化合物。RNAi化合物包括(但不限於)小干擾RNA (siRNA)、單股RNA (ssRNA)、微小RNA (包括微小RNA模擬物)、雙股RNA (dsRNA)、短髮夾RNA (shRNA)及編碼能夠誘導RNA干擾之RNA的表現卡匣。舉例而言,RNAi表現卡匣可在細胞中轉錄以產生siRNA、單獨有義股及反義股線性siRNA或可充當miRNA之小髮夾RNA。如本文中所使用,提及「RNAi」及「siRNA」係指如在最廣泛意義上所使用之術語且涵蓋例如已經修飾(例如化學修飾、連接至少一個受體結合配位體或部分)的任何siRNA,只要分子仍能夠結合至標靶細胞中之標靶核酸,由此降低靶基因之表現。RNAi分子容易藉由此項技術中已知的技術設計及產生。
如本文中所使用,「反義寡核苷酸」或「ASO」係指結合至互補RNA序列,由此抑制其功能之DNA或RNA之短股。ASO可藉由抑制特定RNA序列有效地下調或上調下游之某些下游蛋白質之產生,且理論上可與選擇功能缺失型及功能獲得型突變兩者一起使用。
如本文中所使用,「肝臟靶向部分」包括(但不限於)任何配位體或結合物,其可應用於阻斷AAV結合至AAVR之藥劑(例如siRNA、RNAi或抗AAVR抗體)以增強藥劑之遞送及/或肝臟吸收,該等配位體或結合物包括任何已知的肝臟靶向結合物(包括N-乙醯基半乳胺糖(GalNAc)結合物),及用於藥劑(例如siRNA或RNAi)之肝臟或肝遞送的任何其他遞送系統。將用於靶向siRNA至特定身體系統、器官、組織或細胞之適當配位體或結合物的選擇視為在一般熟習之此技術內。舉例而言,為了將siRNA靶向至肝細胞,膽固醇可在siRNA分子之一或多個端(包括5'端及3'端之任何組合)處連接。將所得膽固醇-siRNA遞送至肝臟中之肝細胞,由此提供將siRNA遞送至此靶向位置之方法。適用於將siRNA靶向至肝臟之其他配位體包括HBV表面抗原及低密度脂蛋白(LDL)。
如本文中所使用,「LNP」或「脂質奈米粒子」係指基於脂質之遞送組合物。LNP為此項技術中已知的且係指包含複數個(亦即超過一個)脂質分子之粒子,該等脂質分子係藉由分子間力以物理方式彼此締合。LNP可例如為微球體(包括單層及多層囊泡,例如「脂質體」—在一些實施例中為實質上球形之層狀相脂質雙層—且在更特定實施例中可包含水性核心,例如包含大部分RNA分子)、乳液中之分散相、微胞或懸浮液中之內相。乳液、微胞及懸浮液可為用於局部及/或體表遞送之適合組合物。亦參見例如WO2017173054A1,其內容特此以全文引用之方式併入本文中。本文中可使用熟習此項技術者已知能夠將核苷酸(包括siRNA或其他RNAi)遞送至個體之任何LNP。
如本文中所使用,「抗體」係以最廣泛意義使用且涵蓋各種抗體結構,包括(但不限於)單株抗體、多株抗體、多特異性抗體(例如雙特異性抗體)、奈米抗體及抗體或抗原結合片段,只要其展現所需之抗原結合活性即可。如本文中所使用,「抗AAVR抗體」係指阻斷AAVR與AAV之間的相互作用之抗體(如在上文所闡述之最廣泛意義上所使用)。
術語「組合物」或「調配物」係指呈准許其中所含活性成分之生物活性有效的此類形式,且不含有對組合物將投與之個體有不可接受毒性之額外組分的製劑。
術語「醫藥學上可接受之載劑」或「醫藥學上可接受之媒劑」係指允許例如促進其中所含活性成分之投與的醫藥組合物中之任何稀釋劑、佐劑、賦形劑或其組合。一般可充當醫藥學上可接受之載劑之物質的非限制性實例包括油、二醇;多元醇,諸如甘油、山梨糖醇、甘露糖醇及聚乙二醇;酯;瓊脂;緩衝劑;水;等張生理鹽水溶液;林格氏溶液(Ringer's solution);乙醇;pH緩衝溶液;及用於醫藥製劑中之任何其他無毒之相容材料。此類載劑或媒劑應為無毒的且不應實質上干擾活性成分之功效。醫藥學上可接受之載劑為熟知的且將由熟習此項技術者依據投藥性質、途徑及模式來調適。
如本文中所使用,「治療(treatment)」(及其變化形式,諸如「治療(treat)」或「治療(treating)」)係指針對個體中之疾病或病症之治療劑的任何投與或施用,且包括抑制疾病或疾病之發展(其可在正式診斷疾病之前或之後發生,例如在個體具有可能或很可能造成疾病發展之基因型的情況下)、遏制其發展、減輕疾病之一或多種症狀、治癒疾病或預防疾病之一或多種症狀復發。如本文中所使用,「治療」可包括投與治療劑或治療方案(包括視情況選用之佐劑或預處理方案)以達成治療或預防益處。如本文中所使用,「治療」亦涵蓋「緩解」,其係指對於表現型或症狀之任何有益作用,諸如降低其嚴重程度、減緩或延遲其發展、遏制其發展,或使其部分或完全逆轉或消除。
「預處理(pre-conditioning)」、「預處理(preconditioning)」或「處理(conditioning)」在本文中可互換地使用且係指為需要基於非肝臟AAV之基因療法的個體製備適合之條件,該適合之條件包括在個體接受基於AAV之基因療法之前阻斷AAV結合至肝臟中之AAV受體。
如本文中所使用,術語「投與」係指使用熟習此項技術者已知的各種方法及遞送系統中之任一者將藥劑物理引入至個體中。本文中所揭示之藥劑之例示性投藥途徑包括靜脈內、肌內、皮下、腹膜內、脊椎或其他非經腸投藥途徑,例如藉由注射或輸注。如本文中所使用之片語「非經腸投與」意謂除經腸及體表投藥以外,通常藉由注射進行之投藥模式,且包括(但不限於)靜脈內、肌內、動脈內、鞘內、淋巴管內、病灶內、囊內、眶內、心內、皮內、腹膜內、經氣管、皮下、表皮下、關節內、囊下、蛛膜下、脊椎內、硬膜外及胸骨內注射及輸注,以及活體內電穿孔。在一些實施例中,本文中所揭示之藥劑可經由非-非經腸途徑(例如經口)投與。其他非-非經腸途徑包括體表、表皮或經黏膜投藥途徑,例如鼻內、經陰道、經直腸、舌下或體表。如本文中所使用之片語「全身性注射」非排他性地係關於靜脈內、腹膜內、皮下、經由鼻黏膜下層、經舌、經由支氣管鏡檢、靜脈內、動脈內、肌內、眼內、紋狀體內、皮下、皮內、藉由真皮貼片、藉由皮膚貼片、藉由貼片、至腦脊髓液中、至門靜脈中、至大腦中、至淋巴系統中、胸膜內、眶後、真皮內、至脾臟中、淋巴內,以及其他。如本文中所使用,「共同投與」意謂複數種物質在時間上足夠接近地一起投與,以使得藥劑一起作用。共同投與涵蓋在單個調配物中一起投與物質及在單獨調配物中在時間上足夠接近地投與物質以使得藥劑一起作用。
如本文中所使用,「個體」可為哺乳動物,諸如靈長類動物、有蹄類動物(例如母牛、豬、馬)、貓、狗、家養寵物或家養哺乳動物。在一些情況下,哺乳動物可為兔、豬、馬、綿羊、母牛、貓或狗或人類。在一些實施例中,個體為人類。在一些實施例中,個體為成人。在一些實施例中,個體為青少年人類。在一些實施例中,個體大於約18歲、大於約25歲或大於約35歲。在一些實施例中,個體小於約18歲、小於約16歲、小於約14歲、小於約12歲、小於約10歲、小於約8歲、小於約6歲、小於約5歲、小於約4歲、小於約3歲、小於約2歲、小於約1歲或小於約6個月。
如本文中所使用,「減弱(knock down)」、「減弱(knockdown)」或其類似者係指對基因產物之表現的抑制,諸如藉由使用特異性地靶向基因之RNA產物的反義寡核苷酸去氧核苷酸及RNAi來達成抑制。基因減弱係指經由基因修飾(生物體之染色體中之一者的DNA中之改變)或藉由用諸如短DNA或RNA寡核苷酸之試劑處理來減少生物體基因中之一或多者之表現的技術,該短DNA或RNA寡核苷酸具有與mRNA轉錄本或基因互補之序列。「減弱」包括部分及完全抑制。
II. 組合物
本文揭示包含阻斷及/或適用於阻斷AAV結合至AAVR受體之藥劑的組合物。在一些實施例中,組合物包含靶向肝臟(例如肝細胞)之遞送分子。在一些實施例中,組合物包含阻斷AAV結合至AAV受體(AAVR)之藥劑及將藥劑遞送至肝臟之遞送分子。
在一些實施例中,組合物及藥劑能夠暫時阻斷AAV結合至肝臟中之AAVR受體,包括持續約48小時至3週。在一些實施例中,組合物及藥劑能夠阻斷AAV結合至肝臟中之AAVR受體持續約2天、約3天、約4天、約5天、約6天、約7天、約8天、約9天、約10天、約11天、約12天、約13天、約14天、約15天、約16天、約17天、約18天、約19天、約20天或約21天。在一些實施例中,組合物能夠阻斷AAV結合至肝臟中之AAVR受體持續約7天、約8天、約9天、約10天、約11天、約12天、約13天、約14天。在一些實施例中,組合物及藥劑能夠阻斷AAV結合至肝臟中之AAVR受體持續1至7、1至10、1至28天、7至28天、14至28天、21至28天、1至21天、7至21天、14至21天、1至14天、7至14天或1至7天。
在一些實施例中,組合物及藥劑能夠長期阻斷AAV結合至肝臟中之AAVR受體,包括持續長於約3週、長於約4週、長於約5週、長於約6週、長於約7週、長於約8週、長於約9週及長於約10週。在一些實施例中,組合物及藥劑能夠長期阻斷AAV結合至肝臟中之AAVR受體,包括持續長於10週。
A. RNAi 及 siRNA
在一些實施例中,RNAi為用於阻斷AAV結合至肝臟中之AAVR的藥劑。RNA干擾係指在大體上不抑制其他蛋白質合成之情況下,生物體中由RNAi/siRNA介導之基因表現(蛋白質合成)之序列或基因特異性抑制。RNAi藉由與哺乳動物細胞之RNA干擾路徑方法相互作用誘導RNA干擾,以便以序列特異性方式降解或抑制轉殖基因之信使RNA (mRNA)轉錄本的轉譯。針對主要受體蛋白之RNAi活性可引起向彼等細胞之進入或與彼等細胞之結合減少。RNAi包括使用小干擾RNA (siRNA)以靶向細胞中之特定序列。RNAi聚核苷酸包括siRNA、微小RNA (miRNA)、雙股RNA (dsRNA)、短髮夾RNA (shRNA)及編碼能夠誘導RNA干擾之RNA的表現卡匣。
在一些實施例中,阻斷AAV結合至AAV受體(AAVR)之藥劑為小干擾RNA (siRNA)。已知小干擾RNA (siRNA)能夠特異性地干擾標靶中之蛋白質表現。siRNA經設計以與標靶核糖核苷酸序列相互作用,意謂其與標靶序列充分互補以結合至標靶序列。siRNA一般含有15至50個鹼基對,較佳為21至25個鹼基對,且用於編碼表現於細胞中之標靶基因或RNA之序列,其具有核苷酸序列一致性(完全互補)或幾乎雙重一致性(部分互補)。其亦用於藉由用對AAVR具有特異性之siRNA處理來減弱Huh-7細胞中之AAVR表現。在評估ImmTOR恢復經AAVR特異性siRNA轉染之Huh-7細胞轉導之能力的研究中,發現表現大致20%正常AAVR之Huh-7細胞在用siRNA處理時展示AAVAnc80-螢光素酶表現減少50%。參見Ilyinskii等人, Sci. Adv., 7 eabd0321 (2021)。亦已報導,在眼、腦、脊髓、肺、皮下組織、陰道、皮膚、經分離之腫瘤、心臟等之動物實驗中,全身性或局部遞送之siRNA可在48小時至3週誘導至多90%之暫時基因表現減弱作用。參見Kim, Korean J Anesthesiol. 59(6): 369-370 (2010)。因此,在一些實施例中,對AAVR具有特異性之siRNA係用於阻斷AAV結合至肝臟中之AAVR。在一些實施例中,阻斷AAV結合至AAV受體(AAVR)之藥劑為小干擾RNA (siRNA)。在一些實施例中,個體尚未投與結合基於AAV之基因療法的試劑(例如ImmTOR),該試劑增強對肝臟之靶向。
在其他情況下,由於在已投與siRNA之細胞中發現之抑制作用的短暫性質,siRNA可視為用途有限。另外,已知siRNA在活體內不穩定,且長期效用有限。在本文之一些實施例中,組合物包含siRNA且本發明考慮利用常常在不同情形下被視為損害之此時間特質。
在一些實施例中,投與本文中所揭示之RNAi分子中之任一者或其組合物能夠暫時阻斷AAV結合至例如肝臟中之AAVR受體,包括持續約48小時至3週。在一些實施例中,RNAi分子及/或組合物能夠阻斷AAV結合至例如肝臟中之AAVR受體持續約2天、約3天、約4天、約5天、約6天、約7天、約8天、約9天、約10天、約11天、約12天、約13天、約14天、約15天、約16天、約17天、約18天、約19天、約20天或約21天。在一些實施例中,RNAi分子及/或組合物能夠阻斷AAV結合至例如肝臟中之AAVR受體持續約7天、約8天、約9天、約10天、約11天、約12天、約13天、約14天。在一些實施例中,RNAi分子及/或組合物能夠阻斷AAV結合至例如肝臟中之AAVR受體持續1至7、1至10、1至28天、7至28天、14至28天、21至28天、1至21天、7至21天、14至21天、1至14天、7至14天或1至7天。
在一些實施例中,本文中所揭示之RNAi分子中之任一者靶向編碼AAVR之轉錄本。在一些實施例中,編碼AAVR之轉錄本包含與SEQ ID NO: 300之序列或其反向互補序列至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%一致之序列。在一些實施例中,RNAi分子靶向序列之19、20、21、22、23、24、25、26、27、28、29、30、31或32個鄰接核苷酸,該序列與SEQ ID NO: 300之序列或其反向互補序列至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%一致。在一些實施例中,RNAi分子靶向序列之19至32、19至25、19至22或20至21個鄰接核苷酸,該序列與SEQ ID NO: 300之序列或其反向互補序列至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%一致。
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在一些實施例中,組合物包含RNAi (例如siRNA),其中投與組合物能夠減弱AAVR。在一些實施例中,RNAi (例如siRNA)包含與來自AAVR之核糖核苷酸序列至少80%一致的核糖核苷酸序列。較佳地,RNAi (例如siRNA)分子與標靶之核糖核苷酸序列至少90%、95%、96%、97%、98%、99%或100%一致。最佳地,RNAi (例如siRNA)將與標靶之核苷酸序列100%一致。然而,相對於標靶具有插入、缺失或單點突變之siRNA分子亦可為有效的。在一些實施例中,RNAi (例如siRNA)靶向肝臟中之AAVR。在一些實施例中,RNAi為siRNA。用以輔助siRNA設計之工具可容易地為公眾所獲得且為此項技術中已知的。
在一些實施例中,組合物包含長度在18至31個核苷酸之間的RNAi分子。在一些實施例中,RNAi (例如siRNA)之長度在19至27個核苷酸之間。在一些實施例中,RNAi (例如siRNA)之長度在19至25個核苷酸之間。在一些實施例中,RNAi (例如siRNA)之長度在19至23個核苷酸之間。在一些實施例中,RNAi (例如siRNA)之長度在19至21個核苷酸之間。在一些實施例中,RNAi (例如siRNA)之長度不超過21、25或31個核苷酸。在一些實施例中,RNAi (例如siRNA)之長度為21個核苷酸。在一些實施例中,RNAi為siRNA且包含表3中之序列(SEQ ID NO: 4300至9507)中之任一者的序列。在一些實施例中,siRNA包含不超過且不少於表3中之序列中之任一者的19個鄰接核苷酸。在一些實施例中,siRNA包含不超過且不少於表3中之序列中之任一者的20個鄰接核苷酸。
表3中之SEQ ID NO: 4300至9507反映siRNA之反義5'至3'股的例示性序列。
具有實例中所使用之修飾的siRNA之19聚體及21聚體股之序列闡述於下表A1、表A2及表A3中。在表A2 (經修飾之序列)中,「dT」指示DNA鹼基而非RNA鹼基。序列中之小寫字母指示2'OMe鹼基。大寫字母指示常規RNA鹼基。朝向有義序列及反義序列之3'端的「s」指示siRNA序列中之兩個鹼基之間的鍵為硫代磷酸酯鍵。圖1K展示經修飾之siRNA序列的代表性結構。
表 A1 例示性 siRNA 序列
表 A2 經修飾之 siRNA 序列
表 A3
表 A3 續
雙螺旋 ID | SEQ ID NO: | siRNA 有義股核心序列 ( 5 ' 至 3 ') 19 聚體 | SEQ ID NO: | siRNA 反義股核心序列 ( 5 ' 至 3 ') 21 聚體 |
XD-51567 | 9508 | GGUACUCCGCAAGUAAAAA | 9509 | UUUUUACUUGCGGAGUACCAG |
XD-51568 | 9510 | CACUCAUCCUACAGACUAA | 9511 | UUAGUCUGUAGGAUGAGUGAU |
XD-51569 | 9512 | GCUUAACUGUUGUCGACUA | 9513 | UAGUCGACAACAGUUAAGCUG |
XD-51570 | 9514 | ACCUUGACUGUCAAAGAUA | 9515 | UAUCUUUGACAGUCAAGGUGA |
XD-51571 | 9516 | CCUACACGUUUCACCUGAA | 9517 | UUCAGGUGAAACGUGUAGGUC |
XD-51572 | 9518 | GGUGCUGGAUUCCGACAUA | 9519 | UAUGUCGGAAUCCAGCACCCC |
XD-51573 | 9520 | CUGGAUUCCGACAUCAUUA | 9521 | UAAUGAUGUCGGAAUCCAGCA |
XD-51574 | 9522 | GCAAAAGAUUCAGCCGUAA | 9523 | UUACGGCUGAAUCUUUUGCAC |
XD-51575 | 9524 | CAAAAGAUUCAGCCGUACA | 9525 | UGUACGGCUGAAUCUUUUGCA |
XD-51576 | 9526 | CUGAUGCAUUCUGAAUCGA | 9527 | UCGAUUCAGAAUGCAUCAGGC |
未經修飾之SiRNA | 9528 | GCGUUCUGUGGUUGUCAACAG | 9529 | GUUGACAACCACAGAACGCUG |
Fluc對照 | 9530 | CUUACGCUGAGUACUUCGA | 9531 | UCGAAGUACUCAGCGUAAGUU |
雙螺旋 ID | SEQ ID NO: | 具有修飾之 siRNA 有義股序列 (5' 至 3') 19 聚體 | SEQ ID NO: | 具有修飾之 siRNA 反義股序列 (5' 至 3') 21 聚體 |
XD-51567 | 9532 | ggUacuCCGcaAguaaAasa | 9533 | dTUUUUACUUGCGgAGUACCasg |
XD-51568 | 9534 | caCucaUCCuaCagacUasa | 9535 | dTUAGUCUGUAGGaUGAGUGasu |
XD-51569 | 9536 | gcUuaaCUGuuGucgaCusa | 9537 | dTAGUCGACAACAgUUAAGCusg |
XD-51570 | 9538 | acCuugACUguCaaagAusa | 9539 | dTAUCUUUGACAGuCAAGGUgsa |
XD-51571 | 9540 | ccUacaCGUuuCaccuGasa | 9541 | dTUCAGGUGAAACgUGUAGGusc |
XD-51572 | 9542 | ggUgcuGGAuuCcgacAusa | 9543 | dTAUGUCGGAAUCcAGCACCcsc |
XD-51573 | 9544 | cuGgauUCCgaCaucaUusa | 9545 | dTAAUGAUGUCGGaAUCCAGcsa |
XD-51574 | 9546 | gcAaaaGAUucAgccgUasa | 9547 | dTUACGGCUGAAUcUUUUGCasc |
XD-51575 | 9548 | caAaagAUUcaGccguAcsa | 9549 | dTGUACGGCUGAAuCUUUUGcsa |
XD-51576 | 9550 | cuGaugCAUucUgaauCgsa | 9551 | dTCGAUUCAGAAUgCAUCAGgsc |
未經修飾之SiRNA | 9552 | GCGUUCUGUGGUUGUCAACAG | 9553 | GUUGACAACCACAGAACGCUG |
Fluc對照 | 9554 | cuUacgCUGagUacuuCgsa | 9555 | dTCGAAGUACUCAgCGUAAGusu |
交叉反應性 | |||||||||||
5 | 10 | 6 | 6 | 5 | 10 | 6 | 6 | ||||
19聚體 | 17聚體 | ||||||||||
SEQ ID NO: | 核心有義股序列(5'至3') 19聚體 | SEQ ID NO: | 核心反義股序列(5'至3') 21聚體 | 人類 | 小鼠 | 恆河猴 | 石蟹獼猴 | 人類 | 小鼠 | 恆河猴 | 石蟹獼猴 |
9508 | GGUACUCCGCAAGUAAAAA | 9509 | UUUUUACUUGCGGAGUACCAG | 0 | 1 | 0 | 0 | 0 | 1 | 0 | 0 |
9510 | CACUCAUCCUACAGACUAA | 9511 | UUAGUCUGUAGGAUGAGUGAU | 0 | 1 | 0 | 0 | 0 | 1 | 0 | 0 |
9512 | GCUUAACUGUUGUCGACUA | 9513 | UAGUCGACAACAGUUAAGCUG | 0 | 1 | 0 | 0 | 0 | 1 | 0 | 0 |
9514 | ACCUUGACUGUCAAAGAUA | 9515 | UAUCUUUGACAGUCAAGGUGA | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 |
9516 | CCUACACGUUUCACCUGAA | 9517 | UUCAGGUGAAACGUGUAGGUC | 0 | 1 | 1 | 1 | 0 | 1 | 1 | 1 |
9518 | GGUGCUGGAUUCCGACAUA | 9519 | UAUGUCGGAAUCCAGCACCCC | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 |
9520 | CUGGAUUCCGACAUCAUUA | 9521 | UAAUGAUGUCGGAAUCCAGCA | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 |
9522 | GCAAAAGAUUCAGCCGUAA | 9523 | UUACGGCUGAAUCUUUUGCAC | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 |
9524 | CAAAAGAUUCAGCCGUACA | 9525 | UGUACGGCUGAAUCUUUUGCA | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 |
9526 | CUGAUGCAUUCUGAAUCGA | 9527 | UCGAUUCAGAAUGCAUCAGGC | 0 | 1 | 0 | 0 | 0 | 1 | 0 | 0 |
具有修飾之siRNA股 | Hepa1-6細胞中之劑量-反應分析 | ||||
雙螺旋ID | 有義股序列(5'至3') | 反義股序列(5'至3') | IC20 [nM] | IC50 [nM] | 抑制最大值[%] |
XD-51567 | ggUacuCCGcaAguaaAasa | dTUUUUACUUGCGgAGUACCasg | 0.326 | 2.1 | 73.1 |
XD-51568 | caCucaUCCuaCagacUasa | dTUAGUCUGUAGGaUGAGUGasu | 0.059 | 0.47 | 73.9 |
XD-51569 | gcUuaaCUGuuGucgaCusa | dTAGUCGACAACAgUUAAGCusg | 0.107 | 0.44 | 76.2 |
XD-51570 | acCuugACUguCaaagAusa | dTAUCUUUGACAGuCAAGGUgsa | 0.034 | 0.27 | 76.4 |
XD-51571 | ccUacaCGUuuCaccuGasa | dTUCAGGUGAAACgUGUAGGusc | 0.089 | 0.49 | 74.1 |
XD-51572 | ggUgcuGGAuuCcgacAusa | dTAUGUCGGAAUCcAGCACCcsc | 0.031 | 0.4 | 74.6 |
XD-51573 | cuGgauUCCgaCaucaUusa | dTAAUGAUGUCGGaAUCCAGcsa | 0.074 | 0.94 | 71.5 |
XD-51574 | gcAaaaGAUucAgccgUasa | dTUACGGCUGAAUcUUUUGCasc | 0.02 | 0.41 | 75.6 |
XD-51575 | caAaagAUUcaGccguAcsa | dTGUACGGCUGAAuCUUUUGcsa | 0.043 | 0.23 | 75.8 |
XD-51576 | cuGaugCAUucUgaauCgsa | dTCGAUUCAGAAUgCAUCAGgsc | 0.139 | 5.39 | 65.6 |
在一些實施例中,RNAi分子為單股的。在一些實施例中,RNAi分子為雙股的。應注意,本申請案中所敍述之任何RNAi分子的任何核苷酸長度係指RNAi分子之單股,即使該單股為雙股RNAi分子之成員。舉例而言,若RNAi分子之長度為21個核苷酸且為雙股的(無突出物),則分子將包含總共42個核苷酸(各股中21個核苷酸)。在一些實施例中,RNAi分子為雙股的且包含鈍端。在一些實施例中,RNAi分子為雙股的且包含一或多個核苷酸之突出物。在一些實施例中,RNAi分子僅一部分分子為雙股的。舉例而言,在一些實施例中,雙股RNAi分子在有義股及/或反義股上包含1、2、3、4或5個或更多個核苷酸之突出物。在一些實施例中,雙股RNAi分子在有義股及/或反義股上包含1、2或3個核苷酸之突出物。
在一些實施例中,本文中所揭示之RNAi分子(例如siRNA分子)中之任一者包含與AAVR RNA轉錄本中之標靶序列共有互補性(例如100%互補性)的核苷酸序列。在一些實施例中,RNAi分子包含至少17、18、19、20或21個與AAVR RNA轉錄本中之標靶序列互補的核苷酸。在一些實施例中,RNAi分子包含至少17、18、19、20或21個與AAVR RNA轉錄本中之標靶序列互補的核苷酸,但其中RNAi分子之3'端上的一或多個核苷酸與AAVR RNA轉錄本中之標靶序列不互補。在一些實施例中,RNAi分子包含至少17、18、19、20或21個與AAVR RNA轉錄本中之標靶序列互補的核苷酸,但其中RNAi分子之5'端上的一或多個核苷酸與AAVR RNA轉錄本中之標靶序列不互補。在一些實施例中,RNAi分子包含至少17、18、19、20或21個與AAVR RNA轉錄本中之標靶序列互補的核苷酸,但其中RNAi分子之3'端及5'端上的一或多個核苷酸與AAVR RNA轉錄本中之標靶序列不互補。
B. 藥劑遞送
在一些實施例中,阻斷AAV結合至AAVR的如本文中所揭示之藥劑中之任一者係「裸(naked)」,亦即在沒有意欲用於細胞或組織特異性遞送之分子的情況下投與。舉例而言,在一些實施例中,藥劑在醫藥學上可接受之緩衝液(例如緩衝鹽水溶液,諸如PBS)中「裸」投與。
在一些實施例中,組合物包含阻斷AAV結合至AAV受體(AAVR)之藥劑及將藥劑遞送至肝臟之遞送分子。在一些實施例中,組合物包含與肝臟靶向部分結合之siRNA。如本文中所使用,「肝臟靶向部分」包括(但不限於)任何結合物(包括任何已知結合物),其可應用於阻斷AAV結合至AAVR (例如siRNA或RNAi)之藥劑中之任一者以增強其遞送及/或肝臟吸收。亦可使用脂質部分(例如結合脂質之siRNA),諸如結合膽固醇之siRNA,及此項技術中已知以有效靶向肝臟之任何其他結合物基團或部分。在一些實施例中,遞送分子包含脂質。在一些實施例中,組合物包含結合脂質之siRNA。
在一些實施例中,遞送分子包含至少一種半乳糖或半乳糖衍生物。在一些實施例中,組合物包含與至少一種半乳糖或半乳糖衍生物結合之siRNA。半乳糖或半乳糖衍生物可經由其結合至對肝細胞獨特且高度表現於肝細胞表面上之脫唾液酸醣蛋白受體(ASGPr)而靶向肝細胞。半乳糖部分與ASGPr之結合促進轉移聚合物之細胞特異性標靶進入至肝細胞且將聚合物遞送至肝細胞的胞內進入。例示性半乳糖或半乳糖衍生物包括乳糖、半乳糖、N-乙醯基半乳胺糖(GalNAc)、半乳胺糖、N-甲醯基半乳胺糖、N-乙醯基半乳胺糖、N-丙醯基半乳胺糖、N-正丁醯基半乳胺糖及N-異丁醯基-半乳胺糖(Iobst, ST及Drickamer, K. JBC 1996, 271 , 6686)。在一些實施例中,遞送分子包含N-乙醯基半乳胺糖(GalNAc)。在一些實施例中,組合物包含結合GalNAc之siRNA。
亦如此項技術中所已知,阻斷AAV結合至AAVR之藥劑可藉由非病毒組織特異性遞送媒劑來遞送。在一些實施例中,奈米粒子、脂質體、核糖核蛋白、帶正電肽、小分子RNA-結合物、適體-RNA嵌合體及RNA-融合蛋白複合物係用於遞送siRNA。在一些實施例中,遞送分子包含脂質奈米粒子(LNP)。在一些實施例中,組合物包含LNP以將藥劑遞送至肝臟。
LNP係指具有小於1000 nm、500 nm、250 nm、200 nm、150 nm、100 nm、75 nm、50 nm或25 nm之直徑的任何粒子。或者,奈米粒子之尺寸可在1至1000 nm、1至500 nm、1至250 nm、25至200 nm、25至100 nm、35至75 nm或25至60 nm之範圍內。
LNP可由陽離子型脂質、陰離子型脂質或中性脂質製成。中性脂質(諸如融合磷脂DOPE或膜組分膽固醇)可包括於LNP中作為『輔助脂質』以增強轉染活性及奈米粒子穩定性。陽離子型脂質之限制包括由於較差穩定性及快速清除率引起之低功效,以及發炎或抗發炎反應之產生。LNP亦可包含疏水性脂質、親水性脂質或疏水性及親水性脂質兩者。此項技術中已知的任何脂質或脂質之組合均可用於產生LNP。用於產生LNP之脂質的實例為:DOTMA、DOSPA、DOTAP、DMRIE、DC-膽固醇、DOTAP-膽固醇、GAP-DMORIE-DPyPE及GL67A-DOPE-DMPE-聚乙二醇(PEG)。陽離子型脂質之實例為:98N12-5、C12-200、DLin-KC2-DMA (KC2)、DLin-MC3-DMA (MC3)、XTC、MD1及7C1。中性脂質之實例為:DPSC、DPPC、POPC、DOPE及SM。經PEG改質之脂質的實例為:PEG-DMG、PEG-CerC14及PEG-CerC20。脂質可以任何數目之莫耳比組合以產生LNP。另外,聚核苷酸可以廣泛範圍之莫耳比與脂質組合以產生LNP。
C. 抗 AAVR 抗體
在一些實施例中,組合物包含抗AAVR抗體以阻斷AAV結合至AAVR且以其他方式減少AAV與受體之間的相互作用。先前發現AAV受體(AAVR,亦稱為KIAA0319L)直接結合至AAV粒子且涉及AAV感染。在研究中,發現抗AAVR抗體可阻斷AAV2感染。參見Pillay,
Nature, 530(7588): 108-112 (2016)。針對AAVR之抗體在感染之前能夠潛在地阻斷超過10倍之AAV2感染,此表明阻斷AAV進入細胞表面上之AAVR實質上限制感染。
在一些實施例中,抗AAVR抗體結合至包含與SEQ ID NO: 301至少85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%一致之序列的AAVR,且抑制AAVR與AAV之間的結合。在一些實施例中,抗AAVR抗體結合至AAVR中之以下殘基中之任一或多者:包含與SEQ ID NO: 301至少85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%一致之序列的蛋白質之Arg406、Ser413、Ile419、Thr423、Ser425、Thr426、Val427、Asp429、Ser431、Gln432、Ser433、Thr434、Asp435、Asp436、Asp437、Lys438、Ile439、Tyr442、Glu458、Asp459、Ile462及/或Lys464。參見例如,Meyer等人, 2019, eLife, 8:e44707。在一些實施例中,抗體結合至AAVR且在空間上阻斷AAV與AAVR之相互作用。在一些實施例中,抗體結合至AAVR且在空間上阻斷AAV與AAVR中之以下殘基中之任一或多者的相互作用:與SEQ ID NO: 301至少85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%一致之序列之Arg406、Ser413、Ile419、Thr423、Ser425、Thr426、Val427、Asp429、Ser431、Gln432、Ser433、Thr434、Asp435、Asp436、Asp437、Lys438、Ile439、Tyr442、Glu458、Asp459、Ile462及/或Lys464。在一些實施例中,組合物包含此項技術中已知的抗AAVR抗體,包括例如ab105385 (Abcam)。
D. 反義寡核苷酸
在一些實施例中,組合物包含能夠結合至標靶序列,例如不活化或干擾相應AAVR mRNA或DNA序列之短單股寡核苷酸(RNA或DNA),由此下調標靶AAVR基因之表現。
在一些實施例中,組合物包含反義寡核苷酸,在本文中亦稱為「ASO」以阻斷AAV結合至肝臟中之AAVR。反義寡核苷酸可為單股或雙股DNA或RNA或嵌合混合物或其衍生物或經修飾之形式。如此項技術中所已知,為了使反義寡核苷酸儘可能有效地充分抑制其標靶序列,在反義寡核苷酸與相應標靶序列之間應存在一定程度的互補性。ASO之化學修飾為此項技術中已知以提高其對各種核酸酶之抗性,以及其對RNA標靶之結合親和力。硫代磷酸酯(PS)修飾,其中非橋接氧係由磷酸酯主鏈中之硫原子置換;2'-O-甲基(2'-O-Me)、2'-O-甲氧基乙基(MOE)修飾;經約束之乙基(cEt)修飾;及雙環核苷修飾(諸如2',4'-亞甲基橋接核酸),通常稱為鎖核酸(LNA)修飾為非限制性實例。因此,在一些實施例中,反義寡核苷酸包含經修飾之序列。在一些實施例中,ASO含有MOE或LNA修飾。
在一些實施例中,反義寡核苷酸係連接至此項技術中已知及/或本文中所描述之配位體或結合物,或藉由可用以例如增加反義寡核苷酸之細胞攝取的非病毒組織特異性遞送媒劑進行遞送。
在一些實施例中,反義寡核苷酸在不結合且無非病毒組織特異性遞送媒劑之情況下投與。在一些實施例中,反義寡核苷酸在無非病毒組織特異性遞送媒劑之情況下投與且以包含醫藥學上可接受之載劑的組合物形式投與。
在一些實施例中,本文中所揭示之ASO中之任一者係「裸」,亦即在沒有意欲用於細胞或組織特異性遞送之分子的情況下投與。舉例而言,在一些實施例中,藥劑在醫藥學上可接受之緩衝液(例如緩衝鹽水溶液,諸如PBS)中「裸」投與。
在一些實施例中,本文中所揭示之ASO中之任一者的長度為至少14、15、16、17、18、19、20、21、22、23、24或25個核苷酸。在一些實施例中,本文中所揭示之ASO中之任一者的長度不超過35、34、33、32、31、30、29、28、27、26或25個核苷酸。在一些實施例中,本文中所揭示之ASO中之任一者的長度在14至35、14至30、14至25、14至20、20至35、20至30、20至25、25至35或25至30個核苷酸之間。在一些實施例中,ASO之長度小於20個核苷酸。在一些實施例中,ASO之長度為14至18、15至17或16個核苷酸。
產生反義寡核苷酸之方法為此項技術中已知的。在一些實施例中,反義寡核苷酸靶向編碼AAVR之轉錄本。在一些實施例中,編碼AAVR之轉錄本包含與SEQ ID NO: 300之序列或其反向互補序列至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%一致之序列。在一些實施例中,反義寡核苷酸靶向序列之19、20、21、22、23、24、25、26、27、28、29、30、31或32個鄰接核苷酸,該序列與SEQ ID NO: 300之序列或其反向互補序列至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%一致。在一些實施例中,反義寡核苷酸靶向序列之19至32、19至25、19至22或20至21個鄰接核苷酸,該序列與SEQ ID NO: 300之序列或其反向互補序列至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%一致。
在一些實施例中,本文中所揭示之ASO中之任一者包含表B中所揭示之序列中之任一者。在一些實施例中,本文中所揭示之ASO中之任一者包含SEQ ID No: 9600至9625之序列中所揭示之序列中之任一者。在一些實施例中,本文中所揭示之ASO中之任一者包含與SEQ ID No: 9600至9625之序列中之任一者至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%一致之序列。在一些實施例中,ASO包含任何一或多個SEQ ID No: 9600至9625之至少14至20、15至20、16至20、17至20、18至20或19至20個連續核苷酸,或與SEQ ID No: 9600至9625之序列中之任一者至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%一致之任何序列的至少14至20、15至20、16至20、17至20、18至20或19至20個連續核苷酸。在一些實施例中,ASO包含SEQ ID NO: 9600之核苷酸序列或具有任何一或多個SEQ ID No: 9600之至少14至20、15至20、16至20、17至20、18至20或19至20個連續核苷酸的核苷酸序列。在一些實施例中,ASO包含SEQ ID NO: 9601之核苷酸序列或具有任何一或多個SEQ ID No: 9601之至少14至20、15至20、16至20、17至20、18至20或19至20個連續核苷酸的核苷酸序列。在一些實施例中,ASO包含SEQ ID NO: 9602之核苷酸序列或具有任何一或多個SEQ ID No: 9602之至少14至20、15至20、16至20、17至20、18至20或19至20個連續核苷酸的核苷酸序列。在一些實施例中,ASO包含SEQ ID NO: 9603之核苷酸序列或具有任何一或多個SEQ ID No: 9603之至少14至20、15至20、16至20、17至20、18至20或19至20個連續核苷酸的核苷酸序列。在一些實施例中,ASO包含SEQ ID NO: 9604之核苷酸序列或具有任何一或多個SEQ ID No: 9604之至少14至20、15至20、16至20、17至20、18至20或19至20個連續核苷酸的核苷酸序列。在一些實施例中,ASO包含SEQ ID NO: 9605之核苷酸序列或具有任何一或多個SEQ ID No: 9605之至少14至20、15至20、16至20、17至20、18至20或19至20個連續核苷酸的核苷酸序列。在一些實施例中,ASO包含SEQ ID NO: 9606之核苷酸序列或具有任何一或多個SEQ ID No: 9606之至少14至20、15至20、16至20、17至20、18至20或19至20個連續核苷酸的核苷酸序列。在一些實施例中,ASO包含SEQ ID NO: 9607之核苷酸序列或具有任何一或多個SEQ ID No: 9607之至少14至20、15至20、16至20、17至20、18至20或19至20個連續核苷酸的核苷酸序列。在一些實施例中,ASO包含SEQ ID NO: 9608之核苷酸序列或具有任何一或多個SEQ ID No: 9608之至少14至20、15至20、16至20、17至20、18至20或19至20個連續核苷酸的核苷酸序列。在一些實施例中,ASO包含SEQ ID NO: 9609之核苷酸序列或具有任何一或多個SEQ ID No: 9609之至少14至20、15至20、16至20、17至20、18至20或19至20個連續核苷酸的核苷酸序列。在一些實施例中,ASO包含SEQ ID NO: 9610之核苷酸序列或具有任何一或多個SEQ ID No: 9610之至少14至20、15至20、16至20、17至20、18至20或19至20個連續核苷酸的核苷酸序列。在一些實施例中,ASO包含SEQ ID NO: 9611之核苷酸序列或具有任何一或多個SEQ ID No: 9611之至少14至20、15至20、16至20、17至20、18至20或19至20個連續核苷酸的核苷酸序列。在一些實施例中,ASO包含SEQ ID NO: 9612之核苷酸序列或具有任何一或多個SEQ ID No: 9612之至少14至20、15至20、16至20、17至20、18至20或19至20個連續核苷酸的核苷酸序列。在一些實施例中,ASO包含SEQ ID NO: 9613之核苷酸序列或具有任何一或多個SEQ ID No: 9613之至少14至20、15至20、16至20、17至20、18至20或19至20個連續核苷酸的核苷酸序列。在一些實施例中,ASO包含SEQ ID NO: 9614之核苷酸序列或具有任何一或多個SEQ ID No: 9614之至少14至20、15至20、16至20、17至20、18至20或19至20個連續核苷酸的核苷酸序列。在一些實施例中,ASO包含SEQ ID NO: 9615之核苷酸序列或具有任何一或多個SEQ ID No: 9615之至少14至20、15至20、16至20、17至20、18至20或19至20個連續核苷酸的核苷酸序列。在一些實施例中,ASO包含SEQ ID NO: 9616之核苷酸序列或具有任何一或多個SEQ ID No: 9616之至少14至20、15至20、16至20、17至20、18至20或19至20個連續核苷酸的核苷酸序列。在一些實施例中,ASO包含SEQ ID NO: 9617之核苷酸序列或具有任何一或多個SEQ ID No: 9617之至少14至20、15至20、16至20、17至20、18至20或19至20個連續核苷酸的核苷酸序列。在一些實施例中,ASO包含SEQ ID NO: 9618之核苷酸序列或具有任何一或多個SEQ ID No: 9618之至少14至20、15至20、16至20、17至20、18至20或19至20個連續核苷酸的核苷酸序列。在一些實施例中,ASO包含SEQ ID NO: 9619之核苷酸序列或具有任何一或多個SEQ ID No: 9619之至少14至20、15至20、16至20、17至20、18至20或19至20個連續核苷酸的核苷酸序列。在一些實施例中,ASO包含SEQ ID NO: 9620之核苷酸序列或具有任何一或多個SEQ ID No: 9620之至少14至20、15至20、16至20、17至20、18至20或19至20個連續核苷酸的核苷酸序列。在一些實施例中,ASO包含SEQ ID NO: 9621之核苷酸序列或具有任何一或多個SEQ ID No: 9621之至少14至20、15至20、16至20、17至20、18至20或19至20個連續核苷酸的核苷酸序列。在一些實施例中,ASO包含SEQ ID NO: 9622之核苷酸序列或具有任何一或多個SEQ ID No: 9622之至少14至20、15至20、16至20、17至20、18至20或19至20個連續核苷酸的核苷酸序列。在一些實施例中,ASO包含SEQ ID NO: 9623之核苷酸序列或具有任何一或多個SEQ ID No: 9623之至少14至20、15至20、16至20、17至20、18至20或19至20個連續核苷酸的核苷酸序列。在一些實施例中,ASO包含SEQ ID NO: 9624之核苷酸序列或具有任何一或多個SEQ ID No: 9624之至少14至20、15至20、16至20、17至20、18至20或19至20個連續核苷酸的核苷酸序列。在一些實施例中,ASO包含SEQ ID NO: 9625之核苷酸序列或具有任何一或多個SEQ ID No: 9625之至少14至20、15至20、16至20、17至20、18至20或19至20個連續核苷酸的核苷酸序列。在一些實施例中,ASO包含SEQ ID NO: 9626之核苷酸序列或具有任何一或多個SEQ ID No: 9626之至少14至20、15至20、16至20、17至20、18至20或19至20個連續核苷酸的核苷酸序列。在一些實施例中,ASO之長度不超過20、不超過19、不超過18、不超過17、不超過16、不超過15或不超過15個核苷酸。在一些實施例中,ASO之長度不超過16個核苷酸。
用於實例中之經修飾之ASO的序列闡述於下表B中。在ASO序列修飾中,「*」指示在兩個鹼基之間的鍵為硫代磷酸酯,而「+」指示核酸為鎖核酸(LNA)。對於經MOE修飾之ASO,「2MOEr」指示特定鹼基為2'-O-甲氧基-乙基鹼基(2'-MOE)。「2MOEr」之前的「5」指示其為寡核苷酸中之第一個(5')鹼基,「3」指示其為寡核苷酸中之最後一個(3')鹼基,且「i」指示其為內部鹼基(寡核苷酸之中間)。最後一個字母為鹼基之屬性(identity),即A、T、C或G;各鹼基之名稱係藉由斜杠分隔開。
表 B
E. 阻斷 AAV 結合至 AAVR 之小分子及其他試劑
CRO / 內部標記 | SEQ ID NO: | 未經修飾之 ASO 序列 | ASO 序列修飾 |
AAVR_ASO_1 | 9600 | CAGCTGCCAGTCGTAGGTGT | +C*+A*+G*+C*+T*G*C*C*A*G*T*C*G*T*A*+G*+G*+T*+G*+T |
AAVR_ASO_2 | 9601 | TAGCCTTCCCCATGGGCATT | +T*+A*+G*+C*+C*T*T*C*C*C*C*A*T*G*G*+G*+C*+A*+T*+T |
AAVR_ASO_3 | 9602 | ATCTCCTGGAACTGAGGTGA | +A*+T*+C*+T*+C*C*T*G*G*A*A*C*T*G*A*+G*+G*+T*+G*+A |
AAVR_ASO_4 | 9603 | GATCACTTGGTTGGGGCCTG | +G*+A*+T*+C*+A*C*T*T*G*G*T*T*G*G*G*+G*+C*+C*+T*+G |
AAVR_ASO_5/ IH_ASO5 | 9604 | CTGCATCTGCCTGAGGAGGC | +C*+T*+G*+C*+A*T*C*T*G*C*C*T*G*A*G*+G*+A*+G*+G*+C |
AAVR_ASO_6/ IH_ASO6 | 9605 | CTCATCTTTGACAGTCAAGG | +C*+T*+C*+A*+T*C*T*T*T*G*A*C*A*G*T*+C*+A*+A*+G*+G |
AAVR_ASO_7 | 9606 | ATCCCCTTCAGCCTCTCAGT | +A*+T*+C*+C*+C*C*T*T*C*A*G*C*C*T*C*+T*+C*+A*+G*+T |
AAVR_ASO_8/IH-ASO8 | 9607 | CCCCCAGGAGGACCCCAATC | +C*+C*+C*+C*+C*A*G*G*A*G*G*A*C*C*C*+C*+A*+A*+T*+C |
LNA_1/ ASOVT002 | 9608 | TCTTTGACAGTCAAGG | +T*+C*+T*T*T*G*A*C*A*G*T*C*A*+A*+G*+G |
LNA_2 | 9609 | TGTCGGAATCCAGCAC | +T*+G*+T*C*G*G*A*A*T*C*C*A*G*+C*+A*+C |
LNA_3 | 9610 | ATGATGTCGGAATCCA | +A*+T*+G*A*T*G*T*C*G*G*A*A*T*+C*+C*+A |
LNA_4 | 9611 | ACGGCTGAATCTTTTG | +A*+C*+G*G*C*T*G*A*A*T*C*T*T*+T*+T*+G |
LNA_5 | 9612 | TACGGCTGAATCTTTT | +T*+A*+C*G*G*C*T*G*A*A*T*C*T*+T*+T*+T |
LNA_IH5 | 9613 | GCATCTGCCTGAGGAG | +G*+C*+A*T*C*T*G*C*C*T*G*A*G*+G*+A*+G |
LNA_IH6 | 9614 | CATCTTTGACAGTCAA | +C*+A*+T*C*T*T*T*G*A*C*A*G*T*+C*+A*+A |
LNA_IH8 | 9615 | CCCAGGAGGACCCCAA | +C*+C*+C*A*G*G*A*G*G*A*C*C*C*+C*+A*+A |
18_MOE_1 | 9616 | ATCTTTGACAGTCAAGGT | /52MOErA//i2MOErT//i2MOErC//i2MOErT/TTGACAGTCA/i2MOErA//i2MOErG//i2MOErG//32MOErT/ |
18_MOE_2 | 9617 | ATGTCGGAATCCAGCACC | /52MOErA//i2MOErT//i2MOErG//i2MOErT/CGGAATCCAG/i2MOErC//i2MOErA//i2MOErC//32MOErC/ |
18_MOE_3 | 9618 | AATGATGTCGGAATCCAG | /52MOErA//i2MOErA//i2MOErT//i2MOErG/ATGTCGGAAT/i2MOErC//i2MOErC//i2MOErA//32MOErG/ |
18_MOE_4 | 9619 | TACGGCTGAATCTTTTGC | /52MOErT//i2MOErA//i2MOErC//i2MOErG/GCTGAATCTT/i2MOErT//i2MOErT//i2MOErG//32MOErC/ |
18_MOE_5 | 9620 | GTACGGCTGAATCTTTTG | /52MOErG//i2MOErT//i2MOErA//i2MOErC/GGCTGAATCT/i2MOErT//i2MOErT//i2MOErT//32MOErG/ |
18_MOE_IH5 | 9621 | TGCATCTGCCTGAGGAGG | /52MOErT//i2MOErG//i2MOErC//i2MOErA/TCTGCCTGAG/i2MOErG//i2MOErA//i2MOErG//32MOErG/ |
18_MOE_IH6 | 9622 | TCATCTTTGACAGTCAAG | /52MOErT//i2MOErC//i2MOErA//i2MOErT/CTTTGACAGT/i2MOErC//i2MOErA//i2MOErA//32MOErG/ |
18_MOE_IH8 | 9623 | CCCCAGGAGGACCCCAAT | /52MOErC//i2MOErC//i2MOErC//i2MOErC/AGGAGGACCC/i2MOErC//i2MOErA//i2MOErA//32MOErT/ |
LNA_對照 | 9624 | GGCTACTACGCCGTCA | GGCTACTACGCCGTCA |
MOE_對照 | 9625 | TTAGTTTAATCACGCTCG | /52MOErT//i2MOErT//i2MOErA//i2MOErG/TTTAATCACG/i2MOErC//i2MOErT//i2MOErC//32MOErG/ |
在一些實施例中,組合物包含小分子,該等小分子阻斷AAVR結合至AAV及/或以其他方式抑制或減少AAV與受體之間的相互作用。經考慮,其他適合之抑制劑可使用一般熟習此項技術者已知的技術產生,包括AAVR表現之抑制劑。
在一些實施例中,組合物包含阻斷AAV粒子與AAVR之間之結合的可溶性變異體多肽。在一些實施例中,可溶性變異體多肽為AAVR之變異體,其具有對於AAV而言足夠以可識別親和力結合,但缺少跨膜域(例如缺少相應野生型蛋白質之天然存在之跨膜域)之蛋白質的一部分。舉例而言,在一些實施例中,可溶性AAVR多肽缺少相應野生型AAVR蛋白之跨膜域或跨膜域及胞質尾區,且能夠與AAV結合,由此阻斷AAV粒子結合至細胞表面上(例如肝臟中)之AAVR。參見例如US10633662B2 (Pillay)。
F. AAV 組合物
在一些實施例中,AAV載體及/或其組合物係在投與以上組合物中之任一者之後進行投與,該等組合物阻斷AAV結合至AAVR且遞送至肝臟,其中投與阻斷AAV結合至AAVR之組合物中之任一者增加遞送至非肝臟標靶之AAV的百分比。因此,本發明涵蓋投與具有非肝臟標靶之單一AAV載體或多種AAV載體及/或其組合物。
在一些實施例中,AAV為AAV1、AAV2、AAV3、AAV4、AAV5、AAV6、AAV7、AAV8、AAVrh10、AAVrh74、AAV9、AAV9P或Myo-AAV載體。在一些實施例中,一或多種AAV載體為重組或經工程改造之AAV載體。在一些實施例中,一或多種AAV載體包含組織特異性(例如肌肉特異性)啟動子,例如其可操作地連接至編碼嚮導RNA之序列。
在一些實施例中,本文中所揭示之AAV中之任一者包含tRNA或編碼tRNA之核苷酸序列。在一些實施例中,tRNA為抑制因子tRNA。在一些實施例中,抑制因子tRNA包含與標靶基因(例如突變肌肉萎縮蛋白基因)中之過早終止密碼子雜交且能夠經胺基酸胺醯基化的反密碼子。在一些實施例中,本文中所揭示之AAV中之任一者包含核苷酸序列,該核苷酸序列編碼以下中之一或多者中所描述之tRNA分子中之任一者:US2020277607、US2022073933、US2020291401、US2022112489、WO2019090154、WO2019090169、WO2020150608、WO2021087401、WO2020069199或WO2018161032,該等申請案中之各者以全文引用之方式併入本文中。
在一些實施例中,一或多種AAV載體包括CRISPR-Cas組分,其任一者為此項技術中已知的。在一些實施例中,一或多種AAV載體包含編碼Cas9蛋白之核酸。此類實施例包括例如,包含編碼金黃色葡萄球菌(SaCas9)及/或路鄧葡萄球菌(SluCas9)之核酸且進一步包含編碼一或多個嚮導RNA之核酸的AAV載體。在此類實施例中,編碼Cas9蛋白之核酸處於CK8e啟動子之控制下。在一些實施例中,編碼嚮導RNA序列之核酸處於hU6c啟動子之控制下。在一些實施例中,載體為AAV9。在一些實施例中,除嚮導RNA及Cas9序列之外,一或多種載體進一步包含不編碼嚮導RNA之核酸。不編碼嚮導RNA及Cas9之核酸包括(但不限於)啟動子、強化子及調節序列。在一些實施例中,載體包含一或多個編碼crRNA、trRNA或crRNA及trRNA之核苷酸序列。
在一些實施例中,肌肉-細胞之細胞特異性啟動子為CK8啟動子之變異體,稱為CK8e。在一些實施例中,CK8e啟動子之尺寸為436 bp。在一些實施例中,CK8e啟動子包含與以下SEQ ID NO: 302之序列至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%一致之核苷酸序列:
在一些實施例中,用於表現本文中所揭示之核酸中之任一者的啟動子為U6啟動子。在一些實施例中,U6啟動子為hU6c啟動子且包含與以下SEQ ID NO: 303之序列至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%一致之核苷酸序列:
。
在一些實施例中,用於表現本文中所揭示之核酸中之任一者的啟動子為H1啟動子。在一些實施例中,H1啟動子包含與以下SEQ ID NO: 304之序列至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%一致之核苷酸序列:
在一些實施例中,用於表現本文中所揭示之核酸中之任一者的啟動子為7SK2啟動子。在一些實施例中,7SK啟動子為7SK2啟動子且包含與以下SEQ ID NO: 305之序列至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%一致之核苷酸序列:
。
在一些實施例中,嚮導RNA經化學修飾。包含一或多個經修飾之核苷或核苷酸的嚮導RNA稱為「經修飾」之嚮導RNA或「經化學修飾」之嚮導RNA,以描述替代典型A、G、C及U殘基使用或除該等殘基之外使用的非天然及/或天然存在之一或多種組分或組態的存在。經修飾之嚮導RNA之論述可見於WO2022/056000中,其以全文引用之方式併入本文中。在一些實施例中,嚮導RNA未經修飾。
在一些實施例中,一或多種載體包含編碼超過一個嚮導RNA之多種核酸。在一些實施例中,一或多種載體包含編碼兩個嚮導RNA序列之兩種核酸。
在一些實施例中,一或多種載體包含編碼Cas9蛋白(例如SaCas9蛋白或SluCas9蛋白)之核酸、編碼第一嚮導RNA之核酸及編碼第二嚮導RNA之核酸。在一些實施例中,一或多種載體不包含編碼超過兩個嚮導RNA之核酸。在一些實施例中,編碼第一嚮導RNA之核酸與編碼第二嚮導RNA之核酸相同。在一些實施例中,編碼第一嚮導RNA之核酸與編碼第二嚮導RNA之核酸不同。在一些實施例中,一或多種載體包含單一核酸分子,其中單一核酸分子包含編碼Cas9蛋白之核酸、編碼第一嚮導RNA之核酸及與第二嚮導RNA之編碼序列為反向互補序列之核酸。在一些實施例中,一或多種載體包含單一核酸分子,其中單一核酸分子包含編碼Cas9蛋白之核酸、與第一嚮導RNA之編碼序列為反向互補序列之核酸及與第二嚮導RNA之編碼序列為反向互補序列之核酸。在一些實施例中,編碼Cas9蛋白(例如SaCas9或SluCas9蛋白)之核酸處於CK8e啟動子之控制下。在一些實施例中,第一嚮導處於7SK2啟動子之控制下,且第二嚮導處於H1m啟動子之控制下。在一些實施例中,第一嚮導處於H1m啟動子之控制下,且第二嚮導處於7SK2啟動子之控制下。在一些實施例中,第一嚮導處於hU6c啟動子之控制下,且第二嚮導處於H1m啟動子之控制下。在一些實施例中,第一嚮導處於H1m啟動子之控制下,且第二嚮導處於hU6c啟動子之控制下。在一些實施例中,編碼Cas9蛋白之核酸:a)在編碼嚮導RNA之核酸之間,b)在與嚮導RNA之編碼序列為反向互補序列之核酸之間,c)在編碼第一嚮導RNA之核酸及與第二嚮導RNA之編碼序列為反向互補序列之核酸之間,d)在編碼第二嚮導RNA之核酸及與第一嚮導RNA之編碼序列為反向互補序列之核酸之間,e)編碼嚮導RNA之核酸的5',f)與嚮導RNA之編碼序列為反向互補序列之核酸的5',g)編碼嚮導RNA中之一者的核酸的5'及與其他嚮導RNA之編碼序列為反向互補序列之核酸的5',h)編碼嚮導RNA之核酸的3',i)與嚮導RNA之編碼序列為反向互補序列之核酸的3',或j)編碼嚮導RNA中之一者的核酸的3'及與其他嚮導RNA之編碼序列為反向互補序列之核酸的3'。
在一些實施例中,本文中所揭示之載體中之任一者為AAV9。在較佳實施例中,AAV9載體自ITR至ITR (包括兩個ITR)之尺寸小於5 kb。在特定實施例中,AAV9載體自ITR至ITR (包括兩個ITR)之尺寸小於4.9 kb。在其他實施例中,AAV9載體自ITR至ITR (包括兩個ITR)之尺寸小於4.85 kb。在其他實施例中,AAV9載體自ITR至ITR (包括兩個ITR)之尺寸小於4.8 kb。在其他實施例中,AAV9載體自ITR至ITR (包括兩個ITR)之尺寸小於4.75 kb。在其他實施例中,AAV9載體自ITR至ITR (包括兩個ITR)之尺寸小於4.7 kb。在一些實施例中,載體自ITR至ITR (包括兩個ITR)之尺寸在3.9至5 kb、4至5 kb、4.2至5 kb、4.4至5 kb、4.6至5 kb、4.7至5 kb、3.9至4.9 kb、4.2至4.9 kb、4.4至4.9 kb、4.7至4.9 kb、3.9至4.85 kb、4.2至4.85 kb、4.4至4.85 kb、4.6至4.85 kb、4.7至4.85 kb、4.7至4.9 kb、3.9至4.8 kb、4.2至4.8 kb、4.4至4.8 kb或4.6至4.8 kb之間。在一些實施例中,載體自ITR至ITR (包括兩個ITR)之尺寸在4.4至4.85 kb之間。在一些實施例中,載體為AAV9載體。
在一些實施例中,本文中所揭示之載體中之任一者包含至少編碼第一嚮導RNA及第二嚮導RNA之核酸。在一些實施例中,核酸包含第一嚮導RNA之間隔子編碼序列、第一嚮導RNA之骨架編碼序列、第二嚮導RNA之間隔子編碼序列及第二嚮導RNA之骨架編碼序列。在一些實施例中,第一嚮導RNA之間隔子編碼序列(例如編碼本文中所揭示之間隔子序列中之任一者)與第二嚮導RNA之間隔子編碼序列一致。在一些實施例中,第一嚮導RNA之間隔子編碼序列(例如編碼本文中所揭示之間隔子序列中之任一者)與第二嚮導RNA之間隔子編碼序列不同。在一些實施例中,第一嚮導RNA之骨架編碼序列與第二嚮導RNA之骨架編碼序列一致。在一些實施例中,第一嚮導RNA之骨架編碼序列與編碼第二嚮導RNA之核酸的骨架編碼序列不同。
在一些實施例中,AAV載體就正股而言自5'至3'包含:第一sgRNA骨架序列之反向互補序列、編碼第一sgRNA嚮導序列之核酸的反向互補序列、用於表現編碼第一sgRNA之核酸之啟動子的反向互補序列、用於表現編碼SaCas9之核酸之啟動子(例如CK8e)、編碼SaCas9之核酸、聚腺苷酸化序列、用於表現第二sgRNA之啟動子、第二sgRNA嚮導序列,及第二sgRNA骨架序列。在一些實施例中,用於表現編碼第一及/或第二sgRNA之核酸的啟動子為hU6c啟動子或7SK2啟動子。在一些實施例中,用於表現編碼第二sgRNA之核酸的啟動子為H1m啟動子。在一些實施例中,用於SaCas9之啟動子為CK8e啟動子。在一些實施例中,編碼SaCas9之核酸序列與編碼核定位序列(NLS)之核酸序列融合。在一些實施例中,編碼SaCas9之核酸序列與各自編碼核定位序列(NLS)之兩個核酸序列融合。在一些實施例中,編碼SaCas9之核酸序列與各自編碼核定位序列(NLS)之三個核酸序列融合。在一些實施例中,一或多個NLS為SV40 NLS。在一些實施例中,一或多個NLS為c-Myc NLS。在一些實施例中,NLS經由連接子與SaCas9融合。
在一些實施例中,非肝臟標靶為肌肉。在此類實施例中,基於非肝臟AAV之基因療法係用於治療DMD。
在一些實施例中,編碼SaCas9之核酸編碼包含與以下SEQ ID NO: 306之序列至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%一致之胺基酸序列的SaCas9:
在一些實施例中,SaCas9包含與以下SEQ ID NO: 307之序列(在本文中稱為SaCas9-KKH或SACAS9KKH)至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%一致之胺基酸序列:
在一些實施例中,編碼SluCas9之核酸編碼包含與以下SEQ ID NO: 308之序列至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%一致之胺基酸序列的SluCas9:
在一些實施例中,Cas蛋白為以下文獻中所揭示的經工程改造之Cas蛋白中之任一者:Schmidt等人, 2021, Nature Communications,「Improved CRISPR genome editing using small highly active and specific engineered RNA-guided nucleases」。
在一些實施例中,Cas9包含與以下SEQ ID NO: 309之序列(在本文中稱為sRGN1)至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%一致之胺基酸序列:
。
在一些實施例中,Cas9包含與以下SEQ ID NO: 310之序列(在本文中稱為sRGN2)至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%一致之胺基酸序列:
。
在一些實施例中,Cas9包含與以下SEQ ID NO: 311之序列(在本文中稱為sRGN3)至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%一致之胺基酸序列:
。
在一些實施例中,Cas9包含與以下SEQ ID NO: 312之序列(在本文中稱為sRGN3.1)至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%一致之胺基酸序列:
。
在一些實施例中,Cas9包含與以下SEQ ID NO: 313之序列(在本文中稱為sRGN3.2)至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%一致之胺基酸序列:
。
在一些實施例中,Cas9包含與以下SEQ ID NO: 314之序列(在本文中稱為sRGN3.3)至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%一致之胺基酸序列:
。
在一些實施例中,Cas9包含與以下SEQ ID NO: 315之序列(在本文中稱為sRGN4)至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%一致之胺基酸序列:
在一些實施例中,嚮導RNA包含作為非限制性實例之下表1A、表1B及表2中所揭示之嚮導序列。舉例而言,當AAV載體包含SaCas9時,一或多個間隔子序列係選自SEQ ID NO: 1至35、1000至1078及3000至3069中之任一者;或當AAV載體包含SluCas9時,一或多個間隔子序列係選自來自下表之SEQ ID NO: 100至225、2000至2116及4000至4251中之任一者。其他例示性AAV組合物,包括各種RNP複合物(包含一或多個包含及saCas9或sluCas9之嚮導RNA,或突變Cas9蛋白)揭示於WO2022/056000中之其他地方,該文獻以全文引用之方式併入本文中。
表 1A : 例示性 DMD 嚮導序列 ( 人類 - hg38 . p12 )
表1B:例示性DMD嚮導序列(20個核苷酸及21個核苷酸)
表2:其他DMD嚮導序列(人類-hg38.p12)
嚮導序列之序列ID編號 | 外顯子 | CAS9 | 股 | 嚮導序列 | pam |
1 | 外顯子43 | SACAS9 | + | GCAATGCTGCTGTCTTCTTGCT | ATGAAT |
2 | 外顯子43 | SACAS9 | - | AACAAAATGTACAAGGACCGAC | AAGGGT |
3 | 外顯子43 | SACAS9 | - | TGCAAAGTGCAACGCCTGTGGA | AAGGGT |
4 | 外顯子43 | SACAS9 | - | ATAGTCTACAACAAAGCTCAGG | TCGGAT |
5 | 外顯子43 | SACAS9 | - | CTGTTTTAAAATTTTTATATTA | CAGAAT |
6 | 外顯子44 | SACAS9 | + | ATTTAGCATGTTCCCAATTCTC | AGGAAT |
7 | 外顯子44 | SACAS9 | + | AATCGCCTGCAGGTAAAAGCAT | ATGGAT |
8 | 外顯子44 | SACAS9 | - | TCTCAGAAAGACACAAATTCCT | GAGAAT |
9 | 外顯子45 | SACAS9 | + | TCAGGCTTCCCAATTTTTCCTG | TAGAAT |
10 | 外顯子45 | SACAS9 | + | TAGAATACTGGCATCTGTTTTT | GAGGAT |
11 | 外顯子45 | SACAS9 | + | TGGCATCTGTTTTTGAGGATTG | CTGAAT |
12 | 外顯子45 | SACAS9 | + | TTGCCGCTGCCCAATGCCATCC | TGGAGT |
13 | 外顯子45 | SACAS9 | - | GAGGTAGGGCGACAGATCTAAT | AGGAAT |
14 | 外顯子45 | SACAS9 | - | TCTACAGGAAAAATTGGGAAGC | CTGAAT |
15 | 外顯子45 | SACAS9 | - | GCGGCAAACTGTTGTCAGAACA | TTGAAT |
16 | 外顯子45 | SACAS9 | - | TTTTGGTATCTTACAGGAACTC | CAGGAT |
17 | 外顯子50 | SACAS9 | - | ACTATTGGAGCCTGTAAGTATA | CTGGAT |
18 | 外顯子50 | SACAS9 | - | AGGAAGTTAGAAGATCTGAGCT | CTGAGT |
19 | 外顯子51 | SACAS9 | + | TAGTAACCACAGGTTGTGTCAC | CAGAGT |
20 | 外顯子51 | SACAS9 | + | GTTGTGTCACCAGAGTAACAGT | CTGAGT |
21 | 外顯子51 | SACAS9 | + | TCTGAGTAGGAGCTAAAATATT | TTGGGT |
22 | 外顯子51 | SACAS9 | - | GAGGGTGATGGTGGGTGACCTT | GAGGAT |
23 | 外顯子51 | SACAS9 | - | TATAAAATCACAGAGGGTGATG | GTGGGT |
24 | 外顯子51 | SACAS9 | - | TTGATCAAGTTATAAAATCACA | GAGGGT |
25 | 外顯子53 | SACAS9 | + | CCTTGGTTTCTGTGATTTTCTT | TTGGAT |
26 | 外顯子53 | SACAS9 | + | TCCTTAGCTTCCAGCCATTGTG | TTGAAT |
27 | 外顯子53 | SACAS9 | + | CTTGTACTTCATCCCACTGATT | CTGAAT |
28 | 外顯子53 | SACAS9 | + | ACTGATTCTGAATTCTTTCAAC | TAGAAT |
29 | 外顯子53 | SACAS9 | - | AGCCAAGCTTGAGTCATGGAAG | GAGGGT |
30 | 外顯子53 | SACAS9 | - | TTAGGACAGGCCAGAGCCAAGC | TTGAGT |
31 | 外顯子53 | SACAS9 | - | GCAACAGTTGAATGAAATGTTA | AAGGAT |
32 | 外顯子53 | SACAS9 | - | CCTTCAGAACCGGAGGCAACAG | TTGAAT |
33 | 外顯子53 | SACAS9 | - | AGTTGAAAGAATTCAGAATCAG | TGGGAT |
34 | 外顯子53 | SACAS9 | - | TTTTATTCTAGTTGAAAGAATT | CAGAAT |
35 | 外顯子53 | SACAS9 | - | TTTTTCCTTTTATTCTAGTTGA | AAGAAT |
100 | 外顯子43 | SLUCAS9 | + | ATATATGTGTTACCTACCCTTG | TCGG |
101 | 外顯子43 | SLUCAS9 | + | ACATTTTGTTAACTTTTTCCCA | TTGG |
102 | 外顯子43 | SLUCAS9 | + | CTTTTTCCCATTGGAAATCAAG | CTGG |
103 | 外顯子43 | SLUCAS9 | + | TTTTTCCCATTGGAAATCAAGC | TGGG |
104 | 外顯子43 | SLUCAS9 | + | TCCTGTAGCTTCACCCTTTCCA | CAGG |
105 | 外顯子43 | SLUCAS9 | - | AATGTACAAGGACCGACAAGGG | TAGG |
106 | 外顯子43 | SLUCAS9 | - | ACAAAATGTACAAGGACCGACA | AGGG |
107 | 外顯子43 | SLUCAS9 | - | AACAAAATGTACAAGGACCGAC | AAGG |
108 | 外顯子43 | SLUCAS9 | - | GGAAAAAGTTAACAAAATGTAC | AAGG |
109 | 外顯子43 | SLUCAS9 | - | TCTCTCCCAGCTTGATTTCCAA | TGGG |
110 | 外顯子43 | SLUCAS9 | - | CTCTCTCCCAGCTTGATTTCCA | ATGG |
111 | 外顯子43 | SLUCAS9 | - | GCCTGTGGAAAGGGTGAAGCTA | CAGG |
112 | 外顯子43 | SLUCAS9 | - | GCAAAGTGCAACGCCTGTGGAA | AGGG |
113 | 外顯子43 | SLUCAS9 | - | TGCAAAGTGCAACGCCTGTGGA | AAGG |
114 | 外顯子43 | SLUCAS9 | - | AGCATTGCAAAGTGCAACGCCT | GTGG |
115 | 外顯子43 | SLUCAS9 | - | ATAGTCTACAACAAAGCTCAGG | TCGG |
116 | 外顯子43 | SLUCAS9 | - | AAAGATAGTCTACAACAAAGCT | CAGG |
117 | 外顯子44 | SLUCAS9 | + | TATTTAGCATGTTCCCAATTCT | CAGG |
118 | 外顯子44 | SLUCAS9 | + | AACAGATCTGTCAAATCGCCTG | CAGG |
119 | 外顯子44 | SLUCAS9 | + | AATCGCCTGCAGGTAAAAGCAT | ATGG |
120 | 外顯子44 | SLUCAS9 | - | TGCTAAATACAAATGGTATCTT | AAGG |
121 | 外顯子44 | SLUCAS9 | - | ATTGGGAACATGCTAAATACAA | ATGG |
122 | 外顯子44 | SLUCAS9 | - | AAAGACACAAATTCCTGAGAAT | TGGG |
123 | 外顯子44 | SLUCAS9 | - | GAAAGACACAAATTCCTGAGAA | TTGG |
124 | 外顯子44 | SLUCAS9 | - | ATGATATAAAGATATTTAATCA | GTGG |
125 | 外顯子44 | SLUCAS9 | - | TTGACAGATCTGTTGAGAAATG | GCGG |
126 | 外顯子44 | SLUCAS9 | - | GATTTGACAGATCTGTTGAGAA | ATGG |
127 | 外顯子44 | SLUCAS9 | - | TTGATCCATATGCTTTTACCTG | CAGG |
128 | 外顯子45 | SLUCAS9 | + | AGACCTCCTGCCACCGCAGATT | CAGG |
129 | 外顯子45 | SLUCAS9 | + | TCCCAATTTTTCCTGTAGAATA | CTGG |
130 | 外顯子45 | SLUCAS9 | + | TAGAATACTGGCATCTGTTTTT | GAGG |
131 | 外顯子45 | SLUCAS9 | + | TTTGCCGCTGCCCAATGCCATC | CTGG |
132 | 外顯子45 | SLUCAS9 | + | GGAGTTCCTGTAAGATACCAAA | AAGG |
133 | 外顯子45 | SLUCAS9 | - | AGAGGTAGGGCGACAGATCTAA | TAGG |
134 | 外顯子45 | SLUCAS9 | - | CTGTCAGACAGAAAAAAGAGGT | AGGG |
135 | 外顯子45 | SLUCAS9 | - | GCTGTCAGACAGAAAAAAGAGG | TAGG |
136 | 外顯子45 | SLUCAS9 | - | AACAGCTGTCAGACAGAAAAAA | GAGG |
137 | 外顯子45 | SLUCAS9 | - | AAGCCTGAATCTGCGGTGGCAG | GAGG |
138 | 外顯子45 | SLUCAS9 | - | GGGAAGCCTGAATCTGCGGTGG | CAGG |
139 | 外顯子45 | SLUCAS9 | - | AATTGGGAAGCCTGAATCTGCG | GTGG |
140 | 外顯子45 | SLUCAS9 | - | AAAAATTGGGAAGCCTGAATCT | GCGG |
141 | 外顯子45 | SLUCAS9 | - | GCCAGTATTCTACAGGAAAAAT | TGGG |
142 | 外顯子45 | SLUCAS9 | - | TGCCAGTATTCTACAGGAAAAA | TTGG |
143 | 外顯子45 | SLUCAS9 | - | AAAAACAGATGCCAGTATTCTA | CAGG |
144 | 外顯子45 | SLUCAS9 | - | TGTCAGAACATTGAATGCAACT | GGGG |
145 | 外顯子45 | SLUCAS9 | - | TTGTCAGAACATTGAATGCAAC | TGGG |
146 | 外顯子45 | SLUCAS9 | - | GTTGTCAGAACATTGAATGCAA | CTGG |
147 | 外顯子45 | SLUCAS9 | - | AACTCCAGGATGGCATTGGGCA | GCGG |
148 | 外顯子45 | SLUCAS9 | - | TACAGGAACTCCAGGATGGCAT | TGGG |
149 | 外顯子45 | SLUCAS9 | - | TTACAGGAACTCCAGGATGGCA | TTGG |
150 | 外顯子45 | SLUCAS9 | - | GGTATCTTACAGGAACTCCAGG | ATGG |
151 | 外顯子45 | SLUCAS9 | - | TTTTGGTATCTTACAGGAACTC | CAGG |
152 | 外顯子45 | SLUCAS9 | - | GTTTTGCCTTTTTGGTATCTTA | CAGG |
153 | 外顯子45 | SLUCAS9 | - | TCTTTTCTCAAATAAAAAGACA | TGGG |
154 | 外顯子50 | SLUCAS9 | + | AGAATGGGATCCAGTATACTTA | CAGG |
155 | 外顯子50 | SLUCAS9 | + | AGTATACTTACAGGCTCCAATA | GTGG |
156 | 外顯子50 | SLUCAS9 | + | CAGGCTCCAATAGTGGTCAGTC | CAGG |
157 | 外顯子50 | SLUCAS9 | + | CAATAGTGGTCAGTCCAGGAGC | TAGG |
158 | 外顯子50 | SLUCAS9 | + | GTGGTCAGTCCAGGAGCTAGGT | CAGG |
159 | 外顯子50 | SLUCAS9 | + | TTGCCCTCAGCTCTTGAAGTAA | ACGG |
160 | 外顯子50 | SLUCAS9 | - | AGTATACTGGATCCCATTCTCT | TTGG |
161 | 外顯子50 | SLUCAS9 | - | ACTATTGGAGCCTGTAAGTATA | CTGG |
162 | 外顯子50 | SLUCAS9 | - | CTAGCTCCTGGACTGACCACTA | TTGG |
163 | 外顯子50 | SLUCAS9 | - | GCAAAGCAGCCTGACCTAGCTC | CTGG |
164 | 外顯子50 | SLUCAS9 | - | AAACCGTTTACTTCAAGAGCTG | AGGG |
165 | 外顯子50 | SLUCAS9 | - | TAAACCGTTTACTTCAAGAGCT | GAGG |
166 | 外顯子50 | SLUCAS9 | - | AGATCTGAGCTCTGAGTGGAAG | GCGG |
167 | 外顯子50 | SLUCAS9 | - | AGAAGATCTGAGCTCTGAGTGG | AAGG |
168 | 外顯子50 | SLUCAS9 | - | AGTTAGAAGATCTGAGCTCTGA | GTGG |
169 | 外顯子50 | SLUCAS9 | - | ATGTGTATGCTTTTCTGTTAAA | GAGG |
170 | 外顯子51 | SLUCAS9 | + | TGATCATCTCGTTGATATCCTC | AAGG |
171 | 外顯子51 | SLUCAS9 | + | TTGATCAAGCAGAGAAAGCCAG | TCGG |
172 | 外顯子51 | SLUCAS9 | + | AGTCGGTAAGTTCTGTCCAAGC | CCGG |
173 | 外顯子51 | SLUCAS9 | + | GCCCGGTTGAAATCTGCCAGAG | CAGG |
174 | 外顯子51 | SLUCAS9 | + | CAGAGCAGGTACCTCCAACATC | AAGG |
175 | 外顯子51 | SLUCAS9 | + | GGTACCTCCAACATCAAGGAAG | ATGG |
176 | 外顯子51 | SLUCAS9 | + | CAAGGAAGATGGCATTTCTAGT | TTGG |
177 | 外顯子51 | SLUCAS9 | + | AGATGGCATTTCTAGTTTGGAG | ATGG |
178 | 外顯子51 | SLUCAS9 | + | ATGGCAGTTTCCTTAGTAACCA | CAGG |
179 | 外顯子51 | SLUCAS9 | + | GTCACCAGAGTAACAGTCTGAG | TAGG |
180 | 外顯子51 | SLUCAS9 | + | TCTGAGTAGGAGCTAAAATATT | TTGG |
181 | 外顯子51 | SLUCAS9 | + | CTGAGTAGGAGCTAAAATATTT | TGGG |
182 | 外顯子51 | SLUCAS9 | + | AAATATTTTGGGTTTTTGCAAA | AAGG |
183 | 外顯子51 | SLUCAS9 | - | GTATGAGAAAAAATGATAAAAG | TTGG |
184 | 外顯子51 | SLUCAS9 | - | CAACGAGATGATCATCAAGCAG | AAGG |
185 | 外顯子51 | SLUCAS9 | - | GAGGGTGATGGTGGGTGACCTT | GAGG |
186 | 外顯子51 | SLUCAS9 | - | ATAAAATCACAGAGGGTGATGG | TGGG |
187 | 外顯子51 | SLUCAS9 | - | TATAAAATCACAGAGGGTGATG | GTGG |
188 | 外顯子51 | SLUCAS9 | - | AGTTATAAAATCACAGAGGGTG | ATGG |
189 | 外顯子51 | SLUCAS9 | - | TGATCAAGTTATAAAATCACAG | AGGG |
190 | 外顯子51 | SLUCAS9 | - | TTGATCAAGTTATAAAATCACA | GAGG |
191 | 外顯子51 | SLUCAS9 | - | GGGCTTGGACAGAACTTACCGA | CTGG |
192 | 外顯子51 | SLUCAS9 | - | CTCTGGCAGATTTCAACCGGGC | TTGG |
193 | 外顯子51 | SLUCAS9 | - | ACCTGCTCTGGCAGATTTCAAC | CGGG |
194 | 外顯子51 | SLUCAS9 | - | TACCTGCTCTGGCAGATTTCAA | CCGG |
195 | 外顯子51 | SLUCAS9 | - | CTTGATGTTGGAGGTACCTGCT | CTGG |
196 | 外顯子51 | SLUCAS9 | - | AATGCCATCTTCCTTGATGTTG | GAGG |
197 | 外顯子51 | SLUCAS9 | - | AGAAATGCCATCTTCCTTGATG | TTGG |
198 | 外顯子51 | SLUCAS9 | - | GGTGACACAACCTGTGGTTACT | AAGG |
199 | 外顯子51 | SLUCAS9 | - | TGTTACTCTGGTGACACAACCT | GTGG |
200 | 外顯子51 | SLUCAS9 | - | AGCTCCTACTCAGACTGTTACT | CTGG |
201 | 外顯子53 | SLUCAS9 | + | AAAGGTATCTTTGATACTAACC | TTGG |
202 | 外顯子53 | SLUCAS9 | + | CCTTGGTTTCTGTGATTTTCTT | TTGG |
203 | 外顯子53 | SLUCAS9 | + | CTTTTGGATTGCATCTACTGTA | TAGG |
204 | 外顯子53 | SLUCAS9 | + | TTTTGGATTGCATCTACTGTAT | AGGG |
205 | 外顯子53 | SLUCAS9 | + | ACCCTCCTTCCATGACTCAAGC | TTGG |
206 | 外顯子53 | SLUCAS9 | + | CTTCCATGACTCAAGCTTGGCT | CTGG |
207 | 外顯子53 | SLUCAS9 | + | ACATTTCATTCAACTGTTGCCT | CCGG |
208 | 外顯子53 | SLUCAS9 | + | TCAACTGTTGCCTCCGGTTCTG | AAGG |
209 | 外顯子53 | SLUCAS9 | + | TGAATTCTTTCAACTAGAATAA | AAGG |
210 | 外顯子53 | SLUCAS9 | - | CCAAAAGAAAATCACAGAAACC | AAGG |
211 | 外顯子53 | SLUCAS9 | - | GCCAAGCTTGAGTCATGGAAGG | AGGG |
212 | 外顯子53 | SLUCAS9 | - | AGCCAAGCTTGAGTCATGGAAG | GAGG |
213 | 外顯子53 | SLUCAS9 | - | CAGAGCCAAGCTTGAGTCATGG | AAGG |
214 | 外顯子53 | SLUCAS9 | - | AGGCCAGAGCCAAGCTTGAGTC | ATGG |
215 | 外顯子53 | SLUCAS9 | - | AGAAGCTGAGCAGGTCTTAGGA | CAGG |
216 | 外顯子53 | SLUCAS9 | - | AAGGAAGAAGCTGAGCAGGTCT | TAGG |
217 | 外顯子53 | SLUCAS9 | - | GGAAGCTAAGGAAGAAGCTGAG | CAGG |
218 | 外顯子53 | SLUCAS9 | - | TTCAACACAATGGCTGGAAGCT | AAGG |
219 | 外顯子53 | SLUCAS9 | - | GTTAAAGGATTCAACACAATGG | CTGG |
220 | 外顯子53 | SLUCAS9 | - | AAATGTTAAAGGATTCAACACA | ATGG |
221 | 外顯子53 | SLUCAS9 | - | GCAACAGTTGAATGAAATGTTA | AAGG |
222 | 外顯子53 | SLUCAS9 | - | TACAAGAACACCTTCAGAACCG | GAGG |
223 | 外顯子53 | SLUCAS9 | - | AAGTACAAGAACACCTTCAGAA | CCGG |
224 | 外顯子53 | SLUCAS9 | - | AGTTGAAAGAATTCAGAATCAG | TGGG |
225 | 外顯子53 | SLUCAS9 | - | TAGTTGAAAGAATTCAGAATCA | GTGG |
嚮導序列之序列ID編號 | 外顯子 | CAS9 | 股 | 嚮導序列 |
3000 | 外顯子43 | SACAS9 | + | AATGCTGCTGTCTTCTTGCT |
3001 | 外顯子43 | SACAS9 | + | CAATGCTGCTGTCTTCTTGCT |
1 | 外顯子43 | SACAS9 | + | GCAATGCTGCTGTCTTCTTGCT |
3002 | 外顯子43 | SACAS9 | - | AACAAAATGTACAAGGACCG |
3003 | 外顯子43 | SACAS9 | - | AACAAAATGTACAAGGACCGA |
2 | 外顯子43 | SACAS9 | - | AACAAAATGTACAAGGACCGAC |
3004 | 外顯子43 | SACAS9 | - | TGCAAAGTGCAACGCCTGTG |
3005 | 外顯子43 | SACAS9 | - | TGCAAAGTGCAACGCCTGTGG |
3 | 外顯子43 | SACAS9 | - | TGCAAAGTGCAACGCCTGTGGA |
3006 | 外顯子43 | SACAS9 | - | ATAGTCTACAACAAAGCTCA |
3007 | 外顯子43 | SACAS9 | - | ATAGTCTACAACAAAGCTCAG |
4 | 外顯子43 | SACAS9 | - | ATAGTCTACAACAAAGCTCAGG |
3008 | 外顯子43 | SACAS9 | - | CTGTTTTAAAATTTTTATAT |
3009 | 外顯子43 | SACAS9 | - | CTGTTTTAAAATTTTTATATT |
5 | 外顯子43 | SACAS9 | - | CTGTTTTAAAATTTTTATATTA |
3010 | 外顯子44 | SACAS9 | + | TTAGCATGTTCCCAATTCTC |
3011 | 外顯子44 | SACAS9 | + | TTTAGCATGTTCCCAATTCTC |
6 | 外顯子44 | SACAS9 | + | ATTTAGCATGTTCCCAATTCTC |
3012 | 外顯子44 | SACAS9 | + | TCGCCTGCAGGTAAAAGCAT |
3013 | 外顯子44 | SACAS9 | + | ATCGCCTGCAGGTAAAAGCAT |
7 | 外顯子44 | SACAS9 | + | AATCGCCTGCAGGTAAAAGCAT |
3014 | 外顯子44 | SACAS9 | - | TCTCAGAAAGACACAAATTC |
3015 | 外顯子44 | SACAS9 | - | TCTCAGAAAGACACAAATTCC |
8 | 外顯子44 | SACAS9 | - | TCTCAGAAAGACACAAATTCCT |
3016 | 外顯子45 | SACAS9 | + | AGGCTTCCCAATTTTTCCTG |
3017 | 外顯子45 | SACAS9 | + | CAGGCTTCCCAATTTTTCCTG |
9 | 外顯子45 | SACAS9 | + | TCAGGCTTCCCAATTTTTCCTG |
3018 | 外顯子45 | SACAS9 | + | GAATACTGGCATCTGTTTTT |
3019 | 外顯子45 | SACAS9 | + | AGAATACTGGCATCTGTTTTT |
10 | 外顯子45 | SACAS9 | + | TAGAATACTGGCATCTGTTTTT |
3020 | 外顯子45 | SACAS9 | + | GCATCTGTTTTTGAGGATTG |
3021 | 外顯子45 | SACAS9 | + | GGCATCTGTTTTTGAGGATTG |
11 | 外顯子45 | SACAS9 | + | TGGCATCTGTTTTTGAGGATTG |
3022 | 外顯子45 | SACAS9 | + | GCCGCTGCCCAATGCCATCC |
3023 | 外顯子45 | SACAS9 | + | TGCCGCTGCCCAATGCCATCC |
12 | 外顯子45 | SACAS9 | + | TTGCCGCTGCCCAATGCCATCC |
3024 | 外顯子45 | SACAS9 | - | GAGGTAGGGCGACAGATCTA |
3025 | 外顯子45 | SACAS9 | - | GAGGTAGGGCGACAGATCTAA |
13 | 外顯子45 | SACAS9 | - | GAGGTAGGGCGACAGATCTAAT |
3026 | 外顯子45 | SACAS9 | - | TCTACAGGAAAAATTGGGAA |
3027 | 外顯子45 | SACAS9 | - | TCTACAGGAAAAATTGGGAAG |
14 | 外顯子45 | SACAS9 | - | TCTACAGGAAAAATTGGGAAGC |
3028 | 外顯子45 | SACAS9 | - | GCGGCAAACTGTTGTCAGAA |
3029 | 外顯子45 | SACAS9 | - | GCGGCAAACTGTTGTCAGAAC |
15 | 外顯子45 | SACAS9 | - | GCGGCAAACTGTTGTCAGAACA |
3030 | 外顯子45 | SACAS9 | - | TTTTGGTATCTTACAGGAAC |
3031 | 外顯子45 | SACAS9 | - | TTTTGGTATCTTACAGGAACT |
16 | 外顯子45 | SACAS9 | - | TTTTGGTATCTTACAGGAACTC |
3032 | 外顯子50 | SACAS9 | - | ACTATTGGAGCCTGTAAGTA |
3033 | 外顯子50 | SACAS9 | - | ACTATTGGAGCCTGTAAGTAT |
17 | 外顯子50 | SACAS9 | - | ACTATTGGAGCCTGTAAGTATA |
3034 | 外顯子50 | SACAS9 | - | AGGAAGTTAGAAGATCTGAG |
3035 | 外顯子50 | SACAS9 | - | AGGAAGTTAGAAGATCTGAGC |
18 | 外顯子50 | SACAS9 | - | AGGAAGTTAGAAGATCTGAGCT |
3036 | 外顯子51 | SACAS9 | + | GTAACCACAGGTTGTGTCAC |
3037 | 外顯子51 | SACAS9 | + | AGTAACCACAGGTTGTGTCAC |
19 | 外顯子51 | SACAS9 | + | TAGTAACCACAGGTTGTGTCAC |
3038 | 外顯子51 | SACAS9 | + | TGTGTCACCAGAGTAACAGT |
3039 | 外顯子51 | SACAS9 | + | TTGTGTCACCAGAGTAACAGT |
20 | 外顯子51 | SACAS9 | + | GTTGTGTCACCAGAGTAACAGT |
3040 | 外顯子51 | SACAS9 | + | TGAGTAGGAGCTAAAATATT |
3041 | 外顯子51 | SACAS9 | + | CTGAGTAGGAGCTAAAATATT |
21 | 外顯子51 | SACAS9 | + | TCTGAGTAGGAGCTAAAATATT |
3042 | 外顯子51 | SACAS9 | - | GAGGGTGATGGTGGGTGACC |
3043 | 外顯子51 | SACAS9 | - | GAGGGTGATGGTGGGTGACCT |
22 | 外顯子51 | SACAS9 | - | GAGGGTGATGGTGGGTGACCTT |
3044 | 外顯子51 | SACAS9 | - | TATAAAATCACAGAGGGTGA |
3045 | 外顯子51 | SACAS9 | - | TATAAAATCACAGAGGGTGAT |
23 | 外顯子51 | SACAS9 | - | TATAAAATCACAGAGGGTGATG |
3046 | 外顯子51 | SACAS9 | - | TTGATCAAGTTATAAAATCA |
3047 | 外顯子51 | SACAS9 | - | TTGATCAAGTTATAAAATCAC |
24 | 外顯子51 | SACAS9 | - | TTGATCAAGTTATAAAATCACA |
3048 | 外顯子53 | SACAS9 | + | TTGGTTTCTGTGATTTTCTT |
3049 | 外顯子53 | SACAS9 | + | CTTGGTTTCTGTGATTTTCTT |
25 | 外顯子53 | SACAS9 | + | CCTTGGTTTCTGTGATTTTCTT |
3050 | 外顯子53 | SACAS9 | + | CTTAGCTTCCAGCCATTGTG |
3051 | 外顯子53 | SACAS9 | + | CCTTAGCTTCCAGCCATTGTG |
26 | 外顯子53 | SACAS9 | + | TCCTTAGCTTCCAGCCATTGTG |
3052 | 外顯子53 | SACAS9 | + | TGTACTTCATCCCACTGATT |
3053 | 外顯子53 | SACAS9 | + | TTGTACTTCATCCCACTGATT |
27 | 外顯子53 | SACAS9 | + | CTTGTACTTCATCCCACTGATT |
3054 | 外顯子53 | SACAS9 | + | TGATTCTGAATTCTTTCAAC |
3055 | 外顯子53 | SACAS9 | + | CTGATTCTGAATTCTTTCAAC |
28 | 外顯子53 | SACAS9 | + | ACTGATTCTGAATTCTTTCAAC |
3056 | 外顯子53 | SACAS9 | - | AGCCAAGCTTGAGTCATGGA |
3057 | 外顯子53 | SACAS9 | - | AGCCAAGCTTGAGTCATGGAA |
29 | 外顯子53 | SACAS9 | - | AGCCAAGCTTGAGTCATGGAAG |
3058 | 外顯子53 | SACAS9 | - | TTAGGACAGGCCAGAGCCAA |
3059 | 外顯子53 | SACAS9 | - | TTAGGACAGGCCAGAGCCAAG |
30 | 外顯子53 | SACAS9 | - | TTAGGACAGGCCAGAGCCAAGC |
3060 | 外顯子53 | SACAS9 | - | GCAACAGTTGAATGAAATGT |
3061 | 外顯子53 | SACAS9 | - | GCAACAGTTGAATGAAATGTT |
31 | 外顯子53 | SACAS9 | - | GCAACAGTTGAATGAAATGTTA |
3062 | 外顯子53 | SACAS9 | - | CCTTCAGAACCGGAGGCAAC |
3063 | 外顯子53 | SACAS9 | - | CCTTCAGAACCGGAGGCAACA |
32 | 外顯子53 | SACAS9 | - | CCTTCAGAACCGGAGGCAACAG |
3064 | 外顯子53 | SACAS9 | - | AGTTGAAAGAATTCAGAATC |
3065 | 外顯子53 | SACAS9 | - | AGTTGAAAGAATTCAGAATCA |
33 | 外顯子53 | SACAS9 | - | AGTTGAAAGAATTCAGAATCAG |
3066 | 外顯子53 | SACAS9 | - | TTTTATTCTAGTTGAAAGAA |
3067 | 外顯子53 | SACAS9 | - | TTTTATTCTAGTTGAAAGAAT |
34 | 外顯子53 | SACAS9 | - | TTTTATTCTAGTTGAAAGAATT |
3068 | 外顯子53 | SACAS9 | - | TTTTTCCTTTTATTCTAGTT |
3069 | 外顯子53 | SACAS9 | - | TTTTTCCTTTTATTCTAGTTG |
35 | 外顯子53 | SACAS9 | - | TTTTTCCTTTTATTCTAGTTGA |
4000 | 外顯子43 | SLUCAS9 | + | ATATGTGTTACCTACCCTTG |
4001 | 外顯子43 | SLUCAS9 | + | TATATGTGTTACCTACCCTTG |
100 | 外顯子43 | SLUCAS9 | + | ATATATGTGTTACCTACCCTTG |
4002 | 外顯子43 | SLUCAS9 | + | ATTTTGTTAACTTTTTCCCA |
4003 | 外顯子43 | SLUCAS9 | + | CATTTTGTTAACTTTTTCCCA |
101 | 外顯子43 | SLUCAS9 | + | ACATTTTGTTAACTTTTTCCCA |
4004 | 外顯子43 | SLUCAS9 | + | TTTTCCCATTGGAAATCAAG |
4005 | 外顯子43 | SLUCAS9 | + | TTTTTCCCATTGGAAATCAAG |
102 | 外顯子43 | SLUCAS9 | + | CTTTTTCCCATTGGAAATCAAG |
4006 | 外顯子43 | SLUCAS9 | + | TTTCCCATTGGAAATCAAGC |
4007 | 外顯子43 | SLUCAS9 | + | TTTTCCCATTGGAAATCAAGC |
103 | 外顯子43 | SLUCAS9 | + | TTTTTCCCATTGGAAATCAAGC |
4008 | 外顯子43 | SLUCAS9 | + | CTGTAGCTTCACCCTTTCCA |
4009 | 外顯子43 | SLUCAS9 | + | CCTGTAGCTTCACCCTTTCCA |
104 | 外顯子43 | SLUCAS9 | + | TCCTGTAGCTTCACCCTTTCCA |
4010 | 外顯子43 | SLUCAS9 | - | AATGTACAAGGACCGACAAG |
4011 | 外顯子43 | SLUCAS9 | - | AATGTACAAGGACCGACAAGG |
105 | 外顯子43 | SLUCAS9 | - | AATGTACAAGGACCGACAAGGG |
4012 | 外顯子43 | SLUCAS9 | - | ACAAAATGTACAAGGACCGA |
4013 | 外顯子43 | SLUCAS9 | - | ACAAAATGTACAAGGACCGAC |
106 | 外顯子43 | SLUCAS9 | - | ACAAAATGTACAAGGACCGACA |
4014 | 外顯子43 | SLUCAS9 | - | AACAAAATGTACAAGGACCG |
4015 | 外顯子43 | SLUCAS9 | - | AACAAAATGTACAAGGACCGA |
107 | 外顯子43 | SLUCAS9 | - | AACAAAATGTACAAGGACCGAC |
4016 | 外顯子43 | SLUCAS9 | - | GGAAAAAGTTAACAAAATGT |
4017 | 外顯子43 | SLUCAS9 | - | GGAAAAAGTTAACAAAATGTA |
108 | 外顯子43 | SLUCAS9 | - | GGAAAAAGTTAACAAAATGTAC |
4018 | 外顯子43 | SLUCAS9 | - | TCTCTCCCAGCTTGATTTCC |
4019 | 外顯子43 | SLUCAS9 | - | TCTCTCCCAGCTTGATTTCCA |
109 | 外顯子43 | SLUCAS9 | - | TCTCTCCCAGCTTGATTTCCAA |
4020 | 外顯子43 | SLUCAS9 | - | CTCTCTCCCAGCTTGATTTC |
4021 | 外顯子43 | SLUCAS9 | - | CTCTCTCCCAGCTTGATTTCC |
110 | 外顯子43 | SLUCAS9 | - | CTCTCTCCCAGCTTGATTTCCA |
4022 | 外顯子43 | SLUCAS9 | - | GCCTGTGGAAAGGGTGAAGC |
4023 | 外顯子43 | SLUCAS9 | - | GCCTGTGGAAAGGGTGAAGCT |
111 | 外顯子43 | SLUCAS9 | - | GCCTGTGGAAAGGGTGAAGCTA |
4024 | 外顯子43 | SLUCAS9 | - | GCAAAGTGCAACGCCTGTGG |
4025 | 外顯子43 | SLUCAS9 | - | GCAAAGTGCAACGCCTGTGGA |
112 | 外顯子43 | SLUCAS9 | - | GCAAAGTGCAACGCCTGTGGAA |
4026 | 外顯子43 | SLUCAS9 | - | TGCAAAGTGCAACGCCTGTG |
4027 | 外顯子43 | SLUCAS9 | - | TGCAAAGTGCAACGCCTGTGG |
113 | 外顯子43 | SLUCAS9 | - | TGCAAAGTGCAACGCCTGTGGA |
4028 | 外顯子43 | SLUCAS9 | - | AGCATTGCAAAGTGCAACGC |
4029 | 外顯子43 | SLUCAS9 | - | AGCATTGCAAAGTGCAACGCC |
114 | 外顯子43 | SLUCAS9 | - | AGCATTGCAAAGTGCAACGCCT |
4030 | 外顯子43 | SLUCAS9 | - | ATAGTCTACAACAAAGCTCA |
4031 | 外顯子43 | SLUCAS9 | - | ATAGTCTACAACAAAGCTCAG |
115 | 外顯子43 | SLUCAS9 | - | ATAGTCTACAACAAAGCTCAGG |
4032 | 外顯子43 | SLUCAS9 | - | AAAGATAGTCTACAACAAAG |
4033 | 外顯子43 | SLUCAS9 | - | AAAGATAGTCTACAACAAAGC |
116 | 外顯子43 | SLUCAS9 | - | AAAGATAGTCTACAACAAAGCT |
4034 | 外顯子44 | SLUCAS9 | + | TTTAGCATGTTCCCAATTCT |
4035 | 外顯子44 | SLUCAS9 | + | ATTTAGCATGTTCCCAATTCT |
117 | 外顯子44 | SLUCAS9 | + | TATTTAGCATGTTCCCAATTCT |
4036 | 外顯子44 | SLUCAS9 | + | CAGATCTGTCAAATCGCCTG |
4037 | 外顯子44 | SLUCAS9 | + | ACAGATCTGTCAAATCGCCTG |
118 | 外顯子44 | SLUCAS9 | + | AACAGATCTGTCAAATCGCCTG |
4038 | 外顯子44 | SLUCAS9 | + | TCGCCTGCAGGTAAAAGCAT |
4039 | 外顯子44 | SLUCAS9 | + | ATCGCCTGCAGGTAAAAGCAT |
119 | 外顯子44 | SLUCAS9 | + | AATCGCCTGCAGGTAAAAGCAT |
4040 | 外顯子44 | SLUCAS9 | - | TGCTAAATACAAATGGTATC |
4041 | 外顯子44 | SLUCAS9 | - | TGCTAAATACAAATGGTATCT |
120 | 外顯子44 | SLUCAS9 | - | TGCTAAATACAAATGGTATCTT |
4042 | 外顯子44 | SLUCAS9 | - | ATTGGGAACATGCTAAATAC |
4043 | 外顯子44 | SLUCAS9 | - | ATTGGGAACATGCTAAATACA |
121 | 外顯子44 | SLUCAS9 | - | ATTGGGAACATGCTAAATACAA |
4044 | 外顯子44 | SLUCAS9 | - | AAAGACACAAATTCCTGAGA |
4045 | 外顯子44 | SLUCAS9 | - | AAAGACACAAATTCCTGAGAA |
122 | 外顯子44 | SLUCAS9 | - | AAAGACACAAATTCCTGAGAAT |
4046 | 外顯子44 | SLUCAS9 | - | GAAAGACACAAATTCCTGAG |
4047 | 外顯子44 | SLUCAS9 | - | GAAAGACACAAATTCCTGAGA |
123 | 外顯子44 | SLUCAS9 | - | GAAAGACACAAATTCCTGAGAA |
4048 | 外顯子44 | SLUCAS9 | - | ATGATATAAAGATATTTAAT |
4049 | 外顯子44 | SLUCAS9 | - | ATGATATAAAGATATTTAATC |
124 | 外顯子44 | SLUCAS9 | - | ATGATATAAAGATATTTAATCA |
4050 | 外顯子44 | SLUCAS9 | - | TTGACAGATCTGTTGAGAAA |
4051 | 外顯子44 | SLUCAS9 | - | TTGACAGATCTGTTGAGAAAT |
125 | 外顯子44 | SLUCAS9 | - | TTGACAGATCTGTTGAGAAATG |
4052 | 外顯子44 | SLUCAS9 | - | GATTTGACAGATCTGTTGAG |
4053 | 外顯子44 | SLUCAS9 | - | GATTTGACAGATCTGTTGAGA |
126 | 外顯子44 | SLUCAS9 | - | GATTTGACAGATCTGTTGAGAA |
4054 | 外顯子44 | SLUCAS9 | - | TTGATCCATATGCTTTTACC |
4055 | 外顯子44 | SLUCAS9 | - | TTGATCCATATGCTTTTACCT |
127 | 外顯子44 | SLUCAS9 | - | TTGATCCATATGCTTTTACCTG |
4056 | 外顯子45 | SLUCAS9 | + | ACCTCCTGCCACCGCAGATT |
4057 | 外顯子45 | SLUCAS9 | + | GACCTCCTGCCACCGCAGATT |
128 | 外顯子45 | SLUCAS9 | + | AGACCTCCTGCCACCGCAGATT |
4058 | 外顯子45 | SLUCAS9 | + | CCAATTTTTCCTGTAGAATA |
4059 | 外顯子45 | SLUCAS9 | + | CCCAATTTTTCCTGTAGAATA |
129 | 外顯子45 | SLUCAS9 | + | TCCCAATTTTTCCTGTAGAATA |
4060 | 外顯子45 | SLUCAS9 | + | GAATACTGGCATCTGTTTTT |
4061 | 外顯子45 | SLUCAS9 | + | AGAATACTGGCATCTGTTTTT |
130 | 外顯子45 | SLUCAS9 | + | TAGAATACTGGCATCTGTTTTT |
4062 | 外顯子45 | SLUCAS9 | + | TGCCGCTGCCCAATGCCATC |
4063 | 外顯子45 | SLUCAS9 | + | TTGCCGCTGCCCAATGCCATC |
131 | 外顯子45 | SLUCAS9 | + | TTTGCCGCTGCCCAATGCCATC |
4064 | 外顯子45 | SLUCAS9 | + | AGTTCCTGTAAGATACCAAA |
4065 | 外顯子45 | SLUCAS9 | + | GAGTTCCTGTAAGATACCAAA |
132 | 外顯子45 | SLUCAS9 | + | GGAGTTCCTGTAAGATACCAAA |
4066 | 外顯子45 | SLUCAS9 | - | AGAGGTAGGGCGACAGATCT |
4067 | 外顯子45 | SLUCAS9 | - | AGAGGTAGGGCGACAGATCTA |
133 | 外顯子45 | SLUCAS9 | - | AGAGGTAGGGCGACAGATCTAA |
4068 | 外顯子45 | SLUCAS9 | - | CTGTCAGACAGAAAAAAGAG |
4069 | 外顯子45 | SLUCAS9 | - | CTGTCAGACAGAAAAAAGAGG |
134 | 外顯子45 | SLUCAS9 | - | CTGTCAGACAGAAAAAAGAGGT |
4070 | 外顯子45 | SLUCAS9 | - | GCTGTCAGACAGAAAAAAGA |
4071 | 外顯子45 | SLUCAS9 | - | GCTGTCAGACAGAAAAAAGAG |
135 | 外顯子45 | SLUCAS9 | - | GCTGTCAGACAGAAAAAAGAGG |
4072 | 外顯子45 | SLUCAS9 | - | AACAGCTGTCAGACAGAAAA |
4073 | 外顯子45 | SLUCAS9 | - | AACAGCTGTCAGACAGAAAAA |
136 | 外顯子45 | SLUCAS9 | - | AACAGCTGTCAGACAGAAAAAA |
4074 | 外顯子45 | SLUCAS9 | - | AAGCCTGAATCTGCGGTGGC |
4075 | 外顯子45 | SLUCAS9 | - | AAGCCTGAATCTGCGGTGGCA |
137 | 外顯子45 | SLUCAS9 | - | AAGCCTGAATCTGCGGTGGCAG |
4076 | 外顯子45 | SLUCAS9 | - | GGGAAGCCTGAATCTGCGGT |
4077 | 外顯子45 | SLUCAS9 | - | GGGAAGCCTGAATCTGCGGTG |
138 | 外顯子45 | SLUCAS9 | - | GGGAAGCCTGAATCTGCGGTGG |
4078 | 外顯子45 | SLUCAS9 | - | AATTGGGAAGCCTGAATCTG |
4079 | 外顯子45 | SLUCAS9 | - | AATTGGGAAGCCTGAATCTGC |
139 | 外顯子45 | SLUCAS9 | - | AATTGGGAAGCCTGAATCTGCG |
4080 | 外顯子45 | SLUCAS9 | - | AAAAATTGGGAAGCCTGAAT |
4081 | 外顯子45 | SLUCAS9 | - | AAAAATTGGGAAGCCTGAATC |
140 | 外顯子45 | SLUCAS9 | - | AAAAATTGGGAAGCCTGAATCT |
4082 | 外顯子45 | SLUCAS9 | - | GCCAGTATTCTACAGGAAAA |
4083 | 外顯子45 | SLUCAS9 | - | GCCAGTATTCTACAGGAAAAA |
141 | 外顯子45 | SLUCAS9 | - | GCCAGTATTCTACAGGAAAAAT |
4084 | 外顯子45 | SLUCAS9 | - | TGCCAGTATTCTACAGGAAA |
4085 | 外顯子45 | SLUCAS9 | - | TGCCAGTATTCTACAGGAAAA |
142 | 外顯子45 | SLUCAS9 | - | TGCCAGTATTCTACAGGAAAAA |
4086 | 外顯子45 | SLUCAS9 | - | AAAAACAGATGCCAGTATTC |
4087 | 外顯子45 | SLUCAS9 | - | AAAAACAGATGCCAGTATTCT |
143 | 外顯子45 | SLUCAS9 | - | AAAAACAGATGCCAGTATTCTA |
4088 | 外顯子45 | SLUCAS9 | - | TGTCAGAACATTGAATGCAA |
4089 | 外顯子45 | SLUCAS9 | - | TGTCAGAACATTGAATGCAAC |
144 | 外顯子45 | SLUCAS9 | - | TGTCAGAACATTGAATGCAACT |
4090 | 外顯子45 | SLUCAS9 | - | TTGTCAGAACATTGAATGCA |
4091 | 外顯子45 | SLUCAS9 | - | TTGTCAGAACATTGAATGCAA |
145 | 外顯子45 | SLUCAS9 | - | TTGTCAGAACATTGAATGCAAC |
4092 | 外顯子45 | SLUCAS9 | - | GTTGTCAGAACATTGAATGC |
4093 | 外顯子45 | SLUCAS9 | - | GTTGTCAGAACATTGAATGCA |
146 | 外顯子45 | SLUCAS9 | - | GTTGTCAGAACATTGAATGCAA |
4094 | 外顯子45 | SLUCAS9 | - | AACTCCAGGATGGCATTGGG |
4095 | 外顯子45 | SLUCAS9 | - | AACTCCAGGATGGCATTGGGC |
147 | 外顯子45 | SLUCAS9 | - | AACTCCAGGATGGCATTGGGCA |
4096 | 外顯子45 | SLUCAS9 | - | TACAGGAACTCCAGGATGGC |
4097 | 外顯子45 | SLUCAS9 | - | TACAGGAACTCCAGGATGGCA |
148 | 外顯子45 | SLUCAS9 | - | TACAGGAACTCCAGGATGGCAT |
4098 | 外顯子45 | SLUCAS9 | - | TTACAGGAACTCCAGGATGG |
4099 | 外顯子45 | SLUCAS9 | - | TTACAGGAACTCCAGGATGGC |
149 | 外顯子45 | SLUCAS9 | - | TTACAGGAACTCCAGGATGGCA |
4100 | 外顯子45 | SLUCAS9 | - | GGTATCTTACAGGAACTCCA |
4101 | 外顯子45 | SLUCAS9 | - | GGTATCTTACAGGAACTCCAG |
150 | 外顯子45 | SLUCAS9 | - | GGTATCTTACAGGAACTCCAGG |
4102 | 外顯子45 | SLUCAS9 | - | TTTTGGTATCTTACAGGAAC |
4103 | 外顯子45 | SLUCAS9 | - | TTTTGGTATCTTACAGGAACT |
151 | 外顯子45 | SLUCAS9 | - | TTTTGGTATCTTACAGGAACTC |
4104 | 外顯子45 | SLUCAS9 | - | GTTTTGCCTTTTTGGTATCT |
4105 | 外顯子45 | SLUCAS9 | - | GTTTTGCCTTTTTGGTATCTT |
152 | 外顯子45 | SLUCAS9 | - | GTTTTGCCTTTTTGGTATCTTA |
4106 | 外顯子45 | SLUCAS9 | - | TCTTTTCTCAAATAAAAAGA |
4107 | 外顯子45 | SLUCAS9 | - | TCTTTTCTCAAATAAAAAGAC |
153 | 外顯子45 | SLUCAS9 | - | TCTTTTCTCAAATAAAAAGACA |
4108 | 外顯子50 | SLUCAS9 | + | AATGGGATCCAGTATACTTA |
4109 | 外顯子50 | SLUCAS9 | + | GAATGGGATCCAGTATACTTA |
154 | 外顯子50 | SLUCAS9 | + | AGAATGGGATCCAGTATACTTA |
4110 | 外顯子50 | SLUCAS9 | + | TATACTTACAGGCTCCAATA |
4111 | 外顯子50 | SLUCAS9 | + | GTATACTTACAGGCTCCAATA |
155 | 外顯子50 | SLUCAS9 | + | AGTATACTTACAGGCTCCAATA |
4112 | 外顯子50 | SLUCAS9 | + | GGCTCCAATAGTGGTCAGTC |
4113 | 外顯子50 | SLUCAS9 | + | AGGCTCCAATAGTGGTCAGTC |
156 | 外顯子50 | SLUCAS9 | + | CAGGCTCCAATAGTGGTCAGTC |
4114 | 外顯子50 | SLUCAS9 | + | ATAGTGGTCAGTCCAGGAGC |
4115 | 外顯子50 | SLUCAS9 | + | AATAGTGGTCAGTCCAGGAGC |
157 | 外顯子50 | SLUCAS9 | + | CAATAGTGGTCAGTCCAGGAGC |
4116 | 外顯子50 | SLUCAS9 | + | GGTCAGTCCAGGAGCTAGGT |
4117 | 外顯子50 | SLUCAS9 | + | TGGTCAGTCCAGGAGCTAGGT |
158 | 外顯子50 | SLUCAS9 | + | GTGGTCAGTCCAGGAGCTAGGT |
4118 | 外顯子50 | SLUCAS9 | + | GCCCTCAGCTCTTGAAGTAA |
4119 | 外顯子50 | SLUCAS9 | + | TGCCCTCAGCTCTTGAAGTAA |
159 | 外顯子50 | SLUCAS9 | + | TTGCCCTCAGCTCTTGAAGTAA |
4120 | 外顯子50 | SLUCAS9 | - | AGTATACTGGATCCCATTCT |
4121 | 外顯子50 | SLUCAS9 | - | AGTATACTGGATCCCATTCTC |
160 | 外顯子50 | SLUCAS9 | - | AGTATACTGGATCCCATTCTCT |
4122 | 外顯子50 | SLUCAS9 | - | ACTATTGGAGCCTGTAAGTA |
4123 | 外顯子50 | SLUCAS9 | - | ACTATTGGAGCCTGTAAGTAT |
161 | 外顯子50 | SLUCAS9 | - | ACTATTGGAGCCTGTAAGTATA |
4124 | 外顯子50 | SLUCAS9 | - | CTAGCTCCTGGACTGACCAC |
4125 | 外顯子50 | SLUCAS9 | - | CTAGCTCCTGGACTGACCACT |
162 | 外顯子50 | SLUCAS9 | - | CTAGCTCCTGGACTGACCACTA |
4126 | 外顯子50 | SLUCAS9 | - | GCAAAGCAGCCTGACCTAGC |
4127 | 外顯子50 | SLUCAS9 | - | GCAAAGCAGCCTGACCTAGCT |
163 | 外顯子50 | SLUCAS9 | - | GCAAAGCAGCCTGACCTAGCTC |
4128 | 外顯子50 | SLUCAS9 | - | AAACCGTTTACTTCAAGAGC |
4129 | 外顯子50 | SLUCAS9 | - | AAACCGTTTACTTCAAGAGCT |
164 | 外顯子50 | SLUCAS9 | - | AAACCGTTTACTTCAAGAGCTG |
4130 | 外顯子50 | SLUCAS9 | - | TAAACCGTTTACTTCAAGAG |
4131 | 外顯子50 | SLUCAS9 | - | TAAACCGTTTACTTCAAGAGC |
165 | 外顯子50 | SLUCAS9 | - | TAAACCGTTTACTTCAAGAGCT |
4132 | 外顯子50 | SLUCAS9 | - | AGATCTGAGCTCTGAGTGGA |
4133 | 外顯子50 | SLUCAS9 | - | AGATCTGAGCTCTGAGTGGAA |
166 | 外顯子50 | SLUCAS9 | - | AGATCTGAGCTCTGAGTGGAAG |
4134 | 外顯子50 | SLUCAS9 | - | AGAAGATCTGAGCTCTGAGT |
4135 | 外顯子50 | SLUCAS9 | - | AGAAGATCTGAGCTCTGAGTG |
167 | 外顯子50 | SLUCAS9 | - | AGAAGATCTGAGCTCTGAGTGG |
4135 | 外顯子50 | SLUCAS9 | - | AGTTAGAAGATCTGAGCTCT |
4137 | 外顯子50 | SLUCAS9 | - | AGTTAGAAGATCTGAGCTCTG |
168 | 外顯子50 | SLUCAS9 | - | AGTTAGAAGATCTGAGCTCTGA |
4138 | 外顯子50 | SLUCAS9 | - | ATGTGTATGCTTTTCTGTTA |
4139 | 外顯子50 | SLUCAS9 | - | ATGTGTATGCTTTTCTGTTAA |
169 | 外顯子50 | SLUCAS9 | - | ATGTGTATGCTTTTCTGTTAAA |
4140 | 外顯子51 | SLUCAS9 | + | ATCATCTCGTTGATATCCTC |
4141 | 外顯子51 | SLUCAS9 | + | GATCATCTCGTTGATATCCTC |
170 | 外顯子51 | SLUCAS9 | + | TGATCATCTCGTTGATATCCTC |
4142 | 外顯子51 | SLUCAS9 | + | GATCAAGCAGAGAAAGCCAG |
4143 | 外顯子51 | SLUCAS9 | + | TGATCAAGCAGAGAAAGCCAG |
171 | 外顯子51 | SLUCAS9 | + | TTGATCAAGCAGAGAAAGCCAG |
4144 | 外顯子51 | SLUCAS9 | + | TCGGTAAGTTCTGTCCAAGC |
4145 | 外顯子51 | SLUCAS9 | + | GTCGGTAAGTTCTGTCCAAGC |
172 | 外顯子51 | SLUCAS9 | + | AGTCGGTAAGTTCTGTCCAAGC |
4146 | 外顯子51 | SLUCAS9 | + | CCGGTTGAAATCTGCCAGAG |
4147 | 外顯子51 | SLUCAS9 | + | CCCGGTTGAAATCTGCCAGAG |
173 | 外顯子51 | SLUCAS9 | + | GCCCGGTTGAAATCTGCCAGAG |
4148 | 外顯子51 | SLUCAS9 | + | GAGCAGGTACCTCCAACATC |
4149 | 外顯子51 | SLUCAS9 | + | AGAGCAGGTACCTCCAACATC |
174 | 外顯子51 | SLUCAS9 | + | CAGAGCAGGTACCTCCAACATC |
4150 | 外顯子51 | SLUCAS9 | + | TACCTCCAACATCAAGGAAG |
4151 | 外顯子51 | SLUCAS9 | + | GTACCTCCAACATCAAGGAAG |
175 | 外顯子51 | SLUCAS9 | + | GGTACCTCCAACATCAAGGAAG |
4152 | 外顯子51 | SLUCAS9 | + | AGGAAGATGGCATTTCTAGT |
4153 | 外顯子51 | SLUCAS9 | + | AAGGAAGATGGCATTTCTAGT |
176 | 外顯子51 | SLUCAS9 | + | CAAGGAAGATGGCATTTCTAGT |
4154 | 外顯子51 | SLUCAS9 | + | ATGGCATTTCTAGTTTGGAG |
4155 | 外顯子51 | SLUCAS9 | + | GATGGCATTTCTAGTTTGGAG |
177 | 外顯子51 | SLUCAS9 | + | AGATGGCATTTCTAGTTTGGAG |
4156 | 外顯子51 | SLUCAS9 | + | GGCAGTTTCCTTAGTAACCA |
4157 | 外顯子51 | SLUCAS9 | + | TGGCAGTTTCCTTAGTAACCA |
178 | 外顯子51 | SLUCAS9 | + | ATGGCAGTTTCCTTAGTAACCA |
4158 | 外顯子51 | SLUCAS9 | + | CACCAGAGTAACAGTCTGAG |
4159 | 外顯子51 | SLUCAS9 | + | TCACCAGAGTAACAGTCTGAG |
179 | 外顯子51 | SLUCAS9 | + | GTCACCAGAGTAACAGTCTGAG |
4160 | 外顯子51 | SLUCAS9 | + | TGAGTAGGAGCTAAAATATT |
4161 | 外顯子51 | SLUCAS9 | + | CTGAGTAGGAGCTAAAATATT |
180 | 外顯子51 | SLUCAS9 | + | TCTGAGTAGGAGCTAAAATATT |
4162 | 外顯子51 | SLUCAS9 | + | GAGTAGGAGCTAAAATATTT |
4163 | 外顯子51 | SLUCAS9 | + | TGAGTAGGAGCTAAAATATTT |
181 | 外顯子51 | SLUCAS9 | + | CTGAGTAGGAGCTAAAATATTT |
4164 | 外顯子51 | SLUCAS9 | + | ATATTTTGGGTTTTTGCAAA |
4165 | 外顯子51 | SLUCAS9 | + | AATATTTTGGGTTTTTGCAAA |
182 | 外顯子51 | SLUCAS9 | + | AAATATTTTGGGTTTTTGCAAA |
4166 | 外顯子51 | SLUCAS9 | - | GTATGAGAAAAAATGATAAA |
4167 | 外顯子51 | SLUCAS9 | - | GTATGAGAAAAAATGATAAAA |
183 | 外顯子51 | SLUCAS9 | - | GTATGAGAAAAAATGATAAAAG |
4168 | 外顯子51 | SLUCAS9 | - | CAACGAGATGATCATCAAGC |
4169 | 外顯子51 | SLUCAS9 | - | CAACGAGATGATCATCAAGCA |
184 | 外顯子51 | SLUCAS9 | - | CAACGAGATGATCATCAAGCAG |
4170 | 外顯子51 | SLUCAS9 | - | GAGGGTGATGGTGGGTGACC |
4171 | 外顯子51 | SLUCAS9 | - | GAGGGTGATGGTGGGTGACCT |
185 | 外顯子51 | SLUCAS9 | - | GAGGGTGATGGTGGGTGACCTT |
4172 | 外顯子51 | SLUCAS9 | - | ATAAAATCACAGAGGGTGAT |
4173 | 外顯子51 | SLUCAS9 | - | ATAAAATCACAGAGGGTGATG |
186 | 外顯子51 | SLUCAS9 | - | ATAAAATCACAGAGGGTGATGG |
4174 | 外顯子51 | SLUCAS9 | - | TATAAAATCACAGAGGGTGA |
4175 | 外顯子51 | SLUCAS9 | - | TATAAAATCACAGAGGGTGAT |
187 | 外顯子51 | SLUCAS9 | - | TATAAAATCACAGAGGGTGATG |
4176 | 外顯子51 | SLUCAS9 | - | AGTTATAAAATCACAGAGGG |
4177 | 外顯子51 | SLUCAS9 | - | AGTTATAAAATCACAGAGGGT |
188 | 外顯子51 | SLUCAS9 | - | AGTTATAAAATCACAGAGGGTG |
4178 | 外顯子51 | SLUCAS9 | - | TGATCAAGTTATAAAATCAC |
4179 | 外顯子51 | SLUCAS9 | - | TGATCAAGTTATAAAATCACA |
189 | 外顯子51 | SLUCAS9 | - | TGATCAAGTTATAAAATCACAG |
4180 | 外顯子51 | SLUCAS9 | - | TTGATCAAGTTATAAAATCA |
4181 | 外顯子51 | SLUCAS9 | - | TTGATCAAGTTATAAAATCAC |
190 | 外顯子51 | SLUCAS9 | - | TTGATCAAGTTATAAAATCACA |
4182 | 外顯子51 | SLUCAS9 | - | GGGCTTGGACAGAACTTACC |
4183 | 外顯子51 | SLUCAS9 | - | GGGCTTGGACAGAACTTACCG |
191 | 外顯子51 | SLUCAS9 | - | GGGCTTGGACAGAACTTACCGA |
4184 | 外顯子51 | SLUCAS9 | - | CTCTGGCAGATTTCAACCGG |
4185 | 外顯子51 | SLUCAS9 | - | CTCTGGCAGATTTCAACCGGG |
192 | 外顯子51 | SLUCAS9 | - | CTCTGGCAGATTTCAACCGGGC |
4186 | 外顯子51 | SLUCAS9 | - | ACCTGCTCTGGCAGATTTCA |
4187 | 外顯子51 | SLUCAS9 | - | ACCTGCTCTGGCAGATTTCAA |
193 | 外顯子51 | SLUCAS9 | - | ACCTGCTCTGGCAGATTTCAAC |
4188 | 外顯子51 | SLUCAS9 | - | TACCTGCTCTGGCAGATTTC |
4189 | 外顯子51 | SLUCAS9 | - | TACCTGCTCTGGCAGATTTCA |
194 | 外顯子51 | SLUCAS9 | - | TACCTGCTCTGGCAGATTTCAA |
4190 | 外顯子51 | SLUCAS9 | - | CTTGATGTTGGAGGTACCTG |
4191 | 外顯子51 | SLUCAS9 | - | CTTGATGTTGGAGGTACCTGC |
195 | 外顯子51 | SLUCAS9 | - | CTTGATGTTGGAGGTACCTGCT |
4192 | 外顯子51 | SLUCAS9 | - | AATGCCATCTTCCTTGATGT |
4193 | 外顯子51 | SLUCAS9 | - | AATGCCATCTTCCTTGATGTT |
196 | 外顯子51 | SLUCAS9 | - | AATGCCATCTTCCTTGATGTTG |
4194 | 外顯子51 | SLUCAS9 | - | AGAAATGCCATCTTCCTTGA |
4195 | 外顯子51 | SLUCAS9 | - | AGAAATGCCATCTTCCTTGAT |
197 | 外顯子51 | SLUCAS9 | - | AGAAATGCCATCTTCCTTGATG |
4196 | 外顯子51 | SLUCAS9 | - | GGTGACACAACCTGTGGTTA |
4197 | 外顯子51 | SLUCAS9 | - | GGTGACACAACCTGTGGTTAC |
198 | 外顯子51 | SLUCAS9 | - | GGTGACACAACCTGTGGTTACT |
4198 | 外顯子51 | SLUCAS9 | - | TGTTACTCTGGTGACACAAC |
4199 | 外顯子51 | SLUCAS9 | - | TGTTACTCTGGTGACACAACC |
199 | 外顯子51 | SLUCAS9 | - | TGTTACTCTGGTGACACAACCT |
4200 | 外顯子51 | SLUCAS9 | - | AGCTCCTACTCAGACTGTTA |
4201 | 外顯子51 | SLUCAS9 | - | AGCTCCTACTCAGACTGTTAC |
200 | 外顯子51 | SLUCAS9 | - | AGCTCCTACTCAGACTGTTACT |
4202 | 外顯子53 | SLUCAS9 | + | AGGTATCTTTGATACTAACC |
4203 | 外顯子53 | SLUCAS9 | + | AAGGTATCTTTGATACTAACC |
201 | 外顯子53 | SLUCAS9 | + | AAAGGTATCTTTGATACTAACC |
4204 | 外顯子53 | SLUCAS9 | + | TTGGTTTCTGTGATTTTCTT |
4205 | 外顯子53 | SLUCAS9 | + | CTTGGTTTCTGTGATTTTCTT |
202 | 外顯子53 | SLUCAS9 | + | CCTTGGTTTCTGTGATTTTCTT |
4206 | 外顯子53 | SLUCAS9 | + | TTTGGATTGCATCTACTGTA |
4207 | 外顯子53 | SLUCAS9 | + | TTTTGGATTGCATCTACTGTA |
203 | 外顯子53 | SLUCAS9 | + | CTTTTGGATTGCATCTACTGTA |
4208 | 外顯子53 | SLUCAS9 | + | TTGGATTGCATCTACTGTAT |
4209 | 外顯子53 | SLUCAS9 | + | TTTGGATTGCATCTACTGTAT |
204 | 外顯子53 | SLUCAS9 | + | TTTTGGATTGCATCTACTGTAT |
4210 | 外顯子53 | SLUCAS9 | + | CCTCCTTCCATGACTCAAGC |
4211 | 外顯子53 | SLUCAS9 | + | CCCTCCTTCCATGACTCAAGC |
205 | 外顯子53 | SLUCAS9 | + | ACCCTCCTTCCATGACTCAAGC |
4212 | 外顯子53 | SLUCAS9 | + | TCCATGACTCAAGCTTGGCT |
4213 | 外顯子53 | SLUCAS9 | + | TTCCATGACTCAAGCTTGGCT |
206 | 外顯子53 | SLUCAS9 | + | CTTCCATGACTCAAGCTTGGCT |
4214 | 外顯子53 | SLUCAS9 | + | ATTTCATTCAACTGTTGCCT |
4215 | 外顯子53 | SLUCAS9 | + | CATTTCATTCAACTGTTGCCT |
207 | 外顯子53 | SLUCAS9 | + | ACATTTCATTCAACTGTTGCCT |
4216 | 外顯子53 | SLUCAS9 | + | AACTGTTGCCTCCGGTTCTG |
4217 | 外顯子53 | SLUCAS9 | + | CAACTGTTGCCTCCGGTTCTG |
208 | 外顯子53 | SLUCAS9 | + | TCAACTGTTGCCTCCGGTTCTG |
4218 | 外顯子53 | SLUCAS9 | + | AATTCTTTCAACTAGAATAA |
4219 | 外顯子53 | SLUCAS9 | + | GAATTCTTTCAACTAGAATAA |
209 | 外顯子53 | SLUCAS9 | + | TGAATTCTTTCAACTAGAATAA |
4220 | 外顯子53 | SLUCAS9 | - | CCAAAAGAAAATCACAGAAA |
4221 | 外顯子53 | SLUCAS9 | - | CCAAAAGAAAATCACAGAAAC |
210 | 外顯子53 | SLUCAS9 | - | CCAAAAGAAAATCACAGAAACC |
4222 | 外顯子53 | SLUCAS9 | - | GCCAAGCTTGAGTCATGGAA |
4223 | 外顯子53 | SLUCAS9 | - | GCCAAGCTTGAGTCATGGAAG |
211 | 外顯子53 | SLUCAS9 | - | GCCAAGCTTGAGTCATGGAAGG |
4224 | 外顯子53 | SLUCAS9 | - | AGCCAAGCTTGAGTCATGGA |
4225 | 外顯子53 | SLUCAS9 | - | AGCCAAGCTTGAGTCATGGAA |
212 | 外顯子53 | SLUCAS9 | - | AGCCAAGCTTGAGTCATGGAAG |
4226 | 外顯子53 | SLUCAS9 | - | CAGAGCCAAGCTTGAGTCAT |
4227 | 外顯子53 | SLUCAS9 | - | CAGAGCCAAGCTTGAGTCATG |
213 | 外顯子53 | SLUCAS9 | - | CAGAGCCAAGCTTGAGTCATGG |
4228 | 外顯子53 | SLUCAS9 | - | AGGCCAGAGCCAAGCTTGAG |
4229 | 外顯子53 | SLUCAS9 | - | AGGCCAGAGCCAAGCTTGAGT |
214 | 外顯子53 | SLUCAS9 | - | AGGCCAGAGCCAAGCTTGAGTC |
4230 | 外顯子53 | SLUCAS9 | - | AGAAGCTGAGCAGGTCTTAG |
4231 | 外顯子53 | SLUCAS9 | - | AGAAGCTGAGCAGGTCTTAGG |
215 | 外顯子53 | SLUCAS9 | - | AGAAGCTGAGCAGGTCTTAGGA |
4232 | 外顯子53 | SLUCAS9 | - | AAGGAAGAAGCTGAGCAGGT |
4233 | 外顯子53 | SLUCAS9 | - | AAGGAAGAAGCTGAGCAGGTC |
216 | 外顯子53 | SLUCAS9 | - | AAGGAAGAAGCTGAGCAGGTCT |
4234 | 外顯子53 | SLUCAS9 | - | GGAAGCTAAGGAAGAAGCTG |
4235 | 外顯子53 | SLUCAS9 | - | GGAAGCTAAGGAAGAAGCTGA |
217 | 外顯子53 | SLUCAS9 | - | GGAAGCTAAGGAAGAAGCTGAG |
4236 | 外顯子53 | SLUCAS9 | - | TTCAACACAATGGCTGGAAG |
4237 | 外顯子53 | SLUCAS9 | - | TTCAACACAATGGCTGGAAGC |
218 | 外顯子53 | SLUCAS9 | - | TTCAACACAATGGCTGGAAGCT |
4238 | 外顯子53 | SLUCAS9 | - | GTTAAAGGATTCAACACAAT |
4239 | 外顯子53 | SLUCAS9 | - | GTTAAAGGATTCAACACAATG |
219 | 外顯子53 | SLUCAS9 | - | GTTAAAGGATTCAACACAATGG |
4240 | 外顯子53 | SLUCAS9 | - | AAATGTTAAAGGATTCAACA |
4241 | 外顯子53 | SLUCAS9 | - | AAATGTTAAAGGATTCAACAC |
220 | 外顯子53 | SLUCAS9 | - | AAATGTTAAAGGATTCAACACA |
4242 | 外顯子53 | SLUCAS9 | - | GCAACAGTTGAATGAAATGT |
4243 | 外顯子53 | SLUCAS9 | - | GCAACAGTTGAATGAAATGTT |
221 | 外顯子53 | SLUCAS9 | - | GCAACAGTTGAATGAAATGTTA |
4244 | 外顯子53 | SLUCAS9 | - | TACAAGAACACCTTCAGAAC |
4245 | 外顯子53 | SLUCAS9 | - | TACAAGAACACCTTCAGAACC |
222 | 外顯子53 | SLUCAS9 | - | TACAAGAACACCTTCAGAACCG |
4246 | 外顯子53 | SLUCAS9 | - | AAGTACAAGAACACCTTCAG |
4247 | 外顯子53 | SLUCAS9 | - | AAGTACAAGAACACCTTCAGA |
223 | 外顯子53 | SLUCAS9 | - | AAGTACAAGAACACCTTCAGAA |
4248 | 外顯子53 | SLUCAS9 | - | AGTTGAAAGAATTCAGAATC |
4249 | 外顯子53 | SLUCAS9 | - | AGTTGAAAGAATTCAGAATCA |
224 | 外顯子53 | SLUCAS9 | - | AGTTGAAAGAATTCAGAATCAG |
4250 | 外顯子53 | SLUCAS9 | - | TAGTTGAAAGAATTCAGAAT |
4251 | 外顯子53 | SLUCAS9 | - | TAGTTGAAAGAATTCAGAATC |
225 | 外顯子53 | SLUCAS9 | - | TAGTTGAAAGAATTCAGAATCA |
外顯子 | CAS9 | ID | 基因體座標chrX_起始 | 基因體座標chrX_終止(包括PAM座標) | 股 | SEQ ID NO嚮導序列 | 嚮導序列 | PAM | 脫靶_分組 |
45 | SACAS9KKH | E45SaCas9KKH1 | 31968359 | 31968387 | + | 1000 | TGTTTGCAGACCTCCTGCCACC | GCAGAT | 20 |
45 | SACAS9KKH | E45SaCas9KKH2 | 31968373 | 31968401 | + | 1001 | CTGCCACCGCAGATTCAGGCTT | CCCAAT | 9 |
45 | SACAS9KKH | E45SaCas9KKH3 | 31968387 | 31968415 | + | 9 | TCAGGCTTCCCAATTTTTCCTG | TAGAAT | 37 |
45 | SACAS9KKH | E45SaCas9KKH4 | 31968409 | 31968437 | + | 10 | TAGAATACTGGCATCTGTTTTT | GAGGAT | 63 |
45 | SACAS9KKH | E45SaCas9KKH5 | 31968417 | 31968445 | + | 11 | TGGCATCTGTTTTTGAGGATTG | CTGAAT | 35 |
45 | SACAS9KKH | E45SaCas9KKH6 | 31968432 | 31968460 | + | 1002 | AGGATTGCTGAATTATTTCTTC | CCCAGT | 42 |
45 | SACAS9KKH | E45SaCas9KKH7 | 31968442 | 31968470 | + | 1003 | AATTATTTCTTCCCCAGTTGCA | TTCAAT | 68 |
45 | SACAS9KKH | E45SaCas9KKH8 | 31968456 | 31968484 | + | 1004 | CAGTTGCATTCAATGTTCTGAC | AACAGT | 17 |
45 | SACAS9KKH | E45SaCas9KKH9 | 31968471 | 31968499 | + | 1005 | TTCTGACAACAGTTTGCCGCTG | CCCAAT | 6 |
45 | SACAS9KKH | E45SaCas9KKH10 | 31968484 | 31968512 | + | 12 | TTGCCGCTGCCCAATGCCATCC | TGGAGT | 5 |
45 | SACAS9KKH | E45SaCas9KKH11 | 31968495 | 31968523 | + | 1006 | CAATGCCATCCTGGAGTTCCTG | TAAGAT | 27 |
45 | SACAS9KKH | E45SaCas9KKH12 | 31968517 | 31968545 | + | 1007 | TAAGATACCAAAAAGGCAAAAC | AAAAAT | 96 |
45 | SACAS9KKH | E45SaCas9KKH13 | 31968313 | 31968341 | - | 13 | GAGGTAGGGCGACAGATCTAAT | AGGAAT | 10 |
45 | SACAS9KKH | E45SaCas9KKH14 | 31968319 | 31968347 | - | 1008 | AAAAAAGAGGTAGGGCGACAGA | TCTAAT | 75 |
45 | SACAS9KKH | E45SaCas9KKH15 | 31968324 | 31968352 | - | 1009 | GACAGAAAAAAGAGGTAGGGCG | ACAGAT | 51 |
45 | SACAS9KKH | E45SaCas9KKH16 | 31968336 | 31968364 | - | 1010 | AAACAGCTGTCAGACAGAAAAA | AGAGGT | 123 |
45 | SACAS9KKH | E45SaCas9KKH17 | 31968368 | 31968396 | - | 1011 | GAAGCCTGAATCTGCGGTGGCA | GGAGGT | 19 |
45 | SACAS9KKH | E45SaCas9KKH18 | 31968378 | 31968406 | - | 1012 | GAAAAATTGGGAAGCCTGAATC | TGCGGT | 29 |
45 | SACAS9KKH | E45SaCas9KKH19 | 31968385 | 31968413 | - | 14 | TCTACAGGAAAAATTGGGAAGC | CTGAAT | 64 |
45 | SACAS9KKH | E45SaCas9KKH20 | 31968399 | 31968427 | - | 1013 | ACAGATGCCAGTATTCTACAGG | AAAAAT | 22 |
45 | SACAS9KKH | E45SaCas9KKH21 | 31968415 | 31968443 | - | 1014 | TCAGCAATCCTCAAAAACAGAT | GCCAGT | 50 |
45 | SACAS9KKH | E45SaCas9KKH22 | 31968421 | 31968449 | - | 1015 | AATAATTCAGCAATCCTCAAAA | ACAGAT | 99 |
45 | SACAS9KKH | E45SaCas9KKH23 | 31968435 | 31968463 | - | 1016 | GCAACTGGGGAAGAAATAATTC | AGCAAT | 43 |
45 | SACAS9KKH | E45SaCas9KKH24 | 31968443 | 31968471 | - | 1017 | CATTGAATGCAACTGGGGAAGA | AATAAT | 54 |
45 | SACAS9KKH | E45SaCas9KKH25 | 31968446 | 31968474 | - | 1018 | GAACATTGAATGCAACTGGGGA | AGAAAT | 23 |
45 | SACAS9KKH | E45SaCas9KKH26 | 31968463 | 31968491 | - | 15 | GCGGCAAACTGTTGTCAGAACA | TTGAAT | 5 |
45 | SACAS9KKH | E45SaCas9KKH27 | 31968502 | 31968530 | - | 16 | TTTTGGTATCTTACAGGAACTC | CAGGAT | 52 |
45 | SLUCAS9KH | E45SLCas9KH1 | 31968332 | 31968358 | + | 2000 | CCCTACCTCTTTTTTCTGTCTG | ACAG | 23 |
45 | SLUCAS9KH | E45SLCas9KH2 | 31968342 | 31968368 | + | 2001 | TTTTTCTGTCTGACAGCTGTTT | GCAG | 22 |
45 | SLUCAS9KH | E45SLCas9KH3 | 31968359 | 31968385 | + | 2002 | TGTTTGCAGACCTCCTGCCACC | GCAG | 9 |
45 | SLUCAS9KH | E45SLCas9KH4 | 31968365 | 31968391 | + | 2003 | CAGACCTCCTGCCACCGCAGAT | TCAG | 9 |
45 | SLUCAS9KH | E45SLCas9KH5 | 31968366 | 31968392 | + | 128 | AGACCTCCTGCCACCGCAGATT | CAGG | 10 |
45 | SLUCAS9KH | E45SLCas9KH6 | 31968386 | 31968412 | + | 2004 | TTCAGGCTTCCCAATTTTTCCT | GTAG | 11 |
45 | SLUCAS9KH | E45SLCas9KH7 | 31968394 | 31968420 | + | 129 | TCCCAATTTTTCCTGTAGAATA | CTGG | 19 |
45 | SLUCAS9KH | E45SLCas9KH8 | 31968408 | 31968434 | + | 2005 | GTAGAATACTGGCATCTGTTTT | TGAG | 16 |
45 | SLUCAS9KH | E45SLCas9KH9 | 31968409 | 31968435 | + | 130 | TAGAATACTGGCATCTGTTTTT | GAGG | 19 |
45 | SLUCAS9KH | E45SLCas9KH10 | 31968433 | 31968459 | + | 2006 | GGATTGCTGAATTATTTCTTCC | CCAG | 18 |
45 | SLUCAS9KH | E45SLCas9KH11 | 31968457 | 31968483 | + | 2007 | AGTTGCATTCAATGTTCTGACA | ACAG | 10 |
45 | SLUCAS9KH | E45SLCas9KH12 | 31968483 | 31968509 | + | 131 | TTTGCCGCTGCCCAATGCCATC | CTGG | 2 |
45 | SLUCAS9KH | E45SLCas9KH13 | 31968485 | 31968511 | + | 2008 | TGCCGCTGCCCAATGCCATCCT | GGAG | 7 |
45 | SLUCAS9KH | E45SLCas9KH14 | 31968495 | 31968521 | + | 2009 | CAATGCCATCCTGGAGTTCCTG | TAAG | 14 |
45 | SLUCAS9KH | E45SLCas9KH15 | 31968506 | 31968532 | + | 2010 | TGGAGTTCCTGTAAGATACCAA | AAAG | 10 |
45 | SLUCAS9KH | E45SLCas9KH16 | 31968507 | 31968533 | + | 132 | GGAGTTCCTGTAAGATACCAAA | AAGG | 9 |
45 | SLUCAS9KH | E45SLCas9KH17 | 31968316 | 31968342 | - | 133 | AGAGGTAGGGCGACAGATCTAA | TAGG | 6 |
45 | SLUCAS9KH | E45SLCas9KH18 | 31968317 | 31968343 | - | 2011 | AAGAGGTAGGGCGACAGATCTA | ATAG | 5 |
45 | SLUCAS9KH | E45SLCas9KH19 | 31968326 | 31968352 | - | 2012 | GACAGAAAAAAGAGGTAGGGCG | ACAG | 31 |
45 | SLUCAS9KH | E45SLCas9KH20 | 31968332 | 31968358 | - | 134 | CTGTCAGACAGAAAAAAGAGGT | AGGG | 28 |
45 | SLUCAS9KH | E45SLCas9KH21 | 31968333 | 31968359 | - | 135 | GCTGTCAGACAGAAAAAAGAGG | TAGG | 43 |
45 | SLUCAS9KH | E45SLCas9KH22 | 31968334 | 31968360 | - | 2013 | AGCTGTCAGACAGAAAAAAGAG | GTAG | 67 |
45 | SLUCAS9KH | E45SLCas9KH23 | 31968337 | 31968363 | - | 136 | AACAGCTGTCAGACAGAAAAAA | GAGG | 55 |
45 | SLUCAS9KH | E45SLCas9KH24 | 31968338 | 31968364 | - | 2014 | AAACAGCTGTCAGACAGAAAAA | AGAG | 37 |
45 | SLUCAS9KH | E45SLCas9KH25 | 31968340 | 31968366 | - | 2015 | GCAAACAGCTGTCAGACAGAAA | AAAG | 27 |
45 | SLUCAS9KH | E45SLCas9KH26 | 31968347 | 31968373 | - | 2016 | GAGGTCTGCAAACAGCTGTCAG | ACAG | 23 |
45 | SLUCAS9KH | E45SLCas9KH27 | 31968351 | 31968377 | - | 2017 | GCAGGAGGTCTGCAAACAGCTG | TCAG | 16 |
45 | SLUCAS9KH | E45SLCas9KH28 | 31968358 | 31968384 | - | 2018 | TGCGGTGGCAGGAGGTCTGCAA | ACAG | 14 |
45 | SLUCAS9KH | E45SLCas9KH29 | 31968369 | 31968395 | - | 137 | AAGCCTGAATCTGCGGTGGCAG | GAGG | 11 |
45 | SLUCAS9KH | E45SLCas9KH30 | 31968370 | 31968396 | - | 2019 | GAAGCCTGAATCTGCGGTGGCA | GGAG | 15 |
45 | SLUCAS9KH | E45SLCas9KH31 | 31968372 | 31968398 | - | 138 | GGGAAGCCTGAATCTGCGGTGG | CAGG | 8 |
45 | SLUCAS9KH | E45SLCas9KH32 | 31968373 | 31968399 | - | 2020 | TGGGAAGCCTGAATCTGCGGTG | GCAG | 6 |
45 | SLUCAS9KH | E45SLCas9KH33 | 31968376 | 31968402 | - | 139 | AATTGGGAAGCCTGAATCTGCG | GTGG | 7 |
45 | SLUCAS9KH | E45SLCas9KH34 | 31968379 | 31968405 | - | 140 | AAAAATTGGGAAGCCTGAATCT | GCGG | 26 |
45 | SLUCAS9KH | E45SLCas9KH35 | 31968392 | 31968418 | - | 2021 | AGTATTCTACAGGAAAAATTGG | GAAG | 28 |
45 | SLUCAS9KH | E45SLCas9KH36 | 31968395 | 31968421 | - | 141 | GCCAGTATTCTACAGGAAAAAT | TGGG | 16 |
45 | SLUCAS9KH | E45SLCas9KH37 | 31968396 | 31968422 | - | 142 | TGCCAGTATTCTACAGGAAAAA | TTGG | 17 |
45 | SLUCAS9KH | E45SLCas9KH38 | 31968405 | 31968431 | - | 143 | AAAAACAGATGCCAGTATTCTA | CAGG | 21 |
45 | SLUCAS9KH | E45SLCas9KH39 | 31968406 | 31968432 | - | 2022 | CAAAAACAGATGCCAGTATTCT | ACAG | 28 |
45 | SLUCAS9KH | E45SLCas9KH40 | 31968416 | 31968442 | - | 2023 | CAGCAATCCTCAAAAACAGATG | CCAG | 23 |
45 | SLUCAS9KH | E45SLCas9KH41 | 31968423 | 31968449 | - | 2024 | AATAATTCAGCAATCCTCAAAA | ACAG | 31 |
45 | SLUCAS9KH | E45SLCas9KH42 | 31968439 | 31968465 | - | 2025 | ATGCAACTGGGGAAGAAATAAT | TCAG | 33 |
45 | SLUCAS9KH | E45SLCas9KH43 | 31968450 | 31968476 | - | 2026 | CAGAACATTGAATGCAACTGGG | GAAG | 11 |
45 | SLUCAS9KH | E45SLCas9KH44 | 31968453 | 31968479 | - | 144 | TGTCAGAACATTGAATGCAACT | GGGG | 12 |
45 | SLUCAS9KH | E45SLCas9KH45 | 31968454 | 31968480 | - | 145 | TTGTCAGAACATTGAATGCAAC | TGGG | 30 |
45 | SLUCAS9KH | E45SLCas9KH46 | 31968455 | 31968481 | - | 146 | GTTGTCAGAACATTGAATGCAA | CTGG | 12 |
45 | SLUCAS9KH | E45SLCas9KH47 | 31968473 | 31968499 | - | 2027 | ATTGGGCAGCGGCAAACTGTTG | TCAG | 3 |
45 | SLUCAS9KH | E45SLCas9KH48 | 31968487 | 31968513 | - | 147 | AACTCCAGGATGGCATTGGGCA | GCGG | 9 |
45 | SLUCAS9KH | E45SLCas9KH49 | 31968490 | 31968516 | - | 2028 | AGGAACTCCAGGATGGCATTGG | GCAG | 16 |
45 | SLUCAS9KH | E45SLCas9KH50 | 31968493 | 31968519 | - | 148 | TACAGGAACTCCAGGATGGCAT | TGGG | 10 |
45 | SLUCAS9KH | E45SLCas9KH51 | 31968494 | 31968520 | - | 149 | TTACAGGAACTCCAGGATGGCA | TTGG | 13 |
45 | SLUCAS9KH | E45SLCas9KH52 | 31968500 | 31968526 | - | 150 | GGTATCTTACAGGAACTCCAGG | ATGG | 7 |
45 | SLUCAS9KH | E45SLCas9KH53 | 31968504 | 31968530 | - | 151 | TTTTGGTATCTTACAGGAACTC | CAGG | 35 |
45 | SLUCAS9KH | E45SLCas9KH54 | 31968505 | 31968531 | - | 2029 | TTTTTGGTATCTTACAGGAACT | CCAG | 21 |
45 | SLUCAS9KH | E45SLCas9KH55 | 31968513 | 31968539 | - | 152 | GTTTTGCCTTTTTGGTATCTTA | CAGG | 32 |
45 | SLUCAS9KH | E45SLCas9KH56 | 31968514 | 31968540 | - | 2030 | TGTTTTGCCTTTTTGGTATCTT | ACAG | 58 |
51 | SACAS9KKH | E51SaCas9KKH1 | 31773943 | 31773971 | + | 1019 | TCATTTTTTCTCATACCTTCTG | CTTGAT | 91 |
51 | SACAS9KKH | E51SaCas9KKH2 | 31773946 | 31773974 | + | 1020 | TTTTTTCTCATACCTTCTGCTT | GATGAT | 132 |
51 | SACAS9KKH | E51SaCas9KKH3 | 31773958 | 31773986 | + | 1021 | CCTTCTGCTTGATGATCATCTC | GTTGAT | 23 |
51 | SACAS9KKH | E51SaCas9KKH4 | 31773969 | 31773997 | + | 1022 | ATGATCATCTCGTTGATATCCT | CAAGGT | 15 |
51 | SACAS9KKH | E51SaCas9KKH5 | 31773992 | 31774020 | + | 1023 | AAGGTCACCCACCATCACCCTC | TGTGAT | 33 |
51 | SACAS9KKH | E51SaCas9KKH6 | 31774005 | 31774033 | + | 1024 | ATCACCCTCTGTGATTTTATAA | CTTGAT | 45 |
51 | SACAS9KKH | E51SaCas9KKH7 | 31774023 | 31774051 | + | 1025 | ATAACTTGATCAAGCAGAGAAA | GCCAGT | 101 |
51 | SACAS9KKH | E51SaCas9KKH8 | 31774027 | 31774055 | + | 1026 | CTTGATCAAGCAGAGAAAGCCA | GTCGGT | 55 |
51 | SACAS9KKH | E51SaCas9KKH9 | 31774031 | 31774059 | + | 1027 | ATCAAGCAGAGAAAGCCAGTCG | GTAAGT | 16 |
51 | SACAS9KKH | E51SaCas9KKH10 | 31774047 | 31774075 | + | 1028 | CAGTCGGTAAGTTCTGTCCAAG | CCCGGT | 7 |
51 | SACAS9KKH | E51SaCas9KKH11 | 31774053 | 31774081 | + | 1029 | GTAAGTTCTGTCCAAGCCCGGT | TGAAAT | 4 |
51 | SACAS9KKH | E51SaCas9KKH12 | 31774067 | 31774095 | + | 1030 | AGCCCGGTTGAAATCTGCCAGA | GCAGGT | 7 |
51 | SACAS9KKH | E51SaCas9KKH13 | 31774088 | 31774116 | + | 1031 | AGCAGGTACCTCCAACATCAAG | GAAGAT | 23 |
51 | SACAS9KKH | E51SaCas9KKH14 | 31774100 | 31774128 | + | 1032 | CAACATCAAGGAAGATGGCATT | TCTAGT | 54 |
51 | SACAS9KKH | E51SaCas9KKH15 | 31774108 | 31774136 | + | 1033 | AGGAAGATGGCATTTCTAGTTT | GGAGAT | 62 |
51 | SACAS9KKH | E51SaCas9KKH16 | 31774114 | 31774142 | + | 1034 | ATGGCATTTCTAGTTTGGAGAT | GGCAGT | 56 |
51 | SACAS9KKH | E51SaCas9KKH17 | 31774123 | 31774151 | + | 1035 | CTAGTTTGGAGATGGCAGTTTC | CTTAGT | 32 |
51 | SACAS9KKH | E51SaCas9KKH18 | 31774133 | 31774161 | + | 1036 | GATGGCAGTTTCCTTAGTAACC | ACAGGT | 24 |
51 | SACAS9KKH | E51SaCas9KKH19 | 31774147 | 31774175 | + | 19 | TAGTAACCACAGGTTGTGTCAC | CAGAGT | 18 |
51 | SACAS9KKH | E51SaCas9KKH20 | 31774153 | 31774181 | + | 1037 | CCACAGGTTGTGTCACCAGAGT | AACAGT | 20 |
51 | SACAS9KKH | E51SaCas9KKH21 | 31774159 | 31774187 | + | 20 | GTTGTGTCACCAGAGTAACAGT | CTGAGT | 21 |
51 | SACAS9KKH | E51SaCas9KKH22 | 31774171 | 31774199 | + | 1038 | GAGTAACAGTCTGAGTAGGAGC | TAAAAT | 18 |
51 | SACAS9KKH | E51SaCas9KKH23 | 31774180 | 31774208 | + | 21 | TCTGAGTAGGAGCTAAAATATT | TTGGGT | 38 |
51 | SACAS9KKH | E51SaCas9KKH24 | 31773936 | 31773964 | - | 1039 | AGAAGGTATGAGAAAAAATGAT | AAAAGT | 236 |
51 | SACAS9KKH | E51SaCas9KKH25 | 31773942 | 31773970 | - | 1040 | TCAAGCAGAAGGTATGAGAAAA | AATGAT | 99 |
51 | SACAS9KKH | E51SaCas9KKH26 | 31773945 | 31773973 | - | 1041 | TCATCAAGCAGAAGGTATGAGA | AAAAAT | 43 |
51 | SACAS9KKH | E51SaCas9KKH27 | 31773957 | 31773985 | - | 1042 | TCAACGAGATGATCATCAAGCA | GAAGGT | 10 |
51 | SACAS9KKH | E51SaCas9KKH28 | 31773972 | 31774000 | - | 1043 | GTGACCTTGAGGATATCAACGA | GATGAT | 7 |
51 | SACAS9KKH | E51SaCas9KKH29 | 31773975 | 31774003 | - | 1044 | TGGGTGACCTTGAGGATATCAA | CGAGAT | 68 |
51 | SACAS9KKH | E51SaCas9KKH30 | 31773986 | 31774014 | - | 22 | GAGGGTGATGGTGGGTGACCTT | GAGGAT | 46 |
51 | SACAS9KKH | E51SaCas9KKH31 | 31773998 | 31774026 | - | 23 | TATAAAATCACAGAGGGTGATG | GTGGGT | 42 |
51 | SACAS9KKH | E51SaCas9KKH32 | 31774002 | 31774030 | - | 1045 | AAGTTATAAAATCACAGAGGGT | GATGGT | 77 |
51 | SACAS9KKH | E51SaCas9KKH33 | 31774005 | 31774033 | - | 1046 | ATCAAGTTATAAAATCACAGAG | GGTGAT | 90 |
51 | SACAS9KKH | E51SaCas9KKH34 | 31774008 | 31774036 | - | 24 | TTGATCAAGTTATAAAATCACA | GAGGGT | 86 |
51 | SACAS9KKH | E51SaCas9KKH35 | 31774018 | 31774046 | - | 1047 | CTTTCTCTGCTTGATCAAGTTA | TAAAAT | 45 |
51 | SACAS9KKH | E51SaCas9KKH36 | 31774026 | 31774054 | - | 1048 | CCGACTGGCTTTCTCTGCTTGA | TCAAGT | 18 |
51 | SACAS9KKH | E51SaCas9KKH37 | 31774031 | 31774059 | - | 1049 | ACTTACCGACTGGCTTTCTCTG | CTTGAT | 11 |
51 | SACAS9KKH | E51SaCas9KKH38 | 31774079 | 31774107 | - | 1050 | GATGTTGGAGGTACCTGCTCTG | GCAGAT | 22 |
51 | SACAS9KKH | E51SaCas9KKH39 | 31774095 | 31774123 | - | 1051 | AAATGCCATCTTCCTTGATGTT | GGAGGT | 57 |
51 | SACAS9KKH | E51SaCas9KKH40 | 31774104 | 31774132 | - | 1052 | CCAAACTAGAAATGCCATCTTC | CTTGAT | 46 |
51 | SACAS9KKH | E51SaCas9KKH41 | 31774119 | 31774147 | - | 1053 | AGGAAACTGCCATCTCCAAACT | AGAAAT | 63 |
51 | SACAS9KKH | E51SaCas9KKH42 | 31774152 | 31774180 | - | 1054 | CTGTTACTCTGGTGACACAACC | TGTGGT | 27 |
51 | SACAS9KKH | E51SaCas9KKH43 | 31774167 | 31774195 | - | 1055 | TAGCTCCTACTCAGACTGTTAC | TCTGGT | 13 |
51 | SLUCAS9KH | E51SLCas9KH1 | 31773969 | 31773995 | + | 2031 | ATGATCATCTCGTTGATATCCT | CAAG | 6 |
51 | SLUCAS9KH | E51SLCas9KH2 | 31773970 | 31773996 | + | 170 | TGATCATCTCGTTGATATCCTC | AAGG | 6 |
51 | SLUCAS9KH | E51SLCas9KH3 | 31774011 | 31774037 | + | 2032 | CTCTGTGATTTTATAACTTGAT | CAAG | 18 |
51 | SLUCAS9KH | E51SLCas9KH4 | 31774014 | 31774040 | + | 2033 | TGTGATTTTATAACTTGATCAA | GCAG | 29 |
51 | SLUCAS9KH | E51SLCas9KH5 | 31774016 | 31774042 | + | 2034 | TGATTTTATAACTTGATCAAGC | AGAG | 15 |
51 | SLUCAS9KH | E51SLCas9KH6 | 31774020 | 31774046 | + | 2035 | TTTATAACTTGATCAAGCAGAG | AAAG | 7 |
51 | SLUCAS9KH | E51SLCas9KH7 | 31774024 | 31774050 | + | 2036 | TAACTTGATCAAGCAGAGAAAG | CCAG | 24 |
51 | SLUCAS9KH | E51SLCas9KH8 | 31774028 | 31774054 | + | 171 | TTGATCAAGCAGAGAAAGCCAG | TCGG | 23 |
51 | SLUCAS9KH | E51SLCas9KH9 | 31774032 | 31774058 | + | 2037 | TCAAGCAGAGAAAGCCAGTCGG | TAAG | 7 |
51 | SLUCAS9KH | E51SLCas9KH10 | 31774043 | 31774069 | + | 2038 | AAGCCAGTCGGTAAGTTCTGTC | CAAG | 7 |
51 | SLUCAS9KH | E51SLCas9KH11 | 31774048 | 31774074 | + | 172 | AGTCGGTAAGTTCTGTCCAAGC | CCGG | 2 |
51 | SLUCAS9KH | E51SLCas9KH12 | 31774062 | 31774088 | + | 2039 | GTCCAAGCCCGGTTGAAATCTG | CCAG | 1 |
51 | SLUCAS9KH | E51SLCas9KH13 | 31774064 | 31774090 | + | 2040 | CCAAGCCCGGTTGAAATCTGCC | AGAG | 2 |
51 | SLUCAS9KH | E51SLCas9KH14 | 31774067 | 31774093 | + | 2041 | AGCCCGGTTGAAATCTGCCAGA | GCAG | 4 |
51 | SLUCAS9KH | E51SLCas9KH15 | 31774068 | 31774094 | + | 173 | GCCCGGTTGAAATCTGCCAGAG | CAGG | 5 |
51 | SLUCAS9KH | E51SLCas9KH16 | 31774084 | 31774110 | + | 2042 | CCAGAGCAGGTACCTCCAACAT | CAAG | 14 |
51 | SLUCAS9KH | E51SLCas9KH17 | 31774085 | 31774111 | + | 174 | CAGAGCAGGTACCTCCAACATC | AAGG | 13 |
51 | SLUCAS9KH | E51SLCas9KH18 | 31774088 | 31774114 | + | 2043 | AGCAGGTACCTCCAACATCAAG | GAAG | 12 |
51 | SLUCAS9KH | E51SLCas9KH19 | 31774092 | 31774118 | + | 175 | GGTACCTCCAACATCAAGGAAG | ATGG | 6 |
51 | SLUCAS9KH | E51SLCas9KH20 | 31774101 | 31774127 | + | 2044 | AACATCAAGGAAGATGGCATTT | CTAG | 32 |
51 | SLUCAS9KH | E51SLCas9KH21 | 31774106 | 31774132 | + | 176 | CAAGGAAGATGGCATTTCTAGT | TTGG | 21 |
51 | SLUCAS9KH | E51SLCas9KH22 | 31774108 | 31774134 | + | 2045 | AGGAAGATGGCATTTCTAGTTT | GGAG | 50 |
51 | SLUCAS9KH | E51SLCas9KH23 | 31774112 | 31774138 | + | 177 | AGATGGCATTTCTAGTTTGGAG | ATGG | 10 |
51 | SLUCAS9KH | E51SLCas9KH24 | 31774115 | 31774141 | + | 2046 | TGGCATTTCTAGTTTGGAGATG | GCAG | 22 |
51 | SLUCAS9KH | E51SLCas9KH25 | 31774124 | 31774150 | + | 2047 | TAGTTTGGAGATGGCAGTTTCC | TTAG | 20 |
51 | SLUCAS9KH | E51SLCas9KH26 | 31774133 | 31774159 | + | 2048 | GATGGCAGTTTCCTTAGTAACC | ACAG | 11 |
51 | SLUCAS9KH | E51SLCas9KH27 | 31774134 | 31774160 | + | 178 | ATGGCAGTTTCCTTAGTAACCA | CAGG | 14 |
51 | SLUCAS9KH | E51SLCas9KH28 | 31774146 | 31774172 | + | 2049 | TTAGTAACCACAGGTTGTGTCA | CCAG | 7 |
51 | SLUCAS9KH | E51SLCas9KH29 | 31774148 | 31774174 | + | 2050 | AGTAACCACAGGTTGTGTCACC | AGAG | 7 |
51 | SLUCAS9KH | E51SLCas9KH30 | 31774154 | 31774180 | + | 2051 | CACAGGTTGTGTCACCAGAGTA | ACAG | 14 |
51 | SLUCAS9KH | E51SLCas9KH31 | 31774160 | 31774186 | + | 2052 | TTGTGTCACCAGAGTAACAGTC | TGAG | 9 |
51 | SLUCAS9KH | E51SLCas9KH32 | 31774163 | 31774189 | + | 2053 | TGTCACCAGAGTAACAGTCTGA | GTAG | 9 |
51 | SLUCAS9KH | E51SLCas9KH33 | 31774164 | 31774190 | + | 179 | GTCACCAGAGTAACAGTCTGAG | TAGG | 14 |
51 | SLUCAS9KH | E51SLCas9KH34 | 31774166 | 31774192 | + | 2054 | CACCAGAGTAACAGTCTGAGTA | GGAG | 11 |
51 | SLUCAS9KH | E51SLCas9KH35 | 31774180 | 31774206 | + | 180 | TCTGAGTAGGAGCTAAAATATT | TTGG | 11 |
51 | SLUCAS9KH | E51SLCas9KH36 | 31774181 | 31774207 | + | 181 | CTGAGTAGGAGCTAAAATATTT | TGGG | 21 |
51 | SLUCAS9KH | E51SLCas9KH37 | 31774194 | 31774220 | + | 2055 | AAAATATTTTGGGTTTTTGCAA | AAAG | 56 |
51 | SLUCAS9KH | E51SLCas9KH38 | 31774195 | 31774221 | + | 182 | AAATATTTTGGGTTTTTGCAAA | AAGG | 61 |
51 | SLUCAS9KH | E51SLCas9KH39 | 31773927 | 31773953 | - | 2056 | GAAAAAATGATAAAAGTTGGCA | GAAG | 77 |
51 | SLUCAS9KH | E51SLCas9KH40 | 31773930 | 31773956 | - | 2057 | TGAGAAAAAATGATAAAAGTTG | GCAG | 124 |
51 | SLUCAS9KH | E51SLCas9KH41 | 31773933 | 31773959 | - | 183 | GTATGAGAAAAAATGATAAAAG | TTGG | 99 |
51 | SLUCAS9KH | E51SLCas9KH42 | 31773937 | 31773963 | - | 2058 | GAAGGTATGAGAAAAAATGATA | AAAG | 64 |
51 | SLUCAS9KH | E51SLCas9KH43 | 31773952 | 31773978 | - | 2059 | GATGATCATCAAGCAGAAGGTA | TGAG | 11 |
51 | SLUCAS9KH | E51SLCas9KH44 | 31773958 | 31773984 | - | 184 | CAACGAGATGATCATCAAGCAG | AAGG | 7 |
51 | SLUCAS9KH | E51SLCas9KH45 | 31773959 | 31773985 | - | 2060 | TCAACGAGATGATCATCAAGCA | GAAG | 3 |
51 | SLUCAS9KH | E51SLCas9KH46 | 31773962 | 31773988 | - | 2061 | ATATCAACGAGATGATCATCAA | GCAG | 7 |
51 | SLUCAS9KH | E51SLCas9KH47 | 31773965 | 31773991 | - | 2062 | AGGATATCAACGAGATGATCAT | CAAG | 7 |
51 | SLUCAS9KH | E51SLCas9KH48 | 31773977 | 31774003 | - | 2063 | TGGGTGACCTTGAGGATATCAA | CGAG | 17 |
51 | SLUCAS9KH | E51SLCas9KH49 | 31773988 | 31774014 | - | 185 | GAGGGTGATGGTGGGTGACCTT | GAGG | 22 |
51 | SLUCAS9KH | E51SLCas9KH50 | 31773989 | 31774015 | - | 2064 | AGAGGGTGATGGTGGGTGACCT | TGAG | 48 |
51 | SLUCAS9KH | E51SLCas9KH51 | 31773999 | 31774025 | - | 186 | ATAAAATCACAGAGGGTGATGG | TGGG | 27 |
51 | SLUCAS9KH | E51SLCas9KH52 | 31774000 | 31774026 | - | 187 | TATAAAATCACAGAGGGTGATG | GTGG | 23 |
51 | SLUCAS9KH | E51SLCas9KH53 | 31774003 | 31774029 | - | 188 | AGTTATAAAATCACAGAGGGTG | ATGG | 20 |
51 | SLUCAS9KH | E51SLCas9KH54 | 31774009 | 31774035 | - | 189 | TGATCAAGTTATAAAATCACAG | AGGG | 29 |
51 | SLUCAS9KH | E51SLCas9KH55 | 31774010 | 31774036 | - | 190 | TTGATCAAGTTATAAAATCACA | GAGG | 30 |
51 | SLUCAS9KH | E51SLCas9KH56 | 31774011 | 31774037 | - | 2065 | CTTGATCAAGTTATAAAATCAC | AGAG | 14 |
51 | SLUCAS9KH | E51SLCas9KH57 | 31774013 | 31774039 | - | 2066 | TGCTTGATCAAGTTATAAAATC | ACAG | 11 |
51 | SLUCAS9KH | E51SLCas9KH58 | 31774027 | 31774053 | - | 2067 | CGACTGGCTTTCTCTGCTTGAT | CAAG | 8 |
51 | SLUCAS9KH | E51SLCas9KH59 | 31774046 | 31774072 | - | 191 | GGGCTTGGACAGAACTTACCGA | CTGG | 2 |
51 | SLUCAS9KH | E51SLCas9KH60 | 31774060 | 31774086 | - | 2068 | GGCAGATTTCAACCGGGCTTGG | ACAG | 5 |
51 | SLUCAS9KH | E51SLCas9KH61 | 31774064 | 31774090 | - | 192 | CTCTGGCAGATTTCAACCGGGC | TTGG | 1 |
51 | SLUCAS9KH | E51SLCas9KH62 | 31774069 | 31774095 | - | 193 | ACCTGCTCTGGCAGATTTCAAC | CGGG | 10 |
51 | SLUCAS9KH | E51SLCas9KH63 | 31774070 | 31774096 | - | 194 | TACCTGCTCTGGCAGATTTCAA | CCGG | 10 |
51 | SLUCAS9KH | E51SLCas9KH64 | 31774081 | 31774107 | - | 2069 | GATGTTGGAGGTACCTGCTCTG | GCAG | 7 |
51 | SLUCAS9KH | E51SLCas9KH65 | 31774084 | 31774110 | - | 195 | CTTGATGTTGGAGGTACCTGCT | CTGG | 7 |
51 | SLUCAS9KH | E51SLCas9KH66 | 31774096 | 31774122 | - | 196 | AATGCCATCTTCCTTGATGTTG | GAGG | 22 |
51 | SLUCAS9KH | E51SLCas9KH67 | 31774097 | 31774123 | - | 2070 | AAATGCCATCTTCCTTGATGTT | GGAG | 19 |
51 | SLUCAS9KH | E51SLCas9KH68 | 31774099 | 31774125 | - | 197 | AGAAATGCCATCTTCCTTGATG | TTGG | 26 |
51 | SLUCAS9KH | E51SLCas9KH69 | 31774123 | 31774149 | - | 2071 | TAAGGAAACTGCCATCTCCAAA | CTAG | 41 |
51 | SLUCAS9KH | E51SLCas9KH70 | 31774144 | 31774170 | - | 198 | GGTGACACAACCTGTGGTTACT | AAGG | 6 |
51 | SLUCAS9KH | E51SLCas9KH71 | 31774145 | 31774171 | - | 2072 | TGGTGACACAACCTGTGGTTAC | TAAG | 10 |
51 | SLUCAS9KH | E51SLCas9KH72 | 31774153 | 31774179 | - | 199 | TGTTACTCTGGTGACACAACCT | GTGG | 22 |
51 | SLUCAS9KH | E51SLCas9KH73 | 31774168 | 31774194 | - | 200 | AGCTCCTACTCAGACTGTTACT | CTGG | 2 |
51 | SLUCAS9KH | E51SLCas9KH74 | 31774181 | 31774207 | - | 2073 | CCCAAAATATTTTAGCTCCTAC | TCAG | 10 |
51 | SLUCAS9KH | E51SLCas9KH75 | 31774192 | 31774218 | - | 2074 | TTTTGCAAAAACCCAAAATATT | TTAG | 43 |
53 | SACAS9KKH | E53SaCas9KKH1 | 31679352 | 31679380 | + | 1056 | AAAAGGTATCTTTGATACTAAC | CTTGGT | 45 |
53 | SACAS9KKH | E53SaCas9KKH2 | 31679361 | 31679389 | + | 1057 | CTTTGATACTAACCTTGGTTTC | TGTGAT | 20 |
53 | SACAS9KKH | E53SaCas9KKH3 | 31679373 | 31679401 | + | 25 | CCTTGGTTTCTGTGATTTTCTT | TTGGAT | 122 |
53 | SACAS9KKH | E53SaCas9KKH4 | 31679477 | 31679505 | + | 26 | TCCTTAGCTTCCAGCCATTGTG | TTGAAT | 42 |
53 | SACAS9KKH | E53SaCas9KKH5 | 31679510 | 31679538 | + | 1058 | AACATTTCATTCAACTGTTGCC | TCCGGT | 46 |
53 | SACAS9KKH | E53SaCas9KKH6 | 31679519 | 31679547 | + | 1059 | TTCAACTGTTGCCTCCGGTTCT | GAAGGT | 9 |
53 | SACAS9KKH | E53SaCas9KKH7 | 31679543 | 31679571 | + | 1060 | AGGTGTTCTTGTACTTCATCCC | ACTGAT | 16 |
53 | SACAS9KKH | E53SaCas9KKH8 | 31679550 | 31679578 | + | 27 | CTTGTACTTCATCCCACTGATT | CTGAAT | 58 |
53 | SACAS9KKH | E53SaCas9KKH9 | 31679565 | 31679593 | + | 28 | ACTGATTCTGAATTCTTTCAAC | TAGAAT | 78 |
53 | SACAS9KKH | E53SaCas9KKH10 | 31679577 | 31679605 | + | 1061 | TTCTTTCAACTAGAATAAAAGG | AAAAAT | 86 |
53 | SACAS9KKH | E53SaCas9KKH11 | 31679581 | 31679609 | + | 1062 | TTCAACTAGAATAAAAGGAAAA | ATAAAT | 420 |
53 | SACAS9KKH | E53SaCas9KKH12 | 31679588 | 31679616 | + | 1063 | AGAATAAAAGGAAAAATAAATA | TATAGT | 5266 |
53 | SACAS9KKH | E53SaCas9KKH13 | 31679346 | 31679374 | - | 1064 | GTTAGTATCAAAGATACCTTTT | TAAAAT | 31 |
53 | SACAS9KKH | E53SaCas9KKH14 | 31679359 | 31679387 | - | 1065 | CACAGAAACCAAGGTTAGTATC | AAAGAT | 33 |
53 | SACAS9KKH | E53SaCas9KKH15 | 31679368 | 31679396 | - | 1066 | AAAGAAAATCACAGAAACCAAG | GTTAGT | 456 |
53 | SACAS9KKH | E53SaCas9KKH16 | 31679372 | 31679400 | - | 1067 | TCCAAAAGAAAATCACAGAAAC | CAAGGT | 246 |
53 | SACAS9KKH | E53SaCas9KKH17 | 31679387 | 31679415 | - | 1068 | ATACAGTAGATGCAATCCAAAA | GAAAAT | 49 |
53 | SACAS9KKH | E53SaCas9KKH18 | 31679399 | 31679427 | - | 1069 | AGGAGGGTCCCTATACAGTAGA | TGCAAT | 13 |
53 | SACAS9KKH | E53SaCas9KKH19 | 31679404 | 31679432 | - | 1070 | ATGGAAGGAGGGTCCCTATACA | GTAGAT | 20 |
53 | SACAS9KKH | E53SaCas9KKH20 | 31679408 | 31679436 | - | 1071 | AGTCATGGAAGGAGGGTCCCTA | TACAGT | 27 |
53 | SACAS9KKH | E53SaCas9KKH21 | 31679419 | 31679447 | - | 29 | AGCCAAGCTTGAGTCATGGAAG | GAGGGT | 36 |
53 | SACAS9KKH | E53SaCas9KKH22 | 31679433 | 31679461 | - | 30 | TTAGGACAGGCCAGAGCCAAGC | TTGAGT | 30 |
53 | SACAS9KKH | E53SaCas9KKH23 | 31679462 | 31679490 | - | 1072 | TGGAAGCTAAGGAAGAAGCTGA | GCAGGT | 103 |
53 | SACAS9KKH | E53SaCas9KKH24 | 31679493 | 31679521 | - | 1073 | AATGAAATGTTAAAGGATTCAA | CACAAT | 200 |
53 | SACAS9KKH | E53SaCas9KKH25 | 31679503 | 31679531 | - | 31 | GCAACAGTTGAATGAAATGTTA | AAGGAT | 155 |
53 | SACAS9KKH | E53SaCas9KKH26 | 31679513 | 31679541 | - | 1074 | AGAACCGGAGGCAACAGTTGAA | TGAAAT | 11 |
53 | SACAS9KKH | E53SaCas9KKH27 | 31679518 | 31679546 | - | 32 | CCTTCAGAACCGGAGGCAACAG | TTGAAT | 8 |
53 | SACAS9KKH | E53SaCas9KKH28 | 31679523 | 31679551 | - | 1075 | GAACACCTTCAGAACCGGAGGC | AACAGT | 10 |
53 | SACAS9KKH | E53SaCas9KKH29 | 31679555 | 31679583 | - | 1076 | AAAGAATTCAGAATCAGTGGGA | TGAAGT | 106 |
53 | SACAS9KKH | E53SaCas9KKH30 | 31679560 | 31679588 | - | 33 | AGTTGAAAGAATTCAGAATCAG | TGGGAT | 110 |
53 | SACAS9KKH | E53SaCas9KKH31 | 31679565 | 31679593 | - | 1077 | ATTCTAGTTGAAAGAATTCAGA | ATCAGT | 134 |
53 | SACAS9KKH | E53SaCas9KKH32 | 31679569 | 31679597 | - | 34 | TTTTATTCTAGTTGAAAGAATT | CAGAAT | 399 |
53 | SACAS9KKH | E53SaCas9KKH33 | 31679576 | 31679604 | - | 35 | TTTTTCCTTTTATTCTAGTTGA | AAGAAT | 475 |
53 | SACAS9KKH | E53SaCas9KKH34 | 31679585 | 31679613 | - | 1078 | ATATATTTATTTTTCCTTTTAT | TCTAGT | 2133 |
53 | SLUCAS9KH | E53SLCas9KH1 | 31679353 | 31679379 | + | 201 | AAAGGTATCTTTGATACTAACC | TTGG | 13 |
53 | SLUCAS9KH | E53SLCas9KH2 | 31679373 | 31679399 | + | 202 | CCTTGGTTTCTGTGATTTTCTT | TTGG | 51 |
53 | SLUCAS9KH | E53SLCas9KH3 | 31679391 | 31679417 | + | 2075 | TCTTTTGGATTGCATCTACTGT | ATAG | 18 |
53 | SLUCAS9KH | E53SLCas9KH4 | 31679392 | 31679418 | + | 203 | CTTTTGGATTGCATCTACTGTA | TAGG | 12 |
53 | SLUCAS9KH | E53SLCas9KH5 | 31679393 | 31679419 | + | 204 | TTTTGGATTGCATCTACTGTAT | AGGG | 15 |
53 | SLUCAS9KH | E53SLCas9KH6 | 31679414 | 31679440 | + | 2076 | TAGGGACCCTCCTTCCATGACT | CAAG | 11 |
53 | SLUCAS9KH | E53SLCas9KH7 | 31679419 | 31679445 | + | 205 | ACCCTCCTTCCATGACTCAAGC | TTGG | 11 |
53 | SLUCAS9KH | E53SLCas9KH8 | 31679425 | 31679451 | + | 206 | CTTCCATGACTCAAGCTTGGCT | CTGG | 10 |
53 | SLUCAS9KH | E53SLCas9KH9 | 31679436 | 31679462 | + | 2077 | CAAGCTTGGCTCTGGCCTGTCC | TAAG | 16 |
53 | SLUCAS9KH | E53SLCas9KH10 | 31679446 | 31679472 | + | 2078 | TCTGGCCTGTCCTAAGACCTGC | TCAG | 18 |
53 | SLUCAS9KH | E53SLCas9KH11 | 31679458 | 31679484 | + | 2079 | TAAGACCTGCTCAGCTTCTTCC | TTAG | 16 |
53 | SLUCAS9KH | E53SLCas9KH12 | 31679465 | 31679491 | + | 2080 | TGCTCAGCTTCTTCCTTAGCTT | CCAG | 24 |
53 | SLUCAS9KH | E53SLCas9KH13 | 31679511 | 31679537 | + | 207 | ACATTTCATTCAACTGTTGCCT | CCGG | 15 |
53 | SLUCAS9KH | E53SLCas9KH14 | 31679519 | 31679545 | + | 2081 | TTCAACTGTTGCCTCCGGTTCT | GAAG | 6 |
53 | SLUCAS9KH | E53SLCas9KH15 | 31679520 | 31679546 | + | 208 | TCAACTGTTGCCTCCGGTTCTG | AAGG | 4 |
53 | SLUCAS9KH | E53SLCas9KH16 | 31679564 | 31679590 | + | 2082 | CACTGATTCTGAATTCTTTCAA | CTAG | 32 |
53 | SLUCAS9KH | E53SLCas9KH17 | 31679572 | 31679598 | + | 2083 | CTGAATTCTTTCAACTAGAATA | AAAG | 71 |
53 | SLUCAS9KH | E53SLCas9KH18 | 31679573 | 31679599 | + | 209 | TGAATTCTTTCAACTAGAATAA | AAGG | 48 |
53 | SLUCAS9KH | E53SLCas9KH19 | 31679589 | 31679615 | + | 2084 | GAATAAAAGGAAAAATAAATAT | ATAG | 574 |
53 | SLUCAS9KH | E53SLCas9KH20 | 31679592 | 31679618 | + | 2085 | TAAAAGGAAAAATAAATATATA | GTAG | 765 |
53 | SLUCAS9KH | E53SLCas9KH21 | 31679361 | 31679387 | - | 2086 | CACAGAAACCAAGGTTAGTATC | AAAG | 6 |
53 | SLUCAS9KH | E53SLCas9KH22 | 31679369 | 31679395 | - | 2087 | AAGAAAATCACAGAAACCAAGG | TTAG | 88 |
53 | SLUCAS9KH | E53SLCas9KH23 | 31679373 | 31679399 | - | 210 | CCAAAAGAAAATCACAGAAACC | AAGG | 52 |
53 | SLUCAS9KH | E53SLCas9KH24 | 31679374 | 31679400 | - | 2088 | TCCAAAAGAAAATCACAGAAAC | CAAG | 75 |
53 | SLUCAS9KH | E53SLCas9KH25 | 31679382 | 31679408 | - | 2089 | AGATGCAATCCAAAAGAAAATC | ACAG | 89 |
53 | SLUCAS9KH | E53SLCas9KH26 | 31679392 | 31679418 | - | 2090 | CCTATACAGTAGATGCAATCCA | AAAG | 4 |
53 | SLUCAS9KH | E53SLCas9KH27 | 31679406 | 31679432 | - | 2091 | ATGGAAGGAGGGTCCCTATACA | GTAG | 8 |
53 | SLUCAS9KH | E53SLCas9KH28 | 31679409 | 31679435 | - | 2092 | GTCATGGAAGGAGGGTCCCTAT | ACAG | 12 |
53 | SLUCAS9KH | E53SLCas9KH29 | 31679420 | 31679446 | - | 211 | GCCAAGCTTGAGTCATGGAAGG | AGGG | 10 |
53 | SLUCAS9KH | E53SLCas9KH30 | 31679421 | 31679447 | - | 212 | AGCCAAGCTTGAGTCATGGAAG | GAGG | 21 |
53 | SLUCAS9KH | E53SLCas9KH31 | 31679422 | 31679448 | - | 2093 | GAGCCAAGCTTGAGTCATGGAA | GGAG | 14 |
53 | SLUCAS9KH | E53SLCas9KH32 | 31679424 | 31679450 | - | 213 | CAGAGCCAAGCTTGAGTCATGG | AAGG | 18 |
53 | SLUCAS9KH | E53SLCas9KH33 | 31679425 | 31679451 | - | 2094 | CCAGAGCCAAGCTTGAGTCATG | GAAG | 18 |
53 | SLUCAS9KH | E53SLCas9KH34 | 31679428 | 31679454 | - | 214 | AGGCCAGAGCCAAGCTTGAGTC | ATGG | 23 |
53 | SLUCAS9KH | E53SLCas9KH35 | 31679434 | 31679460 | - | 2095 | TAGGACAGGCCAGAGCCAAGCT | TGAG | 17 |
53 | SLUCAS9KH | E53SLCas9KH36 | 31679440 | 31679466 | - | 2096 | AGGTCTTAGGACAGGCCAGAGC | CAAG | 23 |
53 | SLUCAS9KH | E53SLCas9KH37 | 31679445 | 31679471 | - | 2097 | TGAGCAGGTCTTAGGACAGGCC | AGAG | 27 |
53 | SLUCAS9KH | E53SLCas9KH38 | 31679447 | 31679473 | - | 2098 | GCTGAGCAGGTCTTAGGACAGG | CCAG | 35 |
53 | SLUCAS9KH | E53SLCas9KH39 | 31679451 | 31679477 | - | 215 | AGAAGCTGAGCAGGTCTTAGGA | CAGG | 44 |
53 | SLUCAS9KH | E53SLCas9KH40 | 31679452 | 31679478 | - | 2099 | AAGAAGCTGAGCAGGTCTTAGG | ACAG | 16 |
53 | SLUCAS9KH | E53SLCas9KH41 | 31679456 | 31679482 | - | 216 | AAGGAAGAAGCTGAGCAGGTCT | TAGG | 53 |
53 | SLUCAS9KH | E53SLCas9KH42 | 31679457 | 31679483 | - | 2100 | TAAGGAAGAAGCTGAGCAGGTC | TTAG | 25 |
53 | SLUCAS9KH | E53SLCas9KH43 | 31679463 | 31679489 | - | 217 | GGAAGCTAAGGAAGAAGCTGAG | CAGG | 70 |
53 | SLUCAS9KH | E53SLCas9KH44 | 31679464 | 31679490 | - | 2101 | TGGAAGCTAAGGAAGAAGCTGA | GCAG | 52 |
53 | SLUCAS9KH | E53SLCas9KH45 | 31679467 | 31679493 | - | 2102 | GGCTGGAAGCTAAGGAAGAAGC | TGAG | 41 |
53 | SLUCAS9KH | E53SLCas9KH46 | 31679472 | 31679498 | - | 2103 | ACAATGGCTGGAAGCTAAGGAA | GAAG | 27 |
53 | SLUCAS9KH | E53SLCas9KH47 | 31679475 | 31679501 | - | 2104 | AACACAATGGCTGGAAGCTAAG | GAAG | 18 |
53 | SLUCAS9KH | E53SLCas9KH48 | 31679478 | 31679504 | - | 218 | TTCAACACAATGGCTGGAAGCT | AAGG | 87 |
53 | SLUCAS9KH | E53SLCas9KH49 | 31679479 | 31679505 | - | 2015 | ATTCAACACAATGGCTGGAAGC | TAAG | 24 |
53 | SLUCAS9KH | E53SLCas9KH50 | 31679484 | 31679510 | - | 2016 | AAAGGATTCAACACAATGGCTG | GAAG | 12 |
53 | SLUCAS9KH | E53SLCas9KH51 | 31679487 | 31679513 | - | 219 | GTTAAAGGATTCAACACAATGG | CTGG | 12 |
53 | SLUCAS9KH | E53SLCas9KH52 | 31679491 | 31679517 | - | 220 | AAATGTTAAAGGATTCAACACA | ATGG | 37 |
53 | SLUCAS9KH | E53SLCas9KH53 | 31679505 | 31679531 | - | 221 | GCAACAGTTGAATGAAATGTTA | AAGG | 28 |
53 | SLUCAS9KH | E53SLCas9KH54 | 31679506 | 31679532 | - | 2107 | GGCAACAGTTGAATGAAATGTT | AAAG | 25 |
53 | SLUCAS9KH | E53SLCas9KH55 | 31679524 | 31679550 | - | 2108 | AACACCTTCAGAACCGGAGGCA | ACAG | 7 |
53 | SLUCAS9KH | E53SLCas9KH56 | 31679530 | 31679556 | - | 222 | TACAAGAACACCTTCAGAACCG | GAGG | 10 |
53 | SLUCAS9KH | E53SLCas9KH57 | 31679531 | 31679557 | - | 2109 | GTACAAGAACACCTTCAGAACC | GGAG | 10 |
53 | SLUCAS9KH | E53SLCas9KH58 | 31679533 | 31679559 | - | 223 | AAGTACAAGAACACCTTCAGAA | CCGG | 17 |
53 | SLUCAS9KH | E53SLCas9KH59 | 31679539 | 31679565 | - | 2110 | GGGATGAAGTACAAGAACACCT | TCAG | 18 |
53 | SLUCAS9KH | E53SLCas9KH60 | 31679550 | 31679576 | - | 2111 | TCAGAATCAGTGGGATGAAGTA | CAAG | 27 |
53 | SLUCAS9KH | E53SLCas9KH61 | 31679556 | 31679582 | - | 2112 | AAGAATTCAGAATCAGTGGGAT | GAAG | 27 |
53 | SLUCAS9KH | E53SLCas9KH62 | 31679562 | 31679588 | - | 224 | AGTTGAAAGAATTCAGAATCAG | TGGG | 95 |
53 | SLUCAS9KH | E53SLCas9KH63 | 31679563 | 31679589 | - | 225 | TAGTTGAAAGAATTCAGAATCA | GTGG | 33 |
53 | SLUCAS9KH | E53SLCas9KH64 | 31679566 | 31679592 | - | 2113 | TTCTAGTTGAAAGAATTCAGAA | TCAG | 43 |
53 | SLUCAS9KH | E53SLCas9KH65 | 31679572 | 31679598 | - | 2114 | CTTTTATTCTAGTTGAAAGAAT | TCAG | 61 |
53 | SLUCAS9KH | E53SLCas9KH66 | 31679579 | 31679605 | - | 2115 | ATTTTTCCTTTTATTCTAGTTG | AAAG | 122 |
53 | SLUCAS9KH | E53SLCas9KH67 | 31679586 | 31679612 | - | 2116 | TATATTTATTTTTCCTTTTATT | CTAG | 978 |
在一些實施例中,AAV載體及/或其組合物包含單一核酸分子,該單一核酸分子包含:i)編碼金黃色葡萄球菌Cas9 (SaCas9)或路鄧葡萄球菌(SluCas9)之核酸及至少一個、至少兩個或至少三個嚮導RNA;或ii)編碼金黃色葡萄球菌Cas9 (SaCas9)或路鄧葡萄球菌(SluCas9)之核酸及一至n個嚮導RNA,其中n不超過可自該核酸表現之嚮導RNA的最大數目;或iii)編碼金黃色葡萄球菌Cas9 (SaCas9)或路鄧葡萄球菌(SluCas9)之核酸及一至三個嚮導RNA。
在一些實施例中,AAV載體及/或其組合物包含至少兩個核酸分子,該等至少兩個核酸分子包含編碼金黃色葡萄球菌Cas9 (SaCas9)或路鄧葡萄球菌(SluCas9)之第一核酸;及不編碼SaCas9或SluCas9且編碼以下中之任一者的第二核酸:i)至少一個、至少兩個、至少三個、至少四個、至少五個或至少六個嚮導RNA;或ii)一至n個嚮導RNA,其中n不超過可自該核酸表現之嚮導RNA的最大數目;或iii)一至六個嚮導RNA。
在一些實施例中,AAV載體及/或其組合物包含至少兩個核酸分子,該等至少兩個核酸分子包含第一核酸,其編碼金黃色葡萄球菌Cas9 (SaCas9)或路鄧葡萄球菌(SluCas9)及i)至少一個、至少兩個或至少三個嚮導RNA;或ii)一至n個嚮導RNA,其中n不超過可自該核酸表現之嚮導RNA的最大數目;或iii)一至三個嚮導RNA;以及第二核酸,其不編碼SaCas9或SluCas9,視情況其中第二核酸包含以下中之任一者:i)至少一個、至少兩個、至少三個、至少四個、至少五個或至少六個嚮導RNA;或ii)一至n個嚮導RNA,其中n不超過可自該核酸表現之嚮導RNA的最大數目;或iii)一至六個嚮導RNA。
在一些實施例中,AAV載體及/或其組合物包含至少兩個核酸分子,該等至少兩個核酸分子包含編碼金黃色葡萄球菌Cas9 (SaCas9)或路鄧葡萄球菌(SluCas9)及至少一個、至少兩個或至少三個嚮導RNA之第一核酸;及不編碼SaCas9或SluCas9且編碼一至六個嚮導RNA之第二核酸。
在一些實施例中,AAV載體及/或其組合物包含至少兩個核酸分子,該等至少兩個核酸分子包含編碼金黃色葡萄球菌Cas9 (SaCas9)或路鄧葡萄球菌(SluCas9)及至少兩個嚮導RNA之第一核酸,其中至少一個嚮導RNA結合所切除序列之上游且至少一個嚮導RNA結合所切除序列之下游;及不編碼SaCas9或SluCas9且編碼在第一核酸中編碼之嚮導RNA之至少一個額外複本的第二核酸。在一些實施例中,嚮導RNA切除DMD基因之一部分,視情況切除外顯子、內含子或外顯子/內含子接合點。
在一些實施例中,提供包含至少兩個核酸分子、由其組成或基本上由其組成之組合物,該等至少兩個核酸分子包含第一核酸,其編碼金黃色葡萄球菌Cas9 (SaCas9)或路鄧葡萄球菌(SluCas9)及用於切除DMD基因之一部分的第一及第二嚮導RNA;及第二核酸,其編碼第一嚮導RNA之至少2個或至少3個複本及第二嚮導RNA之至少2個或至少3個複本。
在一些實施例中,提供包含一或多個編碼核酸內切酶之核酸分子及嚮導RNA對、由其組成或基本上由其組成之組合物,其中各嚮導RNA靶向DMD基因中之不同序列,其中核酸內切酶及嚮導RNA對能夠切除DNA中長度在5至250個核苷酸之間的標靶序列。在一些實施例中,核酸內切酶為2類、II型Cas核酸內切酶。在一些實施例中,2類、II型Cas核酸內切酶為SpCas9、SaCas9或SluCas9。在一些實施例中,核酸內切酶為2類、V型Cas核酸內切酶。在一些實施例中,所切除之標靶序列包含剪接受體部位或剪接供體部位。在一些實施例中,所切除之標靶序列包含DMD基因中之過早終止密碼子。在一些實施例中,所切除之標靶序列不包含DMD基因之整個外顯子。在一些實施例中,本文中所揭示之方法及/或核糖核蛋白複合物中之任一者不破壞/特異性地改變剪接受體部位、剪接供體部位或過早終止密碼子部位之序列。
III. 方法
本文揭示包含(a)向個體投與阻斷AAV結合至肝臟中之AAV受體(AAVR)之藥劑,及隨後(b)向個體投與AAV載體的方法。
本文揭示包含增加個體中遞送至非肝臟標靶之AAV之百分比的方法,其包含(a)包含向個體投與組合物之預處理步驟,該組合物包含阻斷AAV結合至肝臟中之AAV受體(AAVR)之藥劑,及隨後(b)投與靶向非肝臟組織之AAV載體。舉例而言,在處理或預處理方案中包括此類組合物可減少肝臟感染性、保護肝臟健康且增加對標靶組織之效力。
本文中所揭示之方法可用於改良個體中AAV對非肝臟標靶之趨性,該等方法包含向個體投與組合物,該組合物包含阻斷AAV結合至AAV受體(AAVR)之藥劑及將藥劑遞送至肝臟之遞送分子,及隨後投與AAV載體,其中AAV載體不意欲靶向肝臟。
本文中所揭示之方法亦可用於降低個體中AAV向肝臟之趨性,該等方法包含向個體投與組合物,該組合物包含阻斷AAV結合至包含小分子或大分子之AAV受體(AAVR)的藥劑及將藥劑遞送至肝臟之遞送分子,及隨後投與AAV載體,其中AAV載體不意欲用於肝臟。在一些實施例中,投與包含阻斷AAV結合至AAV受體之藥劑的組合物增加遞送至非肝臟標靶之AAV的百分比。
在一些實施例中,方法包含投與阻斷AAV結合至AAV受體(AAVR)之藥劑及將藥劑遞送至肝臟且誘導AAV結合至AAVR之長期阻斷(例如長於約3週)的遞送分子。在一些實施例中,對AAV結合至肝臟中之AAV受體的阻斷並非暫時的。在一些實施例中,對AAV結合至肝臟中之AAV受體的阻斷為暫時的。
在一些實施例中,向有需要之個體投與用於阻斷AAV結合至肝臟中之AAV受體的組合物發生在投與基於非肝臟AAV之基因療法之前,例如在投與AAV之前至少約3週、至少約4週、至少約5週、至少約6週、至少約7週、至少約8週、至少約9週或至少約10週。在特定實施例中,在投與本文中所揭示之AAV中之任一者之前,向個體投與阻斷與肝臟中之AAV受體結合之藥劑(例如本文中所揭示之siRNA或ASO中之任一者)1至2、1至3、2至5、4至7、6至9、8至11、10至13或12至15天。在一些實施例中,阻斷AAV結合至AAV受體(AAVR)之組合物包含siRNA。在一些實施例中,阻斷AAV結合至AAV受體(AAVR)之組合物包含ASO。在一些實施例中,阻斷AAV結合至AAV受體(AAVR)之組合物包含阻斷AAV結合至AAV受體之抗AAV抗體。在一些實施例中,阻斷AAV結合至AAV受體(AAVR)之組合物包含非RNAi及非抗體抑制劑。在一些實施例中,組合物包含至少一種小分子抑制劑或反義寡核苷酸。
如上文所詳細闡述,用於阻斷AAV結合至肝臟中之AAV受體之組合物包括(但不限於)包含對AAVR具有特異性之RNAi的組合物及包含靶向AAVR編碼轉錄本之反義寡核苷酸(ASO)的組合物。
在一些實施例中,在眼、大腦、脊髓、肺、皮下組織、陰道、皮膚、經分離之腫瘤、心臟等之動物實驗中,全身性或局部遞送之siRNA在48小時至3週誘導至多90%之暫時基因表現減弱作用。參見Kim, Korean J Anesthesiol. 59(6): 369-370 (2010)。靶向肝臟(包括藉助於經結合之siRNA及siRNA-LNP靶向遞送)之小干擾RNA可暫時阻斷AAV結合至肝臟中之AAVR。在投與靶向肝臟之siRNA且誘導AAVR之暫時阻斷後,可投與基於非肝臟AAV之基因療法。
在一些實施例中,根據本文中所呈現之實例及圖式,全身性或局部遞送之ASO經遞送以在約24小時至約48小時至大於或約10天誘導約50%、約60%、約70%或約80%之暫時基因表現減弱作用。在投與ASO且誘導AAVR之暫時減弱後,可投與基於非肝臟AAV之基因療法。
基於非肝臟AAV之基因療法增強,因為基因療法可藉助於降低AAV向肝臟之趨性更有效地引導至預期標靶。因為已展示AAVR可顯著促進AAV載體轉導效率及趨性且已展示直接結合至AAV粒子且對病毒轉導具有速率限制,所以阻斷AAVR減少AAV向此等細胞(例如肝細胞)之趨性。藉由降低AAV向肝臟之趨性,基於非肝臟AAV之基因療法由於降低之脫靶肝毒性風險而增強或改良。因此,在一些實施例中,向個體投與阻斷AAV結合至AAV受體(AAVR)之藥劑暫時阻斷AAV結合至肝臟中之AAV受體。在一些實施例中,與用AAV治療但未用藥劑治療之個體相比,a)用阻斷AAV結合至AAV受體(AAVR)之藥劑治療且b)隨後用AAV治療的個體展現肝臟內之AAV含量減少至少10%、20%、30%、40%、50%、60%、70%、80%、90%、95%或99%。
在一些實施例中,方法包括投與能夠暫時阻斷AAV結合至肝臟中之AAVR受體之siRNA或ASO,包括持續約48小時至3週。在一些實施例中,siRNA或ASO阻斷AAV結合至肝臟中之AAVR受體持續約2天、約3天、約4天、約5天、約6天、約7天、約8天、約9天、約10天、約11天、約12天、約13天、約14天、約15天、約16天、約17天、約18天、約19天、約20天或約21天。在一些實施例中,siRNA或ASO阻斷AAV結合至肝臟中之AAVR受體持續約7天、約8天、約9天、約10天、約11天、約12天、約13天、約14天。在一些實施例中,組合物能夠阻斷AAV結合至肝臟中之AAVR受體持續1至28天、2至28天、3至28天、7至28天、10至28天、14至28天、21至28天、1至21天、2至21天、3至21天、7至21天、10至21天、14至21天、1至14天、2至14天、3至14天、7至14天、1至10天、2至10天、3至10天、7至10天、1至7天、2至7天、3至7天、1至4天、1至3天或約24小時至約48小時。
在一些實施例中,siRNA或ASO減弱AAVR且包含與來自AAVR之核糖核苷酸序列至少80%一致之核糖核苷酸序列。較佳地,siRNA或ASO分子與標靶之核糖核苷酸序列至少90%、95%、96%、97%、98%、99%或100%一致。最佳地,siRNA或ASO將與標靶藥劑或病毒之核苷酸序列100%一致。然而,相對於標靶具有插入、缺失或單點突變之siRNA或ASO分子亦可為有效的。用以輔助siRNA設計或ASO設計之工具可容易地為公眾所獲得且為此項技術中已知的。
在一些實施例中,向個體投與使肝臟中之AAVR含量與未投與siRNA之對照個體相比減弱至少10%、20%、30%、40%、50%、60%、70%、80%、90%、95%或99%之量的siRNA。在一些實施例中,向個體投與使肝臟中之AAVR含量與未投與siRNA之對照個體相比減弱至少80%至100%、80%至95%、10%至90%、10%至70%、10%至50%、10%至30%、30%至90%、30%至70%、30%至50%、50%至90%、50%至70%或70%至90%之量的siRNA。
在一些實施例中,向個體投與使肝臟中之AAVR含量減弱持續1至28天、2至28天、3至28天、7至28天、10至28天、14至28天、21至28天、1至21天、2至21天、3至21天、7至21天、10至21天、14至21天、1至14天、2至14天、3至14天、7至14天、1至10天、2至10天、3至10天、7至10天、1至7天、2至7天、3至7天、1至4天、1至3天或約24小時至約48小時之量的siRNA。
在一些實施例中,向個體投與使肝臟中之AAVR含量與未投與ASO之對照個體相比減弱至少10%、20%、30%、40%、50%、60%、70%、80%、90%、95%或99%之量的ASO。在一些實施例中,向個體投與使肝臟中之AAVR含量與未投與ASO之對照個體相比減弱至少80%至100%、80%至95%、10%至90%、10%至70%、10%至50%、10%至30%、30%至90%、30%至70%、30%至50%、50%至90%、50%至70%或70%至90%之量的ASO。
在一些實施例中,向個體投與使肝臟中之AAVR含量減弱持續1至28天、2至28天、3至28天、7至28天、10至28天、14至28天、21至28天、1至21天、2至21天、3至21天、7至21天、10至21天、14至21天、1至14天、2至14天、3至14天、7至14天、1至10天、2至10天、3至10天、7至10天、1至7天、2至7天、3至7天、1至4天、1至3天或約24小時至約48小時之量的ASO。在一些實施例中,向個體投與使肝臟中之AAVR含量減弱持續1至14天、2至14天、3至14天、7至14天、1至10天、2至10天、3至10天、7至10天、1至7天、2至7天、3至7天、1至4天、1至3天或約24小時至約48小時之量的ASO。
在一些實施例中,方法包括投與阻斷AAV結合至AAV受體(AAVR)之藥劑(例如siRNA或ASO),該AAV受體結合至肝臟靶向部分。在一些實施例中,方法增強其遞送及/或肝臟吸收。在一些實施例中,方法包括投與結合至脂質(諸如膽固醇)之siRNA或ASO。在一些實施例中,方法包括投與結合至至少一種半乳糖或半乳糖衍生物之siRNA或ASO,該至少一種半乳糖或半乳糖衍生物包括(但不限於)乳糖、半乳糖、N-乙醯基半乳胺糖(GalNAc)、半乳胺糖、N-甲醯基半乳胺糖、N-乙醯基半乳胺糖、N-丙醯基半乳胺糖、N-正丁醯基半乳胺糖及N-異丁醯基-半乳胺糖(Iobst, ST及Drickamer, K. JBC 1996, 271 , 6686)。在一些實施例中,方法包括投與結合GalNAc之siRNA。
在一些實施例中,方法包括投與包含阻斷AAV結合至AAV受體(AAVR)之藥劑的組合物,該藥劑係藉由非病毒組織特異性遞送媒劑遞送,該等遞送媒劑包括(但不限於)奈米粒子、脂質體、核糖核蛋白、帶正電肽、小分子RNA-結合物、適體-RNA嵌合體及RNA-融合蛋白複合物。在一些實施例中,藥劑係藉由脂質奈米粒子(LNP)遞送至細胞或患者。在一些實施例中,方法包括投與包含囊封於LNP中之siRNA的組合物。在一些實施例中,藥劑在不結合及/或無非病毒組織特異性遞送媒劑之情況下遞送至細胞或患者。在一些實施例中,方法包括投與包含ASO及醫藥學上可接受之載劑(例如,磷酸鹽緩衝鹽水(PBS))之組合物。
用於阻斷AAV結合至肝臟中之AAV受體的組合物(例如經結合之siRNA或siRNA-LNP遞送系統或ASO)之例示性投藥模式包括經口投與、非經腸投與、藉由注射進行之投與(例如靜脈內、皮下、肌內、鞘內(IT)、腦室內(ICV)等),及任何其他適合之投藥模式。在一些實施例中,用於阻斷AAV結合至肝臟中之AAV受體之藥劑(例如siRNA或ASO)及其組合物的投與包括眼內投與,諸如玻璃體內、視網膜內、視網膜下、結膜下、眶周及眶後、經角膜及經鞏膜投與。在一些實施例中,可藉由靜脈內注射、皮下注射、經口遞送、脂質體遞送或鼻內遞送向患者投與藥劑。藥劑隨後可積聚於患者之標靶身體系統、器官、組織或細胞類型中。
在一些實施例中,促進肝臟中之藥劑(例如siRNA)吸收增加的其他藥物亦可與結合至肝臟靶向部分之藥劑(例如siRNA)共同投與。在一些實施例中,方法包含共同投與結合膽固醇之藥劑(例如siRNA)與斯他汀(statin)類藥物以阻斷AAV結合至肝臟中之AAVR。在一些實施例中,斯他汀類藥物可與膽固醇藥劑共同投與以增強肝臟中結合膽固醇之藥劑的吸收。關於共同投與斯他汀類藥物與膽固醇-siRNA以增加肝臟肝細胞表面上之LDL受體之表現的一般論述參見US20150361432A1。由於LDL受體表現增加,血漿中之膽固醇含量降低。在不希望受理論所束縛之情況下,藉由投與斯他汀類藥物,血漿中之競爭膽固醇之含量降低且肝臟中之結合膽固醇-藥劑之LDL受體的含量增加,此允許肝細胞對經膽固醇標記之藥劑的吸收更有效。可在投與膽固醇-藥劑之前、同時或之後投與斯他汀。
在一些實施例中,方法包括投與AAV載體,其包括本文中所描述之AAV載體中之任一者。在一些實施例中,AAV載體靶向非肝臟組織。在一些實施例中,方法包含在接受或投與針對非肝臟標靶組織之AAV載體或基於AAV之基因療法之前,向個體投與包含阻斷AAV結合至AAV受體(AAVR)之藥劑的組合物作為預處理治療之部分。在一些實施例中,在投與針對非肝臟標靶組織之AAV載體或基於AAV之基因療法之前,向個體投與用於阻斷AAV結合至肝臟中之AAV受體的組合物至少一次。在一些實施例中,在基於AAV之基因療法之前,向個體投與用於阻斷AAV結合至肝臟中之AAV受體的組合物至少一次作為可包括投與其他藥劑之預處理方案之部分。
在特定實施例中,不向個體投與阻斷AAV結合至AAV載體之藥劑,同時投與AAV。
在一些實施例中,本發明提供在投與AAV載體之前約2天、約3天、約4天、約5天、約6天、約7天、約8天、約9天、約10天、約11天、約12天、約13天、約14天、約15天、約16天、約17天、約18天、約19天、約20天或約21天,向個體投與包含阻斷AAV結合至AAV受體(AAVR)之藥劑(例如siRNA或ASO)的組合物。在一些實施例中,本發明提供向個體投與包含阻斷AAV結合至AAV受體(AAVR)之藥劑的組合物發生在投與AAV載體之前約2至21、10至21、14至21、2至17、10至17、1至14天、2至14天、3至14天、7至14天、1至10天、2至10天、3至10天、7至10天、1至7天、2至7天、3至7天、1至4天或1至3天,或約24小時至約48小時。在一些實施例中,投與包含阻斷AAV結合至AAV受體(AAVR)之藥劑的組合物發生在投與AAV載體之前約1天、約2天、約3天、約4天、約5天、約6天、約7天、約8天、約9天、約10天、約11天、約12天、約13天或約14天。在一些實施例中,投與包含阻斷AAV結合至AAV受體(AAVR)之藥劑的組合物發生在投與AAV載體之前約24小時至約48小時。在一些實施例中,在投與AAV之前,向個體投與超過一次劑量(例如2、3或4次)之阻斷AAV結合至AAVR之藥劑。
在一些實施例中,投與包含阻斷AAV結合至AAV受體(AAVR)之藥劑(例如siRNA或ASO)的組合物緊接在投與靶向非肝臟組織之AAV載體之前。在一些實施例中,共同投與包含阻斷AAV結合至AAV受體(AAVR)之藥劑的組合物及AAV載體。
基於非肝臟AAV之基因療法包括治療或預防有需要之個體中之不為肝臟疾病或病症之疾病或病症,諸如遺傳疾病或病症。在一些實施例中,AAV載體意欲用於大腦;中樞神經系統;脊髓;眼;視網膜;骨;心肌、骨骼肌及/或平滑肌;肺;胰臟;心臟;及/或腎臟。在一些實施例中,AAV載體意欲用於心肌、骨骼肌及/或平滑肌。
在一些實施例中,方法引起遞送至非肝臟標靶之AAV之百分比增加。在一些實施例中,方法使得接受阻斷AAV結合至肝臟中之AAV受體(AAVR)之藥劑的個體之大腦、中樞神經系統、脊髓、眼、視網膜、骨、心肌、骨骼肌及/或平滑肌、肺、胰臟、心臟及/或腎臟中之AAV,及隨後與接受AAV但未接受阻斷AAV結合至肝臟中之AAV受體(AAVR)之藥劑的對照個體之相應組織中之AAV相比的AAV,增加至少10%、30%、50%、75%、100%、125%、150%、200%、250%、300%、350%、400%、450%、500%、600%、700%、800%、900%或1000%。在一些實施例中,方法使得接受阻斷AAV結合至肝臟中之AAV受體(AAVR)之藥劑的個體之大腦、中樞神經系統、脊髓、眼、視網膜、骨、心肌、骨骼肌、平滑肌、肺、胰臟、心臟及/或腎臟中之AAV,及隨後與接受AAV但未接受阻斷AAV結合至肝臟中之AAV受體(AAVR)之藥劑的對照個體之相應組織中之AAV相比的AAV,增加10%至50%、50%至100%、100%至250%、250%至500%、500%至750%、750%至1000%或1000%至2000%。在一些實施例中,方法使得接受阻斷AAV結合至肝臟中之AAV受體(AAVR)之藥劑的個體之骨骼肌中之AAV,及隨後與接受AAV但未接受藥劑之對照個體的肌肉中之AAV相比的AAV,增加至少10%、30%、50%、75%、100%、125%、150%、200%、250%、300%、350%、400%、450%、500%、600%、700%、800%、900%或1000%。在一些實施例中,方法使得接受阻斷AAV結合至肝臟中之AAV受體(AAVR)之藥劑的個體之骨骼肌中之AAV,及隨後與接受AAV但未接受藥劑之對照個體的肌肉中之AAV相比的AAV,增加10%至50%、50%至100%、100%至250%、250%至500%、500%至750%、750%至1000%或1000%至2000%。
在一些實施例中,基於非肝臟AAV之基因療法係用於遺傳疾病或病症,其中病症為肌肉疾病或病症。肌肉疾病或病症可選自例如,杜興氏肌肉失養症(Duchenne Muscular Dystrophy;DMD)、貝克氏肌肉失養症(Becker muscular dystrophy;BMD)、埃-德二氏肌肉失養症(Emery-Dreifuss dystrophy)、肌強直性營養不良、肢帶肌肉失養症、眼咽肌肉失養症、先天性肌肉失養症、家族週期性麻痹。在一些實施例中,肌肉疾病或病症可為粒線體氧化磷酸化病症或肝醣貯積病(例如傑耳凱氏病(von Gierke's disease)、龐貝氏病(Pompe's disease)、福貝斯-柯里氏病(Forbes-Cori disease)、安德森病(Andersen's disease)、麥卡德爾氏病(McArdle's disease)、赫爾斯氏病(Hers'disease)、塔瑞斯氏病(Tarui's disease)或範可尼-比克爾症候群(Fanconi-Bickel syndrome)。在特定實施例中,基於非肝臟AAV之基因療法係用於治療DMD。在一些實施例中,基於非肝臟AAV之基因療法係用於治療肌強直性營養不良。
在一些實施例中,方法包括投與具有非肝臟標靶之單一AAV載體或多種AAV載體。在一些實施例中,方法包含投與AAV1、AAV2、AAV3、AAV4、AAV5、AAV6、AAV7、AAV8、AAVrh10、AAVrh74、AAV9、AAV9P或Myo-AAV載體。在一些實施例中,方法包括投與AAV載體,其為重組或經工程改造之AAV載體。在一些實施例中,AAV載體包含組織特異性(例如肌肉特異性)啟動子,例如其可操作地連接至編碼嚮導RNA之序列。在較佳實施例中,AAV載體自ITR至ITR (包括兩個ITR)之尺寸小於5 kb。在特定實施例中,AAV載體自ITR至ITR (包括兩個ITR)之尺寸小於4.9 kb。在其他實施例中,AAV載體自ITR至ITR (包括兩個ITR)之尺寸小於4.85 kb。在其他實施例中,AAV載體自ITR至ITR (包括兩個ITR)之尺寸小於4.8 kb。在其他實施例中,AAV載體自ITR至ITR (包括兩個ITR)之尺寸小於4.75 kb。在其他實施例中,AAV載體自ITR至ITR (包括兩個ITR)之尺寸小於4.7 kb。在一些實施例中,載體自ITR至ITR (包括兩個ITR)之尺寸在3.9至5 kb、4至5 kb、4.2至5 kb、4.4至5 kb、4.6至5 kb、4.7至5 kb、3.9至4.9 kb、4.2至4.9 kb、4.4至4.9 kb、4.7至4.9 kb、3.9至4.85 kb、4.2至4.85 kb、4.4至4.85 kb、4.6至4.85 kb、4.7至4.85 kb、4.7至4.9 kb、3.9至4.8 kb、4.2至4.8 kb、4.4至4.8 kb或4.6至4.8 kb之間。在一些實施例中,載體自ITR至ITR (包括兩個ITR)之尺寸在4.4至4.85 kb之間。在一些實施例中,載體為AAV9載體。
在一些實施例中,AAV載體及基於AAV之基因療法涉及投與CRISPR-Cas組分,其任一者為此項技術中已知的。在一些實施例中,方法包括投與一或多種AAV載體,其包含編碼Cas9蛋白之核酸。此類實施例包括例如,包含編碼金黃色葡萄球菌(SaCas9)及/或路鄧葡萄球菌(SluCas9)之核酸且進一步包含編碼一或多個嚮導RNA之核酸的一或多種AAV載體。在此類實施例中,編碼Cas9蛋白之核酸處於CK8e啟動子之控制下。在一些實施例中,編碼嚮導RNA序列之核酸處於hU6c啟動子之控制下。在一些實施例中,載體為AAV9。在一些實施例中,除嚮導RNA及Cas9序列之外,載體進一步包含不編碼嚮導RNA之核酸。在一些實施例中,載體包含一或多個編碼crRNA、trRNA或crRNA及trRNA之核苷酸序列。適用於本發明方法之不同AAV組合物之論述,包括例示性嚮導RNA、啟動子及特定間隔子序列揭示於WO2022/056000及本文中之其他地方。
在特定實施例中,非肝臟標靶為肌肉,且方法包含在向個體投與阻斷AAV結合至肝臟中之AAV受體(AAVR)之藥劑之後向個體投與AAV載體。在特定實施例中,方法包含在包含向個體投與組合物之預處理步驟之後投與靶向肌肉之AAV載體,該組合物包含阻斷AAV結合至肝臟中之AAV受體(AAVR)之藥劑,其中預處理步驟增加遞送至非肝臟標靶之AAV之百分比。在特定實施例中,基於非肝臟AAV之基因療法係用於治療DMD。在此類實施例中,嚮導RNA包含作為非限制性實例之下表1A、表1B及表2中所揭示之嚮導序列。舉例而言,當AAV載體包含SaCas9時,一或多個間隔子序列係選自SEQ ID NO: 1至35、1000至1078及3000至3069中之任一者;或當AAV載體包含SluCas9時,一或多個間隔子序列係選自SEQ ID NO: 100至225、2000至2116及4000至4251中之任一者。
在一些實施例中,方法包括投與AAV載體,該等AAV載體進一步包含用於增強對標靶宿主細胞或組織之趨性的分子。血管內皮及其他標靶細胞類型對AAV之吸收可進一步藉由使用AAV增強,該等AAV進一步包含用於增強特定標靶宿主細胞之載體之趨性的一或多個分子。在一些實施例中,用於增強趨性之一或多個分子為蛋白質。在一些實施例中,用於增強病毒載體之趨性之一或多個分子為肽。在一些實施例中,一或多個肽將病毒載體靶向在與所治療之特定遺傳疾病或病症相關之細胞中上調之蛋白質。此類肽及蛋白質為此項技術中已知的,其用於增強針對標靶宿主細胞之趨性且可經由此項技術中已知的各種方法中之任一者併入至AAV中。
基於非肝臟AAV之基因療法的例示性投藥模式包括經口、經直腸、經黏膜、體表、經皮、吸入、非經腸(例如靜脈內、皮下、皮內、肌內及關節內,以及直接組織或器官注射,或者鞘內、直接肌內、心室內、靜脈內、腹膜內、鼻內或眼內注射)。可注射劑可呈習知形式以液體溶液或懸浮液形式、以適合於在注射之前在液體中形成溶液或懸浮液之固體形式或以乳液形式製備。或者,病毒可局部投與,例如以儲存物或持續釋放調配物形式投與。
在一些實施例中,個體為人類個體。在一些實施例中,個體正針對不為肝臟疾病或病症之遺傳疾病或病症進行治療。在一些實施例中,個體正針對肌肉疾病或病症進行治療。在一些實施例中,個體已或正用基於非肝臟AAV之基因療法治療。
實例
以下實例係為了說明某些所揭示之實施例而提供且不應解釋為以任何方式限制本發明之範疇。
1. 實例 1 : 抗 AAVR siRNA 對細胞模型中之 AAV 感染力之作用的研究
為評估投與抗AAVR siRNA及ASO對肝臟細胞中之AAV感染力的作用,用靶向AAVR之siRNA (抗AAVR siRNA)、ASO或對照組轉染肝臟細胞模型。使細胞裂解以用於mRNA及蛋白質提取,隨後進行qRT-PCR (mRNA)分析及西方墨點分析(蛋白質)來評估AAVR mRNA減弱之程度。
a) 劑量反應 ( CRO ) :
在96孔組織培養盤中以20k個細胞/孔之密度接種Hepa1-6細胞。使用脂染胺2000 (Invitrogen 11668027)立即用10種不同劑量之靶向mmAu040320 (小鼠AAVR基因)之siRNA轉染細胞。針對標靶mRNA設計Quantigene 2.0分支鏈DNA (bDNA)探針組。將相對mmAu040320/mmGAPDH比率相對於經模擬處理之細胞中之各別平均比率標準化且用對照靶向siRNA轉染細胞。
圖1A至圖1J展示siRNA濃度對相對mRNA表現之作用且展示表A1至表A3中所評估及闡述之10個siRNA序列中之各者的10點劑量反應曲線。表現最佳之mmAu040320靶向siRNA係用於後續研究中。
b) 用 ASO 及 siRNA 減弱小鼠肌母細胞中之 AAVR :
在96孔組織培養盤中以每孔14.4k接種C2C12 (小鼠肌母細胞)細胞。遵循製造商之方案,次日用經RNAiMax調配之50 nM ASO或10 nM siRNA處理細胞。遵循製造商之方案,在48小時之後,使用Cells-to-CT套組裂解細胞。在多重反應中,藉由TaqMan分析法量測mRNA含量,使用β肌動蛋白作為持家對照基因用於樣品間之標準化。使用來自Cells-to-CT 1步TaqMan套組(Invitrogen A25603)之預混物(mastermix)在Quantstudio 6 flex上進行qPCR。根據使用者手冊,針對各RNA樣品以技術性重複三次之方式進行20 μl反應。將2 μl細胞溶解產物添加至各反應中,且使用Taqman探針(小鼠):AAVR:FAM Mm00460200_m1及肌動蛋白-β (Act-B):VIC Mm02619580_g1。進行ΔΔCt (Delta Delta Ct)分析以發現樣品相對於未經處理之對照樣品的倍數變化。
圖2展示相對於C2C12 (小鼠肌母細胞)細胞中未經處理之細胞及β-肌動蛋白標準化之變化量。
c) 用 siRNA 及 ASO 減弱肝臟細胞株中之 AAVR mRNA
在96孔組織培養盤中以每孔15k接種Huh7細胞且使其在補充有10% FBS及PenStrap之生長培養基DMEM中生長隔夜。次日,用10至200 nM之ASO或siRNA對照組(靶向AAVR之siRNAVT011為陽性對照;及非靶向siRNA作為陰性對照)對細胞進行給藥。遵循製造商之方案(www.thermofisher.com/order/catalog/product/13778150),將ASO與Opti-MEM (GIBCO 31985062)混合且與脂染胺RNAiMAx轉染劑(Invitrogen 13778150)之混合物組合,並在室溫下培育15分鐘。靜置未經處理之細胞直至更換培養基。在48小時之後溶解細胞以用於mRNA分析。使用來自Cells-to-CT 1步TaqMan套組(Invitrogen A25603)之溶解緩衝液溶解細胞。使用來自Cells-to-CT 1步TaqMan套組(Invitrogen A25603)之預混物在Quantstudio 6 flex上進行qPCR。根據使用者手冊,針對各RNA樣品以技術性重複兩次之方式進行20 μl反應。將2 μl溶解產物添加至各反應中,且使用Taqman探針(人類):AAVR:FAM Hs00967343_m1及肌動蛋白-β:VIC Hs01060665_g1。進行ΔΔCt分析以發現相對於未經處理之對照樣品的倍數變化。
圖3展示與未經處理之Huh7細胞以及陰性及陽性對照組相比,7種不同ASO對AAVR減弱之作用。
d) ASO 對肝臟細胞株中之 AAVR mRNA 及蛋白質之作用
細胞處理及收穫:自12孔盤收集樣品。以每孔15k接種細胞且在37℃及5% CO2下生長隔夜。根據製造商之程序,使用RNAiMax脂染胺(Invitrogen 13778150)用ASO (50 nM)或siRNA (10 nM)轉染細胞。在給藥後的48小時及168小時更換培養基。
在各時間點收穫樣品。用DPBS洗滌細胞且在37℃及5% CO2下用TrypLE™ Express酶培育5分鐘。一旦分離,則用DMEM中和TrypLE且將細胞轉移至試管中且以1000 rpm粒化5分鐘。移除培養基且將細胞再懸浮於1 mL DPBS中。將100 μL移至新試管中。將新試管及原始試管兩者中之細胞粒化並移除DPBS。經下文進一步描述,使用100 μL試管用於評估mRNA,且使用900 μL試管用於評估蛋白質。在-80℃下儲存細胞集結粒直至處理。
西方墨點法 ( 蛋白質 ):將集結粒再懸浮於冰冷之提取緩衝液:補充有cOmplete™ (微型蛋白酶抑制劑混合物) (Roche)之RIPA緩衝液中。預清除蛋白質提取物(4℃,14,000 G,15分鐘)。遵循製造商之方案(assets.thermofisher.com/TFS-Assets/LSG/manuals/MAN0011430_ Pierce_BCA_Protein_Asy_UG.pdf),藉由Pierce BCA分析法(ThermoFisher, 23227)來量測蛋白質含量。用提取緩衝液將所有樣品稀釋至0.33 mg/mL或最低樣品濃度。
用10 μg與負載緩衝液混合之蛋白質提取物負載4至12% Bis-Tris plus凝膠(Invitrogen第NW04120BOX號)。在+4℃下於MOPS緩衝液中處理凝膠且使用轉移裝置及乾式轉移設備(Trans-Blot Turbo轉移系統上之高分子量設定,Bio-Rad)將蛋白質轉移至硝化纖維素(Trans-Blot轉移包,1704158,Bio-Rad)膜中。遵循製造商之方案(Thermos Scientific, J63139),使用麗春紅(Ponceau)染色劑檢查轉移,在50至75 kDA標記物之間切割膜且在4℃下於5%牛奶中阻斷隔夜。
用TBST洗滌膜且與初級抗體在室溫下培育4小時以用於AAVR (1:2000; 21016-1-AP, Proteintech)或β-肌動蛋白偵測(1:1000; 13E5, Cell Signaling)。接著,用TBST洗滌樣品且與結合HRP之二級抗體(1:200,000; 31460, Thermofisher)在室溫下培育1小時,用TBST洗滌三次且用超靈敏增強型化學發光受質(SuperSignal™ West Femto最高靈敏度受質, 34095, Thermofisher)視覺化。
mRNA qPCR:使用來自Cells-to-CT 1步TaqMan套組(Invitrogen A25603)之溶解緩衝液溶解細胞。使用來自Cells-to-CT 1步TaqMan套組(Invitrogen A25603)之預混物在Quantstudio 6 flex上進行qPCR。根據使用者手冊,針對各RNA樣品以技術性重複三次之方式進行20 μl反應。將2 μl溶解產物添加至各反應中,且使用Taqman探針(人類):AAVR:FAM Hs00967343_m1及肌動蛋白-β:VIC Hs01060665_g1。進行ΔΔCt分析以發現相對於未經處理之對照樣品的倍數變化。
2. 實例 2 : 活體外概念證明 ( Proof of Concept ) 研究
活體外評估AAVR減弱對AAV轉導效率之作用。用siRNA或ASO預處理Huh7細胞或靜置不處理。在48小時後,用攜載pCMV-GFP轉殖基因之AAV9感染細胞。藉由在感染之後72小時進行螢光顯微鏡術來評估在經處理或未經處理之細胞之間的相對轉導效率。
在96孔盤中接種細胞,且根據製造商之程序,使用RNAiMax脂染胺(Invitrogen 13778150)用靶向AAVR之siRNA或ASO轉染。用於治療之劑量根據所選模式在2.5至250 nM之間變化。在給藥後的48小時更換培養基且在4℃下以每孔2E3個病毒粒子以1000×g用AAV9-GFP旋轉感染細胞1.5小時。移除含有AAV之培養基,用200微升/孔之室溫培養基洗滌細胞一次以移除未結合之病毒。添加150微升/孔之新鮮培養基且將細胞放回培育箱中並在37℃及5% CO2下進一步生長。次日,更換培養基且在感染後的72小時使用寬場及FITC設定在4×、10×、40×放大率下對細胞進行成像。
如圖5A至圖5B及圖6A至圖6B中所展示,靶向AAVR之ASO預處理減少Huh7細胞中遞送AAV9之pCMV-GFP轉殖基因表現(圖5B及圖6B)。
3. 實例 3 : 靶向肝臟之抗 AAVR siRNA 對小鼠中之 AAV 生物分佈之作用的研究
為評估投與抗AAVR siRNA對小鼠模型中之AAV感染力的作用,將用靶向AAVR之siRNA (抗AAVR siRNA)或對照非靶向siRNA預處理野生型小鼠,該靶向AAVR之siRNA或對照非靶向siRNA調配為靶向肝臟之LNP或直接結合至肝臟靶向部分,如GalNAc。在經過足夠的時間以達成AAVR減弱之後,將全身性地投與編碼綠色螢光蛋白(GFP)之AAV9,該AAV9由普遍存在之啟動子(CMV或類似物)驅動。
在允許穩固GFP表現之時間後,將處死小鼠,且將收穫一組組織用於DNA提取及組織學分析以表徵AAV生物分佈及定量此等組織中之每個細胞之載體基因體(VG)。將評估與各種肌肉及CNS組織以及其他器官相比,肝臟中之GFP表現及載體基因體定量。投與siRNA及AAV之時序及劑量將由試點劑量範圍研究指導。
將比較來自抗AAVR siRNA及經對照siRNA處理之小鼠之組織的GFP分佈以及每個細胞之載體基因體數目。
4. 實例 4 : 活體內劑量範圍研究
進行活體內劑量範圍研究以評估ASOVT002 (ASO)在6至8週齡野生型(WT)小鼠中之功效以用於劑量選擇。
以2、7及20 mg/kg之劑量經由腹膜內注射投與單次劑量之ASOVT002,且在注射後的7天將小鼠安樂死以用於樣品分析。評估肝臟中之AAV受體(AAVR)蛋白之含量以確定初始ASO劑量。
蛋白質提取 ( 肝臟 ):將預分配之冷凍組織轉移至具有陶瓷珠粒之BeadRupture試管(19-040E, BeadRupture Elite, Omni International)中,並浸沒於RIPA緩衝液(ThermoFisher Scientific, 89901)或補充有HALT蛋白酶抑制劑(200 μL用於10至20 mg冷凍樣品)之10% SDS提取緩衝液(1 mM EDTA pH 8, 100 mM NaCl, 62.5 mM Tris pH 6.5, 10% SDS, 10%甘油,及水)中;且立即置放於BeadRuptor均質機臂中並以6 m/s均質化20秒持續3個週期(總計)。以13,000 RCF快速離心溶解產物5分鐘,且將上清液轉移至新試管中且以15,000 RCF再次快速離心15分鐘以移除殘餘雜質。遵循製造商之方案,用Pierce BCA分析法(ThermoFisher Scientific, 23227)檢查蛋白質濃度且各自稀釋至5 mg/mL。遵循製造商之方案,製備樣品以用於來自SM-W004-1套組之Jess Abby及Wes分離模組(「Jess」)。使用初級抗體(ab105385, Abcam)用於以1:300之稀釋度進行AAVR偵測及以1:100之稀釋度進行持家基因(GAPDH、PA1987或FASN,3180S,來自Fisher Scientific)偵測;使用來自製造商之匹配二級抗體。使用24孔濾筒使用Jess之套組操作樣品。使用毛細管凝膠電泳系統ProteinSimple「Jess」獲得資料且使用Simple Western軟體之Compass進行分析。
如圖7中所展示,在用2、7或20 mg/kg劑量之靶向AAVR之ASO、20 mg/kg之對照ASO或PBS給藥後的7天定量AAV受體蛋白。20 mg劑量之ASO VT002在處理後的7天誘導AAVR蛋白減弱約50%。
蛋白質提取 ( 心臟及肌肉 ):將預分配之冷凍組織轉移至具有陶瓷珠粒之BeadRupture試管(19-040E, BeadRupture Elite, Omni International)中,並浸沒於補充有HALT蛋白酶抑制劑(200 μL用於10至20 mg冷凍樣品)之10% SDS提取緩衝液(1 mM EDTA pH 8, 100 mM NaCl, 62.5 mM Tris pH 6.5, 10% SDS, 10%甘油,及水)中;且立即置放於BeadRuptor均質機臂中並以6 m/s均質化20秒持續3個週期(總計)。以13,000 RCF快速離心溶解產物5分鐘,且將上清液轉移至新試管中且以15,000 RCF再次快速離心15分鐘以移除殘餘雜質。遵循製造商之方案,用Pierce BCA分析法(ThermoFisher Scientific, 23227)檢查蛋白質濃度且各自稀釋至5 mg/mL。遵循製造商之方案,製備樣品以用於來自SM-W004-1套組之Jess Abby及Wes分離模組(「Jess」)。使用初級抗體(ab105385, Abcam)用於以1:300之稀釋度進行AAVR偵測及以1:50之稀釋度進行持家基因(GAPDH、PA1987 Fisher Scientific)偵測;使用來自製造商之匹配二級抗體。使用24孔濾筒使用Jess之套組操作樣品。使用毛細管凝膠電泳系統ProteinSimple「Jess」獲得資料且使用Simple Western軟體之Compass進行分析。
如圖8中所展示,在用20 mg/kg劑量之靶向AAV之ASO或經PBS (對照)處理之動物給藥後的7天定量AAV受體蛋白。靶向AAVR之ASO處理不影響心臟及肌肉組織中之AAVR蛋白表現。
5. 實例 5 : 活體內動力學研究
進行活體內研究以測定AAVR蛋白減弱之動力學。在6至8週齡野生型(WT)小鼠中評估ASOVT002之動力學以用於時間點選擇。以20 mg/kg之劑量經由腹膜內注射投與單次劑量之ASOVT002,且在注射後的3天、7天或10天將小鼠安樂死以用於樣品分析。經由毛細管凝膠電泳系統Jess評估在不同時間點肝臟中之AAV受體(AAVR)蛋白之含量。
蛋白質提取 ( 肝臟 ):將預分配之冷凍組織轉移至具有陶瓷珠粒之BeadRupture試管(19-040E, BeadRupture Elite, Omni International)中,並浸沒於補充有HALT蛋白酶抑制劑(200 μL用於10至20 mg冷凍樣品)之10% SDS提取緩衝液(1 mM EDTA pH 8, 100 mM NaCl, 62.5 mM Tris pH 6.5, 10% SDS, 10%甘油,及水)中;且立即置放於BeadRuptor均質機臂中並以6 m/s均質化20秒持續3個週期(總計)。以13,000 RCF快速離心溶解產物5分鐘。將上清液轉移至新試管中且以15,000 RCF再次快速離心15分鐘以移除殘餘雜質。接著,根據製造商之方案,用Pierce BCA分析法(ThermoFisher Scientific, 23227)檢查蛋白質濃度且各自稀釋至5 mg/mL。接著,根據製造商之方案,製備樣品以用於來自SM-W004-1套組之Jess Abby及Wes分離模組(「Jess」)。使用初級抗體(ab105385, Abcam)用於以1:300之稀釋度進行AAVR偵測及以1:50之稀釋度進行持家基因(FASN,3180S,來自Fisher Scientific)偵測;使用來自製造商之匹配二級抗體。使用24孔濾筒使用Jess之套組操作樣品。使用毛細管凝膠電泳系統ProteinSimple「Jess」獲得資料且使用Simple Western軟體之Compass進行分析。如圖9中所展示,在用20 mg/kg之AAVR ASO或PBS (對照)處理給藥後的3天、7天及10天後定量AAV受體蛋白。
6. 實例 6 : 為期一週之處理研究
此研究經設計以在ASO減弱肝臟中之AAVR後評估AAV9-CMV-EGFP表現。在第0天,將ASOVT002以20 mg/kg之劑量腹膜內注射至6至8週齡野生型(WT)小鼠中,隨後在第3天以2×10
12(vg/kg)之劑量進行靜脈內注射AAV9-CMV-EGFP,且在研究第10天(在AAV9-CMV-EGFP給藥後的7天)進行安樂死。收集RNA及DNA之組織。藉由qPCR及qRT-PCR來評估AAV9-CMV-EGFP載體基因體及轉殖基因表現,其中分別藉由Jess及qRT-PCR來評估肝臟、骨胳肌及心臟中之AAVR蛋白及mRNA表現。
表 3 : 其他 siRNA 序列 | |||
SEQ ID NO | siRNA 序列反義 _5' 至 3'_rna | SEQ ID NO | siRNA 序列反義 _5' 至 3'_rna |
4300 | CAGUUAAAUACCAUGUUUAAU | 6904 | UUAGCAUUCUCGAGCUGCACC |
4301 | AGUUAAAUACCAUGUUUAAUC | 6905 | UAGCAUUCUCGAGCUGCACCC |
4302 | GUUAAAUACCAUGUUUAAUCA | 6906 | AGCAUUCUCGAGCUGCACCCC |
4303 | UUAAAUACCAUGUUUAAUCAU | 6907 | GCAUUCUCGAGCUGCACCCCA |
4304 | UAAAUACCAUGUUUAAUCAUC | 6908 | CAUUCUCGAGCUGCACCCCAU |
4305 | AAAUACCAUGUUUAAUCAUCC | 6909 | AUUCUCGAGCUGCACCCCAUC |
4306 | AAUACCAUGUUUAAUCAUCCC | 6910 | UUCUCGAGCUGCACCCCAUCA |
4307 | AUACCAUGUUUAAUCAUCCCA | 6911 | UCUCGAGCUGCACCCCAUCAG |
4308 | UACCAUGUUUAAUCAUCCCAC | 6912 | CUCGAGCUGCACCCCAUCAGG |
4309 | ACCAUGUUUAAUCAUCCCACA | 6913 | UCGAGCUGCACCCCAUCAGGU |
4310 | CCAUGUUUAAUCAUCCCACAA | 6914 | CGAGCUGCACCCCAUCAGGUC |
4311 | CAUGUUUAAUCAUCCCACAAU | 6915 | GAGCUGCACCCCAUCAGGUCC |
4312 | AUGUUUAAUCAUCCCACAAUG | 6916 | AGCUGCACCCCAUCAGGUCCC |
4313 | UGUUUAAUCAUCCCACAAUGG | 6917 | GCUGCACCCCAUCAGGUCCCU |
4314 | GUUUAAUCAUCCCACAAUGGA | 6918 | CUGCACCCCAUCAGGUCCCUG |
4315 | UUUAAUCAUCCCACAAUGGAC | 6919 | UGCACCCCAUCAGGUCCCUGU |
4316 | UUAAUCAUCCCACAAUGGACA | 6920 | GCACCCCAUCAGGUCCCUGUG |
4317 | UAAUCAUCCCACAAUGGACAG | 6921 | CACCCCAUCAGGUCCCUGUGU |
4318 | AAUCAUCCCACAAUGGACAGU | 6922 | ACCCCAUCAGGUCCCUGUGUU |
4319 | AUCAUCCCACAAUGGACAGUA | 6923 | CCCCAUCAGGUCCCUGUGUUU |
4320 | UCAUCCCACAAUGGACAGUAG | 6924 | CCCAUCAGGUCCCUGUGUUUU |
4321 | CAUCCCACAAUGGACAGUAGU | 6925 | CCAUCAGGUCCCUGUGUUUUU |
4322 | AUCCCACAAUGGACAGUAGUG | 6926 | CAUCAGGUCCCUGUGUUUUUU |
4323 | UCCCACAAUGGACAGUAGUGC | 6927 | AUCAGGUCCCUGUGUUUUUUC |
4324 | CCCACAAUGGACAGUAGUGCA | 6928 | UCAGGUCCCUGUGUUUUUUCC |
4325 | CCACAAUGGACAGUAGUGCAG | 6929 | CAGGUCCCUGUGUUUUUUCCC |
4326 | CACAAUGGACAGUAGUGCAGU | 6930 | AGGUCCCUGUGUUUUUUCCCA |
4327 | ACAAUGGACAGUAGUGCAGUA | 6931 | GGUCCCUGUGUUUUUUCCCAG |
4328 | CAAUGGACAGUAGUGCAGUAG | 6932 | GUCCCUGUGUUUUUUCCCAGA |
4329 | AAUGGACAGUAGUGCAGUAGU | 6933 | UCCCUGUGUUUUUUCCCAGAG |
4330 | AUGGACAGUAGUGCAGUAGUA | 6934 | CCCUGUGUUUUUUCCCAGAGA |
4331 | UGGACAGUAGUGCAGUAGUAG | 6935 | CCUGUGUUUUUUCCCAGAGAU |
4332 | GGACAGUAGUGCAGUAGUAGA | 6936 | CUGUGUUUUUUCCCAGAGAUA |
4333 | GACAGUAGUGCAGUAGUAGAA | 6937 | UGUGUUUUUUCCCAGAGAUAU |
4334 | ACAGUAGUGCAGUAGUAGAAA | 6938 | GUGUUUUUUCCCAGAGAUAUG |
4335 | CAGUAGUGCAGUAGUAGAAAU | 6939 | UGUUUUUUCCCAGAGAUAUGA |
4336 | AGUAGUGCAGUAGUAGAAAUU | 6940 | GUUUUUUCCCAGAGAUAUGAG |
4337 | GUAGUGCAGUAGUAGAAAUUA | 6941 | UUUUUUCCCAGAGAUAUGAGA |
4338 | UAGUGCAGUAGUAGAAAUUAU | 6942 | UUUUUCCCAGAGAUAUGAGAU |
4339 | AGUGCAGUAGUAGAAAUUAUA | 6943 | UUUUCCCAGAGAUAUGAGAUA |
4340 | GUGCAGUAGUAGAAAUUAUAA | 6944 | UUUCCCAGAGAUAUGAGAUAA |
4341 | UGCAGUAGUAGAAAUUAUAAG | 6945 | UUCCCAGAGAUAUGAGAUAAU |
4342 | GCAGUAGUAGAAAUUAUAAGU | 6946 | UCCCAGAGAUAUGAGAUAAUU |
4343 | CAGUAGUAGAAAUUAUAAGUG | 6947 | CCCAGAGAUAUGAGAUAAUUU |
4344 | AGUAGUAGAAAUUAUAAGUGU | 6948 | CCAGAGAUAUGAGAUAAUUUU |
4345 | GUAGUAGAAAUUAUAAGUGUC | 6949 | CAGAGAUAUGAGAUAAUUUUC |
4346 | UAGUAGAAAUUAUAAGUGUCU | 6950 | AGAGAUAUGAGAUAAUUUUCU |
4347 | AGUAGAAAUUAUAAGUGUCUC | 6951 | GAGAUAUGAGAUAAUUUUCUG |
4348 | GUAGAAAUUAUAAGUGUCUCU | 6952 | AGAUAUGAGAUAAUUUUCUGA |
4349 | UAGAAAUUAUAAGUGUCUCUU | 6953 | GAUAUGAGAUAAUUUUCUGAU |
4350 | AGAAAUUAUAAGUGUCUCUUU | 6954 | AUAUGAGAUAAUUUUCUGAUC |
4351 | GAAAUUAUAAGUGUCUCUUUA | 6955 | UAUGAGAUAAUUUUCUGAUCA |
4352 | AAAUUAUAAGUGUCUCUUUAA | 6956 | AUGAGAUAAUUUUCUGAUCAU |
4353 | AAUUAUAAGUGUCUCUUUAAA | 6957 | UGAGAUAAUUUUCUGAUCAUC |
4354 | AUUAUAAGUGUCUCUUUAAAA | 6958 | GAGAUAAUUUUCUGAUCAUCU |
4355 | UUAUAAGUGUCUCUUUAAAAA | 6959 | AGAUAAUUUUCUGAUCAUCUG |
4356 | UAUAAGUGUCUCUUUAAAAAG | 6960 | GAUAAUUUUCUGAUCAUCUGA |
4357 | AUAAGUGUCUCUUUAAAAAGU | 6961 | AUAAUUUUCUGAUCAUCUGAG |
4358 | UAAGUGUCUCUUUAAAAAGUC | 6962 | UAAUUUUCUGAUCAUCUGAGC |
4359 | AAGUGUCUCUUUAAAAAGUCA | 6963 | AAUUUUCUGAUCAUCUGAGCU |
4360 | AGUGUCUCUUUAAAAAGUCAC | 6964 | AUUUUCUGAUCAUCUGAGCUC |
4361 | GUGUCUCUUUAAAAAGUCACU | 6965 | UUUUCUGAUCAUCUGAGCUCU |
4362 | UGUCUCUUUAAAAAGUCACUC | 6966 | UUUCUGAUCAUCUGAGCUCUU |
4363 | GUCUCUUUAAAAAGUCACUCC | 6967 | UUCUGAUCAUCUGAGCUCUUG |
4364 | UCUCUUUAAAAAGUCACUCCC | 6968 | UCUGAUCAUCUGAGCUCUUGC |
4365 | CUCUUUAAAAAGUCACUCCCC | 6969 | CUGAUCAUCUGAGCUCUUGCU |
4366 | UCUUUAAAAAGUCACUCCCCC | 6970 | UGAUCAUCUGAGCUCUUGCUG |
4367 | CUUUAAAAAGUCACUCCCCCA | 6971 | GAUCAUCUGAGCUCUUGCUGC |
4368 | UUUAAAAAGUCACUCCCCCAA | 6972 | AUCAUCUGAGCUCUUGCUGCC |
4369 | UUAAAAAGUCACUCCCCCAAA | 6973 | UCAUCUGAGCUCUUGCUGCCA |
4370 | UAAAAAGUCACUCCCCCAAAG | 6974 | CAUCUGAGCUCUUGCUGCCAU |
4371 | AAAAAGUCACUCCCCCAAAGU | 6975 | AUCUGAGCUCUUGCUGCCAUC |
4372 | AAAAGUCACUCCCCCAAAGUU | 6976 | UCUGAGCUCUUGCUGCCAUCC |
4373 | AAAGUCACUCCCCCAAAGUUU | 6977 | CUGAGCUCUUGCUGCCAUCCA |
4374 | AAGUCACUCCCCCAAAGUUUC | 6978 | UGAGCUCUUGCUGCCAUCCAG |
4375 | AGUCACUCCCCCAAAGUUUCC | 6979 | GAGCUCUUGCUGCCAUCCAGG |
4376 | GUCACUCCCCCAAAGUUUCCA | 6980 | AGCUCUUGCUGCCAUCCAGGG |
4377 | UCACUCCCCCAAAGUUUCCAU | 6981 | GCUCUUGCUGCCAUCCAGGGU |
4378 | CACUCCCCCAAAGUUUCCAUU | 6982 | CUCUUGCUGCCAUCCAGGGUU |
4379 | ACUCCCCCAAAGUUUCCAUUC | 6983 | UCUUGCUGCCAUCCAGGGUUG |
4380 | CUCCCCCAAAGUUUCCAUUCC | 6984 | CUUGCUGCCAUCCAGGGUUGU |
4381 | UCCCCCAAAGUUUCCAUUCCC | 6985 | UUGCUGCCAUCCAGGGUUGUG |
4382 | CCCCCAAAGUUUCCAUUCCCC | 6986 | UGCUGCCAUCCAGGGUUGUGC |
4383 | CCCCAAAGUUUCCAUUCCCCA | 6987 | GCUGCCAUCCAGGGUUGUGCU |
4384 | CCCAAAGUUUCCAUUCCCCAA | 6988 | CUGCCAUCCAGGGUUGUGCUA |
4385 | CCAAAGUUUCCAUUCCCCAAU | 6989 | UGCCAUCCAGGGUUGUGCUAU |
4386 | CAAAGUUUCCAUUCCCCAAUA | 6990 | GCCAUCCAGGGUUGUGCUAUC |
4387 | AAAGUUUCCAUUCCCCAAUAC | 6991 | CCAUCCAGGGUUGUGCUAUCC |
4388 | AAGUUUCCAUUCCCCAAUACC | 6992 | CAUCCAGGGUUGUGCUAUCCA |
4389 | AGUUUCCAUUCCCCAAUACCC | 6993 | AUCCAGGGUUGUGCUAUCCAC |
4390 | GUUUCCAUUCCCCAAUACCCA | 6994 | UCCAGGGUUGUGCUAUCCACA |
4391 | UUUCCAUUCCCCAAUACCCAG | 6995 | CCAGGGUUGUGCUAUCCACAG |
4392 | UUCCAUUCCCCAAUACCCAGA | 6996 | CAGGGUUGUGCUAUCCACAGG |
4393 | UCCAUUCCCCAAUACCCAGAU | 6997 | AGGGUUGUGCUAUCCACAGGA |
4394 | CCAUUCCCCAAUACCCAGAUA | 6998 | GGGUUGUGCUAUCCACAGGAA |
4395 | CAUUCCCCAAUACCCAGAUAA | 6999 | GGUUGUGCUAUCCACAGGAAG |
4396 | AUUCCCCAAUACCCAGAUAAC | 7000 | GUUGUGCUAUCCACAGGAAGG |
4397 | UUCCCCAAUACCCAGAUAACC | 7001 | UUGUGCUAUCCACAGGAAGGG |
4398 | UCCCCAAUACCCAGAUAACCA | 7002 | UGUGCUAUCCACAGGAAGGGU |
4399 | CCCCAAUACCCAGAUAACCAU | 7003 | GUGCUAUCCACAGGAAGGGUC |
4400 | CCCAAUACCCAGAUAACCAUG | 7004 | UGCUAUCCACAGGAAGGGUCA |
4401 | CCAAUACCCAGAUAACCAUGG | 7005 | GCUAUCCACAGGAAGGGUCAG |
4402 | CAAUACCCAGAUAACCAUGGU | 7006 | CUAUCCACAGGAAGGGUCAGC |
4403 | AAUACCCAGAUAACCAUGGUG | 7007 | UAUCCACAGGAAGGGUCAGCU |
4404 | AUACCCAGAUAACCAUGGUGG | 7008 | AUCCACAGGAAGGGUCAGCUC |
4405 | UACCCAGAUAACCAUGGUGGA | 7009 | UCCACAGGAAGGGUCAGCUCU |
4406 | ACCCAGAUAACCAUGGUGGAA | 7010 | CCACAGGAAGGGUCAGCUCUU |
4407 | CCCAGAUAACCAUGGUGGAAC | 7011 | CACAGGAAGGGUCAGCUCUUU |
4408 | CCAGAUAACCAUGGUGGAACA | 7012 | ACAGGAAGGGUCAGCUCUUUA |
4409 | CAGAUAACCAUGGUGGAACAG | 7013 | CAGGAAGGGUCAGCUCUUUAU |
4410 | AGAUAACCAUGGUGGAACAGG | 7014 | AGGAAGGGUCAGCUCUUUAUC |
4411 | GAUAACCAUGGUGGAACAGGG | 7015 | GGAAGGGUCAGCUCUUUAUCU |
4412 | AUAACCAUGGUGGAACAGGGC | 7016 | GAAGGGUCAGCUCUUUAUCUG |
4413 | UAACCAUGGUGGAACAGGGCC | 7017 | AAGGGUCAGCUCUUUAUCUGG |
4414 | AACCAUGGUGGAACAGGGCCA | 7018 | AGGGUCAGCUCUUUAUCUGGG |
4415 | ACCAUGGUGGAACAGGGCCAG | 7019 | GGGUCAGCUCUUUAUCUGGGC |
4416 | CCAUGGUGGAACAGGGCCAGG | 7020 | GGUCAGCUCUUUAUCUGGGCC |
4417 | CAUGGUGGAACAGGGCCAGGG | 7021 | GUCAGCUCUUUAUCUGGGCCU |
4418 | AUGGUGGAACAGGGCCAGGGU | 7022 | UCAGCUCUUUAUCUGGGCCUG |
4419 | UGGUGGAACAGGGCCAGGGUG | 7023 | CAGCUCUUUAUCUGGGCCUGC |
4420 | GGUGGAACAGGGCCAGGGUGA | 7024 | AGCUCUUUAUCUGGGCCUGCA |
4421 | GUGGAACAGGGCCAGGGUGAG | 7025 | GCUCUUUAUCUGGGCCUGCAU |
4422 | UGGAACAGGGCCAGGGUGAGG | 7026 | CUCUUUAUCUGGGCCUGCAUC |
4423 | GGAACAGGGCCAGGGUGAGGG | 7027 | UCUUUAUCUGGGCCUGCAUCU |
4424 | GAACAGGGCCAGGGUGAGGGG | 7028 | CUUUAUCUGGGCCUGCAUCUG |
4425 | AACAGGGCCAGGGUGAGGGGG | 7029 | UUUAUCUGGGCCUGCAUCUGC |
4426 | ACAGGGCCAGGGUGAGGGGGA | 7030 | UUAUCUGGGCCUGCAUCUGCC |
4427 | CAGGGCCAGGGUGAGGGGGAC | 7031 | UAUCUGGGCCUGCAUCUGCCU |
4428 | AGGGCCAGGGUGAGGGGGACU | 7032 | AUCUGGGCCUGCAUCUGCCUG |
4429 | GGGCCAGGGUGAGGGGGACUC | 7033 | UCUGGGCCUGCAUCUGCCUGA |
4430 | GGCCAGGGUGAGGGGGACUCA | 7034 | CUGGGCCUGCAUCUGCCUGAG |
4431 | GCCAGGGUGAGGGGGACUCAG | 7035 | UGGGCCUGCAUCUGCCUGAGG |
4432 | CCAGGGUGAGGGGGACUCAGG | 7036 | GGGCCUGCAUCUGCCUGAGGA |
4433 | CAGGGUGAGGGGGACUCAGGA | 7037 | GGCCUGCAUCUGCCUGAGGAG |
4434 | AGGGUGAGGGGGACUCAGGAA | 7038 | GCCUGCAUCUGCCUGAGGAGG |
4435 | GGGUGAGGGGGACUCAGGAAG | 7039 | CCUGCAUCUGCCUGAGGAGGC |
4436 | GGUGAGGGGGACUCAGGAAGU | 7040 | CUGCAUCUGCCUGAGGAGGCU |
4437 | GUGAGGGGGACUCAGGAAGUC | 7041 | UGCAUCUGCCUGAGGAGGCUU |
4438 | UGAGGGGGACUCAGGAAGUCU | 7042 | GCAUCUGCCUGAGGAGGCUUA |
4439 | GAGGGGGACUCAGGAAGUCUU | 7043 | CAUCUGCCUGAGGAGGCUUAU |
4440 | AGGGGGACUCAGGAAGUCUUG | 7044 | AUCUGCCUGAGGAGGCUUAUU |
4441 | GGGGGACUCAGGAAGUCUUGG | 7045 | UCUGCCUGAGGAGGCUUAUUG |
4442 | GGGGACUCAGGAAGUCUUGGU | 7046 | CUGCCUGAGGAGGCUUAUUGU |
4443 | GGGACUCAGGAAGUCUUGGUU | 7047 | UGCCUGAGGAGGCUUAUUGUU |
4444 | GGACUCAGGAAGUCUUGGUUC | 7048 | GCCUGAGGAGGCUUAUUGUUU |
4445 | GACUCAGGAAGUCUUGGUUCC | 7049 | CCUGAGGAGGCUUAUUGUUUU |
4446 | ACUCAGGAAGUCUUGGUUCCA | 7050 | CUGAGGAGGCUUAUUGUUUUC |
4447 | CUCAGGAAGUCUUGGUUCCAA | 7051 | UGAGGAGGCUUAUUGUUUUCA |
4448 | UCAGGAAGUCUUGGUUCCAAG | 7052 | GAGGAGGCUUAUUGUUUUCAG |
4449 | CAGGAAGUCUUGGUUCCAAGG | 7053 | AGGAGGCUUAUUGUUUUCAGG |
4450 | AGGAAGUCUUGGUUCCAAGGA | 7054 | GGAGGCUUAUUGUUUUCAGGU |
4451 | GGAAGUCUUGGUUCCAAGGAG | 7055 | GAGGCUUAUUGUUUUCAGGUU |
4452 | GAAGUCUUGGUUCCAAGGAGA | 7056 | AGGCUUAUUGUUUUCAGGUUG |
4453 | AAGUCUUGGUUCCAAGGAGAU | 7057 | GGCUUAUUGUUUUCAGGUUGC |
4454 | AGUCUUGGUUCCAAGGAGAUG | 7058 | GCUUAUUGUUUUCAGGUUGCA |
4455 | GUCUUGGUUCCAAGGAGAUGA | 7059 | CUUAUUGUUUUCAGGUUGCAC |
4456 | UCUUGGUUCCAAGGAGAUGAA | 7060 | UUAUUGUUUUCAGGUUGCACA |
4457 | CUUGGUUCCAAGGAGAUGAAA | 7061 | UAUUGUUUUCAGGUUGCACAA |
4458 | UUGGUUCCAAGGAGAUGAAAG | 7062 | AUUGUUUUCAGGUUGCACAAU |
4459 | UGGUUCCAAGGAGAUGAAAGU | 7063 | UUGUUUUCAGGUUGCACAAUA |
4460 | GGUUCCAAGGAGAUGAAAGUC | 7064 | UGUUUUCAGGUUGCACAAUAA |
4461 | GUUCCAAGGAGAUGAAAGUCU | 7065 | GUUUUCAGGUUGCACAAUAAC |
4462 | UUCCAAGGAGAUGAAAGUCUU | 7066 | UUUUCAGGUUGCACAAUAACA |
4463 | UCCAAGGAGAUGAAAGUCUUU | 7067 | UUUCAGGUUGCACAAUAACAG |
4464 | CCAAGGAGAUGAAAGUCUUUC | 7068 | UUCAGGUUGCACAAUAACAGU |
4465 | CAAGGAGAUGAAAGUCUUUCC | 7069 | UCAGGUUGCACAAUAACAGUC |
4466 | AAGGAGAUGAAAGUCUUUCCA | 7070 | CAGGUUGCACAAUAACAGUCA |
4467 | AGGAGAUGAAAGUCUUUCCAA | 7071 | AGGUUGCACAAUAACAGUCAC |
4468 | GGAGAUGAAAGUCUUUCCAAG | 7072 | GGUUGCACAAUAACAGUCACU |
4469 | GAGAUGAAAGUCUUUCCAAGU | 7073 | GUUGCACAAUAACAGUCACUU |
4470 | AGAUGAAAGUCUUUCCAAGUC | 7074 | UUGCACAAUAACAGUCACUUG |
4471 | GAUGAAAGUCUUUCCAAGUCA | 7075 | UGCACAAUAACAGUCACUUGA |
4472 | AUGAAAGUCUUUCCAAGUCAA | 7076 | GCACAAUAACAGUCACUUGAG |
4473 | UGAAAGUCUUUCCAAGUCAAA | 7077 | CACAAUAACAGUCACUUGAGC |
4474 | GAAAGUCUUUCCAAGUCAAAU | 7078 | ACAAUAACAGUCACUUGAGCA |
4475 | AAAGUCUUUCCAAGUCAAAUU | 7079 | CAAUAACAGUCACUUGAGCAG |
4476 | AAGUCUUUCCAAGUCAAAUUU | 7080 | AAUAACAGUCACUUGAGCAGU |
4477 | AGUCUUUCCAAGUCAAAUUUG | 7081 | AUAACAGUCACUUGAGCAGUG |
4478 | GUCUUUCCAAGUCAAAUUUGC | 7082 | UAACAGUCACUUGAGCAGUGG |
4479 | UCUUUCCAAGUCAAAUUUGCC | 7083 | AACAGUCACUUGAGCAGUGGC |
4480 | CUUUCCAAGUCAAAUUUGCCU | 7084 | ACAGUCACUUGAGCAGUGGCC |
4481 | UUUCCAAGUCAAAUUUGCCUU | 7085 | CAGUCACUUGAGCAGUGGCCU |
4482 | UUCCAAGUCAAAUUUGCCUUG | 7086 | AGUCACUUGAGCAGUGGCCUG |
4483 | UCCAAGUCAAAUUUGCCUUGU | 7087 | GUCACUUGAGCAGUGGCCUGC |
4484 | CCAAGUCAAAUUUGCCUUGUG | 7088 | UCACUUGAGCAGUGGCCUGCU |
4485 | CAAGUCAAAUUUGCCUUGUGA | 7089 | CACUUGAGCAGUGGCCUGCUG |
4486 | AAGUCAAAUUUGCCUUGUGAG | 7090 | ACUUGAGCAGUGGCCUGCUGU |
4487 | AGUCAAAUUUGCCUUGUGAGC | 7091 | CUUGAGCAGUGGCCUGCUGUC |
4488 | GUCAAAUUUGCCUUGUGAGCA | 7092 | UUGAGCAGUGGCCUGCUGUCC |
4489 | UCAAAUUUGCCUUGUGAGCAG | 7093 | UGAGCAGUGGCCUGCUGUCCU |
4490 | CAAAUUUGCCUUGUGAGCAGC | 7094 | GAGCAGUGGCCUGCUGUCCUA |
4491 | AAAUUUGCCUUGUGAGCAGCC | 7095 | AGCAGUGGCCUGCUGUCCUAU |
4492 | AAUUUGCCUUGUGAGCAGCCA | 7096 | GCAGUGGCCUGCUGUCCUAUU |
4493 | AUUUGCCUUGUGAGCAGCCAA | 7097 | CAGUGGCCUGCUGUCCUAUUG |
4494 | UUUGCCUUGUGAGCAGCCAAG | 7098 | AGUGGCCUGCUGUCCUAUUGU |
4495 | UUGCCUUGUGAGCAGCCAAGA | 7099 | GUGGCCUGCUGUCCUAUUGUG |
4496 | UGCCUUGUGAGCAGCCAAGAG | 7100 | UGGCCUGCUGUCCUAUUGUGU |
4497 | GCCUUGUGAGCAGCCAAGAGC | 7101 | GGCCUGCUGUCCUAUUGUGUC |
4498 | CCUUGUGAGCAGCCAAGAGCC | 7102 | GCCUGCUGUCCUAUUGUGUCA |
4499 | CUUGUGAGCAGCCAAGAGCCC | 7103 | CCUGCUGUCCUAUUGUGUCAG |
4500 | UUGUGAGCAGCCAAGAGCCCA | 7104 | CUGCUGUCCUAUUGUGUCAGU |
4501 | UGUGAGCAGCCAAGAGCCCAA | 7105 | UGCUGUCCUAUUGUGUCAGUC |
4502 | GUGAGCAGCCAAGAGCCCAAU | 7106 | GCUGUCCUAUUGUGUCAGUCA |
4503 | UGAGCAGCCAAGAGCCCAAUG | 7107 | CUGUCCUAUUGUGUCAGUCAC |
4504 | GAGCAGCCAAGAGCCCAAUGA | 7108 | UGUCCUAUUGUGUCAGUCACU |
4505 | AGCAGCCAAGAGCCCAAUGAG | 7109 | GUCCUAUUGUGUCAGUCACUG |
4506 | GCAGCCAAGAGCCCAAUGAGU | 7110 | UCCUAUUGUGUCAGUCACUGU |
4507 | CAGCCAAGAGCCCAAUGAGUU | 7111 | CCUAUUGUGUCAGUCACUGUG |
4508 | AGCCAAGAGCCCAAUGAGUUG | 7112 | CUAUUGUGUCAGUCACUGUGA |
4509 | GCCAAGAGCCCAAUGAGUUGA | 7113 | UAUUGUGUCAGUCACUGUGAG |
4510 | CCAAGAGCCCAAUGAGUUGAU | 7114 | AUUGUGUCAGUCACUGUGAGC |
4511 | CAAGAGCCCAAUGAGUUGAUG | 7115 | UUGUGUCAGUCACUGUGAGCU |
4512 | AAGAGCCCAAUGAGUUGAUGC | 7116 | UGUGUCAGUCACUGUGAGCUG |
4513 | AGAGCCCAAUGAGUUGAUGCA | 7117 | GUGUCAGUCACUGUGAGCUGG |
4514 | GAGCCCAAUGAGUUGAUGCAU | 7118 | UGUCAGUCACUGUGAGCUGGU |
4515 | AGCCCAAUGAGUUGAUGCAUA | 7119 | GUCAGUCACUGUGAGCUGGUA |
4516 | GCCCAAUGAGUUGAUGCAUAC | 7120 | UCAGUCACUGUGAGCUGGUAA |
4517 | CCCAAUGAGUUGAUGCAUACG | 7121 | CAGUCACUGUGAGCUGGUAAG |
4518 | CCAAUGAGUUGAUGCAUACGC | 7122 | AGUCACUGUGAGCUGGUAAGU |
4519 | CAAUGAGUUGAUGCAUACGCG | 7123 | GUCACUGUGAGCUGGUAAGUG |
4520 | AAUGAGUUGAUGCAUACGCGC | 7124 | UCACUGUGAGCUGGUAAGUGU |
4521 | AUGAGUUGAUGCAUACGCGCU | 7125 | CACUGUGAGCUGGUAAGUGUA |
4522 | UGAGUUGAUGCAUACGCGCUC | 7126 | ACUGUGAGCUGGUAAGUGUAG |
4523 | GAGUUGAUGCAUACGCGCUCA | 7127 | CUGUGAGCUGGUAAGUGUAGU |
4524 | AGUUGAUGCAUACGCGCUCAC | 7128 | UGUGAGCUGGUAAGUGUAGUC |
4525 | GUUGAUGCAUACGCGCUCACU | 7129 | GUGAGCUGGUAAGUGUAGUCU |
4526 | UUGAUGCAUACGCGCUCACUC | 7130 | UGAGCUGGUAAGUGUAGUCUC |
4527 | UGAUGCAUACGCGCUCACUCU | 7131 | GAGCUGGUAAGUGUAGUCUCC |
4528 | GAUGCAUACGCGCUCACUCUA | 7132 | AGCUGGUAAGUGUAGUCUCCU |
4529 | AUGCAUACGCGCUCACUCUAA | 7133 | GCUGGUAAGUGUAGUCUCCUU |
4530 | UGCAUACGCGCUCACUCUAAC | 7134 | CUGGUAAGUGUAGUCUCCUUC |
4531 | GCAUACGCGCUCACUCUAACA | 7135 | UGGUAAGUGUAGUCUCCUUCU |
4532 | CAUACGCGCUCACUCUAACAC | 7136 | GGUAAGUGUAGUCUCCUUCUU |
4533 | AUACGCGCUCACUCUAACACG | 7137 | GUAAGUGUAGUCUCCUUCUUG |
4534 | UACGCGCUCACUCUAACACGC | 7138 | UAAGUGUAGUCUCCUUCUUGC |
4535 | ACGCGCUCACUCUAACACGCA | 7139 | AAGUGUAGUCUCCUUCUUGCA |
4536 | CGCGCUCACUCUAACACGCAC | 7140 | AGUGUAGUCUCCUUCUUGCAU |
4537 | GCGCUCACUCUAACACGCACA | 7141 | GUGUAGUCUCCUUCUUGCAUC |
4538 | CGCUCACUCUAACACGCACAC | 7142 | UGUAGUCUCCUUCUUGCAUCG |
4539 | GCUCACUCUAACACGCACACA | 7143 | GUAGUCUCCUUCUUGCAUCGC |
4540 | CUCACUCUAACACGCACACAU | 7144 | UAGUCUCCUUCUUGCAUCGCA |
4541 | UCACUCUAACACGCACACAUG | 7145 | AGUCUCCUUCUUGCAUCGCAG |
4542 | CACUCUAACACGCACACAUGC | 7146 | GUCUCCUUCUUGCAUCGCAGA |
4543 | ACUCUAACACGCACACAUGCA | 7147 | UCUCCUUCUUGCAUCGCAGAG |
4544 | CUCUAACACGCACACAUGCAA | 7148 | CUCCUUCUUGCAUCGCAGAGA |
4545 | UCUAACACGCACACAUGCAAG | 7149 | UCCUUCUUGCAUCGCAGAGAG |
4546 | CUAACACGCACACAUGCAAGG | 7150 | CCUUCUUGCAUCGCAGAGAGC |
4547 | UAACACGCACACAUGCAAGGG | 7151 | CUUCUUGCAUCGCAGAGAGCU |
4548 | AACACGCACACAUGCAAGGGA | 7152 | UUCUUGCAUCGCAGAGAGCUG |
4549 | ACACGCACACAUGCAAGGGAC | 7153 | UCUUGCAUCGCAGAGAGCUGU |
4550 | CACGCACACAUGCAAGGGACA | 7154 | CUUGCAUCGCAGAGAGCUGUA |
4551 | ACGCACACAUGCAAGGGACAC | 7155 | UUGCAUCGCAGAGAGCUGUAA |
4552 | CGCACACAUGCAAGGGACACA | 7156 | UGCAUCGCAGAGAGCUGUAAG |
4553 | GCACACAUGCAAGGGACACAG | 7157 | GCAUCGCAGAGAGCUGUAAGG |
4554 | CACACAUGCAAGGGACACAGA | 7158 | CAUCGCAGAGAGCUGUAAGGU |
4555 | ACACAUGCAAGGGACACAGAA | 7159 | AUCGCAGAGAGCUGUAAGGUU |
4556 | CACAUGCAAGGGACACAGAAC | 7160 | UCGCAGAGAGCUGUAAGGUUG |
4557 | ACAUGCAAGGGACACAGAACA | 7161 | CGCAGAGAGCUGUAAGGUUGG |
4558 | CAUGCAAGGGACACAGAACAC | 7162 | GCAGAGAGCUGUAAGGUUGGU |
4559 | AUGCAAGGGACACAGAACACA | 7163 | CAGAGAGCUGUAAGGUUGGUG |
4560 | UGCAAGGGACACAGAACACAU | 7164 | AGAGAGCUGUAAGGUUGGUGU |
4561 | GCAAGGGACACAGAACACAUA | 7165 | GAGAGCUGUAAGGUUGGUGUU |
4562 | CAAGGGACACAGAACACAUAC | 7166 | AGAGCUGUAAGGUUGGUGUUC |
4563 | AAGGGACACAGAACACAUACA | 7167 | GAGCUGUAAGGUUGGUGUUCU |
4564 | AGGGACACAGAACACAUACAG | 7168 | AGCUGUAAGGUUGGUGUUCUA |
4565 | GGGACACAGAACACAUACAGA | 7169 | GCUGUAAGGUUGGUGUUCUAA |
4566 | GGACACAGAACACAUACAGAU | 7170 | CUGUAAGGUUGGUGUUCUAAC |
4567 | GACACAGAACACAUACAGAUG | 7171 | UGUAAGGUUGGUGUUCUAACA |
4568 | ACACAGAACACAUACAGAUGG | 7172 | GUAAGGUUGGUGUUCUAACAC |
4569 | CACAGAACACAUACAGAUGGA | 7173 | UAAGGUUGGUGUUCUAACACC |
4570 | ACAGAACACAUACAGAUGGAG | 7174 | AAGGUUGGUGUUCUAACACCC |
4571 | CAGAACACAUACAGAUGGAGG | 7175 | AGGUUGGUGUUCUAACACCCU |
4572 | AGAACACAUACAGAUGGAGGG | 7176 | GGUUGGUGUUCUAACACCCUG |
4573 | GAACACAUACAGAUGGAGGGA | 7177 | GUUGGUGUUCUAACACCCUGC |
4574 | AACACAUACAGAUGGAGGGAC | 7178 | UUGGUGUUCUAACACCCUGCA |
4575 | ACACAUACAGAUGGAGGGACA | 7179 | UGGUGUUCUAACACCCUGCAU |
4576 | CACAUACAGAUGGAGGGACAG | 7180 | GGUGUUCUAACACCCUGCAUC |
4577 | ACAUACAGAUGGAGGGACAGA | 7181 | GUGUUCUAACACCCUGCAUCU |
4578 | CAUACAGAUGGAGGGACAGAG | 7182 | UGUUCUAACACCCUGCAUCUC |
4579 | AUACAGAUGGAGGGACAGAGA | 7183 | GUUCUAACACCCUGCAUCUCC |
4580 | UACAGAUGGAGGGACAGAGAG | 7184 | UUCUAACACCCUGCAUCUCCA |
4581 | ACAGAUGGAGGGACAGAGAGG | 7185 | UCUAACACCCUGCAUCUCCAC |
4582 | CAGAUGGAGGGACAGAGAGGG | 7186 | CUAACACCCUGCAUCUCCACC |
4583 | AGAUGGAGGGACAGAGAGGGG | 7187 | UAACACCCUGCAUCUCCACCA |
4584 | GAUGGAGGGACAGAGAGGGGA | 7188 | AACACCCUGCAUCUCCACCAC |
4585 | AUGGAGGGACAGAGAGGGGAC | 7189 | ACACCCUGCAUCUCCACCACU |
4586 | UGGAGGGACAGAGAGGGGACC | 7190 | CACCCUGCAUCUCCACCACUU |
4587 | GGAGGGACAGAGAGGGGACCA | 7191 | ACCCUGCAUCUCCACCACUUU |
4588 | GAGGGACAGAGAGGGGACCAC | 7192 | CCCUGCAUCUCCACCACUUUC |
4589 | AGGGACAGAGAGGGGACCACA | 7193 | CCUGCAUCUCCACCACUUUCC |
4590 | GGGACAGAGAGGGGACCACAG | 7194 | CUGCAUCUCCACCACUUUCCC |
4591 | GGACAGAGAGGGGACCACAGC | 7195 | UGCAUCUCCACCACUUUCCCU |
4592 | GACAGAGAGGGGACCACAGCG | 7196 | GCAUCUCCACCACUUUCCCUU |
4593 | ACAGAGAGGGGACCACAGCGG | 7197 | CAUCUCCACCACUUUCCCUUU |
4594 | CAGAGAGGGGACCACAGCGGG | 7198 | AUCUCCACCACUUUCCCUUUG |
4595 | AGAGAGGGGACCACAGCGGGG | 7199 | UCUCCACCACUUUCCCUUUGC |
4596 | GAGAGGGGACCACAGCGGGGC | 7200 | CUCCACCACUUUCCCUUUGCU |
4597 | AGAGGGGACCACAGCGGGGCC | 7201 | UCCACCACUUUCCCUUUGCUG |
4598 | GAGGGGACCACAGCGGGGCCA | 7202 | CCACCACUUUCCCUUUGCUGC |
4599 | AGGGGACCACAGCGGGGCCAU | 7203 | CACCACUUUCCCUUUGCUGCU |
4600 | GGGGACCACAGCGGGGCCAUC | 7204 | ACCACUUUCCCUUUGCUGCUU |
4601 | GGGACCACAGCGGGGCCAUCG | 7205 | CCACUUUCCCUUUGCUGCUUG |
4602 | GGACCACAGCGGGGCCAUCGC | 7206 | CACUUUCCCUUUGCUGCUUGG |
4603 | GACCACAGCGGGGCCAUCGCA | 7207 | ACUUUCCCUUUGCUGCUUGGG |
4604 | ACCACAGCGGGGCCAUCGCAC | 7208 | CUUUCCCUUUGCUGCUUGGGC |
4605 | CCACAGCGGGGCCAUCGCACA | 7209 | UUUCCCUUUGCUGCUUGGGCU |
4606 | CACAGCGGGGCCAUCGCACAC | 7210 | UUCCCUUUGCUGCUUGGGCUG |
4607 | ACAGCGGGGCCAUCGCACACA | 7211 | UCCCUUUGCUGCUUGGGCUGA |
4608 | CAGCGGGGCCAUCGCACACAU | 7212 | CCCUUUGCUGCUUGGGCUGAG |
4609 | AGCGGGGCCAUCGCACACAUG | 7213 | CCUUUGCUGCUUGGGCUGAGU |
4610 | GCGGGGCCAUCGCACACAUGC | 7214 | CUUUGCUGCUUGGGCUGAGUG |
4611 | CGGGGCCAUCGCACACAUGCG | 7215 | UUUGCUGCUUGGGCUGAGUGA |
4612 | GGGGCCAUCGCACACAUGCGC | 7216 | UUGCUGCUUGGGCUGAGUGAC |
4613 | GGGCCAUCGCACACAUGCGCU | 7217 | UGCUGCUUGGGCUGAGUGACC |
4614 | GGCCAUCGCACACAUGCGCUC | 7218 | GCUGCUUGGGCUGAGUGACCA |
4615 | GCCAUCGCACACAUGCGCUCU | 7219 | CUGCUUGGGCUGAGUGACCAC |
4616 | CCAUCGCACACAUGCGCUCUC | 7220 | UGCUUGGGCUGAGUGACCACU |
4617 | CAUCGCACACAUGCGCUCUCA | 7221 | GCUUGGGCUGAGUGACCACUC |
4618 | AUCGCACACAUGCGCUCUCAU | 7222 | CUUGGGCUGAGUGACCACUCA |
4619 | UCGCACACAUGCGCUCUCAUG | 7223 | UUGGGCUGAGUGACCACUCAU |
4620 | CGCACACAUGCGCUCUCAUGC | 7224 | UGGGCUGAGUGACCACUCAUA |
4621 | GCACACAUGCGCUCUCAUGCC | 7225 | GGGCUGAGUGACCACUCAUAG |
4622 | CACACAUGCGCUCUCAUGCCA | 7226 | GGCUGAGUGACCACUCAUAGC |
4623 | ACACAUGCGCUCUCAUGCCAC | 7227 | GCUGAGUGACCACUCAUAGCU |
4624 | CACAUGCGCUCUCAUGCCACA | 7228 | CUGAGUGACCACUCAUAGCUG |
4625 | ACAUGCGCUCUCAUGCCACAA | 7229 | UGAGUGACCACUCAUAGCUGG |
4626 | CAUGCGCUCUCAUGCCACAAC | 7230 | GAGUGACCACUCAUAGCUGGU |
4627 | AUGCGCUCUCAUGCCACAACA | 7231 | AGUGACCACUCAUAGCUGGUG |
4628 | UGCGCUCUCAUGCCACAACAU | 7232 | GUGACCACUCAUAGCUGGUGA |
4629 | GCGCUCUCAUGCCACAACAUU | 7233 | UGACCACUCAUAGCUGGUGAU |
4630 | CGCUCUCAUGCCACAACAUUC | 7234 | GACCACUCAUAGCUGGUGAUG |
4631 | GCUCUCAUGCCACAACAUUCC | 7235 | ACCACUCAUAGCUGGUGAUGC |
4632 | CUCUCAUGCCACAACAUUCCA | 7236 | CCACUCAUAGCUGGUGAUGCC |
4633 | UCUCAUGCCACAACAUUCCAG | 7237 | CACUCAUAGCUGGUGAUGCCA |
4634 | CUCAUGCCACAACAUUCCAGU | 7238 | ACUCAUAGCUGGUGAUGCCAU |
4635 | UCAUGCCACAACAUUCCAGUC | 7239 | CUCAUAGCUGGUGAUGCCAUG |
4636 | CAUGCCACAACAUUCCAGUCC | 7240 | UCAUAGCUGGUGAUGCCAUGA |
4637 | AUGCCACAACAUUCCAGUCCA | 7241 | CAUAGCUGGUGAUGCCAUGAU |
4638 | UGCCACAACAUUCCAGUCCAU | 7242 | AUAGCUGGUGAUGCCAUGAUC |
4639 | GCCACAACAUUCCAGUCCAUC | 7243 | UAGCUGGUGAUGCCAUGAUCA |
4640 | CCACAACAUUCCAGUCCAUCU | 7244 | AGCUGGUGAUGCCAUGAUCAU |
4641 | CACAACAUUCCAGUCCAUCUG | 7245 | GCUGGUGAUGCCAUGAUCAUC |
4642 | ACAACAUUCCAGUCCAUCUGG | 7246 | CUGGUGAUGCCAUGAUCAUCA |
4643 | CAACAUUCCAGUCCAUCUGGG | 7247 | UGGUGAUGCCAUGAUCAUCAG |
4644 | AACAUUCCAGUCCAUCUGGGG | 7248 | GGUGAUGCCAUGAUCAUCAGU |
4645 | ACAUUCCAGUCCAUCUGGGGC | 7249 | GUGAUGCCAUGAUCAUCAGUG |
4646 | CAUUCCAGUCCAUCUGGGGCU | 7250 | UGAUGCCAUGAUCAUCAGUGC |
4647 | AUUCCAGUCCAUCUGGGGCUA | 7251 | GAUGCCAUGAUCAUCAGUGCU |
4648 | UUCCAGUCCAUCUGGGGCUAU | 7252 | AUGCCAUGAUCAUCAGUGCUC |
4649 | UCCAGUCCAUCUGGGGCUAUC | 7253 | UGCCAUGAUCAUCAGUGCUCU |
4650 | CCAGUCCAUCUGGGGCUAUCU | 7254 | GCCAUGAUCAUCAGUGCUCUG |
4651 | CAGUCCAUCUGGGGCUAUCUC | 7255 | CCAUGAUCAUCAGUGCUCUGG |
4652 | AGUCCAUCUGGGGCUAUCUCC | 7256 | CAUGAUCAUCAGUGCUCUGGU |
4653 | GUCCAUCUGGGGCUAUCUCCU | 7257 | AUGAUCAUCAGUGCUCUGGUU |
4654 | UCCAUCUGGGGCUAUCUCCUC | 7258 | UGAUCAUCAGUGCUCUGGUUC |
4655 | CCAUCUGGGGCUAUCUCCUCU | 7259 | GAUCAUCAGUGCUCUGGUUCC |
4656 | CAUCUGGGGCUAUCUCCUCUG | 7260 | AUCAUCAGUGCUCUGGUUCCC |
4657 | AUCUGGGGCUAUCUCCUCUGG | 7261 | UCAUCAGUGCUCUGGUUCCCA |
4658 | UCUGGGGCUAUCUCCUCUGGG | 7262 | CAUCAGUGCUCUGGUUCCCAA |
4659 | CUGGGGCUAUCUCCUCUGGGG | 7263 | AUCAGUGCUCUGGUUCCCAAA |
4660 | UGGGGCUAUCUCCUCUGGGGA | 7264 | UCAGUGCUCUGGUUCCCAAAG |
4661 | GGGGCUAUCUCCUCUGGGGAC | 7265 | CAGUGCUCUGGUUCCCAAAGA |
4662 | GGGCUAUCUCCUCUGGGGACA | 7266 | AGUGCUCUGGUUCCCAAAGAG |
4663 | GGCUAUCUCCUCUGGGGACAG | 7267 | GUGCUCUGGUUCCCAAAGAGG |
4664 | GCUAUCUCCUCUGGGGACAGG | 7268 | UGCUCUGGUUCCCAAAGAGGG |
4665 | CUAUCUCCUCUGGGGACAGGG | 7269 | GCUCUGGUUCCCAAAGAGGGU |
4666 | UAUCUCCUCUGGGGACAGGGA | 7270 | CUCUGGUUCCCAAAGAGGGUG |
4667 | AUCUCCUCUGGGGACAGGGAG | 7271 | UCUGGUUCCCAAAGAGGGUGA |
4668 | UCUCCUCUGGGGACAGGGAGC | 7272 | CUGGUUCCCAAAGAGGGUGAU |
4669 | CUCCUCUGGGGACAGGGAGCG | 7273 | UGGUUCCCAAAGAGGGUGAUG |
4670 | UCCUCUGGGGACAGGGAGCGG | 7274 | GGUUCCCAAAGAGGGUGAUGG |
4671 | CCUCUGGGGACAGGGAGCGGU | 7275 | GUUCCCAAAGAGGGUGAUGGA |
4672 | CUCUGGGGACAGGGAGCGGUG | 7276 | UUCCCAAAGAGGGUGAUGGAG |
4673 | UCUGGGGACAGGGAGCGGUGG | 7277 | UCCCAAAGAGGGUGAUGGAGU |
4674 | CUGGGGACAGGGAGCGGUGGC | 7278 | CCCAAAGAGGGUGAUGGAGUU |
4675 | UGGGGACAGGGAGCGGUGGCC | 7279 | CCAAAGAGGGUGAUGGAGUUU |
4676 | GGGGACAGGGAGCGGUGGCCU | 7280 | CAAAGAGGGUGAUGGAGUUUU |
4677 | GGGACAGGGAGCGGUGGCCUA | 7281 | AAAGAGGGUGAUGGAGUUUUG |
4678 | GGACAGGGAGCGGUGGCCUAA | 7282 | AAGAGGGUGAUGGAGUUUUGG |
4679 | GACAGGGAGCGGUGGCCUAAG | 7283 | AGAGGGUGAUGGAGUUUUGGG |
4680 | ACAGGGAGCGGUGGCCUAAGC | 7284 | GAGGGUGAUGGAGUUUUGGGG |
4681 | CAGGGAGCGGUGGCCUAAGCC | 7285 | AGGGUGAUGGAGUUUUGGGGC |
4682 | AGGGAGCGGUGGCCUAAGCCC | 7286 | GGGUGAUGGAGUUUUGGGGCA |
4683 | GGGAGCGGUGGCCUAAGCCCC | 7287 | GGUGAUGGAGUUUUGGGGCAG |
4684 | GGAGCGGUGGCCUAAGCCCCG | 7288 | GUGAUGGAGUUUUGGGGCAGG |
4685 | GAGCGGUGGCCUAAGCCCCGA | 7289 | UGAUGGAGUUUUGGGGCAGGG |
4686 | AGCGGUGGCCUAAGCCCCGAA | 7290 | GAUGGAGUUUUGGGGCAGGGU |
4687 | GCGGUGGCCUAAGCCCCGAAG | 7291 | AUGGAGUUUUGGGGCAGGGUG |
4688 | CGGUGGCCUAAGCCCCGAAGC | 7292 | UGGAGUUUUGGGGCAGGGUGA |
4689 | GGUGGCCUAAGCCCCGAAGCA | 7293 | GGAGUUUUGGGGCAGGGUGAU |
4690 | GUGGCCUAAGCCCCGAAGCAG | 7294 | GAGUUUUGGGGCAGGGUGAUC |
4691 | UGGCCUAAGCCCCGAAGCAGC | 7295 | AGUUUUGGGGCAGGGUGAUCA |
4692 | GGCCUAAGCCCCGAAGCAGCA | 7296 | GUUUUGGGGCAGGGUGAUCAC |
4693 | GCCUAAGCCCCGAAGCAGCAG | 7297 | UUUUGGGGCAGGGUGAUCACU |
4694 | CCUAAGCCCCGAAGCAGCAGG | 7298 | UUUGGGGCAGGGUGAUCACUU |
4695 | CUAAGCCCCGAAGCAGCAGGU | 7299 | UUGGGGCAGGGUGAUCACUUG |
4696 | UAAGCCCCGAAGCAGCAGGUG | 7300 | UGGGGCAGGGUGAUCACUUGG |
4697 | AAGCCCCGAAGCAGCAGGUGC | 7301 | GGGGCAGGGUGAUCACUUGGU |
4698 | AGCCCCGAAGCAGCAGGUGCC | 7302 | GGGCAGGGUGAUCACUUGGUU |
4699 | GCCCCGAAGCAGCAGGUGCCG | 7303 | GGCAGGGUGAUCACUUGGUUG |
4700 | CCCCGAAGCAGCAGGUGCCGG | 7304 | GCAGGGUGAUCACUUGGUUGG |
4701 | CCCGAAGCAGCAGGUGCCGGU | 7305 | CAGGGUGAUCACUUGGUUGGG |
4702 | CCGAAGCAGCAGGUGCCGGUC | 7306 | AGGGUGAUCACUUGGUUGGGG |
4703 | CGAAGCAGCAGGUGCCGGUCA | 7307 | GGGUGAUCACUUGGUUGGGGC |
4704 | GAAGCAGCAGGUGCCGGUCAG | 7308 | GGUGAUCACUUGGUUGGGGCC |
4705 | AAGCAGCAGGUGCCGGUCAGA | 7309 | GUGAUCACUUGGUUGGGGCCU |
4706 | AGCAGCAGGUGCCGGUCAGAU | 7310 | UGAUCACUUGGUUGGGGCCUG |
4707 | GCAGCAGGUGCCGGUCAGAUG | 7311 | GAUCACUUGGUUGGGGCCUGC |
4708 | CAGCAGGUGCCGGUCAGAUGG | 7312 | AUCACUUGGUUGGGGCCUGCG |
4709 | AGCAGGUGCCGGUCAGAUGGA | 7313 | UCACUUGGUUGGGGCCUGCGU |
4710 | GCAGGUGCCGGUCAGAUGGAG | 7314 | CACUUGGUUGGGGCCUGCGUU |
4711 | CAGGUGCCGGUCAGAUGGAGA | 7315 | ACUUGGUUGGGGCCUGCGUUG |
4712 | AGGUGCCGGUCAGAUGGAGAG | 7316 | CUUGGUUGGGGCCUGCGUUGG |
4713 | GGUGCCGGUCAGAUGGAGAGG | 7317 | UUGGUUGGGGCCUGCGUUGGC |
4714 | GUGCCGGUCAGAUGGAGAGGA | 7318 | UGGUUGGGGCCUGCGUUGGCC |
4715 | UGCCGGUCAGAUGGAGAGGAG | 7319 | GGUUGGGGCCUGCGUUGGCCA |
4716 | GCCGGUCAGAUGGAGAGGAGG | 7320 | GUUGGGGCCUGCGUUGGCCAC |
4717 | CCGGUCAGAUGGAGAGGAGGG | 7321 | UUGGGGCCUGCGUUGGCCACA |
4718 | CGGUCAGAUGGAGAGGAGGGA | 7322 | UGGGGCCUGCGUUGGCCACAG |
4719 | GGUCAGAUGGAGAGGAGGGAG | 7323 | GGGGCCUGCGUUGGCCACAGG |
4720 | GUCAGAUGGAGAGGAGGGAGG | 7324 | GGGCCUGCGUUGGCCACAGGG |
4721 | UCAGAUGGAGAGGAGGGAGGC | 7325 | GGCCUGCGUUGGCCACAGGGG |
4722 | CAGAUGGAGAGGAGGGAGGCC | 7326 | GCCUGCGUUGGCCACAGGGGG |
4723 | AGAUGGAGAGGAGGGAGGCCG | 7327 | CCUGCGUUGGCCACAGGGGGG |
4724 | GAUGGAGAGGAGGGAGGCCGU | 7328 | CUGCGUUGGCCACAGGGGGGU |
4725 | AUGGAGAGGAGGGAGGCCGUC | 7329 | UGCGUUGGCCACAGGGGGGUA |
4726 | UGGAGAGGAGGGAGGCCGUCU | 7330 | GCGUUGGCCACAGGGGGGUAA |
4727 | GGAGAGGAGGGAGGCCGUCUG | 7331 | CGUUGGCCACAGGGGGGUAAU |
4728 | GAGAGGAGGGAGGCCGUCUGU | 7332 | GUUGGCCACAGGGGGGUAAUC |
4729 | AGAGGAGGGAGGCCGUCUGUC | 7333 | UUGGCCACAGGGGGGUAAUCC |
4730 | GAGGAGGGAGGCCGUCUGUCC | 7334 | UGGCCACAGGGGGGUAAUCCA |
4731 | AGGAGGGAGGCCGUCUGUCCA | 7335 | GGCCACAGGGGGGUAAUCCAC |
4732 | GGAGGGAGGCCGUCUGUCCAG | 7336 | GCCACAGGGGGGUAAUCCACA |
4733 | GAGGGAGGCCGUCUGUCCAGC | 7337 | CCACAGGGGGGUAAUCCACAG |
4734 | AGGGAGGCCGUCUGUCCAGCC | 7338 | CACAGGGGGGUAAUCCACAGC |
4735 | GGGAGGCCGUCUGUCCAGCCU | 7339 | ACAGGGGGGUAAUCCACAGCU |
4736 | GGAGGCCGUCUGUCCAGCCUG | 7340 | CAGGGGGGUAAUCCACAGCUU |
4737 | GAGGCCGUCUGUCCAGCCUGG | 7341 | AGGGGGGUAAUCCACAGCUUU |
4738 | AGGCCGUCUGUCCAGCCUGGC | 7342 | GGGGGGUAAUCCACAGCUUUG |
4739 | GGCCGUCUGUCCAGCCUGGCU | 7343 | GGGGGUAAUCCACAGCUUUGU |
4740 | GCCGUCUGUCCAGCCUGGCUG | 7344 | GGGGUAAUCCACAGCUUUGUU |
4741 | CCGUCUGUCCAGCCUGGCUGC | 7345 | GGGUAAUCCACAGCUUUGUUC |
4742 | CGUCUGUCCAGCCUGGCUGCU | 7346 | GGUAAUCCACAGCUUUGUUCA |
4743 | GUCUGUCCAGCCUGGCUGCUC | 7347 | GUAAUCCACAGCUUUGUUCAC |
4744 | UCUGUCCAGCCUGGCUGCUCU | 7348 | UAAUCCACAGCUUUGUUCACU |
4745 | CUGUCCAGCCUGGCUGCUCUG | 7349 | AAUCCACAGCUUUGUUCACUG |
4746 | UGUCCAGCCUGGCUGCUCUGA | 7350 | AUCCACAGCUUUGUUCACUGU |
4747 | GUCCAGCCUGGCUGCUCUGAC | 7351 | UCCACAGCUUUGUUCACUGUC |
4748 | UCCAGCCUGGCUGCUCUGACA | 7352 | CCACAGCUUUGUUCACUGUCA |
4749 | CCAGCCUGGCUGCUCUGACAA | 7353 | CACAGCUUUGUUCACUGUCAG |
4750 | CAGCCUGGCUGCUCUGACAAG | 7354 | ACAGCUUUGUUCACUGUCAGG |
4751 | AGCCUGGCUGCUCUGACAAGG | 7355 | CAGCUUUGUUCACUGUCAGGU |
4752 | GCCUGGCUGCUCUGACAAGGG | 7356 | AGCUUUGUUCACUGUCAGGUU |
4753 | CCUGGCUGCUCUGACAAGGGC | 7357 | GCUUUGUUCACUGUCAGGUUU |
4754 | CUGGCUGCUCUGACAAGGGCC | 7358 | CUUUGUUCACUGUCAGGUUUG |
4755 | UGGCUGCUCUGACAAGGGCCC | 7359 | UUUGUUCACUGUCAGGUUUGC |
4756 | GGCUGCUCUGACAAGGGCCCU | 7360 | UUGUUCACUGUCAGGUUUGCA |
4757 | GCUGCUCUGACAAGGGCCCUG | 7361 | UGUUCACUGUCAGGUUUGCAG |
4758 | CUGCUCUGACAAGGGCCCUGG | 7362 | GUUCACUGUCAGGUUUGCAGU |
4759 | UGCUCUGACAAGGGCCCUGGC | 7363 | UUCACUGUCAGGUUUGCAGUA |
4760 | GCUCUGACAAGGGCCCUGGCA | 7364 | UCACUGUCAGGUUUGCAGUAG |
4761 | CUCUGACAAGGGCCCUGGCAG | 7365 | CACUGUCAGGUUUGCAGUAGU |
4762 | UCUGACAAGGGCCCUGGCAGC | 7366 | ACUGUCAGGUUUGCAGUAGUA |
4763 | CUGACAAGGGCCCUGGCAGCG | 7367 | CUGUCAGGUUUGCAGUAGUAG |
4764 | UGACAAGGGCCCUGGCAGCGA | 7368 | UGUCAGGUUUGCAGUAGUAGA |
4765 | GACAAGGGCCCUGGCAGCGAG | 7369 | GUCAGGUUUGCAGUAGUAGAG |
4766 | ACAAGGGCCCUGGCAGCGAGA | 7370 | UCAGGUUUGCAGUAGUAGAGU |
4767 | CAAGGGCCCUGGCAGCGAGAG | 7371 | CAGGUUUGCAGUAGUAGAGUU |
4768 | AAGGGCCCUGGCAGCGAGAGA | 7372 | AGGUUUGCAGUAGUAGAGUUG |
4769 | AGGGCCCUGGCAGCGAGAGAG | 7373 | GGUUUGCAGUAGUAGAGUUGG |
4770 | GGGCCCUGGCAGCGAGAGAGG | 7374 | GUUUGCAGUAGUAGAGUUGGU |
4771 | GGCCCUGGCAGCGAGAGAGGC | 7375 | UUUGCAGUAGUAGAGUUGGUA |
4772 | GCCCUGGCAGCGAGAGAGGCC | 7376 | UUGCAGUAGUAGAGUUGGUAG |
4773 | CCCUGGCAGCGAGAGAGGCCA | 7377 | UGCAGUAGUAGAGUUGGUAGC |
4774 | CCUGGCAGCGAGAGAGGCCAC | 7378 | GCAGUAGUAGAGUUGGUAGCU |
4775 | CUGGCAGCGAGAGAGGCCACC | 7379 | CAGUAGUAGAGUUGGUAGCUC |
4776 | UGGCAGCGAGAGAGGCCACCC | 7380 | AGUAGUAGAGUUGGUAGCUCC |
4777 | GGCAGCGAGAGAGGCCACCCG | 7381 | GUAGUAGAGUUGGUAGCUCCA |
4778 | GCAGCGAGAGAGGCCACCCGC | 7382 | UAGUAGAGUUGGUAGCUCCAU |
4779 | CAGCGAGAGAGGCCACCCGCC | 7383 | AGUAGAGUUGGUAGCUCCAUC |
4780 | AGCGAGAGAGGCCACCCGCCA | 7384 | GUAGAGUUGGUAGCUCCAUCA |
4781 | GCGAGAGAGGCCACCCGCCAU | 7385 | UAGAGUUGGUAGCUCCAUCAG |
4782 | CGAGAGAGGCCACCCGCCAUC | 7386 | AGAGUUGGUAGCUCCAUCAGA |
4783 | GAGAGAGGCCACCCGCCAUCC | 7387 | GAGUUGGUAGCUCCAUCAGAG |
4784 | AGAGAGGCCACCCGCCAUCCC | 7388 | AGUUGGUAGCUCCAUCAGAGU |
4785 | GAGAGGCCACCCGCCAUCCCU | 7389 | GUUGGUAGCUCCAUCAGAGUC |
4786 | AGAGGCCACCCGCCAUCCCUG | 7390 | UUGGUAGCUCCAUCAGAGUCU |
4787 | GAGGCCACCCGCCAUCCCUGA | 7391 | UGGUAGCUCCAUCAGAGUCUA |
4788 | AGGCCACCCGCCAUCCCUGAC | 7392 | GGUAGCUCCAUCAGAGUCUAC |
4789 | GGCCACCCGCCAUCCCUGACA | 7393 | GUAGCUCCAUCAGAGUCUACU |
4790 | GCCACCCGCCAUCCCUGACAC | 7394 | UAGCUCCAUCAGAGUCUACUA |
4791 | CCACCCGCCAUCCCUGACACA | 7395 | AGCUCCAUCAGAGUCUACUAC |
4792 | CACCCGCCAUCCCUGACACAG | 7396 | GCUCCAUCAGAGUCUACUACA |
4793 | ACCCGCCAUCCCUGACACAGU | 7397 | CUCCAUCAGAGUCUACUACAG |
4794 | CCCGCCAUCCCUGACACAGUC | 7398 | UCCAUCAGAGUCUACUACAGU |
4795 | CCGCCAUCCCUGACACAGUCA | 7399 | CCAUCAGAGUCUACUACAGUC |
4796 | CGCCAUCCCUGACACAGUCAA | 7400 | CAUCAGAGUCUACUACAGUCA |
4797 | GCCAUCCCUGACACAGUCAAU | 7401 | AUCAGAGUCUACUACAGUCAA |
4798 | CCAUCCCUGACACAGUCAAUC | 7402 | UCAGAGUCUACUACAGUCAAG |
4799 | CAUCCCUGACACAGUCAAUCC | 7403 | CAGAGUCUACUACAGUCAAGC |
4800 | AUCCCUGACACAGUCAAUCCU | 7404 | AGAGUCUACUACAGUCAAGCU |
4801 | UCCCUGACACAGUCAAUCCUC | 7405 | GAGUCUACUACAGUCAAGCUG |
4802 | CCCUGACACAGUCAAUCCUCC | 7406 | AGUCUACUACAGUCAAGCUGA |
4803 | CCUGACACAGUCAAUCCUCCC | 7407 | GUCUACUACAGUCAAGCUGAA |
4804 | CUGACACAGUCAAUCCUCCCU | 7408 | UCUACUACAGUCAAGCUGAAA |
4805 | UGACACAGUCAAUCCUCCCUA | 7409 | CUACUACAGUCAAGCUGAAAG |
4806 | GACACAGUCAAUCCUCCCUAA | 7410 | UACUACAGUCAAGCUGAAAGU |
4807 | ACACAGUCAAUCCUCCCUAAU | 7411 | ACUACAGUCAAGCUGAAAGUG |
4808 | CACAGUCAAUCCUCCCUAAUC | 7412 | CUACAGUCAAGCUGAAAGUGU |
4809 | ACAGUCAAUCCUCCCUAAUCU | 7413 | UACAGUCAAGCUGAAAGUGUA |
4810 | CAGUCAAUCCUCCCUAAUCUC | 7414 | ACAGUCAAGCUGAAAGUGUAG |
4811 | AGUCAAUCCUCCCUAAUCUCG | 7415 | CAGUCAAGCUGAAAGUGUAGU |
4812 | GUCAAUCCUCCCUAAUCUCGG | 7416 | AGUCAAGCUGAAAGUGUAGUU |
4813 | UCAAUCCUCCCUAAUCUCGGG | 7417 | GUCAAGCUGAAAGUGUAGUUC |
4814 | CAAUCCUCCCUAAUCUCGGGC | 7418 | UCAAGCUGAAAGUGUAGUUCC |
4815 | AAUCCUCCCUAAUCUCGGGCC | 7419 | CAAGCUGAAAGUGUAGUUCCC |
4816 | AUCCUCCCUAAUCUCGGGCCG | 7420 | AAGCUGAAAGUGUAGUUCCCA |
4817 | UCCUCCCUAAUCUCGGGCCGG | 7421 | AGCUGAAAGUGUAGUUCCCAG |
4818 | CCUCCCUAAUCUCGGGCCGGA | 7422 | GCUGAAAGUGUAGUUCCCAGG |
4819 | CUCCCUAAUCUCGGGCCGGAU | 7423 | CUGAAAGUGUAGUUCCCAGGG |
4820 | UCCCUAAUCUCGGGCCGGAUG | 7424 | UGAAAGUGUAGUUCCCAGGGA |
4821 | CCCUAAUCUCGGGCCGGAUGG | 7425 | GAAAGUGUAGUUCCCAGGGAC |
4822 | CCUAAUCUCGGGCCGGAUGGG | 7426 | AAAGUGUAGUUCCCAGGGACG |
4823 | CUAAUCUCGGGCCGGAUGGGA | 7427 | AAGUGUAGUUCCCAGGGACGA |
4824 | UAAUCUCGGGCCGGAUGGGAG | 7428 | AGUGUAGUUCCCAGGGACGAG |
4825 | AAUCUCGGGCCGGAUGGGAGA | 7429 | GUGUAGUUCCCAGGGACGAGU |
4826 | AUCUCGGGCCGGAUGGGAGAA | 7430 | UGUAGUUCCCAGGGACGAGUU |
4827 | UCUCGGGCCGGAUGGGAGAAG | 7431 | GUAGUUCCCAGGGACGAGUUU |
4828 | CUCGGGCCGGAUGGGAGAAGG | 7432 | UAGUUCCCAGGGACGAGUUUA |
4829 | UCGGGCCGGAUGGGAGAAGGG | 7433 | AGUUCCCAGGGACGAGUUUAC |
4830 | CGGGCCGGAUGGGAGAAGGGA | 7434 | GUUCCCAGGGACGAGUUUACU |
4831 | GGGCCGGAUGGGAGAAGGGAG | 7435 | UUCCCAGGGACGAGUUUACUU |
4832 | GGCCGGAUGGGAGAAGGGAGU | 7436 | UCCCAGGGACGAGUUUACUUA |
4833 | GCCGGAUGGGAGAAGGGAGUG | 7437 | CCCAGGGACGAGUUUACUUAG |
4834 | CCGGAUGGGAGAAGGGAGUGG | 7438 | CCAGGGACGAGUUUACUUAGU |
4835 | CGGAUGGGAGAAGGGAGUGGG | 7439 | CAGGGACGAGUUUACUUAGUU |
4836 | GGAUGGGAGAAGGGAGUGGGG | 7440 | AGGGACGAGUUUACUUAGUUU |
4837 | GAUGGGAGAAGGGAGUGGGGC | 7441 | GGGACGAGUUUACUUAGUUUU |
4838 | AUGGGAGAAGGGAGUGGGGCU | 7442 | GGACGAGUUUACUUAGUUUUA |
4839 | UGGGAGAAGGGAGUGGGGCUC | 7443 | GACGAGUUUACUUAGUUUUAA |
4840 | GGGAGAAGGGAGUGGGGCUCC | 7444 | ACGAGUUUACUUAGUUUUAAU |
4841 | GGAGAAGGGAGUGGGGCUCCA | 7445 | CGAGUUUACUUAGUUUUAAUA |
4842 | GAGAAGGGAGUGGGGCUCCAG | 7446 | GAGUUUACUUAGUUUUAAUAU |
4843 | AGAAGGGAGUGGGGCUCCAGU | 7447 | AGUUUACUUAGUUUUAAUAUG |
4844 | GAAGGGAGUGGGGCUCCAGUG | 7448 | GUUUACUUAGUUUUAAUAUGG |
4845 | AAGGGAGUGGGGCUCCAGUGU | 7449 | UUUACUUAGUUUUAAUAUGGC |
4846 | AGGGAGUGGGGCUCCAGUGUU | 7450 | UUACUUAGUUUUAAUAUGGCU |
4847 | GGGAGUGGGGCUCCAGUGUUA | 7451 | UACUUAGUUUUAAUAUGGCUG |
4848 | GGAGUGGGGCUCCAGUGUUAA | 7452 | ACUUAGUUUUAAUAUGGCUGU |
4849 | GAGUGGGGCUCCAGUGUUAAG | 7453 | CUUAGUUUUAAUAUGGCUGUA |
4850 | AGUGGGGCUCCAGUGUUAAGG | 7454 | UUAGUUUUAAUAUGGCUGUAU |
4851 | GUGGGGCUCCAGUGUUAAGGG | 7455 | UAGUUUUAAUAUGGCUGUAUC |
4852 | UGGGGCUCCAGUGUUAAGGGG | 7456 | AGUUUUAAUAUGGCUGUAUCU |
4853 | GGGGCUCCAGUGUUAAGGGGG | 7457 | GUUUUAAUAUGGCUGUAUCUU |
4854 | GGGCUCCAGUGUUAAGGGGGG | 7458 | UUUUAAUAUGGCUGUAUCUUC |
4855 | GGCUCCAGUGUUAAGGGGGGG | 7459 | UUUAAUAUGGCUGUAUCUUCA |
4856 | GCUCCAGUGUUAAGGGGGGGC | 7460 | UUAAUAUGGCUGUAUCUUCAG |
4857 | CUCCAGUGUUAAGGGGGGGCC | 7461 | UAAUAUGGCUGUAUCUUCAGA |
4858 | UCCAGUGUUAAGGGGGGGCCA | 7462 | AAUAUGGCUGUAUCUUCAGAA |
4859 | CCAGUGUUAAGGGGGGGCCAG | 7463 | AUAUGGCUGUAUCUUCAGAAA |
4860 | CAGUGUUAAGGGGGGGCCAGA | 7464 | UAUGGCUGUAUCUUCAGAAAU |
4861 | AGUGUUAAGGGGGGGCCAGAU | 7465 | AUGGCUGUAUCUUCAGAAAUC |
4862 | GUGUUAAGGGGGGGCCAGAUA | 7466 | UGGCUGUAUCUUCAGAAAUCU |
4863 | UGUUAAGGGGGGGCCAGAUAU | 7467 | GGCUGUAUCUUCAGAAAUCUU |
4864 | GUUAAGGGGGGGCCAGAUAUC | 7468 | GCUGUAUCUUCAGAAAUCUUC |
4865 | UUAAGGGGGGGCCAGAUAUCA | 7469 | CUGUAUCUUCAGAAAUCUUCU |
4866 | UAAGGGGGGGCCAGAUAUCAU | 7470 | UGUAUCUUCAGAAAUCUUCUC |
4867 | AAGGGGGGGCCAGAUAUCAUU | 7471 | GUAUCUUCAGAAAUCUUCUCU |
4868 | AGGGGGGGCCAGAUAUCAUUU | 7472 | UAUCUUCAGAAAUCUUCUCUU |
4869 | GGGGGGGCCAGAUAUCAUUUC | 7473 | AUCUUCAGAAAUCUUCUCUUC |
4870 | GGGGGGCCAGAUAUCAUUUCU | 7474 | UCUUCAGAAAUCUUCUCUUCU |
4871 | GGGGGCCAGAUAUCAUUUCUU | 7475 | CUUCAGAAAUCUUCUCUUCUC |
4872 | GGGGCCAGAUAUCAUUUCUUU | 7476 | UUCAGAAAUCUUCUCUUCUCU |
4873 | GGGCCAGAUAUCAUUUCUUUU | 7477 | UCAGAAAUCUUCUCUUCUCUU |
4874 | GGCCAGAUAUCAUUUCUUUUU | 7478 | CAGAAAUCUUCUCUUCUCUUA |
4875 | GCCAGAUAUCAUUUCUUUUUU | 7479 | AGAAAUCUUCUCUUCUCUUAG |
4876 | CCAGAUAUCAUUUCUUUUUUU | 7480 | GAAAUCUUCUCUUCUCUUAGA |
4877 | CAGAUAUCAUUUCUUUUUUUU | 7481 | AAAUCUUCUCUUCUCUUAGAG |
4878 | AGAUAUCAUUUCUUUUUUUUU | 7482 | AAUCUUCUCUUCUCUUAGAGG |
4879 | GAUAUCAUUUCUUUUUUUUUU | 7483 | AUCUUCUCUUCUCUUAGAGGC |
4880 | AUAUCAUUUCUUUUUUUUUUU | 7484 | UCUUCUCUUCUCUUAGAGGCC |
4881 | UAUCAUUUCUUUUUUUUUUUU | 7485 | CUUCUCUUCUCUUAGAGGCCC |
4882 | AUCAUUUCUUUUUUUUUUUUU | 7486 | UUCUCUUCUCUUAGAGGCCCC |
4883 | UCAUUUCUUUUUUUUUUUUUU | 7487 | UCUCUUCUCUUAGAGGCCCCU |
4884 | CAUUUCUUUUUUUUUUUUUUU | 7488 | CUCUUCUCUUAGAGGCCCCUU |
4885 | AUUUCUUUUUUUUUUUUUUUU | 7489 | UCUUCUCUUAGAGGCCCCUUA |
4886 | UUUCUUUUUUUUUUUUUUUUU | 7490 | CUUCUCUUAGAGGCCCCUUAA |
4887 | UUCUUUUUUUUUUUUUUUUUU | 7491 | UUCUCUUAGAGGCCCCUUAAG |
4888 | UCUUUUUUUUUUUUUUUUUUU | 7492 | UCUCUUAGAGGCCCCUUAAGU |
4889 | CUUUUUUUUUUUUUUUUUUUU | 7493 | CUCUUAGAGGCCCCUUAAGUU |
4890 | UUUUUUUUUUUUUUUUUUUUU | 7494 | UCUUAGAGGCCCCUUAAGUUC |
4891 | UUUUUUUUUUUUUUUUUUUUG | 7495 | CUUAGAGGCCCCUUAAGUUCU |
4892 | UUUUUUUUUUUUUUUUUUUGA | 7496 | UUAGAGGCCCCUUAAGUUCUU |
4893 | UUUUUUUUUUUUUUUUUUGAC | 7497 | UAGAGGCCCCUUAAGUUCUUC |
4894 | UUUUUUUUUUUUUUUUUGACG | 7498 | AGAGGCCCCUUAAGUUCUUCC |
4895 | UUUUUUUUUUUUUUUUGACGG | 7499 | GAGGCCCCUUAAGUUCUUCCC |
4896 | UUUUUUUUUUUUUUUGACGGA | 7500 | AGGCCCCUUAAGUUCUUCCCA |
4897 | UUUUUUUUUUUUUUGACGGAG | 7501 | GGCCCCUUAAGUUCUUCCCAA |
4898 | UUUUUUUUUUUUUGACGGAGU | 7502 | GCCCCUUAAGUUCUUCCCAAU |
4899 | UUUUUUUUUUUUGACGGAGUC | 7503 | CCCCUUAAGUUCUUCCCAAUG |
4900 | UUUUUUUUUUUGACGGAGUCU | 7504 | CCCUUAAGUUCUUCCCAAUGG |
4901 | UUUUUUUUUUGACGGAGUCUU | 7505 | CCUUAAGUUCUUCCCAAUGGU |
4902 | UUUUUUUUUGACGGAGUCUUG | 7506 | CUUAAGUUCUUCCCAAUGGUA |
4903 | UUUUUUUUGACGGAGUCUUGC | 7507 | UUAAGUUCUUCCCAAUGGUAC |
4904 | UUUUUUUGACGGAGUCUUGCU | 7508 | UAAGUUCUUCCCAAUGGUACU |
4905 | UUUUUUGACGGAGUCUUGCUC | 7509 | AAGUUCUUCCCAAUGGUACUG |
4906 | UUUUUGACGGAGUCUUGCUCU | 7510 | AGUUCUUCCCAAUGGUACUGA |
4907 | UUUUGACGGAGUCUUGCUCUG | 7511 | GUUCUUCCCAAUGGUACUGAA |
4908 | UUUGACGGAGUCUUGCUCUGU | 7512 | UUCUUCCCAAUGGUACUGAAC |
4909 | UUGACGGAGUCUUGCUCUGUC | 7513 | UCUUCCCAAUGGUACUGAACG |
4910 | UGACGGAGUCUUGCUCUGUCA | 7514 | CUUCCCAAUGGUACUGAACGA |
4911 | GACGGAGUCUUGCUCUGUCAC | 7515 | UUCCCAAUGGUACUGAACGAU |
4912 | ACGGAGUCUUGCUCUGUCACU | 7516 | UCCCAAUGGUACUGAACGAUU |
4913 | CGGAGUCUUGCUCUGUCACUC | 7517 | CCCAAUGGUACUGAACGAUUU |
4914 | GGAGUCUUGCUCUGUCACUCA | 7518 | CCAAUGGUACUGAACGAUUUU |
4915 | GAGUCUUGCUCUGUCACUCAG | 7519 | CAAUGGUACUGAACGAUUUUA |
4916 | AGUCUUGCUCUGUCACUCAGG | 7520 | AAUGGUACUGAACGAUUUUAU |
4917 | GUCUUGCUCUGUCACUCAGGC | 7521 | AUGGUACUGAACGAUUUUAUC |
4918 | UCUUGCUCUGUCACUCAGGCU | 7522 | UGGUACUGAACGAUUUUAUCA |
4919 | CUUGCUCUGUCACUCAGGCUG | 7523 | GGUACUGAACGAUUUUAUCAU |
4920 | UUGCUCUGUCACUCAGGCUGG | 7524 | GUACUGAACGAUUUUAUCAUC |
4921 | UGCUCUGUCACUCAGGCUGGA | 7525 | UACUGAACGAUUUUAUCAUCA |
4922 | GCUCUGUCACUCAGGCUGGAG | 7526 | ACUGAACGAUUUUAUCAUCAU |
4923 | CUCUGUCACUCAGGCUGGAGU | 7527 | CUGAACGAUUUUAUCAUCAUC |
4924 | UCUGUCACUCAGGCUGGAGUG | 7528 | UGAACGAUUUUAUCAUCAUCA |
4925 | CUGUCACUCAGGCUGGAGUGC | 7529 | GAACGAUUUUAUCAUCAUCAG |
4926 | UGUCACUCAGGCUGGAGUGCA | 7530 | AACGAUUUUAUCAUCAUCAGU |
4927 | GUCACUCAGGCUGGAGUGCAG | 7531 | ACGAUUUUAUCAUCAUCAGUG |
4928 | UCACUCAGGCUGGAGUGCAGU | 7532 | CGAUUUUAUCAUCAUCAGUGC |
4929 | CACUCAGGCUGGAGUGCAGUG | 7533 | GAUUUUAUCAUCAUCAGUGCU |
4930 | ACUCAGGCUGGAGUGCAGUGG | 7534 | AUUUUAUCAUCAUCAGUGCUU |
4931 | CUCAGGCUGGAGUGCAGUGGC | 7535 | UUUUAUCAUCAUCAGUGCUUU |
4932 | UCAGGCUGGAGUGCAGUGGCA | 7536 | UUUAUCAUCAUCAGUGCUUUG |
4933 | CAGGCUGGAGUGCAGUGGCAC | 7537 | UUAUCAUCAUCAGUGCUUUGA |
4934 | AGGCUGGAGUGCAGUGGCACG | 7538 | UAUCAUCAUCAGUGCUUUGAC |
4935 | GGCUGGAGUGCAGUGGCACGA | 7539 | AUCAUCAUCAGUGCUUUGACU |
4936 | GCUGGAGUGCAGUGGCACGAU | 7540 | UCAUCAUCAGUGCUUUGACUG |
4937 | CUGGAGUGCAGUGGCACGAUC | 7541 | CAUCAUCAGUGCUUUGACUGC |
4938 | UGGAGUGCAGUGGCACGAUCU | 7542 | AUCAUCAGUGCUUUGACUGCC |
4939 | GGAGUGCAGUGGCACGAUCUU | 7543 | UCAUCAGUGCUUUGACUGCCA |
4940 | GAGUGCAGUGGCACGAUCUUG | 7544 | CAUCAGUGCUUUGACUGCCAU |
4941 | AGUGCAGUGGCACGAUCUUGG | 7545 | AUCAGUGCUUUGACUGCCAUC |
4942 | GUGCAGUGGCACGAUCUUGGC | 7546 | UCAGUGCUUUGACUGCCAUCA |
4943 | UGCAGUGGCACGAUCUUGGCU | 7547 | CAGUGCUUUGACUGCCAUCAA |
4944 | GCAGUGGCACGAUCUUGGCUC | 7548 | AGUGCUUUGACUGCCAUCAAU |
4945 | CAGUGGCACGAUCUUGGCUCA | 7549 | GUGCUUUGACUGCCAUCAAUG |
4946 | AGUGGCACGAUCUUGGCUCAC | 7550 | UGCUUUGACUGCCAUCAAUGA |
4947 | GUGGCACGAUCUUGGCUCACU | 7551 | GCUUUGACUGCCAUCAAUGAC |
4948 | UGGCACGAUCUUGGCUCACUG | 7552 | CUUUGACUGCCAUCAAUGACU |
4949 | GGCACGAUCUUGGCUCACUGC | 7553 | UUUGACUGCCAUCAAUGACUG |
4950 | GCACGAUCUUGGCUCACUGCA | 7554 | UUGACUGCCAUCAAUGACUGU |
4951 | CACGAUCUUGGCUCACUGCAG | 7555 | UGACUGCCAUCAAUGACUGUA |
4952 | ACGAUCUUGGCUCACUGCAGC | 7556 | GACUGCCAUCAAUGACUGUAG |
4953 | CGAUCUUGGCUCACUGCAGCC | 7557 | ACUGCCAUCAAUGACUGUAGA |
4954 | GAUCUUGGCUCACUGCAGCCU | 7558 | CUGCCAUCAAUGACUGUAGAA |
4955 | AUCUUGGCUCACUGCAGCCUC | 7559 | UGCCAUCAAUGACUGUAGAAG |
4956 | UCUUGGCUCACUGCAGCCUCC | 7560 | GCCAUCAAUGACUGUAGAAGU |
4957 | CUUGGCUCACUGCAGCCUCCA | 7561 | CCAUCAAUGACUGUAGAAGUG |
4958 | UUGGCUCACUGCAGCCUCCAC | 7562 | CAUCAAUGACUGUAGAAGUGG |
4959 | UGGCUCACUGCAGCCUCCACC | 7563 | AUCAAUGACUGUAGAAGUGGU |
4960 | GGCUCACUGCAGCCUCCACCU | 7564 | UCAAUGACUGUAGAAGUGGUU |
4961 | GCUCACUGCAGCCUCCACCUC | 7565 | CAAUGACUGUAGAAGUGGUUG |
4962 | CUCACUGCAGCCUCCACCUCC | 7566 | AAUGACUGUAGAAGUGGUUGG |
4963 | UCACUGCAGCCUCCACCUCCC | 7567 | AUGACUGUAGAAGUGGUUGGC |
4964 | CACUGCAGCCUCCACCUCCCA | 7568 | UGACUGUAGAAGUGGUUGGCA |
4965 | ACUGCAGCCUCCACCUCCCAG | 7569 | GACUGUAGAAGUGGUUGGCAA |
4966 | CUGCAGCCUCCACCUCCCAGG | 7570 | ACUGUAGAAGUGGUUGGCAAA |
4967 | UGCAGCCUCCACCUCCCAGGU | 7571 | CUGUAGAAGUGGUUGGCAAAG |
4968 | GCAGCCUCCACCUCCCAGGUU | 7572 | UGUAGAAGUGGUUGGCAAAGA |
4969 | CAGCCUCCACCUCCCAGGUUU | 7573 | GUAGAAGUGGUUGGCAAAGAG |
4970 | AGCCUCCACCUCCCAGGUUUA | 7574 | UAGAAGUGGUUGGCAAAGAGA |
4971 | GCCUCCACCUCCCAGGUUUAA | 7575 | AGAAGUGGUUGGCAAAGAGAU |
4972 | CCUCCACCUCCCAGGUUUAAG | 7576 | GAAGUGGUUGGCAAAGAGAUC |
4973 | CUCCACCUCCCAGGUUUAAGC | 7577 | AAGUGGUUGGCAAAGAGAUCU |
4974 | UCCACCUCCCAGGUUUAAGCA | 7578 | AGUGGUUGGCAAAGAGAUCUC |
4975 | CCACCUCCCAGGUUUAAGCAA | 7579 | GUGGUUGGCAAAGAGAUCUCC |
4976 | CACCUCCCAGGUUUAAGCAAU | 7580 | UGGUUGGCAAAGAGAUCUCCU |
4977 | ACCUCCCAGGUUUAAGCAAUU | 7581 | GGUUGGCAAAGAGAUCUCCUG |
4978 | CCUCCCAGGUUUAAGCAAUUC | 7582 | GUUGGCAAAGAGAUCUCCUGG |
4979 | CUCCCAGGUUUAAGCAAUUCU | 7583 | UUGGCAAAGAGAUCUCCUGGA |
4980 | UCCCAGGUUUAAGCAAUUCUC | 7584 | UGGCAAAGAGAUCUCCUGGAA |
4981 | CCCAGGUUUAAGCAAUUCUCC | 7585 | GGCAAAGAGAUCUCCUGGAAC |
4982 | CCAGGUUUAAGCAAUUCUCCU | 7586 | GCAAAGAGAUCUCCUGGAACU |
4983 | CAGGUUUAAGCAAUUCUCCUG | 7587 | CAAAGAGAUCUCCUGGAACUG |
4984 | AGGUUUAAGCAAUUCUCCUGC | 7588 | AAAGAGAUCUCCUGGAACUGA |
4985 | GGUUUAAGCAAUUCUCCUGCC | 7589 | AAGAGAUCUCCUGGAACUGAG |
4986 | GUUUAAGCAAUUCUCCUGCCU | 7590 | AGAGAUCUCCUGGAACUGAGG |
4987 | UUUAAGCAAUUCUCCUGCCUC | 7591 | GAGAUCUCCUGGAACUGAGGU |
4988 | UUAAGCAAUUCUCCUGCCUCA | 7592 | AGAUCUCCUGGAACUGAGGUG |
4989 | UAAGCAAUUCUCCUGCCUCAG | 7593 | GAUCUCCUGGAACUGAGGUGA |
4990 | AAGCAAUUCUCCUGCCUCAGC | 7594 | AUCUCCUGGAACUGAGGUGAC |
4991 | AGCAAUUCUCCUGCCUCAGCC | 7595 | UCUCCUGGAACUGAGGUGACA |
4992 | GCAAUUCUCCUGCCUCAGCCU | 7596 | CUCCUGGAACUGAGGUGACAC |
4993 | CAAUUCUCCUGCCUCAGCCUC | 7597 | UCCUGGAACUGAGGUGACACA |
4994 | AAUUCUCCUGCCUCAGCCUCC | 7598 | CCUGGAACUGAGGUGACACAA |
4995 | AUUCUCCUGCCUCAGCCUCCC | 7599 | CUGGAACUGAGGUGACACAAU |
4996 | UUCUCCUGCCUCAGCCUCCCG | 7600 | UGGAACUGAGGUGACACAAUA |
4997 | UCUCCUGCCUCAGCCUCCCGA | 7601 | GGAACUGAGGUGACACAAUAG |
4998 | CUCCUGCCUCAGCCUCCCGAG | 7602 | GAACUGAGGUGACACAAUAGC |
4999 | UCCUGCCUCAGCCUCCCGAGU | 7603 | AACUGAGGUGACACAAUAGCA |
5000 | CCUGCCUCAGCCUCCCGAGUA | 7604 | ACUGAGGUGACACAAUAGCAA |
5001 | CUGCCUCAGCCUCCCGAGUAG | 7605 | CUGAGGUGACACAAUAGCAAU |
5002 | UGCCUCAGCCUCCCGAGUAGC | 7606 | UGAGGUGACACAAUAGCAAUG |
5003 | GCCUCAGCCUCCCGAGUAGCU | 7607 | GAGGUGACACAAUAGCAAUGG |
5004 | CCUCAGCCUCCCGAGUAGCUG | 7608 | AGGUGACACAAUAGCAAUGGG |
5005 | CUCAGCCUCCCGAGUAGCUGG | 7609 | GGUGACACAAUAGCAAUGGGG |
5006 | UCAGCCUCCCGAGUAGCUGGG | 7610 | GUGACACAAUAGCAAUGGGGG |
5007 | CAGCCUCCCGAGUAGCUGGGA | 7611 | UGACACAAUAGCAAUGGGGGG |
5008 | AGCCUCCCGAGUAGCUGGGAU | 7612 | GACACAAUAGCAAUGGGGGGC |
5009 | GCCUCCCGAGUAGCUGGGAUU | 7613 | ACACAAUAGCAAUGGGGGGCC |
5010 | CCUCCCGAGUAGCUGGGAUUA | 7614 | CACAAUAGCAAUGGGGGGCCG |
5011 | CUCCCGAGUAGCUGGGAUUAC | 7615 | ACAAUAGCAAUGGGGGGCCGA |
5012 | UCCCGAGUAGCUGGGAUUACA | 7616 | CAAUAGCAAUGGGGGGCCGAU |
5013 | CCCGAGUAGCUGGGAUUACAG | 7617 | AAUAGCAAUGGGGGGCCGAUU |
5014 | CCGAGUAGCUGGGAUUACAGG | 7618 | AUAGCAAUGGGGGGCCGAUUC |
5015 | CGAGUAGCUGGGAUUACAGGC | 7619 | UAGCAAUGGGGGGCCGAUUCU |
5016 | GAGUAGCUGGGAUUACAGGCA | 7620 | AGCAAUGGGGGGCCGAUUCUU |
5017 | AGUAGCUGGGAUUACAGGCAU | 7621 | GCAAUGGGGGGCCGAUUCUUA |
5018 | GUAGCUGGGAUUACAGGCAUA | 7622 | CAAUGGGGGGCCGAUUCUUAC |
5019 | UAGCUGGGAUUACAGGCAUAC | 7623 | AAUGGGGGGCCGAUUCUUACG |
5020 | AGCUGGGAUUACAGGCAUACG | 7624 | AUGGGGGGCCGAUUCUUACGG |
5021 | GCUGGGAUUACAGGCAUACGC | 7625 | UGGGGGGCCGAUUCUUACGGG |
5022 | CUGGGAUUACAGGCAUACGCC | 7626 | GGGGGGCCGAUUCUUACGGGG |
5023 | UGGGAUUACAGGCAUACGCCA | 7627 | GGGGGCCGAUUCUUACGGGGC |
5024 | GGGAUUACAGGCAUACGCCAC | 7628 | GGGGCCGAUUCUUACGGGGCU |
5025 | GGAUUACAGGCAUACGCCACC | 7629 | GGGCCGAUUCUUACGGGGCUC |
5026 | GAUUACAGGCAUACGCCACCA | 7630 | GGCCGAUUCUUACGGGGCUCU |
5027 | AUUACAGGCAUACGCCACCAA | 7631 | GCCGAUUCUUACGGGGCUCUG |
5028 | UUACAGGCAUACGCCACCAAA | 7632 | CCGAUUCUUACGGGGCUCUGG |
5029 | UACAGGCAUACGCCACCAAAC | 7633 | CGAUUCUUACGGGGCUCUGGC |
5030 | ACAGGCAUACGCCACCAAACC | 7634 | GAUUCUUACGGGGCUCUGGCU |
5031 | CAGGCAUACGCCACCAAACCC | 7635 | AUUCUUACGGGGCUCUGGCUU |
5032 | AGGCAUACGCCACCAAACCCG | 7636 | UUCUUACGGGGCUCUGGCUUG |
5033 | GGCAUACGCCACCAAACCCGG | 7637 | UCUUACGGGGCUCUGGCUUGA |
5034 | GCAUACGCCACCAAACCCGGC | 7638 | CUUACGGGGCUCUGGCUUGAC |
5035 | CAUACGCCACCAAACCCGGCU | 7639 | UUACGGGGCUCUGGCUUGACU |
5036 | AUACGCCACCAAACCCGGCUA | 7640 | UACGGGGCUCUGGCUUGACUG |
5037 | UACGCCACCAAACCCGGCUAA | 7641 | ACGGGGCUCUGGCUUGACUGU |
5038 | ACGCCACCAAACCCGGCUAAU | 7642 | CGGGGCUCUGGCUUGACUGUC |
5039 | CGCCACCAAACCCGGCUAAUU | 7643 | GGGGCUCUGGCUUGACUGUCA |
5040 | GCCACCAAACCCGGCUAAUUU | 7644 | GGGCUCUGGCUUGACUGUCAC |
5041 | CCACCAAACCCGGCUAAUUUU | 7645 | GGCUCUGGCUUGACUGUCACG |
5042 | CACCAAACCCGGCUAAUUUUU | 7646 | GCUCUGGCUUGACUGUCACGU |
5043 | ACCAAACCCGGCUAAUUUUUU | 7647 | CUCUGGCUUGACUGUCACGUU |
5044 | CCAAACCCGGCUAAUUUUUUU | 7648 | UCUGGCUUGACUGUCACGUUC |
5045 | CAAACCCGGCUAAUUUUUUUU | 7649 | CUGGCUUGACUGUCACGUUCA |
5046 | AAACCCGGCUAAUUUUUUUUU | 7650 | UGGCUUGACUGUCACGUUCAC |
5047 | AACCCGGCUAAUUUUUUUUUU | 7651 | GGCUUGACUGUCACGUUCACA |
5048 | ACCCGGCUAAUUUUUUUUUUU | 7652 | GCUUGACUGUCACGUUCACAU |
5049 | CCCGGCUAAUUUUUUUUUUUA | 7653 | CUUGACUGUCACGUUCACAUA |
5050 | CCGGCUAAUUUUUUUUUUUAU | 7654 | UUGACUGUCACGUUCACAUAG |
5051 | CGGCUAAUUUUUUUUUUUAUU | 7655 | UGACUGUCACGUUCACAUAGC |
5052 | GGCUAAUUUUUUUUUUUAUUU | 7656 | GACUGUCACGUUCACAUAGCC |
5053 | GCUAAUUUUUUUUUUUAUUUU | 7657 | ACUGUCACGUUCACAUAGCCU |
5054 | CUAAUUUUUUUUUUUAUUUUU | 7658 | CUGUCACGUUCACAUAGCCUU |
5055 | UAAUUUUUUUUUUUAUUUUUA | 7659 | UGUCACGUUCACAUAGCCUUC |
5056 | AAUUUUUUUUUUUAUUUUUAG | 7660 | GUCACGUUCACAUAGCCUUCC |
5057 | AUUUUUUUUUUUAUUUUUAGU | 7661 | UCACGUUCACAUAGCCUUCCC |
5058 | UUUUUUUUUUUAUUUUUAGUA | 7662 | CACGUUCACAUAGCCUUCCCC |
5059 | UUUUUUUUUUAUUUUUAGUAG | 7663 | ACGUUCACAUAGCCUUCCCCA |
5060 | UUUUUUUUUAUUUUUAGUAGA | 7664 | CGUUCACAUAGCCUUCCCCAU |
5061 | UUUUUUUUAUUUUUAGUAGAG | 7665 | GUUCACAUAGCCUUCCCCAUG |
5062 | UUUUUUUAUUUUUAGUAGAGA | 7666 | UUCACAUAGCCUUCCCCAUGG |
5063 | UUUUUUAUUUUUAGUAGAGAU | 7667 | UCACAUAGCCUUCCCCAUGGG |
5064 | UUUUUAUUUUUAGUAGAGAUG | 7668 | CACAUAGCCUUCCCCAUGGGC |
5065 | UUUUAUUUUUAGUAGAGAUGG | 7669 | ACAUAGCCUUCCCCAUGGGCA |
5066 | UUUAUUUUUAGUAGAGAUGGG | 7670 | CAUAGCCUUCCCCAUGGGCAU |
5067 | UUAUUUUUAGUAGAGAUGGGG | 7671 | AUAGCCUUCCCCAUGGGCAUU |
5068 | UAUUUUUAGUAGAGAUGGGGU | 7672 | UAGCCUUCCCCAUGGGCAUUU |
5069 | AUUUUUAGUAGAGAUGGGGUU | 7673 | AGCCUUCCCCAUGGGCAUUUU |
5070 | UUUUUAGUAGAGAUGGGGUUU | 7674 | GCCUUCCCCAUGGGCAUUUUG |
5071 | UUUUAGUAGAGAUGGGGUUUC | 7675 | CCUUCCCCAUGGGCAUUUUGA |
5072 | UUUAGUAGAGAUGGGGUUUCA | 7676 | CUUCCCCAUGGGCAUUUUGAC |
5073 | UUAGUAGAGAUGGGGUUUCAC | 7677 | UUCCCCAUGGGCAUUUUGACC |
5074 | UAGUAGAGAUGGGGUUUCACC | 7678 | UCCCCAUGGGCAUUUUGACCC |
5075 | AGUAGAGAUGGGGUUUCACCG | 7679 | CCCCAUGGGCAUUUUGACCCU |
5076 | GUAGAGAUGGGGUUUCACCGU | 7680 | CCCAUGGGCAUUUUGACCCUC |
5077 | UAGAGAUGGGGUUUCACCGUG | 7681 | CCAUGGGCAUUUUGACCCUCU |
5078 | AGAGAUGGGGUUUCACCGUGU | 7682 | CAUGGGCAUUUUGACCCUCUA |
5079 | GAGAUGGGGUUUCACCGUGUU | 7683 | AUGGGCAUUUUGACCCUCUAC |
5080 | AGAUGGGGUUUCACCGUGUUA | 7684 | UGGGCAUUUUGACCCUCUACA |
5081 | GAUGGGGUUUCACCGUGUUAG | 7685 | GGGCAUUUUGACCCUCUACAA |
5082 | AUGGGGUUUCACCGUGUUAGC | 7686 | GGCAUUUUGACCCUCUACAAU |
5083 | UGGGGUUUCACCGUGUUAGCC | 7687 | GCAUUUUGACCCUCUACAAUC |
5084 | GGGGUUUCACCGUGUUAGCCA | 7688 | CAUUUUGACCCUCUACAAUCA |
5085 | GGGUUUCACCGUGUUAGCCAG | 7689 | AUUUUGACCCUCUACAAUCAC |
5086 | GGUUUCACCGUGUUAGCCAGG | 7690 | UUUUGACCCUCUACAAUCACU |
5087 | GUUUCACCGUGUUAGCCAGGG | 7691 | UUUGACCCUCUACAAUCACUU |
5088 | UUUCACCGUGUUAGCCAGGGU | 7692 | UUGACCCUCUACAAUCACUUU |
5089 | UUCACCGUGUUAGCCAGGGUG | 7693 | UGACCCUCUACAAUCACUUUG |
5090 | UCACCGUGUUAGCCAGGGUGG | 7694 | GACCCUCUACAAUCACUUUGA |
5091 | CACCGUGUUAGCCAGGGUGGU | 7695 | ACCCUCUACAAUCACUUUGAA |
5092 | ACCGUGUUAGCCAGGGUGGUC | 7696 | CCCUCUACAAUCACUUUGAAU |
5093 | CCGUGUUAGCCAGGGUGGUCU | 7697 | CCUCUACAAUCACUUUGAAUU |
5094 | CGUGUUAGCCAGGGUGGUCUU | 7698 | CUCUACAAUCACUUUGAAUUC |
5095 | GUGUUAGCCAGGGUGGUCUUG | 7699 | UCUACAAUCACUUUGAAUUCA |
5096 | UGUUAGCCAGGGUGGUCUUGA | 7700 | CUACAAUCACUUUGAAUUCAU |
5097 | GUUAGCCAGGGUGGUCUUGAU | 7701 | UACAAUCACUUUGAAUUCAUA |
5098 | UUAGCCAGGGUGGUCUUGAUC | 7702 | ACAAUCACUUUGAAUUCAUAC |
5099 | UAGCCAGGGUGGUCUUGAUCU | 7703 | CAAUCACUUUGAAUUCAUACA |
5100 | AGCCAGGGUGGUCUUGAUCUC | 7704 | AAUCACUUUGAAUUCAUACAG |
5101 | GCCAGGGUGGUCUUGAUCUCC | 7705 | AUCACUUUGAAUUCAUACAGG |
5102 | CCAGGGUGGUCUUGAUCUCCU | 7706 | UCACUUUGAAUUCAUACAGGC |
5103 | CAGGGUGGUCUUGAUCUCCUG | 7707 | CACUUUGAAUUCAUACAGGCC |
5104 | AGGGUGGUCUUGAUCUCCUGA | 7708 | ACUUUGAAUUCAUACAGGCCU |
5105 | GGGUGGUCUUGAUCUCCUGAC | 7709 | CUUUGAAUUCAUACAGGCCUG |
5106 | GGUGGUCUUGAUCUCCUGACC | 7710 | UUUGAAUUCAUACAGGCCUGG |
5107 | GUGGUCUUGAUCUCCUGACCU | 7711 | UUGAAUUCAUACAGGCCUGGA |
5108 | UGGUCUUGAUCUCCUGACCUC | 7712 | UGAAUUCAUACAGGCCUGGAG |
5109 | GGUCUUGAUCUCCUGACCUCA | 7713 | GAAUUCAUACAGGCCUGGAGU |
5110 | GUCUUGAUCUCCUGACCUCAU | 7714 | AAUUCAUACAGGCCUGGAGUG |
5111 | UCUUGAUCUCCUGACCUCAUG | 7715 | AUUCAUACAGGCCUGGAGUGA |
5112 | CUUGAUCUCCUGACCUCAUGA | 7716 | UUCAUACAGGCCUGGAGUGAG |
5113 | UUGAUCUCCUGACCUCAUGAU | 7717 | UCAUACAGGCCUGGAGUGAGC |
5114 | UGAUCUCCUGACCUCAUGAUC | 7718 | CAUACAGGCCUGGAGUGAGCU |
5115 | GAUCUCCUGACCUCAUGAUCC | 7719 | AUACAGGCCUGGAGUGAGCUU |
5116 | AUCUCCUGACCUCAUGAUCCG | 7720 | UACAGGCCUGGAGUGAGCUUC |
5117 | UCUCCUGACCUCAUGAUCCGC | 7721 | ACAGGCCUGGAGUGAGCUUCG |
5118 | CUCCUGACCUCAUGAUCCGCC | 7722 | CAGGCCUGGAGUGAGCUUCGA |
5119 | UCCUGACCUCAUGAUCCGCCC | 7723 | AGGCCUGGAGUGAGCUUCGAU |
5120 | CCUGACCUCAUGAUCCGCCCG | 7724 | GGCCUGGAGUGAGCUUCGAUA |
5121 | CUGACCUCAUGAUCCGCCCGC | 7725 | GCCUGGAGUGAGCUUCGAUAG |
5122 | UGACCUCAUGAUCCGCCCGCC | 7726 | CCUGGAGUGAGCUUCGAUAGU |
5123 | GACCUCAUGAUCCGCCCGCCU | 7727 | CUGGAGUGAGCUUCGAUAGUU |
5124 | ACCUCAUGAUCCGCCCGCCUC | 7728 | UGGAGUGAGCUUCGAUAGUUU |
5125 | CCUCAUGAUCCGCCCGCCUCG | 7729 | GGAGUGAGCUUCGAUAGUUUG |
5126 | CUCAUGAUCCGCCCGCCUCGG | 7730 | GAGUGAGCUUCGAUAGUUUGA |
5127 | UCAUGAUCCGCCCGCCUCGGC | 7731 | AGUGAGCUUCGAUAGUUUGAG |
5128 | CAUGAUCCGCCCGCCUCGGCC | 7732 | GUGAGCUUCGAUAGUUUGAGG |
5129 | AUGAUCCGCCCGCCUCGGCCU | 7733 | UGAGCUUCGAUAGUUUGAGGA |
5130 | UGAUCCGCCCGCCUCGGCCUC | 7734 | GAGCUUCGAUAGUUUGAGGAU |
5131 | GAUCCGCCCGCCUCGGCCUCC | 7735 | AGCUUCGAUAGUUUGAGGAUC |
5132 | AUCCGCCCGCCUCGGCCUCCC | 7736 | GCUUCGAUAGUUUGAGGAUCU |
5133 | UCCGCCCGCCUCGGCCUCCCA | 7737 | CUUCGAUAGUUUGAGGAUCUG |
5134 | CCGCCCGCCUCGGCCUCCCAA | 7738 | UUCGAUAGUUUGAGGAUCUGG |
5135 | CGCCCGCCUCGGCCUCCCAAA | 7739 | UCGAUAGUUUGAGGAUCUGGG |
5136 | GCCCGCCUCGGCCUCCCAAAG | 7740 | CGAUAGUUUGAGGAUCUGGGA |
5137 | CCCGCCUCGGCCUCCCAAAGU | 7741 | GAUAGUUUGAGGAUCUGGGAA |
5138 | CCGCCUCGGCCUCCCAAAGUG | 7742 | AUAGUUUGAGGAUCUGGGAAU |
5139 | CGCCUCGGCCUCCCAAAGUGC | 7743 | UAGUUUGAGGAUCUGGGAAUG |
5140 | GCCUCGGCCUCCCAAAGUGCU | 7744 | AGUUUGAGGAUCUGGGAAUGU |
5141 | CCUCGGCCUCCCAAAGUGCUG | 7745 | GUUUGAGGAUCUGGGAAUGUU |
5142 | CUCGGCCUCCCAAAGUGCUGG | 7746 | UUUGAGGAUCUGGGAAUGUUU |
5143 | UCGGCCUCCCAAAGUGCUGGG | 7747 | UUGAGGAUCUGGGAAUGUUUC |
5144 | CGGCCUCCCAAAGUGCUGGGA | 7748 | UGAGGAUCUGGGAAUGUUUCC |
5145 | GGCCUCCCAAAGUGCUGGGAU | 7749 | GAGGAUCUGGGAAUGUUUCCC |
5146 | GCCUCCCAAAGUGCUGGGAUU | 7750 | AGGAUCUGGGAAUGUUUCCCU |
5147 | CCUCCCAAAGUGCUGGGAUUA | 7751 | GGAUCUGGGAAUGUUUCCCUU |
5148 | CUCCCAAAGUGCUGGGAUUAC | 7752 | GAUCUGGGAAUGUUUCCCUUC |
5149 | UCCCAAAGUGCUGGGAUUACA | 7753 | AUCUGGGAAUGUUUCCCUUCC |
5150 | CCCAAAGUGCUGGGAUUACAG | 7754 | UCUGGGAAUGUUUCCCUUCCA |
5151 | CCAAAGUGCUGGGAUUACAGG | 7755 | CUGGGAAUGUUUCCCUUCCAU |
5152 | CAAAGUGCUGGGAUUACAGGC | 7756 | UGGGAAUGUUUCCCUUCCAUU |
5153 | AAAGUGCUGGGAUUACAGGCG | 7757 | GGGAAUGUUUCCCUUCCAUUU |
5154 | AAGUGCUGGGAUUACAGGCGU | 7758 | GGAAUGUUUCCCUUCCAUUUC |
5155 | AGUGCUGGGAUUACAGGCGUG | 7759 | GAAUGUUUCCCUUCCAUUUCU |
5156 | GUGCUGGGAUUACAGGCGUGA | 7760 | AAUGUUUCCCUUCCAUUUCUC |
5157 | UGCUGGGAUUACAGGCGUGAG | 7761 | AUGUUUCCCUUCCAUUUCUCC |
5158 | GCUGGGAUUACAGGCGUGAGC | 7762 | UGUUUCCCUUCCAUUUCUCCA |
5159 | CUGGGAUUACAGGCGUGAGCC | 7763 | GUUUCCCUUCCAUUUCUCCAC |
5160 | UGGGAUUACAGGCGUGAGCCA | 7764 | UUUCCCUUCCAUUUCUCCACU |
5161 | GGGAUUACAGGCGUGAGCCAC | 7765 | UUCCCUUCCAUUUCUCCACUG |
5162 | GGAUUACAGGCGUGAGCCACC | 7766 | UCCCUUCCAUUUCUCCACUGU |
5163 | GAUUACAGGCGUGAGCCACCG | 7767 | CCCUUCCAUUUCUCCACUGUA |
5164 | AUUACAGGCGUGAGCCACCGC | 7768 | CCUUCCAUUUCUCCACUGUAG |
5165 | UUACAGGCGUGAGCCACCGCG | 7769 | CUUCCAUUUCUCCACUGUAGU |
5166 | UACAGGCGUGAGCCACCGCGC | 7770 | UUCCAUUUCUCCACUGUAGUC |
5167 | ACAGGCGUGAGCCACCGCGCC | 7771 | UCCAUUUCUCCACUGUAGUCU |
5168 | CAGGCGUGAGCCACCGCGCCC | 7772 | CCAUUUCUCCACUGUAGUCUC |
5169 | AGGCGUGAGCCACCGCGCCCG | 7773 | CAUUUCUCCACUGUAGUCUCU |
5170 | GGCGUGAGCCACCGCGCCCGG | 7774 | AUUUCUCCACUGUAGUCUCUA |
5171 | GCGUGAGCCACCGCGCCCGGC | 7775 | UUUCUCCACUGUAGUCUCUAG |
5172 | CGUGAGCCACCGCGCCCGGCC | 7776 | UUCUCCACUGUAGUCUCUAGG |
5173 | GUGAGCCACCGCGCCCGGCCA | 7777 | UCUCCACUGUAGUCUCUAGGA |
5174 | UGAGCCACCGCGCCCGGCCAU | 7778 | CUCCACUGUAGUCUCUAGGAU |
5175 | GAGCCACCGCGCCCGGCCAUC | 7779 | UCCACUGUAGUCUCUAGGAUG |
5176 | AGCCACCGCGCCCGGCCAUCA | 7780 | CCACUGUAGUCUCUAGGAUGA |
5177 | GCCACCGCGCCCGGCCAUCAU | 7781 | CACUGUAGUCUCUAGGAUGAG |
5178 | CCACCGCGCCCGGCCAUCAUU | 7782 | ACUGUAGUCUCUAGGAUGAGU |
5179 | CACCGCGCCCGGCCAUCAUUU | 7783 | CUGUAGUCUCUAGGAUGAGUA |
5180 | ACCGCGCCCGGCCAUCAUUUC | 7784 | UGUAGUCUCUAGGAUGAGUAA |
5181 | CCGCGCCCGGCCAUCAUUUCU | 7785 | GUAGUCUCUAGGAUGAGUAAU |
5182 | CGCGCCCGGCCAUCAUUUCUA | 7786 | UAGUCUCUAGGAUGAGUAAUC |
5183 | GCGCCCGGCCAUCAUUUCUAU | 7787 | AGUCUCUAGGAUGAGUAAUCA |
5184 | CGCCCGGCCAUCAUUUCUAUG | 7788 | GUCUCUAGGAUGAGUAAUCAG |
5185 | GCCCGGCCAUCAUUUCUAUGC | 7789 | UCUCUAGGAUGAGUAAUCAGC |
5186 | CCCGGCCAUCAUUUCUAUGCU | 7790 | CUCUAGGAUGAGUAAUCAGCU |
5187 | CCGGCCAUCAUUUCUAUGCUA | 7791 | UCUAGGAUGAGUAAUCAGCUG |
5188 | CGGCCAUCAUUUCUAUGCUAC | 7792 | CUAGGAUGAGUAAUCAGCUGC |
5189 | GGCCAUCAUUUCUAUGCUACC | 7793 | UAGGAUGAGUAAUCAGCUGCC |
5190 | GCCAUCAUUUCUAUGCUACCA | 7794 | AGGAUGAGUAAUCAGCUGCCA |
5191 | CCAUCAUUUCUAUGCUACCAU | 7795 | GGAUGAGUAAUCAGCUGCCAG |
5192 | CAUCAUUUCUAUGCUACCAUC | 7796 | GAUGAGUAAUCAGCUGCCAGU |
5193 | AUCAUUUCUAUGCUACCAUCU | 7797 | AUGAGUAAUCAGCUGCCAGUC |
5194 | UCAUUUCUAUGCUACCAUCUC | 7798 | UGAGUAAUCAGCUGCCAGUCG |
5195 | CAUUUCUAUGCUACCAUCUCA | 7799 | GAGUAAUCAGCUGCCAGUCGU |
5196 | AUUUCUAUGCUACCAUCUCAG | 7800 | AGUAAUCAGCUGCCAGUCGUA |
5197 | UUUCUAUGCUACCAUCUCAGC | 7801 | GUAAUCAGCUGCCAGUCGUAG |
5198 | UUCUAUGCUACCAUCUCAGCA | 7802 | UAAUCAGCUGCCAGUCGUAGG |
5199 | UCUAUGCUACCAUCUCAGCAU | 7803 | AAUCAGCUGCCAGUCGUAGGU |
5200 | CUAUGCUACCAUCUCAGCAUC | 7804 | AUCAGCUGCCAGUCGUAGGUG |
5201 | UAUGCUACCAUCUCAGCAUCU | 7805 | UCAGCUGCCAGUCGUAGGUGU |
5202 | AUGCUACCAUCUCAGCAUCUG | 7806 | CAGCUGCCAGUCGUAGGUGUA |
5203 | UGCUACCAUCUCAGCAUCUGU | 7807 | AGCUGCCAGUCGUAGGUGUAG |
5204 | GCUACCAUCUCAGCAUCUGUG | 7808 | GCUGCCAGUCGUAGGUGUAGG |
5205 | CUACCAUCUCAGCAUCUGUGG | 7809 | CUGCCAGUCGUAGGUGUAGGU |
5206 | UACCAUCUCAGCAUCUGUGGU | 7810 | UGCCAGUCGUAGGUGUAGGUU |
5207 | ACCAUCUCAGCAUCUGUGGUG | 7811 | GCCAGUCGUAGGUGUAGGUUU |
5208 | CCAUCUCAGCAUCUGUGGUGA | 7812 | CCAGUCGUAGGUGUAGGUUUC |
5209 | CAUCUCAGCAUCUGUGGUGAG | 7813 | CAGUCGUAGGUGUAGGUUUCU |
5210 | AUCUCAGCAUCUGUGGUGAGG | 7814 | AGUCGUAGGUGUAGGUUUCUC |
5211 | UCUCAGCAUCUGUGGUGAGGG | 7815 | GUCGUAGGUGUAGGUUUCUCC |
5212 | CUCAGCAUCUGUGGUGAGGGG | 7816 | UCGUAGGUGUAGGUUUCUCCU |
5213 | UCAGCAUCUGUGGUGAGGGGA | 7817 | CGUAGGUGUAGGUUUCUCCUU |
5214 | CAGCAUCUGUGGUGAGGGGAG | 7818 | GUAGGUGUAGGUUUCUCCUUU |
5215 | AGCAUCUGUGGUGAGGGGAGG | 7819 | UAGGUGUAGGUUUCUCCUUUA |
5216 | GCAUCUGUGGUGAGGGGAGGG | 7820 | AGGUGUAGGUUUCUCCUUUAG |
5217 | CAUCUGUGGUGAGGGGAGGGG | 7821 | GGUGUAGGUUUCUCCUUUAGG |
5218 | AUCUGUGGUGAGGGGAGGGGU | 7822 | GUGUAGGUUUCUCCUUUAGGU |
5219 | UCUGUGGUGAGGGGAGGGGUG | 7823 | UGUAGGUUUCUCCUUUAGGUG |
5220 | CUGUGGUGAGGGGAGGGGUGC | 7824 | GUAGGUUUCUCCUUUAGGUGG |
5221 | UGUGGUGAGGGGAGGGGUGCC | 7825 | UAGGUUUCUCCUUUAGGUGGU |
5222 | GUGGUGAGGGGAGGGGUGCCA | 7826 | AGGUUUCUCCUUUAGGUGGUU |
5223 | UGGUGAGGGGAGGGGUGCCAC | 7827 | GGUUUCUCCUUUAGGUGGUUC |
5224 | GGUGAGGGGAGGGGUGCCACU | 7828 | GUUUCUCCUUUAGGUGGUUCU |
5225 | GUGAGGGGAGGGGUGCCACUU | 7829 | UUUCUCCUUUAGGUGGUUCUU |
5226 | UGAGGGGAGGGGUGCCACUUC | 7830 | UUCUCCUUUAGGUGGUUCUUG |
5227 | GAGGGGAGGGGUGCCACUUCC | 7831 | UCUCCUUUAGGUGGUUCUUGG |
5228 | AGGGGAGGGGUGCCACUUCCU | 7832 | CUCCUUUAGGUGGUUCUUGGA |
5229 | GGGGAGGGGUGCCACUUCCUC | 7833 | UCCUUUAGGUGGUUCUUGGAG |
5230 | GGGAGGGGUGCCACUUCCUCU | 7834 | CCUUUAGGUGGUUCUUGGAGA |
5231 | GGAGGGGUGCCACUUCCUCUU | 7835 | CUUUAGGUGGUUCUUGGAGAA |
5232 | GAGGGGUGCCACUUCCUCUUU | 7836 | UUUAGGUGGUUCUUGGAGAAC |
5233 | AGGGGUGCCACUUCCUCUUUG | 7837 | UUAGGUGGUUCUUGGAGAACA |
5234 | GGGGUGCCACUUCCUCUUUGC | 7838 | UAGGUGGUUCUUGGAGAACAU |
5235 | GGGUGCCACUUCCUCUUUGCC | 7839 | AGGUGGUUCUUGGAGAACAUA |
5236 | GGUGCCACUUCCUCUUUGCCC | 7840 | GGUGGUUCUUGGAGAACAUAU |
5237 | GUGCCACUUCCUCUUUGCCCA | 7841 | GUGGUUCUUGGAGAACAUAUG |
5238 | UGCCACUUCCUCUUUGCCCAG | 7842 | UGGUUCUUGGAGAACAUAUGC |
5239 | GCCACUUCCUCUUUGCCCAGC | 7843 | GGUUCUUGGAGAACAUAUGCA |
5240 | CCACUUCCUCUUUGCCCAGCG | 7844 | GUUCUUGGAGAACAUAUGCAU |
5241 | CACUUCCUCUUUGCCCAGCGA | 7845 | UUCUUGGAGAACAUAUGCAUU |
5242 | ACUUCCUCUUUGCCCAGCGAG | 7846 | UCUUGGAGAACAUAUGCAUUU |
5243 | CUUCCUCUUUGCCCAGCGAGA | 7847 | CUUGGAGAACAUAUGCAUUUA |
5244 | UUCCUCUUUGCCCAGCGAGAG | 7848 | UUGGAGAACAUAUGCAUUUAA |
5245 | UCCUCUUUGCCCAGCGAGAGG | 7849 | UGGAGAACAUAUGCAUUUAAU |
5246 | CCUCUUUGCCCAGCGAGAGGG | 7850 | GGAGAACAUAUGCAUUUAAUU |
5247 | CUCUUUGCCCAGCGAGAGGGC | 7851 | GAGAACAUAUGCAUUUAAUUG |
5248 | UCUUUGCCCAGCGAGAGGGCG | 7852 | AGAACAUAUGCAUUUAAUUGA |
5249 | CUUUGCCCAGCGAGAGGGCGU | 7853 | GAACAUAUGCAUUUAAUUGAA |
5250 | UUUGCCCAGCGAGAGGGCGUA | 7854 | AACAUAUGCAUUUAAUUGAAC |
5251 | UUGCCCAGCGAGAGGGCGUAC | 7855 | ACAUAUGCAUUUAAUUGAACU |
5252 | UGCCCAGCGAGAGGGCGUACU | 7856 | CAUAUGCAUUUAAUUGAACUU |
5253 | GCCCAGCGAGAGGGCGUACUC | 7857 | AUAUGCAUUUAAUUGAACUUC |
5254 | CCCAGCGAGAGGGCGUACUCU | 7858 | UAUGCAUUUAAUUGAACUUCA |
5255 | CCAGCGAGAGGGCGUACUCUA | 7859 | AUGCAUUUAAUUGAACUUCAU |
5256 | CAGCGAGAGGGCGUACUCUAC | 7860 | UGCAUUUAAUUGAACUUCAUU |
5257 | AGCGAGAGGGCGUACUCUACC | 7861 | GCAUUUAAUUGAACUUCAUUC |
5258 | GCGAGAGGGCGUACUCUACCC | 7862 | CAUUUAAUUGAACUUCAUUCU |
5259 | CGAGAGGGCGUACUCUACCCC | 7863 | AUUUAAUUGAACUUCAUUCUU |
5260 | GAGAGGGCGUACUCUACCCCA | 7864 | UUUAAUUGAACUUCAUUCUUA |
5261 | AGAGGGCGUACUCUACCCCAG | 7865 | UUAAUUGAACUUCAUUCUUAG |
5262 | GAGGGCGUACUCUACCCCAGA | 7866 | UAAUUGAACUUCAUUCUUAGG |
5263 | AGGGCGUACUCUACCCCAGAG | 7867 | AAUUGAACUUCAUUCUUAGGC |
5264 | GGGCGUACUCUACCCCAGAGA | 7868 | AUUGAACUUCAUUCUUAGGCA |
5265 | GGCGUACUCUACCCCAGAGAG | 7869 | UUGAACUUCAUUCUUAGGCAG |
5266 | GCGUACUCUACCCCAGAGAGG | 7870 | UGAACUUCAUUCUUAGGCAGG |
5267 | CGUACUCUACCCCAGAGAGGG | 7871 | GAACUUCAUUCUUAGGCAGGG |
5268 | GUACUCUACCCCAGAGAGGGA | 7872 | AACUUCAUUCUUAGGCAGGGU |
5269 | UACUCUACCCCAGAGAGGGAA | 7873 | ACUUCAUUCUUAGGCAGGGUU |
5270 | ACUCUACCCCAGAGAGGGAAA | 7874 | CUUCAUUCUUAGGCAGGGUUA |
5271 | CUCUACCCCAGAGAGGGAAAC | 7875 | UUCAUUCUUAGGCAGGGUUAU |
5272 | UCUACCCCAGAGAGGGAAACA | 7876 | UCAUUCUUAGGCAGGGUUAUC |
5273 | CUACCCCAGAGAGGGAAACAC | 7877 | CAUUCUUAGGCAGGGUUAUCU |
5274 | UACCCCAGAGAGGGAAACACC | 7878 | AUUCUUAGGCAGGGUUAUCUG |
5275 | ACCCCAGAGAGGGAAACACCA | 7879 | UUCUUAGGCAGGGUUAUCUGG |
5276 | CCCCAGAGAGGGAAACACCAU | 7880 | UCUUAGGCAGGGUUAUCUGGA |
5277 | CCCAGAGAGGGAAACACCAUG | 7881 | CUUAGGCAGGGUUAUCUGGAC |
5278 | CCAGAGAGGGAAACACCAUGC | 7882 | UUAGGCAGGGUUAUCUGGACA |
5279 | CAGAGAGGGAAACACCAUGCC | 7883 | UAGGCAGGGUUAUCUGGACAC |
5280 | AGAGAGGGAAACACCAUGCCC | 7884 | AGGCAGGGUUAUCUGGACACU |
5281 | GAGAGGGAAACACCAUGCCCA | 7885 | GGCAGGGUUAUCUGGACACUC |
5282 | AGAGGGAAACACCAUGCCCAC | 7886 | GCAGGGUUAUCUGGACACUCU |
5283 | GAGGGAAACACCAUGCCCACA | 7887 | CAGGGUUAUCUGGACACUCUC |
5284 | AGGGAAACACCAUGCCCACAG | 7888 | AGGGUUAUCUGGACACUCUCU |
5285 | GGGAAACACCAUGCCCACAGU | 7889 | GGGUUAUCUGGACACUCUCUC |
5286 | GGAAACACCAUGCCCACAGUG | 7890 | GGUUAUCUGGACACUCUCUCC |
5287 | GAAACACCAUGCCCACAGUGC | 7891 | GUUAUCUGGACACUCUCUCCA |
5288 | AAACACCAUGCCCACAGUGCU | 7892 | UUAUCUGGACACUCUCUCCAG |
5289 | AACACCAUGCCCACAGUGCUU | 7893 | UAUCUGGACACUCUCUCCAGC |
5290 | ACACCAUGCCCACAGUGCUUG | 7894 | AUCUGGACACUCUCUCCAGCA |
5291 | CACCAUGCCCACAGUGCUUGG | 7895 | UCUGGACACUCUCUCCAGCAG |
5292 | ACCAUGCCCACAGUGCUUGGU | 7896 | CUGGACACUCUCUCCAGCAGA |
5293 | CCAUGCCCACAGUGCUUGGUU | 7897 | UGGACACUCUCUCCAGCAGAU |
5294 | CAUGCCCACAGUGCUUGGUUU | 7898 | GGACACUCUCUCCAGCAGAUA |
5295 | AUGCCCACAGUGCUUGGUUUU | 7899 | GACACUCUCUCCAGCAGAUAC |
5296 | UGCCCACAGUGCUUGGUUUUG | 7900 | ACACUCUCUCCAGCAGAUACC |
5297 | GCCCACAGUGCUUGGUUUUGC | 7901 | CACUCUCUCCAGCAGAUACCA |
5298 | CCCACAGUGCUUGGUUUUGCA | 7902 | ACUCUCUCCAGCAGAUACCAC |
5299 | CCACAGUGCUUGGUUUUGCAC | 7903 | CUCUCUCCAGCAGAUACCACC |
5300 | CACAGUGCUUGGUUUUGCACU | 7904 | UCUCUCCAGCAGAUACCACCA |
5301 | ACAGUGCUUGGUUUUGCACUC | 7905 | CUCUCCAGCAGAUACCACCAG |
5302 | CAGUGCUUGGUUUUGCACUCA | 7906 | UCUCCAGCAGAUACCACCAGU |
5303 | AGUGCUUGGUUUUGCACUCAG | 7907 | CUCCAGCAGAUACCACCAGUU |
5304 | GUGCUUGGUUUUGCACUCAGG | 7908 | UCCAGCAGAUACCACCAGUUC |
5305 | UGCUUGGUUUUGCACUCAGGU | 7909 | CCAGCAGAUACCACCAGUUCC |
5306 | GCUUGGUUUUGCACUCAGGUG | 7910 | CAGCAGAUACCACCAGUUCCU |
5307 | CUUGGUUUUGCACUCAGGUGU | 7911 | AGCAGAUACCACCAGUUCCUU |
5308 | UUGGUUUUGCACUCAGGUGUG | 7912 | GCAGAUACCACCAGUUCCUUU |
5309 | UGGUUUUGCACUCAGGUGUGC | 7913 | CAGAUACCACCAGUUCCUUUA |
5310 | GGUUUUGCACUCAGGUGUGCG | 7914 | AGAUACCACCAGUUCCUUUAU |
5311 | GUUUUGCACUCAGGUGUGCGG | 7915 | GAUACCACCAGUUCCUUUAUA |
5312 | UUUUGCACUCAGGUGUGCGGG | 7916 | AUACCACCAGUUCCUUUAUAA |
5313 | UUUGCACUCAGGUGUGCGGGC | 7917 | UACCACCAGUUCCUUUAUAAC |
5314 | UUGCACUCAGGUGUGCGGGCA | 7918 | ACCACCAGUUCCUUUAUAACU |
5315 | UGCACUCAGGUGUGCGGGCAG | 7919 | CCACCAGUUCCUUUAUAACUG |
5316 | GCACUCAGGUGUGCGGGCAGC | 7920 | CACCAGUUCCUUUAUAACUGG |
5317 | CACUCAGGUGUGCGGGCAGCA | 7921 | ACCAGUUCCUUUAUAACUGGG |
5318 | ACUCAGGUGUGCGGGCAGCAC | 7922 | CCAGUUCCUUUAUAACUGGGU |
5319 | CUCAGGUGUGCGGGCAGCACA | 7923 | CAGUUCCUUUAUAACUGGGUA |
5320 | UCAGGUGUGCGGGCAGCACAG | 7924 | AGUUCCUUUAUAACUGGGUAU |
5321 | CAGGUGUGCGGGCAGCACAGC | 7925 | GUUCCUUUAUAACUGGGUAUG |
5322 | AGGUGUGCGGGCAGCACAGCA | 7926 | UUCCUUUAUAACUGGGUAUGG |
5323 | GGUGUGCGGGCAGCACAGCAG | 7927 | UCCUUUAUAACUGGGUAUGGU |
5324 | GUGUGCGGGCAGCACAGCAGG | 7928 | CCUUUAUAACUGGGUAUGGUG |
5325 | UGUGCGGGCAGCACAGCAGGC | 7929 | CUUUAUAACUGGGUAUGGUGC |
5326 | GUGCGGGCAGCACAGCAGGCC | 7930 | UUUAUAACUGGGUAUGGUGCU |
5327 | UGCGGGCAGCACAGCAGGCCU | 7931 | UUAUAACUGGGUAUGGUGCUG |
5328 | GCGGGCAGCACAGCAGGCCUC | 7932 | UAUAACUGGGUAUGGUGCUGA |
5329 | CGGGCAGCACAGCAGGCCUCA | 7933 | AUAACUGGGUAUGGUGCUGAG |
5330 | GGGCAGCACAGCAGGCCUCAC | 7934 | UAACUGGGUAUGGUGCUGAGG |
5331 | GGCAGCACAGCAGGCCUCACC | 7935 | AACUGGGUAUGGUGCUGAGGU |
5332 | GCAGCACAGCAGGCCUCACCU | 7936 | ACUGGGUAUGGUGCUGAGGUG |
5333 | CAGCACAGCAGGCCUCACCUU | 7937 | CUGGGUAUGGUGCUGAGGUGC |
5334 | AGCACAGCAGGCCUCACCUUG | 7938 | UGGGUAUGGUGCUGAGGUGCU |
5335 | GCACAGCAGGCCUCACCUUGC | 7939 | GGGUAUGGUGCUGAGGUGCUC |
5336 | CACAGCAGGCCUCACCUUGCA | 7940 | GGUAUGGUGCUGAGGUGCUCU |
5337 | ACAGCAGGCCUCACCUUGCAG | 7941 | GUAUGGUGCUGAGGUGCUCUG |
5338 | CAGCAGGCCUCACCUUGCAGC | 7942 | UAUGGUGCUGAGGUGCUCUGG |
5339 | AGCAGGCCUCACCUUGCAGCA | 7943 | AUGGUGCUGAGGUGCUCUGGA |
5340 | GCAGGCCUCACCUUGCAGCAC | 7944 | UGGUGCUGAGGUGCUCUGGAA |
5341 | CAGGCCUCACCUUGCAGCACU | 7945 | GGUGCUGAGGUGCUCUGGAAA |
5342 | AGGCCUCACCUUGCAGCACUC | 7946 | GUGCUGAGGUGCUCUGGAAAG |
5343 | GGCCUCACCUUGCAGCACUCU | 7947 | UGCUGAGGUGCUCUGGAAAGA |
5344 | GCCUCACCUUGCAGCACUCUG | 7948 | GCUGAGGUGCUCUGGAAAGAG |
5345 | CCUCACCUUGCAGCACUCUGG | 7949 | CUGAGGUGCUCUGGAAAGAGG |
5346 | CUCACCUUGCAGCACUCUGGG | 7950 | UGAGGUGCUCUGGAAAGAGGC |
5347 | UCACCUUGCAGCACUCUGGGC | 7951 | GAGGUGCUCUGGAAAGAGGCC |
5348 | CACCUUGCAGCACUCUGGGCA | 7952 | AGGUGCUCUGGAAAGAGGCCU |
5349 | ACCUUGCAGCACUCUGGGCAC | 7953 | GGUGCUCUGGAAAGAGGCCUG |
5350 | CCUUGCAGCACUCUGGGCACA | 7954 | GUGCUCUGGAAAGAGGCCUGG |
5351 | CUUGCAGCACUCUGGGCACAA | 7955 | UGCUCUGGAAAGAGGCCUGGG |
5352 | UUGCAGCACUCUGGGCACAAU | 7956 | GCUCUGGAAAGAGGCCUGGGG |
5353 | UGCAGCACUCUGGGCACAAUG | 7957 | CUCUGGAAAGAGGCCUGGGGG |
5354 | GCAGCACUCUGGGCACAAUGA | 7958 | UCUGGAAAGAGGCCUGGGGGG |
5355 | CAGCACUCUGGGCACAAUGAC | 7959 | CUGGAAAGAGGCCUGGGGGGU |
5356 | AGCACUCUGGGCACAAUGACA | 7960 | UGGAAAGAGGCCUGGGGGGUA |
5357 | GCACUCUGGGCACAAUGACAC | 7961 | GGAAAGAGGCCUGGGGGGUAG |
5358 | CACUCUGGGCACAAUGACACU | 7962 | GAAAGAGGCCUGGGGGGUAGG |
5359 | ACUCUGGGCACAAUGACACUG | 7963 | AAAGAGGCCUGGGGGGUAGGG |
5360 | CUCUGGGCACAAUGACACUGU | 7964 | AAGAGGCCUGGGGGGUAGGGG |
5361 | UCUGGGCACAAUGACACUGUC | 7965 | AGAGGCCUGGGGGGUAGGGGU |
5362 | CUGGGCACAAUGACACUGUCC | 7966 | GAGGCCUGGGGGGUAGGGGUA |
5363 | UGGGCACAAUGACACUGUCCA | 7967 | AGGCCUGGGGGGUAGGGGUAG |
5364 | GGGCACAAUGACACUGUCCAC | 7968 | GGCCUGGGGGGUAGGGGUAGC |
5365 | GGCACAAUGACACUGUCCACU | 7969 | GCCUGGGGGGUAGGGGUAGCA |
5366 | GCACAAUGACACUGUCCACUG | 7970 | CCUGGGGGGUAGGGGUAGCAU |
5367 | CACAAUGACACUGUCCACUGG | 7971 | CUGGGGGGUAGGGGUAGCAUA |
5368 | ACAAUGACACUGUCCACUGGG | 7972 | UGGGGGGUAGGGGUAGCAUAA |
5369 | CAAUGACACUGUCCACUGGGG | 7973 | GGGGGGUAGGGGUAGCAUAAC |
5370 | AAUGACACUGUCCACUGGGGA | 7974 | GGGGGUAGGGGUAGCAUAACU |
5371 | AUGACACUGUCCACUGGGGAG | 7975 | GGGGUAGGGGUAGCAUAACUG |
5372 | UGACACUGUCCACUGGGGAGC | 7976 | GGGUAGGGGUAGCAUAACUGU |
5373 | GACACUGUCCACUGGGGAGCU | 7977 | GGUAGGGGUAGCAUAACUGUA |
5374 | ACACUGUCCACUGGGGAGCUG | 7978 | GUAGGGGUAGCAUAACUGUAG |
5375 | CACUGUCCACUGGGGAGCUGC | 7979 | UAGGGGUAGCAUAACUGUAGG |
5376 | ACUGUCCACUGGGGAGCUGCA | 7980 | AGGGGUAGCAUAACUGUAGGA |
5377 | CUGUCCACUGGGGAGCUGCAG | 7981 | GGGGUAGCAUAACUGUAGGAG |
5378 | UGUCCACUGGGGAGCUGCAGA | 7982 | GGGUAGCAUAACUGUAGGAGG |
5379 | GUCCACUGGGGAGCUGCAGAG | 7983 | GGUAGCAUAACUGUAGGAGGG |
5380 | UCCACUGGGGAGCUGCAGAGC | 7984 | GUAGCAUAACUGUAGGAGGGA |
5381 | CCACUGGGGAGCUGCAGAGCU | 7985 | UAGCAUAACUGUAGGAGGGAG |
5382 | CACUGGGGAGCUGCAGAGCUU | 7986 | AGCAUAACUGUAGGAGGGAGC |
5383 | ACUGGGGAGCUGCAGAGCUUA | 7987 | GCAUAACUGUAGGAGGGAGCC |
5384 | CUGGGGAGCUGCAGAGCUUAG | 7988 | CAUAACUGUAGGAGGGAGCCA |
5385 | UGGGGAGCUGCAGAGCUUAGC | 7989 | AUAACUGUAGGAGGGAGCCAC |
5386 | GGGGAGCUGCAGAGCUUAGCA | 7990 | UAACUGUAGGAGGGAGCCACU |
5387 | GGGAGCUGCAGAGCUUAGCAG | 7991 | AACUGUAGGAGGGAGCCACUG |
5388 | GGAGCUGCAGAGCUUAGCAGC | 7992 | ACUGUAGGAGGGAGCCACUGG |
5389 | GAGCUGCAGAGCUUAGCAGCU | 7993 | CUGUAGGAGGGAGCCACUGGC |
5390 | AGCUGCAGAGCUUAGCAGCUG | 7994 | UGUAGGAGGGAGCCACUGGCU |
5391 | GCUGCAGAGCUUAGCAGCUGG | 7995 | GUAGGAGGGAGCCACUGGCUG |
5392 | CUGCAGAGCUUAGCAGCUGGC | 7996 | UAGGAGGGAGCCACUGGCUGG |
5393 | UGCAGAGCUUAGCAGCUGGCU | 7997 | AGGAGGGAGCCACUGGCUGGG |
5394 | GCAGAGCUUAGCAGCUGGCUG | 7998 | GGAGGGAGCCACUGGCUGGGG |
5395 | CAGAGCUUAGCAGCUGGCUGG | 7999 | GAGGGAGCCACUGGCUGGGGG |
5396 | AGAGCUUAGCAGCUGGCUGGG | 8000 | AGGGAGCCACUGGCUGGGGGA |
5397 | GAGCUUAGCAGCUGGCUGGGU | 8001 | GGGAGCCACUGGCUGGGGGAC |
5398 | AGCUUAGCAGCUGGCUGGGUC | 8002 | GGAGCCACUGGCUGGGGGACA |
5399 | GCUUAGCAGCUGGCUGGGUCU | 8003 | GAGCCACUGGCUGGGGGACAG |
5400 | CUUAGCAGCUGGCUGGGUCUG | 8004 | AGCCACUGGCUGGGGGACAGC |
5401 | UUAGCAGCUGGCUGGGUCUGC | 8005 | GCCACUGGCUGGGGGACAGCA |
5402 | UAGCAGCUGGCUGGGUCUGCC | 8006 | CCACUGGCUGGGGGACAGCAA |
5403 | AGCAGCUGGCUGGGUCUGCCC | 8007 | CACUGGCUGGGGGACAGCAAU |
5404 | GCAGCUGGCUGGGUCUGCCCU | 8008 | ACUGGCUGGGGGACAGCAAUC |
5405 | CAGCUGGCUGGGUCUGCCCUC | 8009 | CUGGCUGGGGGACAGCAAUCU |
5406 | AGCUGGCUGGGUCUGCCCUCG | 8010 | UGGCUGGGGGACAGCAAUCUG |
5407 | GCUGGCUGGGUCUGCCCUCGG | 8011 | GGCUGGGGGACAGCAAUCUGG |
5408 | CUGGCUGGGUCUGCCCUCGGG | 8012 | GCUGGGGGACAGCAAUCUGGG |
5409 | UGGCUGGGUCUGCCCUCGGGG | 8013 | CUGGGGGACAGCAAUCUGGGU |
5410 | GGCUGGGUCUGCCCUCGGGGG | 8014 | UGGGGGACAGCAAUCUGGGUU |
5411 | GCUGGGUCUGCCCUCGGGGGA | 8015 | GGGGGACAGCAAUCUGGGUUU |
5412 | CUGGGUCUGCCCUCGGGGGAG | 8016 | GGGGACAGCAAUCUGGGUUUU |
5413 | UGGGUCUGCCCUCGGGGGAGG | 8017 | GGGACAGCAAUCUGGGUUUUC |
5414 | GGGUCUGCCCUCGGGGGAGGG | 8018 | GGACAGCAAUCUGGGUUUUCU |
5415 | GGUCUGCCCUCGGGGGAGGGG | 8019 | GACAGCAAUCUGGGUUUUCUC |
5416 | GUCUGCCCUCGGGGGAGGGGA | 8020 | ACAGCAAUCUGGGUUUUCUCA |
5417 | UCUGCCCUCGGGGGAGGGGAG | 8021 | CAGCAAUCUGGGUUUUCUCAG |
5418 | CUGCCCUCGGGGGAGGGGAGG | 8022 | AGCAAUCUGGGUUUUCUCAGA |
5419 | UGCCCUCGGGGGAGGGGAGGA | 8023 | GCAAUCUGGGUUUUCUCAGAA |
5420 | GCCCUCGGGGGAGGGGAGGAG | 8024 | CAAUCUGGGUUUUCUCAGAAC |
5421 | CCCUCGGGGGAGGGGAGGAGU | 8025 | AAUCUGGGUUUUCUCAGAACU |
5422 | CCUCGGGGGAGGGGAGGAGUU | 8026 | AUCUGGGUUUUCUCAGAACUU |
5423 | CUCGGGGGAGGGGAGGAGUUU | 8027 | UCUGGGUUUUCUCAGAACUUU |
5424 | UCGGGGGAGGGGAGGAGUUUG | 8028 | CUGGGUUUUCUCAGAACUUUU |
5425 | CGGGGGAGGGGAGGAGUUUGC | 8029 | UGGGUUUUCUCAGAACUUUUU |
5426 | GGGGGAGGGGAGGAGUUUGCA | 8030 | GGGUUUUCUCAGAACUUUUUA |
5427 | GGGGAGGGGAGGAGUUUGCAA | 8031 | GGUUUUCUCAGAACUUUUUAC |
5428 | GGGAGGGGAGGAGUUUGCAAA | 8032 | GUUUUCUCAGAACUUUUUACU |
5429 | GGAGGGGAGGAGUUUGCAAAA | 8033 | UUUUCUCAGAACUUUUUACUU |
5430 | GAGGGGAGGAGUUUGCAAAAA | 8034 | UUUCUCAGAACUUUUUACUUG |
5431 | AGGGGAGGAGUUUGCAAAAAA | 8035 | UUCUCAGAACUUUUUACUUGU |
5432 | GGGGAGGAGUUUGCAAAAAAA | 8036 | UCUCAGAACUUUUUACUUGUU |
5433 | GGGAGGAGUUUGCAAAAAAAG | 8037 | CUCAGAACUUUUUACUUGUUG |
5434 | GGAGGAGUUUGCAAAAAAAGG | 8038 | UCAGAACUUUUUACUUGUUGA |
5435 | GAGGAGUUUGCAAAAAAAGGA | 8039 | CAGAACUUUUUACUUGUUGAG |
5436 | AGGAGUUUGCAAAAAAAGGAG | 8040 | AGAACUUUUUACUUGUUGAGU |
5437 | GGAGUUUGCAAAAAAAGGAGG | 8041 | GAACUUUUUACUUGUUGAGUG |
5438 | GAGUUUGCAAAAAAAGGAGGC | 8042 | AACUUUUUACUUGUUGAGUGC |
5439 | AGUUUGCAAAAAAAGGAGGCC | 8043 | ACUUUUUACUUGUUGAGUGCU |
5440 | GUUUGCAAAAAAAGGAGGCCC | 8044 | CUUUUUACUUGUUGAGUGCUG |
5441 | UUUGCAAAAAAAGGAGGCCCU | 8045 | UUUUUACUUGUUGAGUGCUGG |
5442 | UUGCAAAAAAAGGAGGCCCUG | 8046 | UUUUACUUGUUGAGUGCUGGG |
5443 | UGCAAAAAAAGGAGGCCCUGA | 8047 | UUUACUUGUUGAGUGCUGGGC |
5444 | GCAAAAAAAGGAGGCCCUGAG | 8048 | UUACUUGUUGAGUGCUGGGCG |
5445 | CAAAAAAAGGAGGCCCUGAGG | 8049 | UACUUGUUGAGUGCUGGGCGU |
5446 | AAAAAAAGGAGGCCCUGAGGU | 8050 | ACUUGUUGAGUGCUGGGCGUA |
5447 | AAAAAAGGAGGCCCUGAGGUG | 8051 | CUUGUUGAGUGCUGGGCGUAG |
5448 | AAAAAGGAGGCCCUGAGGUGA | 8052 | UUGUUGAGUGCUGGGCGUAGU |
5449 | AAAAGGAGGCCCUGAGGUGAG | 8053 | UGUUGAGUGCUGGGCGUAGUA |
5450 | AAAGGAGGCCCUGAGGUGAGG | 8054 | GUUGAGUGCUGGGCGUAGUAG |
5451 | AAGGAGGCCCUGAGGUGAGGA | 8055 | UUGAGUGCUGGGCGUAGUAGC |
5452 | AGGAGGCCCUGAGGUGAGGAU | 8056 | UGAGUGCUGGGCGUAGUAGCA |
5453 | GGAGGCCCUGAGGUGAGGAUA | 8057 | GAGUGCUGGGCGUAGUAGCAA |
5454 | GAGGCCCUGAGGUGAGGAUAU | 8058 | AGUGCUGGGCGUAGUAGCAAG |
5455 | AGGCCCUGAGGUGAGGAUAUC | 8059 | GUGCUGGGCGUAGUAGCAAGA |
5456 | GGCCCUGAGGUGAGGAUAUCU | 8060 | UGCUGGGCGUAGUAGCAAGAC |
5457 | GCCCUGAGGUGAGGAUAUCUG | 8061 | GCUGGGCGUAGUAGCAAGACC |
5458 | CCCUGAGGUGAGGAUAUCUGG | 8062 | CUGGGCGUAGUAGCAAGACCC |
5459 | CCUGAGGUGAGGAUAUCUGGG | 8063 | UGGGCGUAGUAGCAAGACCCU |
5460 | CUGAGGUGAGGAUAUCUGGGG | 8064 | GGGCGUAGUAGCAAGACCCUC |
5461 | UGAGGUGAGGAUAUCUGGGGG | 8065 | GGCGUAGUAGCAAGACCCUCU |
5462 | GAGGUGAGGAUAUCUGGGGGC | 8066 | GCGUAGUAGCAAGACCCUCUG |
5463 | AGGUGAGGAUAUCUGGGGGCC | 8067 | CGUAGUAGCAAGACCCUCUGA |
5464 | GGUGAGGAUAUCUGGGGGCCC | 8068 | GUAGUAGCAAGACCCUCUGAU |
5465 | GUGAGGAUAUCUGGGGGCCCA | 8069 | UAGUAGCAAGACCCUCUGAUA |
5466 | UGAGGAUAUCUGGGGGCCCAC | 8070 | AGUAGCAAGACCCUCUGAUAU |
5467 | GAGGAUAUCUGGGGGCCCACC | 8071 | GUAGCAAGACCCUCUGAUAUU |
5468 | AGGAUAUCUGGGGGCCCACCA | 8072 | UAGCAAGACCCUCUGAUAUUU |
5469 | GGAUAUCUGGGGGCCCACCAG | 8073 | AGCAAGACCCUCUGAUAUUUC |
5470 | GAUAUCUGGGGGCCCACCAGA | 8074 | GCAAGACCCUCUGAUAUUUCA |
5471 | AUAUCUGGGGGCCCACCAGAC | 8075 | CAAGACCCUCUGAUAUUUCAG |
5472 | UAUCUGGGGGCCCACCAGACA | 8076 | AAGACCCUCUGAUAUUUCAGG |
5473 | AUCUGGGGGCCCACCAGACAG | 8077 | AGACCCUCUGAUAUUUCAGGU |
5474 | UCUGGGGGCCCACCAGACAGG | 8078 | GACCCUCUGAUAUUUCAGGUU |
5475 | CUGGGGGCCCACCAGACAGGU | 8079 | ACCCUCUGAUAUUUCAGGUUG |
5476 | UGGGGGCCCACCAGACAGGUU | 8080 | CCCUCUGAUAUUUCAGGUUGC |
5477 | GGGGGCCCACCAGACAGGUUU | 8081 | CCUCUGAUAUUUCAGGUUGCA |
5478 | GGGGCCCACCAGACAGGUUUA | 8082 | CUCUGAUAUUUCAGGUUGCAC |
5479 | GGGCCCACCAGACAGGUUUAA | 8083 | UCUGAUAUUUCAGGUUGCACU |
5480 | GGCCCACCAGACAGGUUUAAA | 8084 | CUGAUAUUUCAGGUUGCACUG |
5481 | GCCCACCAGACAGGUUUAAAG | 8085 | UGAUAUUUCAGGUUGCACUGA |
5482 | CCCACCAGACAGGUUUAAAGA | 8086 | GAUAUUUCAGGUUGCACUGAU |
5483 | CCACCAGACAGGUUUAAAGAG | 8087 | AUAUUUCAGGUUGCACUGAUA |
5484 | CACCAGACAGGUUUAAAGAGG | 8088 | UAUUUCAGGUUGCACUGAUAC |
5485 | ACCAGACAGGUUUAAAGAGGA | 8089 | AUUUCAGGUUGCACUGAUACA |
5486 | CCAGACAGGUUUAAAGAGGAA | 8090 | UUUCAGGUUGCACUGAUACAU |
5487 | CAGACAGGUUUAAAGAGGAAA | 8091 | UUCAGGUUGCACUGAUACAUU |
5488 | AGACAGGUUUAAAGAGGAAAC | 8092 | UCAGGUUGCACUGAUACAUUC |
5489 | GACAGGUUUAAAGAGGAAACC | 8093 | CAGGUUGCACUGAUACAUUCU |
5490 | ACAGGUUUAAAGAGGAAACCU | 8094 | AGGUUGCACUGAUACAUUCUU |
5491 | CAGGUUUAAAGAGGAAACCUC | 8095 | GGUUGCACUGAUACAUUCUUU |
5492 | AGGUUUAAAGAGGAAACCUCU | 8096 | GUUGCACUGAUACAUUCUUUG |
5493 | GGUUUAAAGAGGAAACCUCUU | 8097 | UUGCACUGAUACAUUCUUUGG |
5494 | GUUUAAAGAGGAAACCUCUUC | 8098 | UGCACUGAUACAUUCUUUGGC |
5495 | UUUAAAGAGGAAACCUCUUCA | 8099 | GCACUGAUACAUUCUUUGGCC |
5496 | UUAAAGAGGAAACCUCUUCAU | 8100 | CACUGAUACAUUCUUUGGCCC |
5497 | UAAAGAGGAAACCUCUUCAUU | 8101 | ACUGAUACAUUCUUUGGCCCA |
5498 | AAAGAGGAAACCUCUUCAUUC | 8102 | CUGAUACAUUCUUUGGCCCAC |
5499 | AAGAGGAAACCUCUUCAUUCA | 8103 | UGAUACAUUCUUUGGCCCACC |
5500 | AGAGGAAACCUCUUCAUUCAC | 8104 | GAUACAUUCUUUGGCCCACCA |
5501 | GAGGAAACCUCUUCAUUCACA | 8105 | AUACAUUCUUUGGCCCACCAG |
5502 | AGGAAACCUCUUCAUUCACAG | 8106 | UACAUUCUUUGGCCCACCAGA |
5503 | GGAAACCUCUUCAUUCACAGC | 8107 | ACAUUCUUUGGCCCACCAGAC |
5504 | GAAACCUCUUCAUUCACAGCU | 8108 | CAUUCUUUGGCCCACCAGACA |
5505 | AAACCUCUUCAUUCACAGCUU | 8109 | AUUCUUUGGCCCACCAGACAG |
5506 | AACCUCUUCAUUCACAGCUUC | 8110 | UUCUUUGGCCCACCAGACAGC |
5507 | ACCUCUUCAUUCACAGCUUCG | 8111 | UCUUUGGCCCACCAGACAGCU |
5508 | CCUCUUCAUUCACAGCUUCGU | 8112 | CUUUGGCCCACCAGACAGCUC |
5509 | CUCUUCAUUCACAGCUUCGUU | 8113 | UUUGGCCCACCAGACAGCUCU |
5510 | UCUUCAUUCACAGCUUCGUUG | 8114 | UUGGCCCACCAGACAGCUCUG |
5511 | CUUCAUUCACAGCUUCGUUGA | 8115 | UGGCCCACCAGACAGCUCUGC |
5512 | UUCAUUCACAGCUUCGUUGAG | 8116 | GGCCCACCAGACAGCUCUGCA |
5513 | UCAUUCACAGCUUCGUUGAGG | 8117 | GCCCACCAGACAGCUCUGCAG |
5514 | CAUUCACAGCUUCGUUGAGGG | 8118 | CCCACCAGACAGCUCUGCAGU |
5515 | AUUCACAGCUUCGUUGAGGGG | 8119 | CCACCAGACAGCUCUGCAGUC |
5516 | UUCACAGCUUCGUUGAGGGGU | 8120 | CACCAGACAGCUCUGCAGUCA |
5517 | UCACAGCUUCGUUGAGGGGUU | 8121 | ACCAGACAGCUCUGCAGUCAG |
5518 | CACAGCUUCGUUGAGGGGUUC | 8122 | CCAGACAGCUCUGCAGUCAGG |
5519 | ACAGCUUCGUUGAGGGGUUCC | 8123 | CAGACAGCUCUGCAGUCAGGU |
5520 | CAGCUUCGUUGAGGGGUUCCU | 8124 | AGACAGCUCUGCAGUCAGGUC |
5521 | AGCUUCGUUGAGGGGUUCCUG | 8125 | GACAGCUCUGCAGUCAGGUCU |
5522 | GCUUCGUUGAGGGGUUCCUGG | 8126 | ACAGCUCUGCAGUCAGGUCUG |
5523 | CUUCGUUGAGGGGUUCCUGGA | 8127 | CAGCUCUGCAGUCAGGUCUGU |
5524 | UUCGUUGAGGGGUUCCUGGAG | 8128 | AGCUCUGCAGUCAGGUCUGUG |
5525 | UCGUUGAGGGGUUCCUGGAGG | 8129 | GCUCUGCAGUCAGGUCUGUGG |
5526 | CGUUGAGGGGUUCCUGGAGGA | 8130 | CUCUGCAGUCAGGUCUGUGGU |
5527 | GUUGAGGGGUUCCUGGAGGAC | 8131 | UCUGCAGUCAGGUCUGUGGUU |
5528 | UUGAGGGGUUCCUGGAGGACG | 8132 | CUGCAGUCAGGUCUGUGGUUA |
5529 | UGAGGGGUUCCUGGAGGACGU | 8133 | UGCAGUCAGGUCUGUGGUUAG |
5530 | GAGGGGUUCCUGGAGGACGUC | 8134 | GCAGUCAGGUCUGUGGUUAGG |
5531 | AGGGGUUCCUGGAGGACGUCU | 8135 | CAGUCAGGUCUGUGGUUAGGG |
5532 | GGGGUUCCUGGAGGACGUCUC | 8136 | AGUCAGGUCUGUGGUUAGGGG |
5533 | GGGUUCCUGGAGGACGUCUCU | 8137 | GUCAGGUCUGUGGUUAGGGGA |
5534 | GGUUCCUGGAGGACGUCUCUG | 8138 | UCAGGUCUGUGGUUAGGGGAC |
5535 | GUUCCUGGAGGACGUCUCUGG | 8139 | CAGGUCUGUGGUUAGGGGACU |
5536 | UUCCUGGAGGACGUCUCUGGA | 8140 | AGGUCUGUGGUUAGGGGACUG |
5537 | UCCUGGAGGACGUCUCUGGAU | 8141 | GGUCUGUGGUUAGGGGACUGG |
5538 | CCUGGAGGACGUCUCUGGAUU | 8142 | GUCUGUGGUUAGGGGACUGGA |
5539 | CUGGAGGACGUCUCUGGAUUC | 8143 | UCUGUGGUUAGGGGACUGGAA |
5540 | UGGAGGACGUCUCUGGAUUCA | 8144 | CUGUGGUUAGGGGACUGGAAA |
5541 | GGAGGACGUCUCUGGAUUCAA | 8145 | UGUGGUUAGGGGACUGGAAAU |
5542 | GAGGACGUCUCUGGAUUCAAG | 8146 | GUGGUUAGGGGACUGGAAAUU |
5543 | AGGACGUCUCUGGAUUCAAGU | 8147 | UGGUUAGGGGACUGGAAAUUG |
5544 | GGACGUCUCUGGAUUCAAGUC | 8148 | GGUUAGGGGACUGGAAAUUGU |
5545 | GACGUCUCUGGAUUCAAGUCC | 8149 | GUUAGGGGACUGGAAAUUGUA |
5546 | ACGUCUCUGGAUUCAAGUCCC | 8150 | UUAGGGGACUGGAAAUUGUAA |
5547 | CGUCUCUGGAUUCAAGUCCCA | 8151 | UAGGGGACUGGAAAUUGUAAU |
5548 | GUCUCUGGAUUCAAGUCCCAG | 8152 | AGGGGACUGGAAAUUGUAAUC |
5549 | UCUCUGGAUUCAAGUCCCAGG | 8153 | GGGGACUGGAAAUUGUAAUCG |
5550 | CUCUGGAUUCAAGUCCCAGGG | 8154 | GGGACUGGAAAUUGUAAUCGC |
5551 | UCUGGAUUCAAGUCCCAGGGG | 8155 | GGACUGGAAAUUGUAAUCGCC |
5552 | CUGGAUUCAAGUCCCAGGGGU | 8156 | GACUGGAAAUUGUAAUCGCCU |
5553 | UGGAUUCAAGUCCCAGGGGUU | 8157 | ACUGGAAAUUGUAAUCGCCUU |
5554 | GGAUUCAAGUCCCAGGGGUUC | 8158 | CUGGAAAUUGUAAUCGCCUUG |
5555 | GAUUCAAGUCCCAGGGGUUCU | 8159 | UGGAAAUUGUAAUCGCCUUGU |
5556 | AUUCAAGUCCCAGGGGUUCUG | 8160 | GGAAAUUGUAAUCGCCUUGUG |
5557 | UUCAAGUCCCAGGGGUUCUGG | 8161 | GAAAUUGUAAUCGCCUUGUGG |
5558 | UCAAGUCCCAGGGGUUCUGGU | 8162 | AAAUUGUAAUCGCCUUGUGGA |
5559 | CAAGUCCCAGGGGUUCUGGUU | 8163 | AAUUGUAAUCGCCUUGUGGAC |
5560 | AAGUCCCAGGGGUUCUGGUUG | 8164 | AUUGUAAUCGCCUUGUGGACC |
5561 | AGUCCCAGGGGUUCUGGUUGG | 8165 | UUGUAAUCGCCUUGUGGACCU |
5562 | GUCCCAGGGGUUCUGGUUGGG | 8166 | UGUAAUCGCCUUGUGGACCUC |
5563 | UCCCAGGGGUUCUGGUUGGGA | 8167 | GUAAUCGCCUUGUGGACCUCU |
5564 | CCCAGGGGUUCUGGUUGGGAC | 8168 | UAAUCGCCUUGUGGACCUCUG |
5565 | CCAGGGGUUCUGGUUGGGACU | 8169 | AAUCGCCUUGUGGACCUCUGC |
5566 | CAGGGGUUCUGGUUGGGACUG | 8170 | AUCGCCUUGUGGACCUCUGCA |
5567 | AGGGGUUCUGGUUGGGACUGU | 8171 | UCGCCUUGUGGACCUCUGCAG |
5568 | GGGGUUCUGGUUGGGACUGUC | 8172 | CGCCUUGUGGACCUCUGCAGA |
5569 | GGGUUCUGGUUGGGACUGUCA | 8173 | GCCUUGUGGACCUCUGCAGAG |
5570 | GGUUCUGGUUGGGACUGUCAG | 8174 | CCUUGUGGACCUCUGCAGAGC |
5571 | GUUCUGGUUGGGACUGUCAGG | 8175 | CUUGUGGACCUCUGCAGAGCC |
5572 | UUCUGGUUGGGACUGUCAGGG | 8176 | UUGUGGACCUCUGCAGAGCCA |
5573 | UCUGGUUGGGACUGUCAGGGC | 8177 | UGUGGACCUCUGCAGAGCCAC |
5574 | CUGGUUGGGACUGUCAGGGCG | 8178 | GUGGACCUCUGCAGAGCCACU |
5575 | UGGUUGGGACUGUCAGGGCGA | 8179 | UGGACCUCUGCAGAGCCACUG |
5576 | GGUUGGGACUGUCAGGGCGAA | 8180 | GGACCUCUGCAGAGCCACUGG |
5577 | GUUGGGACUGUCAGGGCGAAA | 8181 | GACCUCUGCAGAGCCACUGGU |
5578 | UUGGGACUGUCAGGGCGAAAU | 8182 | ACCUCUGCAGAGCCACUGGUA |
5579 | UGGGACUGUCAGGGCGAAAUG | 8183 | CCUCUGCAGAGCCACUGGUAG |
5580 | GGGACUGUCAGGGCGAAAUGA | 8184 | CUCUGCAGAGCCACUGGUAGU |
5581 | GGACUGUCAGGGCGAAAUGAC | 8185 | UCUGCAGAGCCACUGGUAGUC |
5582 | GACUGUCAGGGCGAAAUGACC | 8186 | CUGCAGAGCCACUGGUAGUCA |
5583 | ACUGUCAGGGCGAAAUGACCA | 8187 | UGCAGAGCCACUGGUAGUCAG |
5584 | CUGUCAGGGCGAAAUGACCAG | 8188 | GCAGAGCCACUGGUAGUCAGA |
5585 | UGUCAGGGCGAAAUGACCAGC | 8189 | CAGAGCCACUGGUAGUCAGAC |
5586 | GUCAGGGCGAAAUGACCAGCA | 8190 | AGAGCCACUGGUAGUCAGACC |
5587 | UCAGGGCGAAAUGACCAGCAG | 8191 | GAGCCACUGGUAGUCAGACCA |
5588 | CAGGGCGAAAUGACCAGCAGA | 8192 | AGCCACUGGUAGUCAGACCAC |
5589 | AGGGCGAAAUGACCAGCAGAU | 8193 | GCCACUGGUAGUCAGACCACC |
5590 | GGGCGAAAUGACCAGCAGAUG | 8194 | CCACUGGUAGUCAGACCACCU |
5591 | GGCGAAAUGACCAGCAGAUGC | 8195 | CACUGGUAGUCAGACCACCUA |
5592 | GCGAAAUGACCAGCAGAUGCU | 8196 | ACUGGUAGUCAGACCACCUAA |
5593 | CGAAAUGACCAGCAGAUGCUG | 8197 | CUGGUAGUCAGACCACCUAAU |
5594 | GAAAUGACCAGCAGAUGCUGG | 8198 | UGGUAGUCAGACCACCUAAUU |
5595 | AAAUGACCAGCAGAUGCUGGG | 8199 | GGUAGUCAGACCACCUAAUUC |
5596 | AAUGACCAGCAGAUGCUGGGA | 8200 | GUAGUCAGACCACCUAAUUCG |
5597 | AUGACCAGCAGAUGCUGGGAC | 8201 | UAGUCAGACCACCUAAUUCGU |
5598 | UGACCAGCAGAUGCUGGGACA | 8202 | AGUCAGACCACCUAAUUCGUU |
5599 | GACCAGCAGAUGCUGGGACAG | 8203 | GUCAGACCACCUAAUUCGUUG |
5600 | ACCAGCAGAUGCUGGGACAGC | 8204 | UCAGACCACCUAAUUCGUUGG |
5601 | CCAGCAGAUGCUGGGACAGCA | 8205 | CAGACCACCUAAUUCGUUGGA |
5602 | CAGCAGAUGCUGGGACAGCAG | 8206 | AGACCACCUAAUUCGUUGGAG |
5603 | AGCAGAUGCUGGGACAGCAGC | 8207 | GACCACCUAAUUCGUUGGAGU |
5604 | GCAGAUGCUGGGACAGCAGCU | 8208 | ACCACCUAAUUCGUUGGAGUC |
5605 | CAGAUGCUGGGACAGCAGCUG | 8209 | CCACCUAAUUCGUUGGAGUCA |
5606 | AGAUGCUGGGACAGCAGCUGC | 8210 | CACCUAAUUCGUUGGAGUCAU |
5607 | GAUGCUGGGACAGCAGCUGCC | 8211 | ACCUAAUUCGUUGGAGUCAUU |
5608 | AUGCUGGGACAGCAGCUGCCC | 8212 | CCUAAUUCGUUGGAGUCAUUC |
5609 | UGCUGGGACAGCAGCUGCCCG | 8213 | CUAAUUCGUUGGAGUCAUUCA |
5610 | GCUGGGACAGCAGCUGCCCGC | 8214 | UAAUUCGUUGGAGUCAUUCAC |
5611 | CUGGGACAGCAGCUGCCCGCA | 8215 | AAUUCGUUGGAGUCAUUCACU |
5612 | UGGGACAGCAGCUGCCCGCAG | 8216 | AUUCGUUGGAGUCAUUCACUU |
5613 | GGGACAGCAGCUGCCCGCAGA | 8217 | UUCGUUGGAGUCAUUCACUUU |
5614 | GGACAGCAGCUGCCCGCAGAC | 8218 | UCGUUGGAGUCAUUCACUUUA |
5615 | GACAGCAGCUGCCCGCAGACU | 8219 | CGUUGGAGUCAUUCACUUUAG |
5616 | ACAGCAGCUGCCCGCAGACUC | 8220 | GUUGGAGUCAUUCACUUUAGA |
5617 | CAGCAGCUGCCCGCAGACUCG | 8221 | UUGGAGUCAUUCACUUUAGAA |
5618 | AGCAGCUGCCCGCAGACUCGG | 8222 | UGGAGUCAUUCACUUUAGAAU |
5619 | GCAGCUGCCCGCAGACUCGGG | 8223 | GGAGUCAUUCACUUUAGAAUG |
5620 | CAGCUGCCCGCAGACUCGGGA | 8224 | GAGUCAUUCACUUUAGAAUGC |
5621 | AGCUGCCCGCAGACUCGGGAG | 8225 | AGUCAUUCACUUUAGAAUGCU |
5622 | GCUGCCCGCAGACUCGGGAGG | 8226 | GUCAUUCACUUUAGAAUGCUG |
5623 | CUGCCCGCAGACUCGGGAGGU | 8227 | UCAUUCACUUUAGAAUGCUGU |
5624 | UGCCCGCAGACUCGGGAGGUA | 8228 | CAUUCACUUUAGAAUGCUGUG |
5625 | GCCCGCAGACUCGGGAGGUAG | 8229 | AUUCACUUUAGAAUGCUGUGU |
5626 | CCCGCAGACUCGGGAGGUAGG | 8230 | UUCACUUUAGAAUGCUGUGUC |
5627 | CCGCAGACUCGGGAGGUAGGA | 8231 | UCACUUUAGAAUGCUGUGUCA |
5628 | CGCAGACUCGGGAGGUAGGAG | 8232 | CACUUUAGAAUGCUGUGUCAC |
5629 | GCAGACUCGGGAGGUAGGAGG | 8233 | ACUUUAGAAUGCUGUGUCACU |
5630 | CAGACUCGGGAGGUAGGAGGA | 8234 | CUUUAGAAUGCUGUGUCACUA |
5631 | AGACUCGGGAGGUAGGAGGAC | 8235 | UUUAGAAUGCUGUGUCACUAU |
5632 | GACUCGGGAGGUAGGAGGACU | 8236 | UUAGAAUGCUGUGUCACUAUA |
5633 | ACUCGGGAGGUAGGAGGACUG | 8237 | UAGAAUGCUGUGUCACUAUAG |
5634 | CUCGGGAGGUAGGAGGACUGG | 8238 | AGAAUGCUGUGUCACUAUAGG |
5635 | UCGGGAGGUAGGAGGACUGGC | 8239 | GAAUGCUGUGUCACUAUAGGU |
5636 | CGGGAGGUAGGAGGACUGGCC | 8240 | AAUGCUGUGUCACUAUAGGUG |
5637 | GGGAGGUAGGAGGACUGGCCG | 8241 | AUGCUGUGUCACUAUAGGUGU |
5638 | GGAGGUAGGAGGACUGGCCGG | 8242 | UGCUGUGUCACUAUAGGUGUA |
5639 | GAGGUAGGAGGACUGGCCGGG | 8243 | GCUGUGUCACUAUAGGUGUAA |
5640 | AGGUAGGAGGACUGGCCGGGC | 8244 | CUGUGUCACUAUAGGUGUAAC |
5641 | GGUAGGAGGACUGGCCGGGCA | 8245 | UGUGUCACUAUAGGUGUAACU |
5642 | GUAGGAGGACUGGCCGGGCAG | 8246 | GUGUCACUAUAGGUGUAACUA |
5643 | UAGGAGGACUGGCCGGGCAGU | 8247 | UGUCACUAUAGGUGUAACUAC |
5644 | AGGAGGACUGGCCGGGCAGUG | 8248 | GUCACUAUAGGUGUAACUACG |
5645 | GGAGGACUGGCCGGGCAGUGU | 8249 | UCACUAUAGGUGUAACUACGU |
5646 | GAGGACUGGCCGGGCAGUGUG | 8250 | CACUAUAGGUGUAACUACGUC |
5647 | AGGACUGGCCGGGCAGUGUGC | 8251 | ACUAUAGGUGUAACUACGUCA |
5648 | GGACUGGCCGGGCAGUGUGCU | 8252 | CUAUAGGUGUAACUACGUCAC |
5649 | GACUGGCCGGGCAGUGUGCUG | 8253 | UAUAGGUGUAACUACGUCACU |
5650 | ACUGGCCGGGCAGUGUGCUGG | 8254 | AUAGGUGUAACUACGUCACUG |
5651 | CUGGCCGGGCAGUGUGCUGGG | 8255 | UAGGUGUAACUACGUCACUGG |
5652 | UGGCCGGGCAGUGUGCUGGGC | 8256 | AGGUGUAACUACGUCACUGGG |
5653 | GGCCGGGCAGUGUGCUGGGCC | 8257 | GGUGUAACUACGUCACUGGGA |
5654 | GCCGGGCAGUGUGCUGGGCCC | 8258 | GUGUAACUACGUCACUGGGAC |
5655 | CCGGGCAGUGUGCUGGGCCCU | 8259 | UGUAACUACGUCACUGGGACU |
5656 | CGGGCAGUGUGCUGGGCCCUG | 8260 | GUAACUACGUCACUGGGACUA |
5657 | GGGCAGUGUGCUGGGCCCUGC | 8261 | UAACUACGUCACUGGGACUAC |
5658 | GGCAGUGUGCUGGGCCCUGCC | 8262 | AACUACGUCACUGGGACUACC |
5659 | GCAGUGUGCUGGGCCCUGCCC | 8263 | ACUACGUCACUGGGACUACCU |
5660 | CAGUGUGCUGGGCCCUGCCCU | 8264 | CUACGUCACUGGGACUACCUC |
5661 | AGUGUGCUGGGCCCUGCCCUG | 8265 | UACGUCACUGGGACUACCUCU |
5662 | GUGUGCUGGGCCCUGCCCUGA | 8266 | ACGUCACUGGGACUACCUCUC |
5663 | UGUGCUGGGCCCUGCCCUGAG | 8267 | CGUCACUGGGACUACCUCUCU |
5664 | GUGCUGGGCCCUGCCCUGAGG | 8268 | GUCACUGGGACUACCUCUCUU |
5665 | UGCUGGGCCCUGCCCUGAGGA | 8269 | UCACUGGGACUACCUCUCUUC |
5666 | GCUGGGCCCUGCCCUGAGGAG | 8270 | CACUGGGACUACCUCUCUUCU |
5667 | CUGGGCCCUGCCCUGAGGAGA | 8271 | ACUGGGACUACCUCUCUUCUG |
5668 | UGGGCCCUGCCCUGAGGAGAC | 8272 | CUGGGACUACCUCUCUUCUGA |
5669 | GGGCCCUGCCCUGAGGAGACA | 8273 | UGGGACUACCUCUCUUCUGAA |
5670 | GGCCCUGCCCUGAGGAGACAG | 8274 | GGGACUACCUCUCUUCUGAAG |
5671 | GCCCUGCCCUGAGGAGACAGA | 8275 | GGACUACCUCUCUUCUGAAGC |
5672 | CCCUGCCCUGAGGAGACAGAC | 8276 | GACUACCUCUCUUCUGAAGCU |
5673 | CCUGCCCUGAGGAGACAGACC | 8277 | ACUACCUCUCUUCUGAAGCUU |
5674 | CUGCCCUGAGGAGACAGACCA | 8278 | CUACCUCUCUUCUGAAGCUUC |
5675 | UGCCCUGAGGAGACAGACCAG | 8279 | UACCUCUCUUCUGAAGCUUCC |
5676 | GCCCUGAGGAGACAGACCAGG | 8280 | ACCUCUCUUCUGAAGCUUCCU |
5677 | CCCUGAGGAGACAGACCAGGU | 8281 | CCUCUCUUCUGAAGCUUCCUG |
5678 | CCUGAGGAGACAGACCAGGUG | 8282 | CUCUCUUCUGAAGCUUCCUGA |
5679 | CUGAGGAGACAGACCAGGUGG | 8283 | UCUCUUCUGAAGCUUCCUGAU |
5680 | UGAGGAGACAGACCAGGUGGC | 8284 | CUCUUCUGAAGCUUCCUGAUU |
5681 | GAGGAGACAGACCAGGUGGCU | 8285 | UCUUCUGAAGCUUCCUGAUUA |
5682 | AGGAGACAGACCAGGUGGCUA | 8286 | CUUCUGAAGCUUCCUGAUUAA |
5683 | GGAGACAGACCAGGUGGCUAC | 8287 | UUCUGAAGCUUCCUGAUUAAG |
5684 | GAGACAGACCAGGUGGCUACA | 8288 | UCUGAAGCUUCCUGAUUAAGC |
5685 | AGACAGACCAGGUGGCUACAG | 8289 | CUGAAGCUUCCUGAUUAAGCU |
5686 | GACAGACCAGGUGGCUACAGG | 8290 | UGAAGCUUCCUGAUUAAGCUC |
5687 | ACAGACCAGGUGGCUACAGGA | 8291 | GAAGCUUCCUGAUUAAGCUCU |
5688 | CAGACCAGGUGGCUACAGGAU | 8292 | AAGCUUCCUGAUUAAGCUCUG |
5689 | AGACCAGGUGGCUACAGGAUC | 8293 | AGCUUCCUGAUUAAGCUCUGC |
5690 | GACCAGGUGGCUACAGGAUCU | 8294 | GCUUCCUGAUUAAGCUCUGCU |
5691 | ACCAGGUGGCUACAGGAUCUC | 8295 | CUUCCUGAUUAAGCUCUGCUG |
5692 | CCAGGUGGCUACAGGAUCUCC | 8296 | UUCCUGAUUAAGCUCUGCUGG |
5693 | CAGGUGGCUACAGGAUCUCCU | 8297 | UCCUGAUUAAGCUCUGCUGGU |
5694 | AGGUGGCUACAGGAUCUCCUC | 8298 | CCUGAUUAAGCUCUGCUGGUC |
5695 | GGUGGCUACAGGAUCUCCUCC | 8299 | CUGAUUAAGCUCUGCUGGUCA |
5696 | GUGGCUACAGGAUCUCCUCCC | 8300 | UGAUUAAGCUCUGCUGGUCAC |
5697 | UGGCUACAGGAUCUCCUCCCG | 8301 | GAUUAAGCUCUGCUGGUCACU |
5698 | GGCUACAGGAUCUCCUCCCGC | 8302 | AUUAAGCUCUGCUGGUCACUG |
5699 | GCUACAGGAUCUCCUCCCGCG | 8303 | UUAAGCUCUGCUGGUCACUGG |
5700 | CUACAGGAUCUCCUCCCGCGG | 8304 | UAAGCUCUGCUGGUCACUGGA |
5701 | UACAGGAUCUCCUCCCGCGGG | 8305 | AAGCUCUGCUGGUCACUGGAA |
5702 | ACAGGAUCUCCUCCCGCGGGC | 8306 | AGCUCUGCUGGUCACUGGAAG |
5703 | CAGGAUCUCCUCCCGCGGGCU | 8307 | GCUCUGCUGGUCACUGGAAGA |
5704 | AGGAUCUCCUCCCGCGGGCUC | 8308 | CUCUGCUGGUCACUGGAAGAU |
5705 | GGAUCUCCUCCCGCGGGCUCC | 8309 | UCUGCUGGUCACUGGAAGAUA |
5706 | GAUCUCCUCCCGCGGGCUCCU | 8310 | CUGCUGGUCACUGGAAGAUAC |
5707 | AUCUCCUCCCGCGGGCUCCUG | 8311 | UGCUGGUCACUGGAAGAUACA |
5708 | UCUCCUCCCGCGGGCUCCUGG | 8312 | GCUGGUCACUGGAAGAUACAG |
5709 | CUCCUCCCGCGGGCUCCUGGC | 8313 | CUGGUCACUGGAAGAUACAGC |
5710 | UCCUCCCGCGGGCUCCUGGCC | 8314 | UGGUCACUGGAAGAUACAGCA |
5711 | CCUCCCGCGGGCUCCUGGCCU | 8315 | GGUCACUGGAAGAUACAGCAG |
5712 | CUCCCGCGGGCUCCUGGCCUU | 8316 | GUCACUGGAAGAUACAGCAGG |
5713 | UCCCGCGGGCUCCUGGCCUUC | 8317 | UCACUGGAAGAUACAGCAGGU |
5714 | CCCGCGGGCUCCUGGCCUUCA | 8318 | CACUGGAAGAUACAGCAGGUC |
5715 | CCGCGGGCUCCUGGCCUUCAG | 8319 | ACUGGAAGAUACAGCAGGUCU |
5716 | CGCGGGCUCCUGGCCUUCAGA | 8320 | CUGGAAGAUACAGCAGGUCUG |
5717 | GCGGGCUCCUGGCCUUCAGAG | 8321 | UGGAAGAUACAGCAGGUCUGA |
5718 | CGGGCUCCUGGCCUUCAGAGG | 8322 | GGAAGAUACAGCAGGUCUGAG |
5719 | GGGCUCCUGGCCUUCAGAGGG | 8323 | GAAGAUACAGCAGGUCUGAGU |
5720 | GGCUCCUGGCCUUCAGAGGGG | 8324 | AAGAUACAGCAGGUCUGAGUG |
5721 | GCUCCUGGCCUUCAGAGGGGU | 8325 | AGAUACAGCAGGUCUGAGUGC |
5722 | CUCCUGGCCUUCAGAGGGGUC | 8326 | GAUACAGCAGGUCUGAGUGCA |
5723 | UCCUGGCCUUCAGAGGGGUCU | 8327 | AUACAGCAGGUCUGAGUGCAG |
5724 | CCUGGCCUUCAGAGGGGUCUG | 8328 | UACAGCAGGUCUGAGUGCAGC |
5725 | CUGGCCUUCAGAGGGGUCUGC | 8329 | ACAGCAGGUCUGAGUGCAGCU |
5726 | UGGCCUUCAGAGGGGUCUGCC | 8330 | CAGCAGGUCUGAGUGCAGCUC |
5727 | GGCCUUCAGAGGGGUCUGCCC | 8331 | AGCAGGUCUGAGUGCAGCUCU |
5728 | GCCUUCAGAGGGGUCUGCCCG | 8332 | GCAGGUCUGAGUGCAGCUCUG |
5729 | CCUUCAGAGGGGUCUGCCCGU | 8333 | CAGGUCUGAGUGCAGCUCUGG |
5730 | CUUCAGAGGGGUCUGCCCGUU | 8334 | AGGUCUGAGUGCAGCUCUGGG |
5731 | UUCAGAGGGGUCUGCCCGUUG | 8335 | GGUCUGAGUGCAGCUCUGGGU |
5732 | UCAGAGGGGUCUGCCCGUUGG | 8336 | GUCUGAGUGCAGCUCUGGGUG |
5733 | CAGAGGGGUCUGCCCGUUGGG | 8337 | UCUGAGUGCAGCUCUGGGUGG |
5734 | AGAGGGGUCUGCCCGUUGGGU | 8338 | CUGAGUGCAGCUCUGGGUGGG |
5735 | GAGGGGUCUGCCCGUUGGGUA | 8339 | UGAGUGCAGCUCUGGGUGGGC |
5736 | AGGGGUCUGCCCGUUGGGUAC | 8340 | GAGUGCAGCUCUGGGUGGGCU |
5737 | GGGGUCUGCCCGUUGGGUACA | 8341 | AGUGCAGCUCUGGGUGGGCUC |
5738 | GGGUCUGCCCGUUGGGUACAG | 8342 | GUGCAGCUCUGGGUGGGCUCU |
5739 | GGUCUGCCCGUUGGGUACAGA | 8343 | UGCAGCUCUGGGUGGGCUCUG |
5740 | GUCUGCCCGUUGGGUACAGAG | 8344 | GCAGCUCUGGGUGGGCUCUGC |
5741 | UCUGCCCGUUGGGUACAGAGC | 8345 | CAGCUCUGGGUGGGCUCUGCC |
5742 | CUGCCCGUUGGGUACAGAGCC | 8346 | AGCUCUGGGUGGGCUCUGCCU |
5743 | UGCCCGUUGGGUACAGAGCCA | 8347 | GCUCUGGGUGGGCUCUGCCUC |
5744 | GCCCGUUGGGUACAGAGCCAU | 8348 | CUCUGGGUGGGCUCUGCCUCC |
5745 | CCCGUUGGGUACAGAGCCAUU | 8349 | UCUGGGUGGGCUCUGCCUCCA |
5746 | CCGUUGGGUACAGAGCCAUUC | 8350 | CUGGGUGGGCUCUGCCUCCAA |
5747 | CGUUGGGUACAGAGCCAUUCU | 8351 | UGGGUGGGCUCUGCCUCCAAG |
5748 | GUUGGGUACAGAGCCAUUCUG | 8352 | GGGUGGGCUCUGCCUCCAAGA |
5749 | UUGGGUACAGAGCCAUUCUGA | 8353 | GGUGGGCUCUGCCUCCAAGAU |
5750 | UGGGUACAGAGCCAUUCUGAC | 8354 | GUGGGCUCUGCCUCCAAGAUG |
5751 | GGGUACAGAGCCAUUCUGACC | 8355 | UGGGCUCUGCCUCCAAGAUGC |
5752 | GGUACAGAGCCAUUCUGACCA | 8356 | GGGCUCUGCCUCCAAGAUGCC |
5753 | GUACAGAGCCAUUCUGACCAU | 8357 | GGCUCUGCCUCCAAGAUGCCC |
5754 | UACAGAGCCAUUCUGACCAUG | 8358 | GCUCUGCCUCCAAGAUGCCCA |
5755 | ACAGAGCCAUUCUGACCAUGC | 8359 | CUCUGCCUCCAAGAUGCCCAG |
5756 | CAGAGCCAUUCUGACCAUGCA | 8360 | UCUGCCUCCAAGAUGCCCAGU |
5757 | AGAGCCAUUCUGACCAUGCAG | 8361 | CUGCCUCCAAGAUGCCCAGUU |
5758 | GAGCCAUUCUGACCAUGCAGG | 8362 | UGCCUCCAAGAUGCCCAGUUC |
5759 | AGCCAUUCUGACCAUGCAGGA | 8363 | GCCUCCAAGAUGCCCAGUUCC |
5760 | GCCAUUCUGACCAUGCAGGAG | 8364 | CCUCCAAGAUGCCCAGUUCCA |
5761 | CCAUUCUGACCAUGCAGGAGU | 8365 | CUCCAAGAUGCCCAGUUCCAA |
5762 | CAUUCUGACCAUGCAGGAGUU | 8366 | UCCAAGAUGCCCAGUUCCAAC |
5763 | AUUCUGACCAUGCAGGAGUUU | 8367 | CCAAGAUGCCCAGUUCCAACC |
5764 | UUCUGACCAUGCAGGAGUUUG | 8368 | CAAGAUGCCCAGUUCCAACCU |
5765 | UCUGACCAUGCAGGAGUUUGC | 8369 | AAGAUGCCCAGUUCCAACCUA |
5766 | CUGACCAUGCAGGAGUUUGCC | 8370 | AGAUGCCCAGUUCCAACCUAG |
5767 | UGACCAUGCAGGAGUUUGCCC | 8371 | GAUGCCCAGUUCCAACCUAGC |
5768 | GACCAUGCAGGAGUUUGCCCU | 8372 | AUGCCCAGUUCCAACCUAGCC |
5769 | ACCAUGCAGGAGUUUGCCCUU | 8373 | UGCCCAGUUCCAACCUAGCCC |
5770 | CCAUGCAGGAGUUUGCCCUUC | 8374 | GCCCAGUUCCAACCUAGCCCC |
5771 | CAUGCAGGAGUUUGCCCUUCU | 8375 | CCCAGUUCCAACCUAGCCCCA |
5772 | AUGCAGGAGUUUGCCCUUCUC | 8376 | CCAGUUCCAACCUAGCCCCAG |
5773 | UGCAGGAGUUUGCCCUUCUCU | 8377 | CAGUUCCAACCUAGCCCCAGA |
5774 | GCAGGAGUUUGCCCUUCUCUC | 8378 | AGUUCCAACCUAGCCCCAGAA |
5775 | CAGGAGUUUGCCCUUCUCUCG | 8379 | GUUCCAACCUAGCCCCAGAAG |
5776 | AGGAGUUUGCCCUUCUCUCGG | 8380 | UUCCAACCUAGCCCCAGAAGA |
5777 | GGAGUUUGCCCUUCUCUCGGU | 8381 | UCCAACCUAGCCCCAGAAGAU |
5778 | GAGUUUGCCCUUCUCUCGGUC | 8382 | CCAACCUAGCCCCAGAAGAUG |
5779 | AGUUUGCCCUUCUCUCGGUCU | 8383 | CAACCUAGCCCCAGAAGAUGU |
5780 | GUUUGCCCUUCUCUCGGUCUG | 8384 | AACCUAGCCCCAGAAGAUGUG |
5781 | UUUGCCCUUCUCUCGGUCUGG | 8385 | ACCUAGCCCCAGAAGAUGUGG |
5782 | UUGCCCUUCUCUCGGUCUGGC | 8386 | CCUAGCCCCAGAAGAUGUGGU |
5783 | UGCCCUUCUCUCGGUCUGGCC | 8387 | CUAGCCCCAGAAGAUGUGGUA |
5784 | GCCCUUCUCUCGGUCUGGCCA | 8388 | UAGCCCCAGAAGAUGUGGUAC |
5785 | CCCUUCUCUCGGUCUGGCCAU | 8389 | AGCCCCAGAAGAUGUGGUACA |
5786 | CCUUCUCUCGGUCUGGCCAUG | 8390 | GCCCCAGAAGAUGUGGUACAU |
5787 | CUUCUCUCGGUCUGGCCAUGU | 8391 | CCCCAGAAGAUGUGGUACAUC |
5788 | UUCUCUCGGUCUGGCCAUGUA | 8392 | CCCAGAAGAUGUGGUACAUCA |
5789 | UCUCUCGGUCUGGCCAUGUAA | 8393 | CCAGAAGAUGUGGUACAUCAU |
5790 | CUCUCGGUCUGGCCAUGUAAA | 8394 | CAGAAGAUGUGGUACAUCAUC |
5791 | UCUCGGUCUGGCCAUGUAAAG | 8395 | AGAAGAUGUGGUACAUCAUCU |
5792 | CUCGGUCUGGCCAUGUAAAGA | 8396 | GAAGAUGUGGUACAUCAUCUU |
5793 | UCGGUCUGGCCAUGUAAAGAU | 8397 | AAGAUGUGGUACAUCAUCUUC |
5794 | CGGUCUGGCCAUGUAAAGAUG | 8398 | AGAUGUGGUACAUCAUCUUCA |
5795 | GGUCUGGCCAUGUAAAGAUGG | 8399 | GAUGUGGUACAUCAUCUUCAG |
5796 | GUCUGGCCAUGUAAAGAUGGC | 8400 | AUGUGGUACAUCAUCUUCAGG |
5797 | UCUGGCCAUGUAAAGAUGGCA | 8401 | UGUGGUACAUCAUCUUCAGGU |
5798 | CUGGCCAUGUAAAGAUGGCAU | 8402 | GUGGUACAUCAUCUUCAGGUA |
5799 | UGGCCAUGUAAAGAUGGCAUC | 8403 | UGGUACAUCAUCUUCAGGUAG |
5800 | GGCCAUGUAAAGAUGGCAUCA | 8404 | GGUACAUCAUCUUCAGGUAGA |
5801 | GCCAUGUAAAGAUGGCAUCAU | 8405 | GUACAUCAUCUUCAGGUAGAA |
5802 | CCAUGUAAAGAUGGCAUCAUC | 8406 | UACAUCAUCUUCAGGUAGAAA |
5803 | CAUGUAAAGAUGGCAUCAUCG | 8407 | ACAUCAUCUUCAGGUAGAAAG |
5804 | AUGUAAAGAUGGCAUCAUCGC | 8408 | CAUCAUCUUCAGGUAGAAAGC |
5805 | UGUAAAGAUGGCAUCAUCGCU | 8409 | AUCAUCUUCAGGUAGAAAGCC |
5806 | GUAAAGAUGGCAUCAUCGCUG | 8410 | UCAUCUUCAGGUAGAAAGCCC |
5807 | UAAAGAUGGCAUCAUCGCUGU | 8411 | CAUCUUCAGGUAGAAAGCCCA |
5808 | AAAGAUGGCAUCAUCGCUGUC | 8412 | AUCUUCAGGUAGAAAGCCCAA |
5809 | AAGAUGGCAUCAUCGCUGUCC | 8413 | UCUUCAGGUAGAAAGCCCAAA |
5810 | AGAUGGCAUCAUCGCUGUCCA | 8414 | CUUCAGGUAGAAAGCCCAAAU |
5811 | GAUGGCAUCAUCGCUGUCCAG | 8415 | UUCAGGUAGAAAGCCCAAAUC |
5812 | AUGGCAUCAUCGCUGUCCAGC | 8416 | UCAGGUAGAAAGCCCAAAUCA |
5813 | UGGCAUCAUCGCUGUCCAGCU | 8417 | CAGGUAGAAAGCCCAAAUCAU |
5814 | GGCAUCAUCGCUGUCCAGCUC | 8418 | AGGUAGAAAGCCCAAAUCAUC |
5815 | GCAUCAUCGCUGUCCAGCUCU | 8419 | GGUAGAAAGCCCAAAUCAUCU |
5816 | CAUCAUCGCUGUCCAGCUCUG | 8420 | GUAGAAAGCCCAAAUCAUCUG |
5817 | AUCAUCGCUGUCCAGCUCUGA | 8421 | UAGAAAGCCCAAAUCAUCUGC |
5818 | UCAUCGCUGUCCAGCUCUGAC | 8422 | AGAAAGCCCAAAUCAUCUGCA |
5819 | CAUCGCUGUCCAGCUCUGACU | 8423 | GAAAGCCCAAAUCAUCUGCAG |
5820 | AUCGCUGUCCAGCUCUGACUC | 8424 | AAAGCCCAAAUCAUCUGCAGU |
5821 | UCGCUGUCCAGCUCUGACUCG | 8425 | AAGCCCAAAUCAUCUGCAGUU |
5822 | CGCUGUCCAGCUCUGACUCGG | 8426 | AGCCCAAAUCAUCUGCAGUUU |
5823 | GCUGUCCAGCUCUGACUCGGA | 8427 | GCCCAAAUCAUCUGCAGUUUG |
5824 | CUGUCCAGCUCUGACUCGGAG | 8428 | CCCAAAUCAUCUGCAGUUUGG |
5825 | UGUCCAGCUCUGACUCGGAGU | 8429 | CCAAAUCAUCUGCAGUUUGGA |
5826 | GUCCAGCUCUGACUCGGAGUG | 8430 | CAAAUCAUCUGCAGUUUGGAA |
5827 | UCCAGCUCUGACUCGGAGUGC | 8431 | AAAUCAUCUGCAGUUUGGAAU |
5828 | CCAGCUCUGACUCGGAGUGCA | 8432 | AAUCAUCUGCAGUUUGGAAUU |
5829 | CAGCUCUGACUCGGAGUGCAU | 8433 | AUCAUCUGCAGUUUGGAAUUU |
5830 | AGCUCUGACUCGGAGUGCAUC | 8434 | UCAUCUGCAGUUUGGAAUUUU |
5831 | GCUCUGACUCGGAGUGCAUCA | 8435 | CAUCUGCAGUUUGGAAUUUUU |
5832 | CUCUGACUCGGAGUGCAUCAG | 8436 | AUCUGCAGUUUGGAAUUUUUU |
5833 | UCUGACUCGGAGUGCAUCAGG | 8437 | UCUGCAGUUUGGAAUUUUUUU |
5834 | CUGACUCGGAGUGCAUCAGGC | 8438 | CUGCAGUUUGGAAUUUUUUUA |
5835 | UGACUCGGAGUGCAUCAGGCU | 8439 | UGCAGUUUGGAAUUUUUUUAA |
5836 | GACUCGGAGUGCAUCAGGCUG | 8440 | GCAGUUUGGAAUUUUUUUAAA |
5837 | ACUCGGAGUGCAUCAGGCUGC | 8441 | CAGUUUGGAAUUUUUUUAAAA |
5838 | CUCGGAGUGCAUCAGGCUGCU | 8442 | AGUUUGGAAUUUUUUUAAAAA |
5839 | UCGGAGUGCAUCAGGCUGCUA | 8443 | GUUUGGAAUUUUUUUAAAAAC |
5840 | CGGAGUGCAUCAGGCUGCUAC | 8444 | UUUGGAAUUUUUUUAAAAACA |
5841 | GGAGUGCAUCAGGCUGCUACU | 8445 | UUGGAAUUUUUUUAAAAACAC |
5842 | GAGUGCAUCAGGCUGCUACUU | 8446 | UGGAAUUUUUUUAAAAACACC |
5843 | AGUGCAUCAGGCUGCUACUUA | 8447 | GGAAUUUUUUUAAAAACACCA |
5844 | GUGCAUCAGGCUGCUACUUAG | 8448 | GAAUUUUUUUAAAAACACCAG |
5845 | UGCAUCAGGCUGCUACUUAGC | 8449 | AAUUUUUUUAAAAACACCAGC |
5846 | GCAUCAGGCUGCUACUUAGCA | 8450 | AUUUUUUUAAAAACACCAGCA |
5847 | CAUCAGGCUGCUACUUAGCAA | 8451 | UUUUUUUAAAAACACCAGCAU |
5848 | AUCAGGCUGCUACUUAGCAAA | 8452 | UUUUUUAAAAACACCAGCAUG |
5849 | UCAGGCUGCUACUUAGCAAAA | 8453 | UUUUUAAAAACACCAGCAUGG |
5850 | CAGGCUGCUACUUAGCAAAAG | 8454 | UUUUAAAAACACCAGCAUGGA |
5851 | AGGCUGCUACUUAGCAAAAGG | 8455 | UUUAAAAACACCAGCAUGGAA |
5852 | GGCUGCUACUUAGCAAAAGGC | 8456 | UUAAAAACACCAGCAUGGAAU |
5853 | GCUGCUACUUAGCAAAAGGCC | 8457 | UAAAAACACCAGCAUGGAAUU |
5854 | CUGCUACUUAGCAAAAGGCCU | 8458 | AAAAACACCAGCAUGGAAUUG |
5855 | UGCUACUUAGCAAAAGGCCUU | 8459 | AAAACACCAGCAUGGAAUUGG |
5856 | GCUACUUAGCAAAAGGCCUUU | 8460 | AAACACCAGCAUGGAAUUGGA |
5857 | CUACUUAGCAAAAGGCCUUUC | 8461 | AACACCAGCAUGGAAUUGGAG |
5858 | UACUUAGCAAAAGGCCUUUCU | 8462 | ACACCAGCAUGGAAUUGGAGG |
5859 | ACUUAGCAAAAGGCCUUUCUG | 8463 | CACCAGCAUGGAAUUGGAGGA |
5860 | CUUAGCAAAAGGCCUUUCUGU | 8464 | ACCAGCAUGGAAUUGGAGGAG |
5861 | UUAGCAAAAGGCCUUUCUGUU | 8465 | CCAGCAUGGAAUUGGAGGAGU |
5862 | UAGCAAAAGGCCUUUCUGUUU | 8466 | CAGCAUGGAAUUGGAGGAGUG |
5863 | AGCAAAAGGCCUUUCUGUUUG | 8467 | AGCAUGGAAUUGGAGGAGUGU |
5864 | GCAAAAGGCCUUUCUGUUUGA | 8468 | GCAUGGAAUUGGAGGAGUGUG |
5865 | CAAAAGGCCUUUCUGUUUGAU | 8469 | CAUGGAAUUGGAGGAGUGUGU |
5866 | AAAAGGCCUUUCUGUUUGAUG | 8470 | AUGGAAUUGGAGGAGUGUGUC |
5867 | AAAGGCCUUUCUGUUUGAUGC | 8471 | UGGAAUUGGAGGAGUGUGUCC |
5868 | AAGGCCUUUCUGUUUGAUGCC | 8472 | GGAAUUGGAGGAGUGUGUCCU |
5869 | AGGCCUUUCUGUUUGAUGCCU | 8473 | GAAUUGGAGGAGUGUGUCCUA |
5870 | GGCCUUUCUGUUUGAUGCCUG | 8474 | AAUUGGAGGAGUGUGUCCUAA |
5871 | GCCUUUCUGUUUGAUGCCUGC | 8475 | AUUGGAGGAGUGUGUCCUAAA |
5872 | CCUUUCUGUUUGAUGCCUGCU | 8476 | UUGGAGGAGUGUGUCCUAAAA |
5873 | CUUUCUGUUUGAUGCCUGCUC | 8477 | UGGAGGAGUGUGUCCUAAAAG |
5874 | UUUCUGUUUGAUGCCUGCUCG | 8478 | GGAGGAGUGUGUCCUAAAAGC |
5875 | UUCUGUUUGAUGCCUGCUCGG | 8479 | GAGGAGUGUGUCCUAAAAGCC |
5876 | UCUGUUUGAUGCCUGCUCGGG | 8480 | AGGAGUGUGUCCUAAAAGCCC |
5877 | CUGUUUGAUGCCUGCUCGGGA | 8481 | GGAGUGUGUCCUAAAAGCCCG |
5878 | UGUUUGAUGCCUGCUCGGGAG | 8482 | GAGUGUGUCCUAAAAGCCCGG |
5879 | GUUUGAUGCCUGCUCGGGAGG | 8483 | AGUGUGUCCUAAAAGCCCGGC |
5880 | UUUGAUGCCUGCUCGGGAGGU | 8484 | GUGUGUCCUAAAAGCCCGGCA |
5881 | UUGAUGCCUGCUCGGGAGGUU | 8485 | UGUGUCCUAAAAGCCCGGCAG |
5882 | UGAUGCCUGCUCGGGAGGUUG | 8486 | GUGUCCUAAAAGCCCGGCAGC |
5883 | GAUGCCUGCUCGGGAGGUUGG | 8487 | UGUCCUAAAAGCCCGGCAGCU |
5884 | AUGCCUGCUCGGGAGGUUGGC | 8488 | GUCCUAAAAGCCCGGCAGCUC |
5885 | UGCCUGCUCGGGAGGUUGGCU | 8489 | UCCUAAAAGCCCGGCAGCUCU |
5886 | GCCUGCUCGGGAGGUUGGCUU | 8490 | CCUAAAAGCCCGGCAGCUCUG |
5887 | CCUGCUCGGGAGGUUGGCUUC | 8491 | CUAAAAGCCCGGCAGCUCUGG |
5888 | CUGCUCGGGAGGUUGGCUUCA | 8492 | UAAAAGCCCGGCAGCUCUGGG |
5889 | UGCUCGGGAGGUUGGCUUCAG | 8493 | AAAAGCCCGGCAGCUCUGGGG |
5890 | GCUCGGGAGGUUGGCUUCAGC | 8494 | AAAGCCCGGCAGCUCUGGGGC |
5891 | CUCGGGAGGUUGGCUUCAGCU | 8495 | AAGCCCGGCAGCUCUGGGGCC |
5892 | UCGGGAGGUUGGCUUCAGCUC | 8496 | AGCCCGGCAGCUCUGGGGCCU |
5893 | CGGGAGGUUGGCUUCAGCUCC | 8497 | GCCCGGCAGCUCUGGGGCCUG |
5894 | GGGAGGUUGGCUUCAGCUCCA | 8498 | CCCGGCAGCUCUGGGGCCUGC |
5895 | GGAGGUUGGCUUCAGCUCCAG | 8499 | CCGGCAGCUCUGGGGCCUGCU |
5896 | GAGGUUGGCUUCAGCUCCAGG | 8500 | CGGCAGCUCUGGGGCCUGCUG |
5897 | AGGUUGGCUUCAGCUCCAGGC | 8501 | GGCAGCUCUGGGGCCUGCUGC |
5898 | GGUUGGCUUCAGCUCCAGGCU | 8502 | GCAGCUCUGGGGCCUGCUGCA |
5899 | GUUGGCUUCAGCUCCAGGCUU | 8503 | CAGCUCUGGGGCCUGCUGCAG |
5900 | UUGGCUUCAGCUCCAGGCUUU | 8504 | AGCUCUGGGGCCUGCUGCAGU |
5901 | UGGCUUCAGCUCCAGGCUUUC | 8505 | GCUCUGGGGCCUGCUGCAGUC |
5902 | GGCUUCAGCUCCAGGCUUUCC | 8506 | CUCUGGGGCCUGCUGCAGUCU |
5903 | GCUUCAGCUCCAGGCUUUCCU | 8507 | UCUGGGGCCUGCUGCAGUCUG |
5904 | CUUCAGCUCCAGGCUUUCCUG | 8508 | CUGGGGCCUGCUGCAGUCUGC |
5905 | UUCAGCUCCAGGCUUUCCUGA | 8509 | UGGGGCCUGCUGCAGUCUGCC |
5906 | UCAGCUCCAGGCUUUCCUGAU | 8510 | GGGGCCUGCUGCAGUCUGCCU |
5907 | CAGCUCCAGGCUUUCCUGAUC | 8511 | GGGCCUGCUGCAGUCUGCCUG |
5908 | AGCUCCAGGCUUUCCUGAUCC | 8512 | GGCCUGCUGCAGUCUGCCUGA |
5909 | GCUCCAGGCUUUCCUGAUCCG | 8513 | GCCUGCUGCAGUCUGCCUGAA |
5910 | CUCCAGGCUUUCCUGAUCCGU | 8514 | CCUGCUGCAGUCUGCCUGAAU |
5911 | UCCAGGCUUUCCUGAUCCGUG | 8515 | CUGCUGCAGUCUGCCUGAAUG |
5912 | CCAGGCUUUCCUGAUCCGUGG | 8516 | UGCUGCAGUCUGCCUGAAUGC |
5913 | CAGGCUUUCCUGAUCCGUGGC | 8517 | GCUGCAGUCUGCCUGAAUGCA |
5914 | AGGCUUUCCUGAUCCGUGGCA | 8518 | CUGCAGUCUGCCUGAAUGCAC |
5915 | GGCUUUCCUGAUCCGUGGCAU | 8519 | UGCAGUCUGCCUGAAUGCACA |
5916 | GCUUUCCUGAUCCGUGGCAUC | 8520 | GCAGUCUGCCUGAAUGCACAU |
5917 | CUUUCCUGAUCCGUGGCAUCC | 8521 | CAGUCUGCCUGAAUGCACAUC |
5918 | UUUCCUGAUCCGUGGCAUCCA | 8522 | AGUCUGCCUGAAUGCACAUCC |
5919 | UUCCUGAUCCGUGGCAUCCAG | 8523 | GUCUGCCUGAAUGCACAUCCC |
5920 | UCCUGAUCCGUGGCAUCCAGG | 8524 | UCUGCCUGAAUGCACAUCCCU |
5921 | CCUGAUCCGUGGCAUCCAGGA | 8525 | CUGCCUGAAUGCACAUCCCUU |
5922 | CUGAUCCGUGGCAUCCAGGAU | 8526 | UGCCUGAAUGCACAUCCCUUC |
5923 | UGAUCCGUGGCAUCCAGGAUC | 8527 | GCCUGAAUGCACAUCCCUUCU |
5924 | GAUCCGUGGCAUCCAGGAUCU | 8528 | CCUGAAUGCACAUCCCUUCUA |
5925 | AUCCGUGGCAUCCAGGAUCUU | 8529 | CUGAAUGCACAUCCCUUCUAG |
5926 | UCCGUGGCAUCCAGGAUCUUG | 8530 | UGAAUGCACAUCCCUUCUAGC |
5927 | CCGUGGCAUCCAGGAUCUUGU | 8531 | GAAUGCACAUCCCUUCUAGCC |
5928 | CGUGGCAUCCAGGAUCUUGUA | 8532 | AAUGCACAUCCCUUCUAGCCA |
5929 | GUGGCAUCCAGGAUCUUGUAC | 8533 | AUGCACAUCCCUUCUAGCCAC |
5930 | UGGCAUCCAGGAUCUUGUACU | 8534 | UGCACAUCCCUUCUAGCCACC |
5931 | GGCAUCCAGGAUCUUGUACUU | 8535 | GCACAUCCCUUCUAGCCACCA |
5932 | GCAUCCAGGAUCUUGUACUUG | 8536 | CACAUCCCUUCUAGCCACCAA |
5933 | CAUCCAGGAUCUUGUACUUGC | 8537 | ACAUCCCUUCUAGCCACCAAA |
5934 | AUCCAGGAUCUUGUACUUGCU | 8538 | CAUCCCUUCUAGCCACCAAAA |
5935 | UCCAGGAUCUUGUACUUGCUU | 8539 | AUCCCUUCUAGCCACCAAAAG |
5936 | CCAGGAUCUUGUACUUGCUUU | 8540 | UCCCUUCUAGCCACCAAAAGA |
5937 | CAGGAUCUUGUACUUGCUUUU | 8541 | CCCUUCUAGCCACCAAAAGAC |
5938 | AGGAUCUUGUACUUGCUUUUC | 8542 | CCUUCUAGCCACCAAAAGACA |
5939 | GGAUCUUGUACUUGCUUUUCC | 8543 | CUUCUAGCCACCAAAAGACAU |
5940 | GAUCUUGUACUUGCUUUUCCU | 8544 | UUCUAGCCACCAAAAGACAUG |
5941 | AUCUUGUACUUGCUUUUCCUC | 8545 | UCUAGCCACCAAAAGACAUGG |
5942 | UCUUGUACUUGCUUUUCCUCU | 8546 | CUAGCCACCAAAAGACAUGGC |
5943 | CUUGUACUUGCUUUUCCUCUU | 8547 | UAGCCACCAAAAGACAUGGCA |
5944 | UUGUACUUGCUUUUCCUCUUG | 8548 | AGCCACCAAAAGACAUGGCAG |
5945 | UGUACUUGCUUUUCCUCUUGG | 8549 | GCCACCAAAAGACAUGGCAGG |
5946 | GUACUUGCUUUUCCUCUUGGG | 8550 | CCACCAAAAGACAUGGCAGGC |
5947 | UACUUGCUUUUCCUCUUGGGU | 8551 | CACCAAAAGACAUGGCAGGCA |
5948 | ACUUGCUUUUCCUCUUGGGUU | 8552 | ACCAAAAGACAUGGCAGGCAG |
5949 | CUUGCUUUUCCUCUUGGGUUU | 8553 | CCAAAAGACAUGGCAGGCAGA |
5950 | UUGCUUUUCCUCUUGGGUUUU | 8554 | CAAAAGACAUGGCAGGCAGAG |
5951 | UGCUUUUCCUCUUGGGUUUUC | 8555 | AAAAGACAUGGCAGGCAGAGU |
5952 | GCUUUUCCUCUUGGGUUUUCC | 8556 | AAAGACAUGGCAGGCAGAGUC |
5953 | CUUUUCCUCUUGGGUUUUCCU | 8557 | AAGACAUGGCAGGCAGAGUCC |
5954 | UUUUCCUCUUGGGUUUUCCUU | 8558 | AGACAUGGCAGGCAGAGUCCU |
5955 | UUUCCUCUUGGGUUUUCCUUU | 8559 | GACAUGGCAGGCAGAGUCCUG |
5956 | UUCCUCUUGGGUUUUCCUUUU | 8560 | ACAUGGCAGGCAGAGUCCUGG |
5957 | UCCUCUUGGGUUUUCCUUUUU | 8561 | CAUGGCAGGCAGAGUCCUGGC |
5958 | CCUCUUGGGUUUUCCUUUUUG | 8562 | AUGGCAGGCAGAGUCCUGGCA |
5959 | CUCUUGGGUUUUCCUUUUUGC | 8563 | UGGCAGGCAGAGUCCUGGCAG |
5960 | UCUUGGGUUUUCCUUUUUGCC | 8564 | GGCAGGCAGAGUCCUGGCAGC |
5961 | CUUGGGUUUUCCUUUUUGCCU | 8565 | GCAGGCAGAGUCCUGGCAGCA |
5962 | UUGGGUUUUCCUUUUUGCCUC | 8566 | CAGGCAGAGUCCUGGCAGCAG |
5963 | UGGGUUUUCCUUUUUGCCUCU | 8567 | AGGCAGAGUCCUGGCAGCAGG |
5964 | GGGUUUUCCUUUUUGCCUCUU | 8568 | GGCAGAGUCCUGGCAGCAGGC |
5965 | GGUUUUCCUUUUUGCCUCUUA | 8569 | GCAGAGUCCUGGCAGCAGGCA |
5966 | GUUUUCCUUUUUGCCUCUUAC | 8570 | CAGAGUCCUGGCAGCAGGCAG |
5967 | UUUUCCUUUUUGCCUCUUACA | 8571 | AGAGUCCUGGCAGCAGGCAGC |
5968 | UUUCCUUUUUGCCUCUUACAA | 8572 | GAGUCCUGGCAGCAGGCAGCC |
5969 | UUCCUUUUUGCCUCUUACAAC | 8573 | AGUCCUGGCAGCAGGCAGCCC |
5970 | UCCUUUUUGCCUCUUACAACA | 8574 | GUCCUGGCAGCAGGCAGCCCA |
5971 | CCUUUUUGCCUCUUACAACAA | 8575 | UCCUGGCAGCAGGCAGCCCAA |
5972 | CUUUUUGCCUCUUACAACAAC | 8576 | CCUGGCAGCAGGCAGCCCAAC |
5973 | UUUUUGCCUCUUACAACAACA | 8577 | CUGGCAGCAGGCAGCCCAACA |
5974 | UUUUGCCUCUUACAACAACAG | 8578 | UGGCAGCAGGCAGCCCAACAU |
5975 | UUUGCCUCUUACAACAACAGA | 8579 | GGCAGCAGGCAGCCCAACAUG |
5976 | UUGCCUCUUACAACAACAGAU | 8580 | GCAGCAGGCAGCCCAACAUGA |
5977 | UGCCUCUUACAACAACAGAUC | 8581 | CAGCAGGCAGCCCAACAUGAC |
5978 | GCCUCUUACAACAACAGAUCA | 8582 | AGCAGGCAGCCCAACAUGACU |
5979 | CCUCUUACAACAACAGAUCAC | 8583 | GCAGGCAGCCCAACAUGACUG |
5980 | CUCUUACAACAACAGAUCACA | 8584 | CAGGCAGCCCAACAUGACUGG |
5981 | UCUUACAACAACAGAUCACAG | 8585 | AGGCAGCCCAACAUGACUGGA |
5982 | CUUACAACAACAGAUCACAGU | 8586 | GGCAGCCCAACAUGACUGGAG |
5983 | UUACAACAACAGAUCACAGUC | 8587 | GCAGCCCAACAUGACUGGAGA |
5984 | UACAACAACAGAUCACAGUCC | 8588 | CAGCCCAACAUGACUGGAGAG |
5985 | ACAACAACAGAUCACAGUCCA | 8589 | AGCCCAACAUGACUGGAGAGA |
5986 | CAACAACAGAUCACAGUCCAA | 8590 | GCCCAACAUGACUGGAGAGAG |
5987 | AACAACAGAUCACAGUCCAAG | 8591 | CCCAACAUGACUGGAGAGAGG |
5988 | ACAACAGAUCACAGUCCAAGA | 8592 | CCAACAUGACUGGAGAGAGGG |
5989 | CAACAGAUCACAGUCCAAGAC | 8593 | CAACAUGACUGGAGAGAGGGG |
5990 | AACAGAUCACAGUCCAAGACA | 8594 | AACAUGACUGGAGAGAGGGGG |
5991 | ACAGAUCACAGUCCAAGACAG | 8595 | ACAUGACUGGAGAGAGGGGGU |
5992 | CAGAUCACAGUCCAAGACAGG | 8596 | CAUGACUGGAGAGAGGGGGUU |
5993 | AGAUCACAGUCCAAGACAGGA | 8597 | AUGACUGGAGAGAGGGGGUUC |
5994 | GAUCACAGUCCAAGACAGGAU | 8598 | UGACUGGAGAGAGGGGGUUCC |
5995 | AUCACAGUCCAAGACAGGAUU | 8599 | GACUGGAGAGAGGGGGUUCCU |
5996 | UCACAGUCCAAGACAGGAUUC | 8600 | ACUGGAGAGAGGGGGUUCCUU |
5997 | CACAGUCCAAGACAGGAUUCC | 8601 | CUGGAGAGAGGGGGUUCCUUC |
5998 | ACAGUCCAAGACAGGAUUCCC | 8602 | UGGAGAGAGGGGGUUCCUUCA |
5999 | CAGUCCAAGACAGGAUUCCCA | 8603 | GGAGAGAGGGGGUUCCUUCAA |
6000 | AGUCCAAGACAGGAUUCCCAA | 8604 | GAGAGAGGGGGUUCCUUCAAG |
6001 | GUCCAAGACAGGAUUCCCAAG | 8605 | AGAGAGGGGGUUCCUUCAAGA |
6002 | UCCAAGACAGGAUUCCCAAGG | 8606 | GAGAGGGGGUUCCUUCAAGAA |
6003 | CCAAGACAGGAUUCCCAAGGC | 8607 | AGAGGGGGUUCCUUCAAGAAG |
6004 | CAAGACAGGAUUCCCAAGGCA | 8608 | GAGGGGGUUCCUUCAAGAAGC |
6005 | AAGACAGGAUUCCCAAGGCAA | 8609 | AGGGGGUUCCUUCAAGAAGCC |
6006 | AGACAGGAUUCCCAAGGCAAC | 8610 | GGGGGUUCCUUCAAGAAGCCA |
6007 | GACAGGAUUCCCAAGGCAACA | 8611 | GGGGUUCCUUCAAGAAGCCAG |
6008 | ACAGGAUUCCCAAGGCAACAA | 8612 | GGGUUCCUUCAAGAAGCCAGA |
6009 | CAGGAUUCCCAAGGCAACAAC | 8613 | GGUUCCUUCAAGAAGCCAGAG |
6010 | AGGAUUCCCAAGGCAACAACA | 8614 | GUUCCUUCAAGAAGCCAGAGG |
6011 | GGAUUCCCAAGGCAACAACAA | 8615 | UUCCUUCAAGAAGCCAGAGGU |
6012 | GAUUCCCAAGGCAACAACAAU | 8616 | UCCUUCAAGAAGCCAGAGGUG |
6013 | AUUCCCAAGGCAACAACAAUG | 8617 | CCUUCAAGAAGCCAGAGGUGA |
6014 | UUCCCAAGGCAACAACAAUGA | 8618 | CUUCAAGAAGCCAGAGGUGAU |
6015 | UCCCAAGGCAACAACAAUGAC | 8619 | UUCAAGAAGCCAGAGGUGAUU |
6016 | CCCAAGGCAACAACAAUGACA | 8620 | UCAAGAAGCCAGAGGUGAUUU |
6017 | CCAAGGCAACAACAAUGACAA | 8621 | CAAGAAGCCAGAGGUGAUUUU |
6018 | CAAGGCAACAACAAUGACAAA | 8622 | AAGAAGCCAGAGGUGAUUUUC |
6019 | AAGGCAACAACAAUGACAAAG | 8623 | AGAAGCCAGAGGUGAUUUUCU |
6020 | AGGCAACAACAAUGACAAAGG | 8624 | GAAGCCAGAGGUGAUUUUCUC |
6021 | GGCAACAACAAUGACAAAGGU | 8625 | AAGCCAGAGGUGAUUUUCUCC |
6022 | GCAACAACAAUGACAAAGGUA | 8626 | AGCCAGAGGUGAUUUUCUCCC |
6023 | CAACAACAAUGACAAAGGUAG | 8627 | GCCAGAGGUGAUUUUCUCCCC |
6024 | AACAACAAUGACAAAGGUAGC | 8628 | CCAGAGGUGAUUUUCUCCCCC |
6025 | ACAACAAUGACAAAGGUAGCA | 8629 | CAGAGGUGAUUUUCUCCCCCA |
6026 | CAACAAUGACAAAGGUAGCAA | 8630 | AGAGGUGAUUUUCUCCCCCAG |
6027 | AACAAUGACAAAGGUAGCAAU | 8631 | GAGGUGAUUUUCUCCCCCAGA |
6028 | ACAAUGACAAAGGUAGCAAUG | 8632 | AGGUGAUUUUCUCCCCCAGAU |
6029 | CAAUGACAAAGGUAGCAAUGA | 8633 | GGUGAUUUUCUCCCCCAGAUC |
6030 | AAUGACAAAGGUAGCAAUGAU | 8634 | GUGAUUUUCUCCCCCAGAUCU |
6031 | AUGACAAAGGUAGCAAUGAUA | 8635 | UGAUUUUCUCCCCCAGAUCUC |
6032 | UGACAAAGGUAGCAAUGAUAA | 8636 | GAUUUUCUCCCCCAGAUCUCA |
6033 | GACAAAGGUAGCAAUGAUAAC | 8637 | AUUUUCUCCCCCAGAUCUCAG |
6034 | ACAAAGGUAGCAAUGAUAACA | 8638 | UUUUCUCCCCCAGAUCUCAGG |
6035 | CAAAGGUAGCAAUGAUAACAU | 8639 | UUUCUCCCCCAGAUCUCAGGC |
6036 | AAAGGUAGCAAUGAUAACAUA | 8640 | UUCUCCCCCAGAUCUCAGGCC |
6037 | AAGGUAGCAAUGAUAACAUAU | 8641 | UCUCCCCCAGAUCUCAGGCCA |
6038 | AGGUAGCAAUGAUAACAUAUA | 8642 | CUCCCCCAGAUCUCAGGCCAA |
6039 | GGUAGCAAUGAUAACAUAUAA | 8643 | UCCCCCAGAUCUCAGGCCAAC |
6040 | GUAGCAAUGAUAACAUAUAAC | 8644 | CCCCCAGAUCUCAGGCCAACU |
6041 | UAGCAAUGAUAACAUAUAACA | 8645 | CCCCAGAUCUCAGGCCAACUC |
6042 | AGCAAUGAUAACAUAUAACAC | 8646 | CCCAGAUCUCAGGCCAACUCC |
6043 | GCAAUGAUAACAUAUAACACG | 8647 | CCAGAUCUCAGGCCAACUCCA |
6044 | CAAUGAUAACAUAUAACACGC | 8648 | CAGAUCUCAGGCCAACUCCAA |
6045 | AAUGAUAACAUAUAACACGCU | 8649 | AGAUCUCAGGCCAACUCCAAA |
6046 | AUGAUAACAUAUAACACGCUC | 8650 | GAUCUCAGGCCAACUCCAAAU |
6047 | UGAUAACAUAUAACACGCUCC | 8651 | AUCUCAGGCCAACUCCAAAUU |
6048 | GAUAACAUAUAACACGCUCCA | 8652 | UCUCAGGCCAACUCCAAAUUG |
6049 | AUAACAUAUAACACGCUCCAC | 8653 | CUCAGGCCAACUCCAAAUUGU |
6050 | UAACAUAUAACACGCUCCACU | 8654 | UCAGGCCAACUCCAAAUUGUG |
6051 | AACAUAUAACACGCUCCACUC | 8655 | CAGGCCAACUCCAAAUUGUGU |
6052 | ACAUAUAACACGCUCCACUCA | 8656 | AGGCCAACUCCAAAUUGUGUC |
6053 | CAUAUAACACGCUCCACUCAC | 8657 | GGCCAACUCCAAAUUGUGUCU |
6054 | AUAUAACACGCUCCACUCACA | 8658 | GCCAACUCCAAAUUGUGUCUU |
6055 | UAUAACACGCUCCACUCACAG | 8659 | CCAACUCCAAAUUGUGUCUUC |
6056 | AUAACACGCUCCACUCACAGU | 8660 | CAACUCCAAAUUGUGUCUUCC |
6057 | UAACACGCUCCACUCACAGUU | 8661 | AACUCCAAAUUGUGUCUUCCC |
6058 | AACACGCUCCACUCACAGUUG | 8662 | ACUCCAAAUUGUGUCUUCCCC |
6059 | ACACGCUCCACUCACAGUUGC | 8663 | CUCCAAAUUGUGUCUUCCCCU |
6060 | CACGCUCCACUCACAGUUGCU | 8664 | UCCAAAUUGUGUCUUCCCCUG |
6061 | ACGCUCCACUCACAGUUGCUG | 8665 | CCAAAUUGUGUCUUCCCCUGC |
6062 | CGCUCCACUCACAGUUGCUGU | 8666 | CAAAUUGUGUCUUCCCCUGCU |
6063 | GCUCCACUCACAGUUGCUGUC | 8667 | AAAUUGUGUCUUCCCCUGCUG |
6064 | CUCCACUCACAGUUGCUGUCU | 8668 | AAUUGUGUCUUCCCCUGCUGG |
6065 | UCCACUCACAGUUGCUGUCUC | 8669 | AUUGUGUCUUCCCCUGCUGGC |
6066 | CCACUCACAGUUGCUGUCUCC | 8670 | UUGUGUCUUCCCCUGCUGGCA |
6067 | CACUCACAGUUGCUGUCUCCA | 8671 | UGUGUCUUCCCCUGCUGGCAC |
6068 | ACUCACAGUUGCUGUCUCCAU | 8672 | GUGUCUUCCCCUGCUGGCACC |
6069 | CUCACAGUUGCUGUCUCCAUC | 8673 | UGUCUUCCCCUGCUGGCACCU |
6070 | UCACAGUUGCUGUCUCCAUCC | 8674 | GUCUUCCCCUGCUGGCACCUG |
6071 | CACAGUUGCUGUCUCCAUCCC | 8675 | UCUUCCCCUGCUGGCACCUGC |
6072 | ACAGUUGCUGUCUCCAUCCCU | 8676 | CUUCCCCUGCUGGCACCUGCU |
6073 | CAGUUGCUGUCUCCAUCCCUC | 8677 | UUCCCCUGCUGGCACCUGCUC |
6074 | AGUUGCUGUCUCCAUCCCUCA | 8678 | UCCCCUGCUGGCACCUGCUCU |
6075 | GUUGCUGUCUCCAUCCCUCAG | 8679 | CCCCUGCUGGCACCUGCUCUC |
6076 | UUGCUGUCUCCAUCCCUCAGC | 8680 | CCCUGCUGGCACCUGCUCUCA |
6077 | UGCUGUCUCCAUCCCUCAGCU | 8681 | CCUGCUGGCACCUGCUCUCAC |
6078 | GCUGUCUCCAUCCCUCAGCUG | 8682 | CUGCUGGCACCUGCUCUCACU |
6079 | CUGUCUCCAUCCCUCAGCUGC | 8683 | UGCUGGCACCUGCUCUCACUG |
6080 | UGUCUCCAUCCCUCAGCUGCA | 8684 | GCUGGCACCUGCUCUCACUGG |
6081 | GUCUCCAUCCCUCAGCUGCAC | 8685 | CUGGCACCUGCUCUCACUGGC |
6082 | UCUCCAUCCCUCAGCUGCACC | 8686 | UGGCACCUGCUCUCACUGGCA |
6083 | CUCCAUCCCUCAGCUGCACCU | 8687 | GGCACCUGCUCUCACUGGCAU |
6084 | UCCAUCCCUCAGCUGCACCUU | 8688 | GCACCUGCUCUCACUGGCAUC |
6085 | CCAUCCCUCAGCUGCACCUUG | 8689 | CACCUGCUCUCACUGGCAUCU |
6086 | CAUCCCUCAGCUGCACCUUGA | 8690 | ACCUGCUCUCACUGGCAUCUG |
6087 | AUCCCUCAGCUGCACCUUGAU | 8691 | CCUGCUCUCACUGGCAUCUGU |
6088 | UCCCUCAGCUGCACCUUGAUG | 8692 | CUGCUCUCACUGGCAUCUGUU |
6089 | CCCUCAGCUGCACCUUGAUGA | 8693 | UGCUCUCACUGGCAUCUGUUG |
6090 | CCUCAGCUGCACCUUGAUGAA | 8694 | GCUCUCACUGGCAUCUGUUGA |
6091 | CUCAGCUGCACCUUGAUGAAA | 8695 | CUCUCACUGGCAUCUGUUGAC |
6092 | UCAGCUGCACCUUGAUGAAAU | 8696 | UCUCACUGGCAUCUGUUGACA |
6093 | CAGCUGCACCUUGAUGAAAUU | 8697 | CUCACUGGCAUCUGUUGACAA |
6094 | AGCUGCACCUUGAUGAAAUUC | 8698 | UCACUGGCAUCUGUUGACAAC |
6095 | GCUGCACCUUGAUGAAAUUCU | 8699 | CACUGGCAUCUGUUGACAACC |
6096 | CUGCACCUUGAUGAAAUUCUC | 8700 | ACUGGCAUCUGUUGACAACCA |
6097 | UGCACCUUGAUGAAAUUCUCC | 8701 | CUGGCAUCUGUUGACAACCAC |
6098 | GCACCUUGAUGAAAUUCUCCA | 8702 | UGGCAUCUGUUGACAACCACA |
6099 | CACCUUGAUGAAAUUCUCCAU | 8703 | GGCAUCUGUUGACAACCACAG |
6100 | ACCUUGAUGAAAUUCUCCAUC | 8704 | GCAUCUGUUGACAACCACAGA |
6101 | CCUUGAUGAAAUUCUCCAUCC | 8705 | CAUCUGUUGACAACCACAGAA |
6102 | CUUGAUGAAAUUCUCCAUCCA | 8706 | AUCUGUUGACAACCACAGAAC |
6103 | UUGAUGAAAUUCUCCAUCCAA | 8707 | UCUGUUGACAACCACAGAACG |
6104 | UGAUGAAAUUCUCCAUCCAAA | 8708 | CUGUUGACAACCACAGAACGC |
6105 | GAUGAAAUUCUCCAUCCAAAA | 8709 | UGUUGACAACCACAGAACGCU |
6106 | AUGAAAUUCUCCAUCCAAAAA | 8710 | GUUGACAACCACAGAACGCUG |
6107 | UGAAAUUCUCCAUCCAAAAAG | 8711 | UUGACAACCACAGAACGCUGA |
6108 | GAAAUUCUCCAUCCAAAAAGG | 8712 | UGACAACCACAGAACGCUGAA |
6109 | AAAUUCUCCAUCCAAAAAGGG | 8713 | GACAACCACAGAACGCUGAAG |
6110 | AAUUCUCCAUCCAAAAAGGGU | 8714 | ACAACCACAGAACGCUGAAGC |
6111 | AUUCUCCAUCCAAAAAGGGUC | 8715 | CAACCACAGAACGCUGAAGCA |
6112 | UUCUCCAUCCAAAAAGGGUCA | 8716 | AACCACAGAACGCUGAAGCAA |
6113 | UCUCCAUCCAAAAAGGGUCAC | 8717 | ACCACAGAACGCUGAAGCAAA |
6114 | CUCCAUCCAAAAAGGGUCACA | 8718 | CCACAGAACGCUGAAGCAAAA |
6115 | UCCAUCCAAAAAGGGUCACAG | 8719 | CACAGAACGCUGAAGCAAAAG |
6116 | CCAUCCAAAAAGGGUCACAGA | 8720 | ACAGAACGCUGAAGCAAAAGC |
6117 | CAUCCAAAAAGGGUCACAGAU | 8721 | CAGAACGCUGAAGCAAAAGCA |
6118 | AUCCAAAAAGGGUCACAGAUA | 8722 | AGAACGCUGAAGCAAAAGCAA |
6119 | UCCAAAAAGGGUCACAGAUAC | 8723 | GAACGCUGAAGCAAAAGCAAG |
6120 | CCAAAAAGGGUCACAGAUACA | 8724 | AACGCUGAAGCAAAAGCAAGU |
6121 | CAAAAAGGGUCACAGAUACAG | 8725 | ACGCUGAAGCAAAAGCAAGUA |
6122 | AAAAAGGGUCACAGAUACAGC | 8726 | CGCUGAAGCAAAAGCAAGUAU |
6123 | AAAAGGGUCACAGAUACAGCG | 8727 | GCUGAAGCAAAAGCAAGUAUA |
6124 | AAAGGGUCACAGAUACAGCGU | 8728 | CUGAAGCAAAAGCAAGUAUAA |
6125 | AAGGGUCACAGAUACAGCGUU | 8729 | UGAAGCAAAAGCAAGUAUAAA |
6126 | AGGGUCACAGAUACAGCGUUU | 8730 | GAAGCAAAAGCAAGUAUAAAA |
6127 | GGGUCACAGAUACAGCGUUUG | 8731 | AAGCAAAAGCAAGUAUAAAAC |
6128 | GGUCACAGAUACAGCGUUUGG | 8732 | AGCAAAAGCAAGUAUAAAACA |
6129 | GUCACAGAUACAGCGUUUGGU | 8733 | GCAAAAGCAAGUAUAAAACAG |
6130 | UCACAGAUACAGCGUUUGGUG | 8734 | CAAAAGCAAGUAUAAAACAGG |
6131 | CACAGAUACAGCGUUUGGUGA | 8735 | AAAAGCAAGUAUAAAACAGGU |
6132 | ACAGAUACAGCGUUUGGUGAA | 8736 | AAAGCAAGUAUAAAACAGGUA |
6133 | CAGAUACAGCGUUUGGUGAAC | 8737 | AAGCAAGUAUAAAACAGGUAC |
6134 | AGAUACAGCGUUUGGUGAACG | 8738 | AGCAAGUAUAAAACAGGUACA |
6135 | GAUACAGCGUUUGGUGAACGA | 8739 | GCAAGUAUAAAACAGGUACAG |
6136 | AUACAGCGUUUGGUGAACGAG | 8740 | CAAGUAUAAAACAGGUACAGG |
6137 | UACAGCGUUUGGUGAACGAGU | 8741 | AAGUAUAAAACAGGUACAGGC |
6138 | ACAGCGUUUGGUGAACGAGUC | 8742 | AGUAUAAAACAGGUACAGGCU |
6139 | CAGCGUUUGGUGAACGAGUCA | 8743 | GUAUAAAACAGGUACAGGCUU |
6140 | AGCGUUUGGUGAACGAGUCAC | 8744 | UAUAAAACAGGUACAGGCUUC |
6141 | GCGUUUGGUGAACGAGUCACA | 8745 | AUAAAACAGGUACAGGCUUCU |
6142 | CGUUUGGUGAACGAGUCACAG | 8746 | UAAAACAGGUACAGGCUUCUC |
6143 | GUUUGGUGAACGAGUCACAGU | 8747 | AAAACAGGUACAGGCUUCUCA |
6144 | UUUGGUGAACGAGUCACAGUG | 8748 | AAACAGGUACAGGCUUCUCAA |
6145 | UUGGUGAACGAGUCACAGUGG | 8749 | AACAGGUACAGGCUUCUCAAC |
6146 | UGGUGAACGAGUCACAGUGGC | 8750 | ACAGGUACAGGCUUCUCAACC |
6147 | GGUGAACGAGUCACAGUGGCC | 8751 | CAGGUACAGGCUUCUCAACCA |
6148 | GUGAACGAGUCACAGUGGCCA | 8752 | AGGUACAGGCUUCUCAACCAC |
6149 | UGAACGAGUCACAGUGGCCAU | 8753 | GGUACAGGCUUCUCAACCACU |
6150 | GAACGAGUCACAGUGGCCAUG | 8754 | GUACAGGCUUCUCAACCACUU |
6151 | AACGAGUCACAGUGGCCAUGG | 8755 | UACAGGCUUCUCAACCACUUC |
6152 | ACGAGUCACAGUGGCCAUGGU | 8756 | ACAGGCUUCUCAACCACUUCG |
6153 | CGAGUCACAGUGGCCAUGGUC | 8757 | CAGGCUUCUCAACCACUUCGC |
6154 | GAGUCACAGUGGCCAUGGUCG | 8758 | AGGCUUCUCAACCACUUCGCA |
6155 | AGUCACAGUGGCCAUGGUCGG | 8759 | GGCUUCUCAACCACUUCGCAG |
6156 | GUCACAGUGGCCAUGGUCGGA | 8760 | GCUUCUCAACCACUUCGCAGA |
6157 | UCACAGUGGCCAUGGUCGGAA | 8761 | CUUCUCAACCACUUCGCAGAU |
6158 | CACAGUGGCCAUGGUCGGAAC | 8762 | UUCUCAACCACUUCGCAGAUG |
6159 | ACAGUGGCCAUGGUCGGAACA | 8763 | UCUCAACCACUUCGCAGAUGU |
6160 | CAGUGGCCAUGGUCGGAACAG | 8764 | CUCAACCACUUCGCAGAUGUC |
6161 | AGUGGCCAUGGUCGGAACAGU | 8765 | UCAACCACUUCGCAGAUGUCU |
6162 | GUGGCCAUGGUCGGAACAGUU | 8766 | CAACCACUUCGCAGAUGUCUG |
6163 | UGGCCAUGGUCGGAACAGUUC | 8767 | AACCACUUCGCAGAUGUCUGC |
6164 | GGCCAUGGUCGGAACAGUUCA | 8768 | ACCACUUCGCAGAUGUCUGCC |
6165 | GCCAUGGUCGGAACAGUUCAG | 8769 | CCACUUCGCAGAUGUCUGCCA |
6166 | CCAUGGUCGGAACAGUUCAGC | 8770 | CACUUCGCAGAUGUCUGCCAA |
6167 | CAUGGUCGGAACAGUUCAGCU | 8771 | ACUUCGCAGAUGUCUGCCAAU |
6168 | AUGGUCGGAACAGUUCAGCUG | 8772 | CUUCGCAGAUGUCUGCCAAUA |
6169 | UGGUCGGAACAGUUCAGCUGA | 8773 | UUCGCAGAUGUCUGCCAAUAA |
6170 | GGUCGGAACAGUUCAGCUGAC | 8774 | UCGCAGAUGUCUGCCAAUAAU |
6171 | GUCGGAACAGUUCAGCUGACA | 8775 | CGCAGAUGUCUGCCAAUAAUA |
6172 | UCGGAACAGUUCAGCUGACAU | 8776 | GCAGAUGUCUGCCAAUAAUAU |
6173 | CGGAACAGUUCAGCUGACAUG | 8777 | CAGAUGUCUGCCAAUAAUAUC |
6174 | GGAACAGUUCAGCUGACAUGU | 8778 | AGAUGUCUGCCAAUAAUAUCC |
6175 | GAACAGUUCAGCUGACAUGUG | 8779 | GAUGUCUGCCAAUAAUAUCCU |
6176 | AACAGUUCAGCUGACAUGUGA | 8780 | AUGUCUGCCAAUAAUAUCCUG |
6177 | ACAGUUCAGCUGACAUGUGAC | 8781 | UGUCUGCCAAUAAUAUCCUGA |
6178 | CAGUUCAGCUGACAUGUGACA | 8782 | GUCUGCCAAUAAUAUCCUGAU |
6179 | AGUUCAGCUGACAUGUGACAG | 8783 | UCUGCCAAUAAUAUCCUGAUA |
6180 | GUUCAGCUGACAUGUGACAGU | 8784 | CUGCCAAUAAUAUCCUGAUAA |
6181 | UUCAGCUGACAUGUGACAGUG | 8785 | UGCCAAUAAUAUCCUGAUAAA |
6182 | UCAGCUGACAUGUGACAGUGU | 8786 | GCCAAUAAUAUCCUGAUAAAA |
6183 | CAGCUGACAUGUGACAGUGUU | 8787 | CCAAUAAUAUCCUGAUAAAAU |
6184 | AGCUGACAUGUGACAGUGUUG | 8788 | CAAUAAUAUCCUGAUAAAAUC |
6185 | GCUGACAUGUGACAGUGUUGA | 8789 | AAUAAUAUCCUGAUAAAAUCC |
6186 | CUGACAUGUGACAGUGUUGAC | 8790 | AUAAUAUCCUGAUAAAAUCCA |
6187 | UGACAUGUGACAGUGUUGACU | 8791 | UAAUAUCCUGAUAAAAUCCAG |
6188 | GACAUGUGACAGUGUUGACUU | 8792 | AAUAUCCUGAUAAAAUCCAGG |
6189 | ACAUGUGACAGUGUUGACUUC | 8793 | AUAUCCUGAUAAAAUCCAGGA |
6190 | CAUGUGACAGUGUUGACUUCC | 8794 | UAUCCUGAUAAAAUCCAGGAA |
6191 | AUGUGACAGUGUUGACUUCCA | 8795 | AUCCUGAUAAAAUCCAGGAAG |
6192 | UGUGACAGUGUUGACUUCCAA | 8796 | UCCUGAUAAAAUCCAGGAAGC |
6193 | GUGACAGUGUUGACUUCCAAG | 8797 | CCUGAUAAAAUCCAGGAAGCA |
6194 | UGACAGUGUUGACUUCCAAGG | 8798 | CUGAUAAAAUCCAGGAAGCAG |
6195 | GACAGUGUUGACUUCCAAGGC | 8799 | UGAUAAAAUCCAGGAAGCAGG |
6196 | ACAGUGUUGACUUCCAAGGCU | 8800 | GAUAAAAUCCAGGAAGCAGGA |
6197 | CAGUGUUGACUUCCAAGGCUC | 8801 | AUAAAAUCCAGGAAGCAGGAU |
6198 | AGUGUUGACUUCCAAGGCUCU | 8802 | UAAAAUCCAGGAAGCAGGAUU |
6199 | GUGUUGACUUCCAAGGCUCUG | 8803 | AAAAUCCAGGAAGCAGGAUUU |
6200 | UGUUGACUUCCAAGGCUCUGA | 8804 | AAAUCCAGGAAGCAGGAUUUG |
6201 | GUUGACUUCCAAGGCUCUGAA | 8805 | AAUCCAGGAAGCAGGAUUUGG |
6202 | UUGACUUCCAAGGCUCUGAAU | 8806 | AUCCAGGAAGCAGGAUUUGGC |
6203 | UGACUUCCAAGGCUCUGAAUA | 8807 | UCCAGGAAGCAGGAUUUGGCU |
6204 | GACUUCCAAGGCUCUGAAUAU | 8808 | CCAGGAAGCAGGAUUUGGCUU |
6205 | ACUUCCAAGGCUCUGAAUAUC | 8809 | CAGGAAGCAGGAUUUGGCUUG |
6206 | CUUCCAAGGCUCUGAAUAUCA | 8810 | AGGAAGCAGGAUUUGGCUUGA |
6207 | UUCCAAGGCUCUGAAUAUCAA | 8811 | GGAAGCAGGAUUUGGCUUGAC |
6208 | UCCAAGGCUCUGAAUAUCAAA | 8812 | GAAGCAGGAUUUGGCUUGACU |
6209 | CCAAGGCUCUGAAUAUCAAAA | 8813 | AAGCAGGAUUUGGCUUGACUC |
6210 | CAAGGCUCUGAAUAUCAAAAA | 8814 | AGCAGGAUUUGGCUUGACUCC |
6211 | AAGGCUCUGAAUAUCAAAAAG | 8815 | GCAGGAUUUGGCUUGACUCCC |
6212 | AGGCUCUGAAUAUCAAAAAGU | 8816 | CAGGAUUUGGCUUGACUCCCA |
6213 | GGCUCUGAAUAUCAAAAAGUC | 8817 | AGGAUUUGGCUUGACUCCCAG |
6214 | GCUCUGAAUAUCAAAAAGUCU | 8818 | GGAUUUGGCUUGACUCCCAGC |
6215 | CUCUGAAUAUCAAAAAGUCUG | 8819 | GAUUUGGCUUGACUCCCAGCC |
6216 | UCUGAAUAUCAAAAAGUCUGC | 8820 | AUUUGGCUUGACUCCCAGCCU |
6217 | CUGAAUAUCAAAAAGUCUGCC | 8821 | UUUGGCUUGACUCCCAGCCUC |
6218 | UGAAUAUCAAAAAGUCUGCCU | 8822 | UUGGCUUGACUCCCAGCCUCU |
6219 | GAAUAUCAAAAAGUCUGCCUU | 8823 | UGGCUUGACUCCCAGCCUCUU |
6220 | AAUAUCAAAAAGUCUGCCUUU | 8824 | GGCUUGACUCCCAGCCUCUUC |
6221 | AUAUCAAAAAGUCUGCCUUUU | 8825 | GCUUGACUCCCAGCCUCUUCU |
6222 | UAUCAAAAAGUCUGCCUUUUG | 8826 | CUUGACUCCCAGCCUCUUCUC |
6223 | AUCAAAAAGUCUGCCUUUUGC | 8827 | UUGACUCCCAGCCUCUUCUCC |
6224 | UCAAAAAGUCUGCCUUUUGCU | 8828 | UGACUCCCAGCCUCUUCUCCA |
6225 | CAAAAAGUCUGCCUUUUGCUU | 8829 | GACUCCCAGCCUCUUCUCCAU |
6226 | AAAAAGUCUGCCUUUUGCUUC | 8830 | ACUCCCAGCCUCUUCUCCAUG |
6227 | AAAAGUCUGCCUUUUGCUUCC | 8831 | CUCCCAGCCUCUUCUCCAUGG |
6228 | AAAGUCUGCCUUUUGCUUCCG | 8832 | UCCCAGCCUCUUCUCCAUGGC |
6229 | AAGUCUGCCUUUUGCUUCCGC | 8833 | CCCAGCCUCUUCUCCAUGGCC |
6230 | AGUCUGCCUUUUGCUUCCGCA | 8834 | CCAGCCUCUUCUCCAUGGCCC |
6231 | GUCUGCCUUUUGCUUCCGCAG | 8835 | CAGCCUCUUCUCCAUGGCCCU |
6232 | UCUGCCUUUUGCUUCCGCAGC | 8836 | AGCCUCUUCUCCAUGGCCCUC |
6233 | CUGCCUUUUGCUUCCGCAGCU | 8837 | GCCUCUUCUCCAUGGCCCUCC |
6234 | UGCCUUUUGCUUCCGCAGCUC | 8838 | CCUCUUCUCCAUGGCCCUCCA |
6235 | GCCUUUUGCUUCCGCAGCUCA | 8839 | CUCUUCUCCAUGGCCCUCCAG |
6236 | CCUUUUGCUUCCGCAGCUCAC | 8840 | UCUUCUCCAUGGCCCUCCAGA |
6237 | CUUUUGCUUCCGCAGCUCACU | 8841 | CUUCUCCAUGGCCCUCCAGAC |
6238 | UUUUGCUUCCGCAGCUCACUC | 8842 | UUCUCCAUGGCCCUCCAGACA |
6239 | UUUGCUUCCGCAGCUCACUCU | 8843 | UCUCCAUGGCCCUCCAGACAG |
6240 | UUGCUUCCGCAGCUCACUCUU | 8844 | CUCCAUGGCCCUCCAGACAGG |
6241 | UGCUUCCGCAGCUCACUCUUG | 8845 | UCCAUGGCCCUCCAGACAGGC |
6242 | GCUUCCGCAGCUCACUCUUGA | 8846 | CCAUGGCCCUCCAGACAGGCA |
6243 | CUUCCGCAGCUCACUCUUGAG | 8847 | CAUGGCCCUCCAGACAGGCAG |
6244 | UUCCGCAGCUCACUCUUGAGC | 8848 | AUGGCCCUCCAGACAGGCAGA |
6245 | UCCGCAGCUCACUCUUGAGCA | 8849 | UGGCCCUCCAGACAGGCAGAA |
6246 | CCGCAGCUCACUCUUGAGCAU | 8850 | GGCCCUCCAGACAGGCAGAAC |
6247 | CGCAGCUCACUCUUGAGCAUC | 8851 | GCCCUCCAGACAGGCAGAACC |
6248 | GCAGCUCACUCUUGAGCAUCG | 8852 | CCCUCCAGACAGGCAGAACCA |
6249 | CAGCUCACUCUUGAGCAUCGC | 8853 | CCUCCAGACAGGCAGAACCAG |
6250 | AGCUCACUCUUGAGCAUCGCU | 8854 | CUCCAGACAGGCAGAACCAGU |
6251 | GCUCACUCUUGAGCAUCGCUG | 8855 | UCCAGACAGGCAGAACCAGUA |
6252 | CUCACUCUUGAGCAUCGCUGC | 8856 | CCAGACAGGCAGAACCAGUAC |
6253 | UCACUCUUGAGCAUCGCUGCC | 8857 | CAGACAGGCAGAACCAGUACA |
6254 | CACUCUUGAGCAUCGCUGCCA | 8858 | AGACAGGCAGAACCAGUACAC |
6255 | ACUCUUGAGCAUCGCUGCCAC | 8859 | GACAGGCAGAACCAGUACACG |
6256 | CUCUUGAGCAUCGCUGCCACC | 8860 | ACAGGCAGAACCAGUACACGG |
6257 | UCUUGAGCAUCGCUGCCACCU | 8861 | CAGGCAGAACCAGUACACGGG |
6258 | CUUGAGCAUCGCUGCCACCUC | 8862 | AGGCAGAACCAGUACACGGGG |
6259 | UUGAGCAUCGCUGCCACCUCA | 8863 | GGCAGAACCAGUACACGGGGC |
6260 | UGAGCAUCGCUGCCACCUCAU | 8864 | GCAGAACCAGUACACGGGGCU |
6261 | GAGCAUCGCUGCCACCUCAUG | 8865 | CAGAACCAGUACACGGGGCUC |
6262 | AGCAUCGCUGCCACCUCAUGG | 8866 | AGAACCAGUACACGGGGCUCA |
6263 | GCAUCGCUGCCACCUCAUGGC | 8867 | GAACCAGUACACGGGGCUCAG |
6264 | CAUCGCUGCCACCUCAUGGCC | 8868 | AACCAGUACACGGGGCUCAGG |
6265 | AUCGCUGCCACCUCAUGGCCU | 8869 | ACCAGUACACGGGGCUCAGGG |
6266 | UCGCUGCCACCUCAUGGCCUU | 8870 | CCAGUACACGGGGCUCAGGGC |
6267 | CGCUGCCACCUCAUGGCCUUU | 8871 | CAGUACACGGGGCUCAGGGCC |
6268 | GCUGCCACCUCAUGGCCUUUG | 8872 | AGUACACGGGGCUCAGGGCCA |
6269 | CUGCCACCUCAUGGCCUUUGA | 8873 | GUACACGGGGCUCAGGGCCAC |
6270 | UGCCACCUCAUGGCCUUUGAA | 8874 | UACACGGGGCUCAGGGCCACA |
6271 | GCCACCUCAUGGCCUUUGAAG | 8875 | ACACGGGGCUCAGGGCCACAU |
6272 | CCACCUCAUGGCCUUUGAAGA | 8876 | CACGGGGCUCAGGGCCACAUA |
6273 | CACCUCAUGGCCUUUGAAGAU | 8877 | ACGGGGCUCAGGGCCACAUAG |
6274 | ACCUCAUGGCCUUUGAAGAUC | 8878 | CGGGGCUCAGGGCCACAUAGC |
6275 | CCUCAUGGCCUUUGAAGAUCU | 8879 | GGGGCUCAGGGCCACAUAGCG |
6276 | CUCAUGGCCUUUGAAGAUCUG | 8880 | GGGCUCAGGGCCACAUAGCGG |
6277 | UCAUGGCCUUUGAAGAUCUGG | 8881 | GGCUCAGGGCCACAUAGCGGG |
6278 | CAUGGCCUUUGAAGAUCUGGU | 8882 | GCUCAGGGCCACAUAGCGGGG |
6279 | AUGGCCUUUGAAGAUCUGGUG | 8883 | CUCAGGGCCACAUAGCGGGGC |
6280 | UGGCCUUUGAAGAUCUGGUGG | 8884 | UCAGGGCCACAUAGCGGGGCC |
6281 | GGCCUUUGAAGAUCUGGUGGG | 8885 | CAGGGCCACAUAGCGGGGCCC |
6282 | GCCUUUGAAGAUCUGGUGGGG | 8886 | AGGGCCACAUAGCGGGGCCCC |
6283 | CCUUUGAAGAUCUGGUGGGGA | 8887 | GGGCCACAUAGCGGGGCCCCG |
6284 | CUUUGAAGAUCUGGUGGGGAG | 8888 | GGCCACAUAGCGGGGCCCCGG |
6285 | UUUGAAGAUCUGGUGGGGAGG | 8889 | GCCACAUAGCGGGGCCCCGGC |
6286 | UUGAAGAUCUGGUGGGGAGGC | 8890 | CCACAUAGCGGGGCCCCGGCU |
6287 | UGAAGAUCUGGUGGGGAGGCU | 8891 | CACAUAGCGGGGCCCCGGCUC |
6288 | GAAGAUCUGGUGGGGAGGCUC | 8892 | ACAUAGCGGGGCCCCGGCUCU |
6289 | AAGAUCUGGUGGGGAGGCUCG | 8893 | CAUAGCGGGGCCCCGGCUCUC |
6290 | AGAUCUGGUGGGGAGGCUCGU | 8894 | AUAGCGGGGCCCCGGCUCUCG |
6291 | GAUCUGGUGGGGAGGCUCGUU | 8895 | UAGCGGGGCCCCGGCUCUCGG |
6292 | AUCUGGUGGGGAGGCUCGUUU | 8896 | AGCGGGGCCCCGGCUCUCGGC |
6293 | UCUGGUGGGGAGGCUCGUUUU | 8897 | GCGGGGCCCCGGCUCUCGGCG |
6294 | CUGGUGGGGAGGCUCGUUUUG | 8898 | CGGGGCCCCGGCUCUCGGCGG |
6295 | UGGUGGGGAGGCUCGUUUUGA | 8899 | GGGGCCCCGGCUCUCGGCGGC |
6296 | GGUGGGGAGGCUCGUUUUGAA | 8900 | GGGCCCCGGCUCUCGGCGGCC |
6297 | GUGGGGAGGCUCGUUUUGAAC | 8901 | GGCCCCGGCUCUCGGCGGCCU |
6298 | UGGGGAGGCUCGUUUUGAACA | 8902 | GCCCCGGCUCUCGGCGGCCUC |
6299 | GGGGAGGCUCGUUUUGAACAA | 8903 | CCCCGGCUCUCGGCGGCCUCC |
6300 | GGGAGGCUCGUUUUGAACAAA | 8904 | CCCGGCUCUCGGCGGCCUCCG |
6301 | GGAGGCUCGUUUUGAACAAAA | 8905 | CCGGCUCUCGGCGGCCUCCGC |
6302 | GAGGCUCGUUUUGAACAAAAA | 8906 | CGGCUCUCGGCGGCCUCCGCC |
6303 | AGGCUCGUUUUGAACAAAAAA | 8907 | GGCUCUCGGCGGCCUCCGCCU |
6304 | GGCUCGUUUUGAACAAAAAAU | 8908 | GCUCUCGGCGGCCUCCGCCUC |
6305 | GCUCGUUUUGAACAAAAAAUA | 8909 | CUCUCGGCGGCCUCCGCCUCC |
6306 | CUCGUUUUGAACAAAAAAUAC | 8910 | UCUCGGCGGCCUCCGCCUCCU |
6307 | UCGUUUUGAACAAAAAAUACC | 8911 | CUCGGCGGCCUCCGCCUCCUC |
6308 | CGUUUUGAACAAAAAAUACCA | 8912 | UCGGCGGCCUCCGCCUCCUCC |
6309 | GUUUUGAACAAAAAAUACCAU | 8913 | CGGCGGCCUCCGCCUCCUCCU |
6310 | UUUUGAACAAAAAAUACCAUU | 8914 | GGCGGCCUCCGCCUCCUCCUG |
6311 | UUUGAACAAAAAAUACCAUUU | 8915 | GCGGCCUCCGCCUCCUCCUGG |
6312 | UUGAACAAAAAAUACCAUUUU | 8916 | CGGCCUCCGCCUCCUCCUGGU |
6313 | UGAACAAAAAAUACCAUUUUG | 8917 | GGCCUCCGCCUCCUCCUGGUC |
6314 | GAACAAAAAAUACCAUUUUGG | 8918 | GCCUCCGCCUCCUCCUGGUCC |
6315 | AACAAAAAAUACCAUUUUGGU | 8919 | CCUCCGCCUCCUCCUGGUCCA |
6316 | ACAAAAAAUACCAUUUUGGUG | 8920 | CUCCGCCUCCUCCUGGUCCAU |
6317 | CAAAAAAUACCAUUUUGGUGC | 8921 | UCCGCCUCCUCCUGGUCCAUG |
6318 | AAAAAAUACCAUUUUGGUGCU | 8922 | CCGCCUCCUCCUGGUCCAUGG |
6319 | AAAAAUACCAUUUUGGUGCUC | 8923 | CGCCUCCUCCUGGUCCAUGGG |
6320 | AAAAUACCAUUUUGGUGCUCU | 8924 | GCCUCCUCCUGGUCCAUGGGC |
6321 | AAAUACCAUUUUGGUGCUCUG | 8925 | CCUCCUCCUGGUCCAUGGGCU |
6322 | AAUACCAUUUUGGUGCUCUGC | 8926 | CUCCUCCUGGUCCAUGGGCUC |
6323 | AUACCAUUUUGGUGCUCUGCU | 8927 | UCCUCCUGGUCCAUGGGCUCG |
6324 | UACCAUUUUGGUGCUCUGCUC | 8928 | CCUCCUGGUCCAUGGGCUCGG |
6325 | ACCAUUUUGGUGCUCUGCUCC | 8929 | CUCCUGGUCCAUGGGCUCGGG |
6326 | CCAUUUUGGUGCUCUGCUCCG | 8930 | UCCUGGUCCAUGGGCUCGGGG |
6327 | CAUUUUGGUGCUCUGCUCCGU | 8931 | CCUGGUCCAUGGGCUCGGGGA |
6328 | AUUUUGGUGCUCUGCUCCGUG | 8932 | CUGGUCCAUGGGCUCGGGGAC |
6329 | UUUUGGUGCUCUGCUCCGUGU | 8933 | UGGUCCAUGGGCUCGGGGACC |
6330 | UUUGGUGCUCUGCUCCGUGUA | 8934 | GGUCCAUGGGCUCGGGGACCC |
6331 | UUGGUGCUCUGCUCCGUGUAC | 8935 | GUCCAUGGGCUCGGGGACCCC |
6332 | UGGUGCUCUGCUCCGUGUACG | 8936 | UCCAUGGGCUCGGGGACCCCC |
6333 | GGUGCUCUGCUCCGUGUACGG | 8937 | CCAUGGGCUCGGGGACCCCCA |
6334 | GUGCUCUGCUCCGUGUACGGC | 8938 | CAUGGGCUCGGGGACCCCCAA |
6335 | UGCUCUGCUCCGUGUACGGCU | 8939 | AUGGGCUCGGGGACCCCCAAC |
6336 | GCUCUGCUCCGUGUACGGCUG | 8940 | UGGGCUCGGGGACCCCCAACC |
6337 | CUCUGCUCCGUGUACGGCUGA | 8941 | GGGCUCGGGGACCCCCAACCU |
6338 | UCUGCUCCGUGUACGGCUGAA | 8942 | GGCUCGGGGACCCCCAACCUU |
6339 | CUGCUCCGUGUACGGCUGAAU | 8943 | GCUCGGGGACCCCCAACCUUC |
6340 | UGCUCCGUGUACGGCUGAAUC | 8944 | CUCGGGGACCCCCAACCUUCG |
6341 | GCUCCGUGUACGGCUGAAUCU | 8945 | UCGGGGACCCCCAACCUUCGC |
6342 | CUCCGUGUACGGCUGAAUCUU | 8946 | CGGGGACCCCCAACCUUCGCU |
6343 | UCCGUGUACGGCUGAAUCUUU | 8947 | GGGGACCCCCAACCUUCGCUC |
6344 | CCGUGUACGGCUGAAUCUUUU | 8948 | GGGACCCCCAACCUUCGCUCC |
6345 | CGUGUACGGCUGAAUCUUUUG | 8949 | GGACCCCCAACCUUCGCUCCC |
6346 | GUGUACGGCUGAAUCUUUUGC | 8950 | GACCCCCAACCUUCGCUCCCC |
6347 | UGUACGGCUGAAUCUUUUGCA | 8951 | ACCCCCAACCUUCGCUCCCCU |
6348 | GUACGGCUGAAUCUUUUGCAC | 8952 | CCCCCAACCUUCGCUCCCCUC |
6349 | UACGGCUGAAUCUUUUGCACA | 8953 | CCCCAACCUUCGCUCCCCUCA |
6350 | ACGGCUGAAUCUUUUGCACAA | 8954 | CCCAACCUUCGCUCCCCUCAC |
6351 | CGGCUGAAUCUUUUGCACAAU | 8955 | CCAACCUUCGCUCCCCUCACC |
6352 | GGCUGAAUCUUUUGCACAAUG | 8956 | CAACCUUCGCUCCCCUCACCC |
6353 | GCUGAAUCUUUUGCACAAUGA | 8957 | AACCUUCGCUCCCCUCACCCG |
6354 | CUGAAUCUUUUGCACAAUGAU | 8958 | ACCUUCGCUCCCCUCACCCGG |
6355 | UGAAUCUUUUGCACAAUGAUG | 8959 | CCUUCGCUCCCCUCACCCGGA |
6356 | GAAUCUUUUGCACAAUGAUGU | 8960 | CUUCGCUCCCCUCACCCGGAG |
6357 | AAUCUUUUGCACAAUGAUGUC | 8961 | UUCGCUCCCCUCACCCGGAGG |
6358 | AUCUUUUGCACAAUGAUGUCG | 8962 | UCGCUCCCCUCACCCGGAGGA |
6359 | UCUUUUGCACAAUGAUGUCGG | 8963 | CGCUCCCCUCACCCGGAGGAG |
6360 | CUUUUGCACAAUGAUGUCGGA | 8964 | GCUCCCCUCACCCGGAGGAGG |
6361 | UUUUGCACAAUGAUGUCGGAA | 8965 | CUCCCCUCACCCGGAGGAGGA |
6362 | UUUGCACAAUGAUGUCGGAAU | 8966 | UCCCCUCACCCGGAGGAGGAG |
6363 | UUGCACAAUGAUGUCGGAAUC | 8967 | CCCCUCACCCGGAGGAGGAGG |
6364 | UGCACAAUGAUGUCGGAAUCC | 8968 | CCCUCACCCGGAGGAGGAGGA |
6365 | GCACAAUGAUGUCGGAAUCCA | 8969 | CCUCACCCGGAGGAGGAGGAG |
6366 | CACAAUGAUGUCGGAAUCCAG | 8970 | CUCACCCGGAGGAGGAGGAGG |
6367 | ACAAUGAUGUCGGAAUCCAGC | 8971 | UCACCCGGAGGAGGAGGAGGA |
6368 | CAAUGAUGUCGGAAUCCAGCA | 8972 | CACCCGGAGGAGGAGGAGGAA |
6369 | AAUGAUGUCGGAAUCCAGCAC | 8973 | ACCCGGAGGAGGAGGAGGAAG |
6370 | AUGAUGUCGGAAUCCAGCACC | 8974 | CCCGGAGGAGGAGGAGGAAGA |
6371 | UGAUGUCGGAAUCCAGCACCC | 8975 | CCGGAGGAGGAGGAGGAAGAG |
6372 | GAUGUCGGAAUCCAGCACCCC | 8976 | CGGAGGAGGAGGAGGAAGAGG |
6373 | AUGUCGGAAUCCAGCACCCCC | 8977 | GGAGGAGGAGGAGGAAGAGGA |
6374 | UGUCGGAAUCCAGCACCCCCA | 8978 | GAGGAGGAGGAGGAAGAGGAA |
6375 | GUCGGAAUCCAGCACCCCCAG | 8979 | AGGAGGAGGAGGAAGAGGAAG |
6376 | UCGGAAUCCAGCACCCCCAGG | 8980 | GGAGGAGGAGGAAGAGGAAGA |
6377 | CGGAAUCCAGCACCCCCAGGA | 8981 | GAGGAGGAGGAAGAGGAAGAA |
6378 | GGAAUCCAGCACCCCCAGGAG | 8982 | AGGAGGAGGAAGAGGAAGAAG |
6379 | GAAUCCAGCACCCCCAGGAGG | 8983 | GGAGGAGGAAGAGGAAGAAGG |
6380 | AAUCCAGCACCCCCAGGAGGA | 8984 | GAGGAGGAAGAGGAAGAAGGU |
6381 | AUCCAGCACCCCCAGGAGGAC | 8985 | AGGAGGAAGAGGAAGAAGGUA |
6382 | UCCAGCACCCCCAGGAGGACC | 8986 | GGAGGAAGAGGAAGAAGGUAG |
6383 | CCAGCACCCCCAGGAGGACCC | 8987 | GAGGAAGAGGAAGAAGGUAGU |
6384 | CAGCACCCCCAGGAGGACCCC | 8988 | AGGAAGAGGAAGAAGGUAGUG |
6385 | AGCACCCCCAGGAGGACCCCA | 8989 | GGAAGAGGAAGAAGGUAGUGC |
6386 | GCACCCCCAGGAGGACCCCAA | 8990 | GAAGAGGAAGAAGGUAGUGCG |
6387 | CACCCCCAGGAGGACCCCAAU | 8991 | AAGAGGAAGAAGGUAGUGCGG |
6388 | ACCCCCAGGAGGACCCCAAUC | 8992 | AGAGGAAGAAGGUAGUGCGGG |
6389 | CCCCCAGGAGGACCCCAAUCU | 8993 | GAGGAAGAAGGUAGUGCGGGC |
6390 | CCCCAGGAGGACCCCAAUCUG | 8994 | AGGAAGAAGGUAGUGCGGGCU |
6391 | CCCAGGAGGACCCCAAUCUGG | 8995 | GGAAGAAGGUAGUGCGGGCUC |
6392 | CCAGGAGGACCCCAAUCUGGC | 8996 | GAAGAAGGUAGUGCGGGCUCC |
6393 | CAGGAGGACCCCAAUCUGGCG | 8997 | AAGAAGGUAGUGCGGGCUCCC |
6394 | AGGAGGACCCCAAUCUGGCGG | 8998 | AGAAGGUAGUGCGGGCUCCCC |
6395 | GGAGGACCCCAAUCUGGCGGA | 8999 | GAAGGUAGUGCGGGCUCCCCA |
6396 | GAGGACCCCAAUCUGGCGGAU | 9000 | AAGGUAGUGCGGGCUCCCCAC |
6397 | AGGACCCCAAUCUGGCGGAUG | 9001 | AGGUAGUGCGGGCUCCCCACC |
6398 | GGACCCCAAUCUGGCGGAUGA | 9002 | GGUAGUGCGGGCUCCCCACCC |
6399 | GACCCCAAUCUGGCGGAUGAA | 9003 | GUAGUGCGGGCUCCCCACCCG |
6400 | ACCCCAAUCUGGCGGAUGAAC | 9004 | UAGUGCGGGCUCCCCACCCGG |
6401 | CCCCAAUCUGGCGGAUGAACA | 9005 | AGUGCGGGCUCCCCACCCGGA |
6402 | CCCAAUCUGGCGGAUGAACAU | 9006 | GUGCGGGCUCCCCACCCGGAC |
6403 | CCAAUCUGGCGGAUGAACAUC | 9007 | UGCGGGCUCCCCACCCGGACA |
6404 | CAAUCUGGCGGAUGAACAUCC | 9008 | GCGGGCUCCCCACCCGGACAG |
6405 | AAUCUGGCGGAUGAACAUCCC | 9009 | CGGGCUCCCCACCCGGACAGC |
6406 | AUCUGGCGGAUGAACAUCCCC | 9010 | GGGCUCCCCACCCGGACAGCU |
6407 | UCUGGCGGAUGAACAUCCCCU | 9011 | GGCUCCCCACCCGGACAGCUA |
6408 | CUGGCGGAUGAACAUCCCCUU | 9012 | GCUCCCCACCCGGACAGCUAC |
6409 | UGGCGGAUGAACAUCCCCUUC | 9013 | CUCCCCACCCGGACAGCUACC |
6410 | GGCGGAUGAACAUCCCCUUCA | 9014 | UCCCCACCCGGACAGCUACCU |
6411 | GCGGAUGAACAUCCCCUUCAG | 9015 | CCCCACCCGGACAGCUACCUC |
6412 | CGGAUGAACAUCCCCUUCAGC | 9016 | CCCACCCGGACAGCUACCUCU |
6413 | GGAUGAACAUCCCCUUCAGCC | 9017 | CCACCCGGACAGCUACCUCUC |
6414 | GAUGAACAUCCCCUUCAGCCU | 9018 | CACCCGGACAGCUACCUCUCG |
6415 | AUGAACAUCCCCUUCAGCCUC | 9019 | ACCCGGACAGCUACCUCUCGC |
6416 | UGAACAUCCCCUUCAGCCUCU | 9020 | CCCGGACAGCUACCUCUCGCC |
6417 | GAACAUCCCCUUCAGCCUCUC | 9021 | CCGGACAGCUACCUCUCGCCU |
6418 | AACAUCCCCUUCAGCCUCUCA | 9022 | CGGACAGCUACCUCUCGCCUC |
6419 | ACAUCCCCUUCAGCCUCUCAG | 9023 | GGACAGCUACCUCUCGCCUCA |
6420 | CAUCCCCUUCAGCCUCUCAGU | 9024 | GACAGCUACCUCUCGCCUCAG |
6421 | AUCCCCUUCAGCCUCUCAGUU | 9025 | ACAGCUACCUCUCGCCUCAGC |
6422 | UCCCCUUCAGCCUCUCAGUUA | 9026 | CAGCUACCUCUCGCCUCAGCC |
6423 | CCCCUUCAGCCUCUCAGUUAG | 9027 | AGCUACCUCUCGCCUCAGCCU |
6424 | CCCUUCAGCCUCUCAGUUAGC | 9028 | GCUACCUCUCGCCUCAGCCUC |
6425 | CCUUCAGCCUCUCAGUUAGCU | 9029 | CUACCUCUCGCCUCAGCCUCC |
6426 | CUUCAGCCUCUCAGUUAGCUG | 9030 | UACCUCUCGCCUCAGCCUCCC |
6427 | UUCAGCCUCUCAGUUAGCUGA | 9031 | ACCUCUCGCCUCAGCCUCCCU |
6428 | UCAGCCUCUCAGUUAGCUGAC | 9032 | CCUCUCGCCUCAGCCUCCCUG |
6429 | CAGCCUCUCAGUUAGCUGACU | 9033 | CUCUCGCCUCAGCCUCCCUGG |
6430 | AGCCUCUCAGUUAGCUGACUG | 9034 | UCUCGCCUCAGCCUCCCUGGA |
6431 | GCCUCUCAGUUAGCUGACUGA | 9035 | CUCGCCUCAGCCUCCCUGGAC |
6432 | CCUCUCAGUUAGCUGACUGAC | 9036 | UCGCCUCAGCCUCCCUGGACA |
6433 | CUCUCAGUUAGCUGACUGACG | 9037 | CGCCUCAGCCUCCCUGGACAG |
6434 | UCUCAGUUAGCUGACUGACGU | 9038 | GCCUCAGCCUCCCUGGACAGC |
6435 | CUCAGUUAGCUGACUGACGUU | 9039 | CCUCAGCCUCCCUGGACAGCG |
6436 | UCAGUUAGCUGACUGACGUUG | 9040 | CUCAGCCUCCCUGGACAGCGA |
6437 | CAGUUAGCUGACUGACGUUGA | 9041 | UCAGCCUCCCUGGACAGCGAC |
6438 | AGUUAGCUGACUGACGUUGAU | 9042 | CAGCCUCCCUGGACAGCGACG |
6439 | GUUAGCUGACUGACGUUGAUA | 9043 | AGCCUCCCUGGACAGCGACGG |
6440 | UUAGCUGACUGACGUUGAUAU | 9044 | GCCUCCCUGGACAGCGACGGC |
6441 | UAGCUGACUGACGUUGAUAUC | 9045 | CCUCCCUGGACAGCGACGGCG |
6442 | AGCUGACUGACGUUGAUAUCC | 9046 | CUCCCUGGACAGCGACGGCGG |
6443 | GCUGACUGACGUUGAUAUCCA | 9047 | UCCCUGGACAGCGACGGCGGC |
6444 | CUGACUGACGUUGAUAUCCAA | 9048 | CCCUGGACAGCGACGGCGGCC |
6445 | UGACUGACGUUGAUAUCCAAG | 9049 | CCUGGACAGCGACGGCGGCCG |
6446 | GACUGACGUUGAUAUCCAAGA | 9050 | CUGGACAGCGACGGCGGCCGG |
6447 | ACUGACGUUGAUAUCCAAGAU | 9051 | UGGACAGCGACGGCGGCCGGA |
6448 | CUGACGUUGAUAUCCAAGAUG | 9052 | GGACAGCGACGGCGGCCGGAA |
6449 | UGACGUUGAUAUCCAAGAUGA | 9053 | GACAGCGACGGCGGCCGGAAA |
6450 | GACGUUGAUAUCCAAGAUGAU | 9054 | ACAGCGACGGCGGCCGGAAAC |
6451 | ACGUUGAUAUCCAAGAUGAUC | 9055 | AGGUUGGUGUUCUAACACCCA |
6452 | CGUUGAUAUCCAAGAUGAUCU | 9056 | GGUUGGUGUUCUAACACCCAG |
6453 | GUUGAUAUCCAAGAUGAUCUC | 9057 | GUUGGUGUUCUAACACCCAGU |
6454 | UUGAUAUCCAAGAUGAUCUCC | 9058 | UUGGUGUUCUAACACCCAGUU |
6455 | UGAUAUCCAAGAUGAUCUCCA | 9059 | UGGUGUUCUAACACCCAGUUC |
6456 | GAUAUCCAAGAUGAUCUCCAC | 9060 | GGUGUUCUAACACCCAGUUCA |
6457 | AUAUCCAAGAUGAUCUCCACC | 9061 | GUGUUCUAACACCCAGUUCAG |
6458 | UAUCCAAGAUGAUCUCCACCA | 9062 | UGUUCUAACACCCAGUUCAGC |
6459 | AUCCAAGAUGAUCUCCACCAG | 9063 | GUUCUAACACCCAGUUCAGCA |
6460 | UCCAAGAUGAUCUCCACCAGG | 9064 | UUCUAACACCCAGUUCAGCAU |
6461 | CCAAGAUGAUCUCCACCAGGU | 9065 | UCUAACACCCAGUUCAGCAUG |
6462 | CAAGAUGAUCUCCACCAGGUU | 9066 | CUAACACCCAGUUCAGCAUGU |
6463 | AAGAUGAUCUCCACCAGGUUG | 9067 | UAACACCCAGUUCAGCAUGUG |
6464 | AGAUGAUCUCCACCAGGUUGU | 9068 | AACACCCAGUUCAGCAUGUGA |
6465 | GAUGAUCUCCACCAGGUUGUU | 9069 | ACACCCAGUUCAGCAUGUGAG |
6466 | AUGAUCUCCACCAGGUUGUUU | 9070 | CACCCAGUUCAGCAUGUGAGU |
6467 | UGAUCUCCACCAGGUUGUUUU | 9071 | ACCCAGUUCAGCAUGUGAGUG |
6468 | GAUCUCCACCAGGUUGUUUUU | 9072 | CCCAGUUCAGCAUGUGAGUGA |
6469 | AUCUCCACCAGGUUGUUUUUC | 9073 | CCAGUUCAGCAUGUGAGUGAA |
6470 | UCUCCACCAGGUUGUUUUUCC | 9074 | CAGUUCAGCAUGUGAGUGAAU |
6471 | CUCCACCAGGUUGUUUUUCCU | 9075 | AGUUCAGCAUGUGAGUGAAUA |
6472 | UCCACCAGGUUGUUUUUCCUG | 9076 | GUUCAGCAUGUGAGUGAAUAU |
6473 | CCACCAGGUUGUUUUUCCUGG | 9077 | UUCAGCAUGUGAGUGAAUAUG |
6474 | CACCAGGUUGUUUUUCCUGGG | 9078 | UCAGCAUGUGAGUGAAUAUGG |
6475 | ACCAGGUUGUUUUUCCUGGGA | 9079 | CAGCAUGUGAGUGAAUAUGGA |
6476 | CCAGGUUGUUUUUCCUGGGAU | 9080 | AGCAUGUGAGUGAAUAUGGAG |
6477 | CAGGUUGUUUUUCCUGGGAUC | 9081 | GCAUGUGAGUGAAUAUGGAGU |
6478 | AGGUUGUUUUUCCUGGGAUCA | 9082 | CAUGUGAGUGAAUAUGGAGUC |
6479 | GGUUGUUUUUCCUGGGAUCAG | 9083 | AUGUGAGUGAAUAUGGAGUCA |
6480 | GUUGUUUUUCCUGGGAUCAGG | 9084 | UGUGAGUGAAUAUGGAGUCAG |
6481 | UUGUUUUUCCUGGGAUCAGGU | 9085 | GUGAGUGAAUAUGGAGUCAGA |
6482 | UGUUUUUCCUGGGAUCAGGUU | 9086 | UGAGUGAAUAUGGAGUCAGAU |
6483 | GUUUUUCCUGGGAUCAGGUUU | 9087 | GAGUGAAUAUGGAGUCAGAUA |
6484 | UUUUUCCUGGGAUCAGGUUUC | 9088 | AGUGAAUAUGGAGUCAGAUAU |
6485 | UUUUCCUGGGAUCAGGUUUCA | 9089 | GUGAAUAUGGAGUCAGAUAUC |
6486 | UUUCCUGGGAUCAGGUUUCAC | 9090 | UGAAUAUGGAGUCAGAUAUCA |
6487 | UUCCUGGGAUCAGGUUUCACC | 9091 | GAAUAUGGAGUCAGAUAUCAU |
6488 | UCCUGGGAUCAGGUUUCACCU | 9092 | AAUAUGGAGUCAGAUAUCAUG |
6489 | CCUGGGAUCAGGUUUCACCUC | 9093 | AUAUGGAGUCAGAUAUCAUGA |
6490 | CUGGGAUCAGGUUUCACCUCC | 9094 | UAUGGAGUCAGAUAUCAUGAG |
6491 | UGGGAUCAGGUUUCACCUCCA | 9095 | AUGGAGUCAGAUAUCAUGAGG |
6492 | GGGAUCAGGUUUCACCUCCAC | 9096 | UGGAGUCAGAUAUCAUGAGGC |
6493 | GGAUCAGGUUUCACCUCCACA | 9097 | GGAGUCAGAUAUCAUGAGGCA |
6494 | GAUCAGGUUUCACCUCCACAG | 9098 | GAGUCAGAUAUCAUGAGGCAC |
6495 | AUCAGGUUUCACCUCCACAGU | 9099 | AGUCAGAUAUCAUGAGGCACC |
6496 | UCAGGUUUCACCUCCACAGUG | 9100 | GUCAGAUAUCAUGAGGCACCU |
6497 | CAGGUUUCACCUCCACAGUGG | 9101 | UCAGAUAUCAUGAGGCACCUU |
6498 | AGGUUUCACCUCCACAGUGGU | 9102 | CAGAUAUCAUGAGGCACCUUG |
6499 | GGUUUCACCUCCACAGUGGUC | 9103 | AGAUAUCAUGAGGCACCUUGC |
6500 | GUUUCACCUCCACAGUGGUCC | 9104 | GAUAUCAUGAGGCACCUUGCU |
6501 | UUUCACCUCCACAGUGGUCCG | 9105 | AUAUCAUGAGGCACCUUGCUA |
6502 | UUCACCUCCACAGUGGUCCGG | 9106 | UAUCAUGAGGCACCUUGCUAA |
6503 | UCACCUCCACAGUGGUCCGGU | 9107 | AUCAUGAGGCACCUUGCUAAG |
6504 | CACCUCCACAGUGGUCCGGUC | 9108 | UCAUGAGGCACCUUGCUAAGG |
6505 | ACCUCCACAGUGGUCCGGUCU | 9109 | CAUGAGGCACCUUGCUAAGGG |
6506 | CCUCCACAGUGGUCCGGUCUG | 9110 | AUGAGGCACCUUGCUAAGGGU |
6507 | CUCCACAGUGGUCCGGUCUGU | 9111 | UGAGGCACCUUGCUAAGGGUU |
6508 | UCCACAGUGGUCCGGUCUGUG | 9112 | GAGGCACCUUGCUAAGGGUUU |
6509 | CCACAGUGGUCCGGUCUGUGU | 9113 | AGGCACCUUGCUAAGGGUUUC |
6510 | CACAGUGGUCCGGUCUGUGUC | 9114 | GGCACCUUGCUAAGGGUUUCC |
6511 | ACAGUGGUCCGGUCUGUGUCA | 9115 | GCACCUUGCUAAGGGUUUCCC |
6512 | CAGUGGUCCGGUCUGUGUCAC | 9116 | CACCUUGCUAAGGGUUUCCCC |
6513 | AGUGGUCCGGUCUGUGUCACU | 9117 | ACCUUGCUAAGGGUUUCCCCC |
6514 | GUGGUCCGGUCUGUGUCACUC | 9118 | CCUUGCUAAGGGUUUCCCCCU |
6515 | UGGUCCGGUCUGUGUCACUCU | 9119 | CUUGCUAAGGGUUUCCCCCUU |
6516 | GGUCCGGUCUGUGUCACUCUC | 9120 | UUGCUAAGGGUUUCCCCCUUC |
6517 | GUCCGGUCUGUGUCACUCUCA | 9121 | UGCUAAGGGUUUCCCCCUUCA |
6518 | UCCGGUCUGUGUCACUCUCAC | 9122 | GCUAAGGGUUUCCCCCUUCAA |
6519 | CCGGUCUGUGUCACUCUCACC | 9123 | CUAAGGGUUUCCCCCUUCAAG |
6520 | CGGUCUGUGUCACUCUCACCC | 9124 | UAAGGGUUUCCCCCUUCAAGG |
6521 | GGUCUGUGUCACUCUCACCCU | 9125 | AAGGGUUUCCCCCUUCAAGGA |
6522 | GUCUGUGUCACUCUCACCCUU | 9126 | AGGGUUUCCCCCUUCAAGGAA |
6523 | UCUGUGUCACUCUCACCCUUU | 9127 | GGGUUUCCCCCUUCAAGGAAA |
6524 | CUGUGUCACUCUCACCCUUUG | 9128 | GGUUUCCCCCUUCAAGGAAAC |
6525 | UGUGUCACUCUCACCCUUUGC | 9129 | GUUUCCCCCUUCAAGGAAACA |
6526 | GUGUCACUCUCACCCUUUGCA | 9130 | UUUCCCCCUUCAAGGAAACAA |
6527 | UGUCACUCUCACCCUUUGCAU | 9131 | UUCCCCCUUCAAGGAAACAAC |
6528 | GUCACUCUCACCCUUUGCAUC | 9132 | UCCCCCUUCAAGGAAACAACC |
6529 | UCACUCUCACCCUUUGCAUCG | 9133 | CCCCCUUCAAGGAAACAACCC |
6530 | CACUCUCACCCUUUGCAUCGG | 9134 | CCCCUUCAAGGAAACAACCCU |
6531 | ACUCUCACCCUUUGCAUCGGU | 9135 | CCCUUCAAGGAAACAACCCUC |
6532 | CUCUCACCCUUUGCAUCGGUC | 9136 | CCUUCAAGGAAACAACCCUCU |
6533 | UCUCACCCUUUGCAUCGGUCA | 9137 | CUUCAAGGAAACAACCCUCUC |
6534 | CUCACCCUUUGCAUCGGUCAC | 9138 | UUCAAGGAAACAACCCUCUCU |
6535 | UCACCCUUUGCAUCGGUCACU | 9139 | UCAAGGAAACAACCCUCUCUG |
6536 | CACCCUUUGCAUCGGUCACUU | 9140 | CAAGGAAACAACCCUCUCUGA |
6537 | ACCCUUUGCAUCGGUCACUUU | 9141 | AAGGAAACAACCCUCUCUGAC |
6538 | CCCUUUGCAUCGGUCACUUUC | 9142 | AGGAAACAACCCUCUCUGACA |
6539 | CCUUUGCAUCGGUCACUUUCA | 9143 | GGAAACAACCCUCUCUGACAC |
6540 | CUUUGCAUCGGUCACUUUCAG | 9144 | GAAACAACCCUCUCUGACACA |
6541 | UUUGCAUCGGUCACUUUCAGG | 9145 | AAACAACCCUCUCUGACACAG |
6542 | UUGCAUCGGUCACUUUCAGGU | 9146 | AACAACCCUCUCUGACACAGC |
6543 | UGCAUCGGUCACUUUCAGGUG | 9147 | ACAACCCUCUCUGACACAGCA |
6544 | GCAUCGGUCACUUUCAGGUGA | 9148 | AGACAGGCAGAACCAGUACAA |
6545 | CAUCGGUCACUUUCAGGUGAA | 9149 | GACAGGCAGAACCAGUACAAA |
6546 | AUCGGUCACUUUCAGGUGAAA | 9150 | ACAGGCAGAACCAGUACAAAG |
6547 | UCGGUCACUUUCAGGUGAAAA | 9151 | CAGGCAGAACCAGUACAAAGC |
6548 | CGGUCACUUUCAGGUGAAAAG | 9152 | AGGCAGAACCAGUACAAAGCG |
6549 | GGUCACUUUCAGGUGAAAAGU | 9153 | GGCAGAACCAGUACAAAGCGA |
6550 | GUCACUUUCAGGUGAAAAGUG | 9154 | GCAGAACCAGUACAAAGCGAA |
6551 | UCACUUUCAGGUGAAAAGUGU | 9155 | CAGAACCAGUACAAAGCGAAG |
6552 | CACUUUCAGGUGAAAAGUGUA | 9156 | AGAACCAGUACAAAGCGAAGG |
6553 | ACUUUCAGGUGAAAAGUGUAG | 9157 | GAACCAGUACAAAGCGAAGGA |
6554 | CUUUCAGGUGAAAAGUGUAGG | 9158 | AACCAGUACAAAGCGAAGGAA |
6555 | UUUCAGGUGAAAAGUGUAGGU | 9159 | ACCAGUACAAAGCGAAGGAAU |
6556 | UUCAGGUGAAAAGUGUAGGUU | 9160 | CCAGUACAAAGCGAAGGAAUC |
6557 | UCAGGUGAAAAGUGUAGGUUC | 9161 | CAGUACAAAGCGAAGGAAUCU |
6558 | CAGGUGAAAAGUGUAGGUUCC | 9162 | AGUACAAAGCGAAGGAAUCUG |
6559 | AGGUGAAAAGUGUAGGUUCCC | 9163 | GUACAAAGCGAAGGAAUCUGG |
6560 | GGUGAAAAGUGUAGGUUCCCU | 9164 | UACAAAGCGAAGGAAUCUGGG |
6561 | GUGAAAAGUGUAGGUUCCCUC | 9165 | ACAAAGCGAAGGAAUCUGGGC |
6562 | UGAAAAGUGUAGGUUCCCUCA | 9166 | CAAAGCGAAGGAAUCUGGGCC |
6563 | GAAAAGUGUAGGUUCCCUCAA | 9167 | AAAGCGAAGGAAUCUGGGCCC |
6564 | AAAAGUGUAGGUUCCCUCAAC | 9168 | AAGCGAAGGAAUCUGGGCCCC |
6565 | AAAGUGUAGGUUCCCUCAACC | 9169 | AGCGAAGGAAUCUGGGCCCCC |
6566 | AAGUGUAGGUUCCCUCAACCA | 9170 | GCGAAGGAAUCUGGGCCCCCA |
6567 | AGUGUAGGUUCCCUCAACCAG | 9171 | CGAAGGAAUCUGGGCCCCCAG |
6568 | GUGUAGGUUCCCUCAACCAGG | 9172 | GAAGGAAUCUGGGCCCCCAGC |
6569 | UGUAGGUUCCCUCAACCAGGU | 9173 | AAGGAAUCUGGGCCCCCAGCC |
6570 | GUAGGUUCCCUCAACCAGGUU | 9174 | AGGAAUCUGGGCCCCCAGCCU |
6571 | UAGGUUCCCUCAACCAGGUUU | 9175 | GGAAUCUGGGCCCCCAGCCUC |
6572 | AGGUUCCCUCAACCAGGUUUG | 9176 | GAAUCUGGGCCCCCAGCCUCU |
6573 | GGUUCCCUCAACCAGGUUUGA | 9177 | AAUCUGGGCCCCCAGCCUCUC |
6574 | GUUCCCUCAACCAGGUUUGAA | 9178 | AUCUGGGCCCCCAGCCUCUCG |
6575 | UUCCCUCAACCAGGUUUGAAA | 9179 | UCUGGGCCCCCAGCCUCUCGC |
6576 | UCCCUCAACCAGGUUUGAAAG | 9180 | CUGGGCCCCCAGCCUCUCGCC |
6577 | CCCUCAACCAGGUUUGAAAGA | 9181 | UGGGCCCCCAGCCUCUCGCCG |
6578 | CCUCAACCAGGUUUGAAAGAA | 9182 | GGGCCCCCAGCCUCUCGCCGC |
6579 | CUCAACCAGGUUUGAAAGAAA | 9183 | GGCCCCCAGCCUCUCGCCGCC |
6580 | UCAACCAGGUUUGAAAGAAAA | 9184 | GCCCCCAGCCUCUCGCCGCCC |
6581 | CAACCAGGUUUGAAAGAAAAA | 9185 | CCCCCAGCCUCUCGCCGCCCG |
6582 | AACCAGGUUUGAAAGAAAAAG | 9186 | CCCCAGCCUCUCGCCGCCCGC |
6583 | ACCAGGUUUGAAAGAAAAAGG | 9187 | CCCAGCCUCUCGCCGCCCGCU |
6584 | CCAGGUUUGAAAGAAAAAGGA | 9188 | CCAGCCUCUCGCCGCCCGCUC |
6585 | CAGGUUUGAAAGAAAAAGGAU | 9189 | CAGCCUCUCGCCGCCCGCUCU |
6586 | AGGUUUGAAAGAAAAAGGAUA | 9190 | AGCCUCUCGCCGCCCGCUCUC |
6587 | GGUUUGAAAGAAAAAGGAUAG | 9191 | GCCUCUCGCCGCCCGCUCUCC |
6588 | GUUUGAAAGAAAAAGGAUAGG | 9192 | CCUCUCGCCGCCCGCUCUCCA |
6589 | UUUGAAAGAAAAAGGAUAGGG | 9193 | CUCUCGCCGCCCGCUCUCCAG |
6590 | UUGAAAGAAAAAGGAUAGGGU | 9194 | UCUCGCCGCCCGCUCUCCAGA |
6591 | UGAAAGAAAAAGGAUAGGGUG | 9195 | CUCGCCGCCCGCUCUCCAGAG |
6592 | GAAAGAAAAAGGAUAGGGUGA | 9196 | UCGCCGCCCGCUCUCCAGAGG |
6593 | AAAGAAAAAGGAUAGGGUGAU | 9197 | CGCCGCCCGCUCUCCAGAGGC |
6594 | AAGAAAAAGGAUAGGGUGAUG | 9198 | GCCGCCCGCUCUCCAGAGGCA |
6595 | AGAAAAAGGAUAGGGUGAUGG | 9199 | CCGCCCGCUCUCCAGAGGCAG |
6596 | GAAAAAGGAUAGGGUGAUGGU | 9200 | CGCCCGCUCUCCAGAGGCAGU |
6597 | AAAAAGGAUAGGGUGAUGGUC | 9201 | GCCCGCUCUCCAGAGGCAGUC |
6598 | AAAAGGAUAGGGUGAUGGUCA | 9202 | CCCGCUCUCCAGAGGCAGUCU |
6599 | AAAGGAUAGGGUGAUGGUCAG | 9203 | CCGCUCUCCAGAGGCAGUCUG |
6600 | AAGGAUAGGGUGAUGGUCAGA | 9204 | CGCUCUCCAGAGGCAGUCUGC |
6601 | AGGAUAGGGUGAUGGUCAGAG | 9205 | GCUCUCCAGAGGCAGUCUGCA |
6602 | GGAUAGGGUGAUGGUCAGAGU | 9206 | CUCUCCAGAGGCAGUCUGCAC |
6603 | GAUAGGGUGAUGGUCAGAGUG | 9207 | UCUCCAGAGGCAGUCUGCACC |
6604 | AUAGGGUGAUGGUCAGAGUGA | 9208 | CUCCAGAGGCAGUCUGCACCU |
6605 | UAGGGUGAUGGUCAGAGUGAU | 9209 | UCCAGAGGCAGUCUGCACCUU |
6606 | AGGGUGAUGGUCAGAGUGAUU | 9210 | CCAGAGGCAGUCUGCACCUUG |
6607 | GGGUGAUGGUCAGAGUGAUUU | 9211 | CAGAGGCAGUCUGCACCUUGC |
6608 | GGUGAUGGUCAGAGUGAUUUA | 9212 | AGAGGCAGUCUGCACCUUGCC |
6609 | GUGAUGGUCAGAGUGAUUUAA | 9213 | GAGGCAGUCUGCACCUUGCCU |
6610 | UGAUGGUCAGAGUGAUUUAAC | 9214 | AGGCAGUCUGCACCUUGCCUC |
6611 | GAUGGUCAGAGUGAUUUAACA | 9215 | GGCAGUCUGCACCUUGCCUCC |
6612 | AUGGUCAGAGUGAUUUAACAC | 9216 | GCAGUCUGCACCUUGCCUCCU |
6613 | UGGUCAGAGUGAUUUAACACC | 9217 | CAGUCUGCACCUUGCCUCCUU |
6614 | GGUCAGAGUGAUUUAACACCU | 9218 | AGUCUGCACCUUGCCUCCUUC |
6615 | GUCAGAGUGAUUUAACACCUC | 9219 | GUCUGCACCUUGCCUCCUUCG |
6616 | UCAGAGUGAUUUAACACCUCC | 9220 | UCUGCACCUUGCCUCCUUCGC |
6617 | CAGAGUGAUUUAACACCUCCC | 9221 | CUGCACCUUGCCUCCUUCGCU |
6618 | AGAGUGAUUUAACACCUCCCC | 9222 | UGCACCUUGCCUCCUUCGCUC |
6619 | GAGUGAUUUAACACCUCCCCU | 9223 | GCACCUUGCCUCCUUCGCUCG |
6620 | AGUGAUUUAACACCUCCCCUG | 9224 | CACCUUGCCUCCUUCGCUCGA |
6621 | GUGAUUUAACACCUCCCCUGC | 9225 | ACCUUGCCUCCUUCGCUCGAG |
6622 | UGAUUUAACACCUCCCCUGCU | 9226 | CCUUGCCUCCUUCGCUCGAGC |
6623 | GAUUUAACACCUCCCCUGCUG | 9227 | CUUGCCUCCUUCGCUCGAGCC |
6624 | AUUUAACACCUCCCCUGCUGC | 9228 | UUGCCUCCUUCGCUCGAGCCC |
6625 | UUUAACACCUCCCCUGCUGCU | 9229 | UGCCUCCUUCGCUCGAGCCCC |
6626 | UUAACACCUCCCCUGCUGCUG | 9230 | GCCUCCUUCGCUCGAGCCCCA |
6627 | UAACACCUCCCCUGCUGCUGG | 9231 | CCUCCUUCGCUCGAGCCCCAG |
6628 | AACACCUCCCCUGCUGCUGGG | 9232 | CUCCUUCGCUCGAGCCCCAGC |
6629 | ACACCUCCCCUGCUGCUGGGC | 9233 | UCCUUCGCUCGAGCCCCAGCC |
6630 | CACCUCCCCUGCUGCUGGGCU | 9234 | CCUUCGCUCGAGCCCCAGCCC |
6631 | ACCUCCCCUGCUGCUGGGCUC | 9235 | CUUCGCUCGAGCCCCAGCCCC |
6632 | CCUCCCCUGCUGCUGGGCUCC | 9236 | UUCGCUCGAGCCCCAGCCCCC |
6633 | CUCCCCUGCUGCUGGGCUCCC | 9237 | UCGCUCGAGCCCCAGCCCCCA |
6634 | UCCCCUGCUGCUGGGCUCCCC | 9238 | CGCUCGAGCCCCAGCCCCCAG |
6635 | CCCCUGCUGCUGGGCUCCCCU | 9239 | GCUCGAGCCCCAGCCCCCAGA |
6636 | CCCUGCUGCUGGGCUCCCCUC | 9240 | CUCGAGCCCCAGCCCCCAGAC |
6637 | CCUGCUGCUGGGCUCCCCUCA | 9241 | UCGAGCCCCAGCCCCCAGACU |
6638 | CUGCUGCUGGGCUCCCCUCAU | 9242 | CGAGCCCCAGCCCCCAGACUC |
6639 | UGCUGCUGGGCUCCCCUCAUC | 9243 | GAGCCCCAGCCCCCAGACUCG |
6640 | GCUGCUGGGCUCCCCUCAUCU | 9244 | AGCCCCAGCCCCCAGACUCGG |
6641 | CUGCUGGGCUCCCCUCAUCUC | 9245 | GCCCCAGCCCCCAGACUCGGG |
6642 | UGCUGGGCUCCCCUCAUCUCG | 9246 | CCCCAGCCCCCAGACUCGGGC |
6643 | GCUGGGCUCCCCUCAUCUCGA | 9247 | CCCAGCCCCCAGACUCGGGCA |
6644 | CUGGGCUCCCCUCAUCUCGAG | 9248 | CCAGCCCCCAGACUCGGGCAA |
6645 | UGGGCUCCCCUCAUCUCGAGU | 9249 | CAGCCCCCAGACUCGGGCAAU |
6646 | GGGCUCCCCUCAUCUCGAGUC | 9250 | AGCCCCCAGACUCGGGCAAUA |
6647 | GGCUCCCCUCAUCUCGAGUCC | 9251 | GCCCCCAGACUCGGGCAAUAC |
6648 | GCUCCCCUCAUCUCGAGUCCA | 9252 | CCCCCAGACUCGGGCAAUACC |
6649 | CUCCCCUCAUCUCGAGUCCAG | 9253 | CCCCAGACUCGGGCAAUACCC |
6650 | UCCCCUCAUCUCGAGUCCAGA | 9254 | AGACAGGCAGAACCAGUACAU |
6651 | CCCCUCAUCUCGAGUCCAGAG | 9255 | GACAGGCAGAACCAGUACAUU |
6652 | CCCUCAUCUCGAGUCCAGAGG | 9256 | ACAGGCAGAACCAGUACAUUU |
6653 | CCUCAUCUCGAGUCCAGAGGU | 9257 | CAGGCAGAACCAGUACAUUUU |
6654 | CUCAUCUCGAGUCCAGAGGUA | 9258 | AGGCAGAACCAGUACAUUUUG |
6655 | UCAUCUCGAGUCCAGAGGUAG | 9259 | GGCAGAACCAGUACAUUUUGA |
6656 | CAUCUCGAGUCCAGAGGUAGC | 9260 | GCAGAACCAGUACAUUUUGAG |
6657 | AUCUCGAGUCCAGAGGUAGCU | 9261 | CAGAACCAGUACAUUUUGAGG |
6658 | UCUCGAGUCCAGAGGUAGCUG | 9262 | AGAACCAGUACAUUUUGAGGA |
6659 | CUCGAGUCCAGAGGUAGCUGA | 9263 | GAACCAGUACAUUUUGAGGAG |
6660 | UCGAGUCCAGAGGUAGCUGAC | 9264 | AACCAGUACAUUUUGAGGAGA |
6661 | CGAGUCCAGAGGUAGCUGACU | 9265 | ACCAGUACAUUUUGAGGAGAA |
6662 | GAGUCCAGAGGUAGCUGACUA | 9266 | CCAGUACAUUUUGAGGAGAAG |
6663 | AGUCCAGAGGUAGCUGACUAU | 9267 | CAGUACAUUUUGAGGAGAAGA |
6664 | GUCCAGAGGUAGCUGACUAUU | 9268 | AGUACAUUUUGAGGAGAAGAG |
6665 | UCCAGAGGUAGCUGACUAUUC | 9269 | GUACAUUUUGAGGAGAAGAGG |
6666 | CCAGAGGUAGCUGACUAUUCC | 9270 | UACAUUUUGAGGAGAAGAGGU |
6667 | CAGAGGUAGCUGACUAUUCCC | 9271 | ACAUUUUGAGGAGAAGAGGUU |
6668 | AGAGGUAGCUGACUAUUCCCU | 9272 | CAUUUUGAGGAGAAGAGGUUG |
6669 | GAGGUAGCUGACUAUUCCCUU | 9273 | AUUUUGAGGAGAAGAGGUUGC |
6670 | AGGUAGCUGACUAUUCCCUUG | 9274 | UUUUGAGGAGAAGAGGUUGCA |
6671 | GGUAGCUGACUAUUCCCUUGU | 9275 | UUUGAGGAGAAGAGGUUGCAC |
6672 | GUAGCUGACUAUUCCCUUGUC | 9276 | UUGAGGAGAAGAGGUUGCACC |
6673 | UAGCUGACUAUUCCCUUGUCA | 9277 | UGAGGAGAAGAGGUUGCACCC |
6674 | AGCUGACUAUUCCCUUGUCAU | 9278 | GAGGAGAAGAGGUUGCACCCU |
6675 | GCUGACUAUUCCCUUGUCAUC | 9279 | AGGAGAAGAGGUUGCACCCUC |
6676 | CUGACUAUUCCCUUGUCAUCU | 9280 | GGAGAAGAGGUUGCACCCUCA |
6677 | UGACUAUUCCCUUGUCAUCUG | 9281 | GAGAAGAGGUUGCACCCUCAG |
6678 | GACUAUUCCCUUGUCAUCUGA | 9282 | AGAAGAGGUUGCACCCUCAGA |
6679 | ACUAUUCCCUUGUCAUCUGAG | 9283 | GAAGAGGUUGCACCCUCAGAG |
6680 | CUAUUCCCUUGUCAUCUGAGG | 9284 | AAGAGGUUGCACCCUCAGAGG |
6681 | UAUUCCCUUGUCAUCUGAGGA | 9285 | AGAGGUUGCACCCUCAGAGGU |
6682 | AUUCCCUUGUCAUCUGAGGAC | 9286 | GAGGUUGCACCCUCAGAGGUA |
6683 | UUCCCUUGUCAUCUGAGGACU | 9287 | AGGUUGCACCCUCAGAGGUAA |
6684 | UCCCUUGUCAUCUGAGGACUU | 9288 | GGUUGCACCCUCAGAGGUAAA |
6685 | CCCUUGUCAUCUGAGGACUUA | 9289 | GUUGCACCCUCAGAGGUAAAG |
6686 | CCUUGUCAUCUGAGGACUUAG | 9290 | UUGCACCCUCAGAGGUAAAGU |
6687 | CUUGUCAUCUGAGGACUUAGA | 9291 | UGCACCCUCAGAGGUAAAGUA |
6688 | UUGUCAUCUGAGGACUUAGAG | 9292 | GCACCCUCAGAGGUAAAGUAA |
6689 | UGUCAUCUGAGGACUUAGAGC | 9293 | CACCCUCAGAGGUAAAGUAAC |
6690 | GUCAUCUGAGGACUUAGAGCC | 9294 | ACCCUCAGAGGUAAAGUAACC |
6691 | UCAUCUGAGGACUUAGAGCCA | 9295 | CCCUCAGAGGUAAAGUAACCU |
6692 | CAUCUGAGGACUUAGAGCCAU | 9296 | CCUCAGAGGUAAAGUAACCUG |
6693 | AUCUGAGGACUUAGAGCCAUC | 9297 | CUCAGAGGUAAAGUAACCUGA |
6694 | UCUGAGGACUUAGAGCCAUCC | 9298 | UCAGAGGUAAAGUAACCUGAG |
6695 | CUGAGGACUUAGAGCCAUCCA | 9299 | CAGAGGUAAAGUAACCUGAGG |
6696 | UGAGGACUUAGAGCCAUCCAG | 9300 | AGAGGUAAAGUAACCUGAGGG |
6697 | GAGGACUUAGAGCCAUCCAGC | 9301 | GAGGUAAAGUAACCUGAGGGU |
6698 | AGGACUUAGAGCCAUCCAGCU | 9302 | AGGUAAAGUAACCUGAGGGUU |
6699 | GGACUUAGAGCCAUCCAGCUC | 9303 | GGUAAAGUAACCUGAGGGUUA |
6700 | GACUUAGAGCCAUCCAGCUCU | 9304 | GUAAAGUAACCUGAGGGUUAU |
6701 | ACUUAGAGCCAUCCAGCUCUG | 9305 | UAAAGUAACCUGAGGGUUAUG |
6702 | CUUAGAGCCAUCCAGCUCUGC | 9306 | AAAGUAACCUGAGGGUUAUGU |
6703 | UUAGAGCCAUCCAGCUCUGCU | 9307 | AAGUAACCUGAGGGUUAUGUC |
6704 | UAGAGCCAUCCAGCUCUGCUG | 9308 | AGUAACCUGAGGGUUAUGUCU |
6705 | AGAGCCAUCCAGCUCUGCUGU | 9309 | GUAACCUGAGGGUUAUGUCUG |
6706 | GAGCCAUCCAGCUCUGCUGUG | 9310 | UAACCUGAGGGUUAUGUCUGG |
6707 | AGCCAUCCAGCUCUGCUGUGC | 9311 | AACCUGAGGGUUAUGUCUGGC |
6708 | GCCAUCCAGCUCUGCUGUGCU | 9312 | ACCUGAGGGUUAUGUCUGGCC |
6709 | CCAUCCAGCUCUGCUGUGCUC | 9313 | CCUGAGGGUUAUGUCUGGCCC |
6710 | CAUCCAGCUCUGCUGUGCUCG | 9314 | CUGAGGGUUAUGUCUGGCCCA |
6711 | AUCCAGCUCUGCUGUGCUCGU | 9315 | UGAGGGUUAUGUCUGGCCCAG |
6712 | UCCAGCUCUGCUGUGCUCGUG | 9316 | GAGGGUUAUGUCUGGCCCAGU |
6713 | CCAGCUCUGCUGUGCUCGUGG | 9317 | AGGGUUAUGUCUGGCCCAGUA |
6714 | CAGCUCUGCUGUGCUCGUGGG | 9318 | GGGUUAUGUCUGGCCCAGUAU |
6715 | AGCUCUGCUGUGCUCGUGGGU | 9319 | GGUUAUGUCUGGCCCAGUAUU |
6716 | GCUCUGCUGUGCUCGUGGGUA | 9320 | GUUAUGUCUGGCCCAGUAUUU |
6717 | CUCUGCUGUGCUCGUGGGUAG | 9321 | UUAUGUCUGGCCCAGUAUUUU |
6718 | UCUGCUGUGCUCGUGGGUAGG | 9322 | UAUGUCUGGCCCAGUAUUUUU |
6719 | CUGCUGUGCUCGUGGGUAGGG | 9323 | AUGUCUGGCCCAGUAUUUUUU |
6720 | UGCUGUGCUCGUGGGUAGGGU | 9324 | UGUCUGGCCCAGUAUUUUUUA |
6721 | GCUGUGCUCGUGGGUAGGGUA | 9325 | GUCUGGCCCAGUAUUUUUUAA |
6722 | CUGUGCUCGUGGGUAGGGUAA | 9326 | UCUGGCCCAGUAUUUUUUAAA |
6723 | UGUGCUCGUGGGUAGGGUAAU | 9327 | CUGGCCCAGUAUUUUUUAAAU |
6724 | GUGCUCGUGGGUAGGGUAAUC | 9328 | UGGCCCAGUAUUUUUUAAAUU |
6725 | UGCUCGUGGGUAGGGUAAUCA | 9329 | GGCCCAGUAUUUUUUAAAUUU |
6726 | GCUCGUGGGUAGGGUAAUCAC | 9330 | GCCCAGUAUUUUUUAAAUUUC |
6727 | CUCGUGGGUAGGGUAAUCACC | 9331 | CCCAGUAUUUUUUAAAUUUCU |
6728 | UCGUGGGUAGGGUAAUCACCA | 9332 | CCAGUAUUUUUUAAAUUUCUG |
6729 | CGUGGGUAGGGUAAUCACCAC | 9333 | CAGUAUUUUUUAAAUUUCUGA |
6730 | GUGGGUAGGGUAAUCACCACA | 9334 | AGUAUUUUUUAAAUUUCUGAA |
6731 | UGGGUAGGGUAAUCACCACAU | 9335 | GUAUUUUUUAAAUUUCUGAAU |
6732 | GGGUAGGGUAAUCACCACAUU | 9336 | UAUUUUUUAAAUUUCUGAAUG |
6733 | GGUAGGGUAAUCACCACAUUC | 9337 | AUUUUUUAAAUUUCUGAAUGC |
6734 | GUAGGGUAAUCACCACAUUCC | 9338 | UUUUUUAAAUUUCUGAAUGCA |
6735 | UAGGGUAAUCACCACAUUCCC | 9339 | UUUUUAAAUUUCUGAAUGCAA |
6736 | AGGGUAAUCACCACAUUCCCA | 9340 | UUUUAAAUUUCUGAAUGCAAA |
6737 | GGGUAAUCACCACAUUCCCAG | 9341 | UUUAAAUUUCUGAAUGCAAAU |
6738 | GGUAAUCACCACAUUCCCAGU | 9342 | CGUAGGUGUAGGUUUCUCCUG |
6739 | GUAAUCACCACAUUCCCAGUU | 9343 | GUAGGUGUAGGUUUCUCCUGG |
6740 | UAAUCACCACAUUCCCAGUUA | 9344 | UAGGUGUAGGUUUCUCCUGGG |
6741 | AAUCACCACAUUCCCAGUUAU | 9345 | AGGUGUAGGUUUCUCCUGGGU |
6742 | AUCACCACAUUCCCAGUUAUC | 9346 | GGUGUAGGUUUCUCCUGGGUA |
6743 | UCACCACAUUCCCAGUUAUCU | 9347 | GUGUAGGUUUCUCCUGGGUAU |
6744 | CACCACAUUCCCAGUUAUCUU | 9348 | UGUAGGUUUCUCCUGGGUAUG |
6745 | ACCACAUUCCCAGUUAUCUUG | 9349 | GUAGGUUUCUCCUGGGUAUGG |
6746 | CCACAUUCCCAGUUAUCUUGG | 9350 | UAGGUUUCUCCUGGGUAUGGU |
6747 | CACAUUCCCAGUUAUCUUGGC | 9351 | AGGUUUCUCCUGGGUAUGGUG |
6748 | ACAUUCCCAGUUAUCUUGGCU | 9352 | GGUUUCUCCUGGGUAUGGUGC |
6749 | CAUUCCCAGUUAUCUUGGCUA | 9353 | GUUUCUCCUGGGUAUGGUGCU |
6750 | AUUCCCAGUUAUCUUGGCUAU | 9354 | UUUCUCCUGGGUAUGGUGCUG |
6751 | UUCCCAGUUAUCUUGGCUAUA | 9355 | UUCUCCUGGGUAUGGUGCUGA |
6752 | UCCCAGUUAUCUUGGCUAUAG | 9356 | UCUCCUGGGUAUGGUGCUGAG |
6753 | CCCAGUUAUCUUGGCUAUAGG | 9357 | CUCCUGGGUAUGGUGCUGAGG |
6754 | CCAGUUAUCUUGGCUAUAGGU | 9358 | UCCUGGGUAUGGUGCUGAGGU |
6755 | CAGUUAUCUUGGCUAUAGGUG | 9359 | CCUGGGUAUGGUGCUGAGGUG |
6756 | AGUUAUCUUGGCUAUAGGUGG | 9360 | GACAGGCAGAACCAGUACACU |
6757 | GUUAUCUUGGCUAUAGGUGGU | 9361 | ACAGGCAGAACCAGUACACUC |
6758 | UUAUCUUGGCUAUAGGUGGUU | 9362 | CAGGCAGAACCAGUACACUCU |
6759 | UAUCUUGGCUAUAGGUGGUUU | 9363 | AGGCAGAACCAGUACACUCUC |
6760 | AUCUUGGCUAUAGGUGGUUUG | 9364 | GGCAGAACCAGUACACUCUCG |
6761 | UCUUGGCUAUAGGUGGUUUGU | 9365 | GCAGAACCAGUACACUCUCGC |
6762 | CUUGGCUAUAGGUGGUUUGUU | 9366 | CAGAACCAGUACACUCUCGCC |
6763 | UUGGCUAUAGGUGGUUUGUUU | 9367 | AGAACCAGUACACUCUCGCCU |
6764 | UGGCUAUAGGUGGUUUGUUUA | 9368 | GAACCAGUACACUCUCGCCUC |
6765 | GGCUAUAGGUGGUUUGUUUAU | 9369 | AACCAGUACACUCUCGCCUCA |
6766 | GCUAUAGGUGGUUUGUUUAUU | 9370 | ACCAGUACACUCUCGCCUCAG |
6767 | CUAUAGGUGGUUUGUUUAUUU | 9371 | CCAGUACACUCUCGCCUCAGC |
6768 | UAUAGGUGGUUUGUUUAUUUC | 9372 | CAGUACACUCUCGCCUCAGCC |
6769 | AUAGGUGGUUUGUUUAUUUCU | 9373 | AGUACACUCUCGCCUCAGCCU |
6770 | UAGGUGGUUUGUUUAUUUCUU | 9374 | GUACACUCUCGCCUCAGCCUC |
6771 | AGGUGGUUUGUUUAUUUCUUC | 9375 | UACACUCUCGCCUCAGCCUCC |
6772 | GGUGGUUUGUUUAUUUCUUCU | 9376 | ACACUCUCGCCUCAGCCUCCC |
6773 | GUGGUUUGUUUAUUUCUUCUU | 9377 | CACUCUCGCCUCAGCCUCCCU |
6774 | UGGUUUGUUUAUUUCUUCUUU | 9378 | ACUCUCGCCUCAGCCUCCCUG |
6775 | GGUUUGUUUAUUUCUUCUUUG | 9379 | ACAGGCAGAACCAGUACACUA |
6776 | GUUUGUUUAUUUCUUCUUUGA | 9380 | CAGGCAGAACCAGUACACUAU |
6777 | UUUGUUUAUUUCUUCUUUGAC | 9381 | AGGCAGAACCAGUACACUAUG |
6778 | UUGUUUAUUUCUUCUUUGACA | 9382 | GGCAGAACCAGUACACUAUGU |
6779 | UGUUUAUUUCUUCUUUGACAA | 9383 | GCAGAACCAGUACACUAUGUG |
6780 | GUUUAUUUCUUCUUUGACAAU | 9384 | CAGAACCAGUACACUAUGUGG |
6781 | UUUAUUUCUUCUUUGACAAUG | 9385 | AGAACCAGUACACUAUGUGGU |
6782 | UUAUUUCUUCUUUGACAAUGA | 9386 | GAACCAGUACACUAUGUGGUA |
6783 | UAUUUCUUCUUUGACAAUGAC | 9387 | AACCAGUACACUAUGUGGUAG |
6784 | AUUUCUUCUUUGACAAUGACA | 9388 | ACCAGUACACUAUGUGGUAGA |
6785 | UUUCUUCUUUGACAAUGACAU | 9389 | CCAGUACACUAUGUGGUAGAA |
6786 | UUCUUCUUUGACAAUGACAUU | 9390 | CAGUACACUAUGUGGUAGAAU |
6787 | UCUUCUUUGACAAUGACAUUC | 9391 | AGUACACUAUGUGGUAGAAUG |
6788 | CUUCUUUGACAAUGACAUUCA | 9392 | GUACACUAUGUGGUAGAAUGG |
6789 | UUCUUUGACAAUGACAUUCAC | 9393 | UACACUAUGUGGUAGAAUGGA |
6790 | UCUUUGACAAUGACAUUCACA | 9394 | ACACUAUGUGGUAGAAUGGAA |
6791 | CUUUGACAAUGACAUUCACAG | 9395 | CACUAUGUGGUAGAAUGGAAA |
6792 | UUUGACAAUGACAUUCACAGA | 9396 | ACUAUGUGGUAGAAUGGAAAG |
6793 | UUGACAAUGACAUUCACAGAG | 9397 | CUAUGUGGUAGAAUGGAAAGA |
6794 | UGACAAUGACAUUCACAGAGC | 9398 | UAUGUGGUAGAAUGGAAAGAG |
6795 | GACAAUGACAUUCACAGAGCU | 9399 | AUGUGGUAGAAUGGAAAGAGU |
6796 | ACAAUGACAUUCACAGAGCUC | 9400 | UGUGGUAGAAUGGAAAGAGUA |
6797 | CAAUGACAUUCACAGAGCUCU | 9401 | GUGGUAGAAUGGAAAGAGUAC |
6798 | AAUGACAUUCACAGAGCUCUG | 9402 | UGGUAGAAUGGAAAGAGUACC |
6799 | AUGACAUUCACAGAGCUCUGG | 9403 | GGUAGAAUGGAAAGAGUACCA |
6800 | UGACAUUCACAGAGCUCUGGC | 9404 | GUAGAAUGGAAAGAGUACCAG |
6801 | GACAUUCACAGAGCUCUGGCU | 9405 | UAGAAUGGAAAGAGUACCAGC |
6802 | ACAUUCACAGAGCUCUGGCUU | 9406 | AGAAUGGAAAGAGUACCAGCC |
6803 | CAUUCACAGAGCUCUGGCUUU | 9407 | GAAUGGAAAGAGUACCAGCCC |
6804 | AUUCACAGAGCUCUGGCUUUG | 9408 | AAUGGAAAGAGUACCAGCCCG |
6805 | UUCACAGAGCUCUGGCUUUGC | 9409 | AUGGAAAGAGUACCAGCCCGC |
6806 | UCACAGAGCUCUGGCUUUGCA | 9410 | UGGAAAGAGUACCAGCCCGCA |
6807 | CACAGAGCUCUGGCUUUGCAG | 9411 | GGAAAGAGUACCAGCCCGCAG |
6808 | ACAGAGCUCUGGCUUUGCAGG | 9412 | GAAAGAGUACCAGCCCGCAGA |
6809 | CAGAGCUCUGGCUUUGCAGGU | 9413 | AAAGAGUACCAGCCCGCAGAC |
6810 | AGAGCUCUGGCUUUGCAGGUU | 9414 | AAGAGUACCAGCCCGCAGACA |
6811 | GAGCUCUGGCUUUGCAGGUUC | 9415 | AGAGUACCAGCCCGCAGACAA |
6812 | AGCUCUGGCUUUGCAGGUUCC | 9416 | GAGUACCAGCCCGCAGACAAG |
6813 | GCUCUGGCUUUGCAGGUUCCU | 9417 | AGUACCAGCCCGCAGACAAGA |
6814 | CUCUGGCUUUGCAGGUUCCUC | 9418 | GUACCAGCCCGCAGACAAGAA |
6815 | UCUGGCUUUGCAGGUUCCUCU | 9419 | UACCAGCCCGCAGACAAGAAG |
6816 | CUGGCUUUGCAGGUUCCUCUC | 9420 | ACCAGCCCGCAGACAAGAAGA |
6817 | UGGCUUUGCAGGUUCCUCUCA | 9421 | CCAGCCCGCAGACAAGAAGAU |
6818 | GGCUUUGCAGGUUCCUCUCAU | 9422 | CAGCCCGCAGACAAGAAGAUC |
6819 | GCUUUGCAGGUUCCUCUCAUC | 9423 | AGCCCGCAGACAAGAAGAUCU |
6820 | CUUUGCAGGUUCCUCUCAUCU | 9424 | GCCCGCAGACAAGAAGAUCUC |
6821 | UUUGCAGGUUCCUCUCAUCUU | 9425 | CCCGCAGACAAGAAGAUCUCU |
6822 | UUGCAGGUUCCUCUCAUCUUU | 9426 | CCGCAGACAAGAAGAUCUCUG |
6823 | UGCAGGUUCCUCUCAUCUUUG | 9427 | CGCAGACAAGAAGAUCUCUGA |
6824 | GCAGGUUCCUCUCAUCUUUGA | 9428 | GCAGACAAGAAGAUCUCUGAG |
6825 | CAGGUUCCUCUCAUCUUUGAC | 9429 | CAGACAAGAAGAUCUCUGAGU |
6826 | AGGUUCCUCUCAUCUUUGACA | 9430 | AGACAAGAAGAUCUCUGAGUU |
6827 | GGUUCCUCUCAUCUUUGACAG | 9431 | GACAAGAAGAUCUCUGAGUUU |
6828 | GUUCCUCUCAUCUUUGACAGU | 9432 | ACAAGAAGAUCUCUGAGUUUU |
6829 | UUCCUCUCAUCUUUGACAGUC | 9433 | CAAGAAGAUCUCUGAGUUUUA |
6830 | UCCUCUCAUCUUUGACAGUCA | 9434 | AAGAAGAUCUCUGAGUUUUAG |
6831 | CCUCUCAUCUUUGACAGUCAA | 9435 | AGAAGAUCUCUGAGUUUUAGU |
6832 | CUCUCAUCUUUGACAGUCAAG | 9436 | GAAGAUCUCUGAGUUUUAGUU |
6833 | UCUCAUCUUUGACAGUCAAGG | 9437 | AAGAUCUCUGAGUUUUAGUUG |
6834 | CUCAUCUUUGACAGUCAAGGU | 9438 | AGAUCUCUGAGUUUUAGUUGC |
6835 | UCAUCUUUGACAGUCAAGGUG | 9439 | GAUCUCUGAGUUUUAGUUGCA |
6836 | CAUCUUUGACAGUCAAGGUGA | 9440 | AUCUCUGAGUUUUAGUUGCAG |
6837 | AUCUUUGACAGUCAAGGUGAA | 9441 | UCUCUGAGUUUUAGUUGCAGU |
6838 | UCUUUGACAGUCAAGGUGAAC | 9442 | CUCUGAGUUUUAGUUGCAGUU |
6839 | CUUUGACAGUCAAGGUGAACA | 9443 | UCUGAGUUUUAGUUGCAGUUC |
6840 | UUUGACAGUCAAGGUGAACAC | 9444 | CUGAGUUUUAGUUGCAGUUCU |
6841 | UUGACAGUCAAGGUGAACACA | 9445 | UGAGUUUUAGUUGCAGUUCUG |
6842 | UGACAGUCAAGGUGAACACAU | 9446 | GAGUUUUAGUUGCAGUUCUGC |
6843 | GACAGUCAAGGUGAACACAUA | 9447 | AGUUUUAGUUGCAGUUCUGCU |
6844 | ACAGUCAAGGUGAACACAUAG | 9448 | GUUUUAGUUGCAGUUCUGCUA |
6845 | CAGUCAAGGUGAACACAUAGG | 9449 | UUUUAGUUGCAGUUCUGCUAC |
6846 | AGUCAAGGUGAACACAUAGGU | 9450 | UUUAGUUGCAGUUCUGCUACU |
6847 | GUCAAGGUGAACACAUAGGUC | 9451 | UUAGUUGCAGUUCUGCUACUA |
6848 | UCAAGGUGAACACAUAGGUCC | 9452 | UAGUUGCAGUUCUGCUACUAA |
6849 | CAAGGUGAACACAUAGGUCCC | 9453 | AGUUGCAGUUCUGCUACUAAC |
6850 | AAGGUGAACACAUAGGUCCCC | 9454 | GUUGCAGUUCUGCUACUAACA |
6851 | AGGUGAACACAUAGGUCCCCA | 9455 | UUGCAGUUCUGCUACUAACAG |
6852 | GGUGAACACAUAGGUCCCCAC | 9456 | UGCAGUUCUGCUACUAACAGC |
6853 | GUGAACACAUAGGUCCCCACU | 9457 | GCAGUUCUGCUACUAACAGCU |
6854 | UGAACACAUAGGUCCCCACUU | 9458 | CAGUUCUGCUACUAACAGCUU |
6855 | GAACACAUAGGUCCCCACUUG | 9459 | AGUUCUGCUACUAACAGCUUU |
6856 | AACACAUAGGUCCCCACUUGC | 9460 | GUUCUGCUACUAACAGCUUUG |
6857 | ACACAUAGGUCCCCACUUGCA | 9461 | UUCUGCUACUAACAGCUUUGU |
6858 | CACAUAGGUCCCCACUUGCAG | 9462 | UCUGCUACUAACAGCUUUGUG |
6859 | ACAUAGGUCCCCACUUGCAGC | 9463 | CUGCUACUAACAGCUUUGUGA |
6860 | CAUAGGUCCCCACUUGCAGCC | 9464 | UGCUACUAACAGCUUUGUGAC |
6861 | AUAGGUCCCCACUUGCAGCCC | 9465 | GCUACUAACAGCUUUGUGACU |
6862 | UAGGUCCCCACUUGCAGCCCA | 9466 | CUACUAACAGCUUUGUGACUU |
6863 | AGGUCCCCACUUGCAGCCCAG | 9467 | UACUAACAGCUUUGUGACUUU |
6864 | GGUCCCCACUUGCAGCCCAGU | 9468 | ACUAACAGCUUUGUGACUUUG |
6865 | GUCCCCACUUGCAGCCCAGUC | 9469 | CUAACAGCUUUGUGACUUUGA |
6866 | UCCCCACUUGCAGCCCAGUCA | 9470 | UAACAGCUUUGUGACUUUGAC |
6867 | CCCCACUUGCAGCCCAGUCAC | 9471 | AACAGCUUUGUGACUUUGACC |
6868 | CCCACUUGCAGCCCAGUCACA | 9472 | ACAGCUUUGUGACUUUGACCA |
6869 | CCACUUGCAGCCCAGUCACAG | 9473 | CAGCUUUGUGACUUUGACCAA |
6870 | CACUUGCAGCCCAGUCACAGU | 9474 | AGCUUUGUGACUUUGACCAAA |
6871 | ACUUGCAGCCCAGUCACAGUA | 9475 | GCUUUGUGACUUUGACCAAAC |
6872 | CUUGCAGCCCAGUCACAGUAG | 9476 | CUUUGUGACUUUGACCAAACA |
6873 | UUGCAGCCCAGUCACAGUAGC | 9477 | UUUGUGACUUUGACCAAACAC |
6874 | UGCAGCCCAGUCACAGUAGCA | 9478 | UUGUGACUUUGACCAAACACA |
6875 | GCAGCCCAGUCACAGUAGCAA | 9479 | UGUGACUUUGACCAAACACAC |
6876 | CAGCCCAGUCACAGUAGCAAC | 9480 | GUGACUUUGACCAAACACACU |
6877 | AGCCCAGUCACAGUAGCAACA | 9481 | UGACUUUGACCAAACACACUU |
6878 | GCCCAGUCACAGUAGCAACAC | 9482 | GACUUUGACCAAACACACUUU |
6879 | CCCAGUCACAGUAGCAACACU | 9483 | ACUUUGACCAAACACACUUUC |
6880 | CCAGUCACAGUAGCAACACUG | 9484 | CUUUGACCAAACACACUUUCU |
6881 | CAGUCACAGUAGCAACACUGC | 9485 | UUUGACCAAACACACUUUCUU |
6882 | AGUCACAGUAGCAACACUGCU | 9486 | UUGACCAAACACACUUUCUUA |
6883 | GUCACAGUAGCAACACUGCUG | 9487 | UGACCAAACACACUUUCUUAC |
6884 | UCACAGUAGCAACACUGCUGU | 9488 | GACCAAACACACUUUCUUACU |
6885 | CACAGUAGCAACACUGCUGUU | 9489 | ACCAAACACACUUUCUUACUU |
6886 | ACAGUAGCAACACUGCUGUUA | 9490 | CCAAACACACUUUCUUACUUU |
6887 | CAGUAGCAACACUGCUGUUAG | 9491 | CAAACACACUUUCUUACUUUU |
6888 | AGUAGCAACACUGCUGUUAGC | 9492 | AAACACACUUUCUUACUUUUG |
6889 | GUAGCAACACUGCUGUUAGCA | 9493 | AACACACUUUCUUACUUUUGA |
6890 | UAGCAACACUGCUGUUAGCAU | 9494 | ACACACUUUCUUACUUUUGAG |
6891 | AGCAACACUGCUGUUAGCAUU | 9495 | CACACUUUCUUACUUUUGAGG |
6892 | GCAACACUGCUGUUAGCAUUC | 9496 | ACACUUUCUUACUUUUGAGGA |
6893 | CAACACUGCUGUUAGCAUUCU | 9497 | CACUUUCUUACUUUUGAGGAG |
6894 | AACACUGCUGUUAGCAUUCUC | 9498 | ACUUUCUUACUUUUGAGGAGA |
6895 | ACACUGCUGUUAGCAUUCUCG | 9499 | CUUUCUUACUUUUGAGGAGAA |
6896 | CACUGCUGUUAGCAUUCUCGA | 9500 | UUUCUUACUUUUGAGGAGAAG |
6897 | ACUGCUGUUAGCAUUCUCGAG | 9501 | UUCUUACUUUUGAGGAGAAGA |
6898 | CUGCUGUUAGCAUUCUCGAGC | 9502 | UCUUACUUUUGAGGAGAAGAG |
6899 | UGCUGUUAGCAUUCUCGAGCU | 9503 | CUUACUUUUGAGGAGAAGAGG |
6900 | GCUGUUAGCAUUCUCGAGCUG | 9504 | UUACUUUUGAGGAGAAGAGGU |
6901 | CUGUUAGCAUUCUCGAGCUGC | 9505 | UACUUUUGAGGAGAAGAGGUU |
6902 | UGUUAGCAUUCUCGAGCUGCA | 9506 | ACUUUUGAGGAGAAGAGGUUG |
6903 | GUUAGCAUUCUCGAGCUGCAC | 9507 | CUUUUGAGGAGAAGAGGUUGC |
本說明書及例示性實施例不應視為限制性的。出於本說明書及所附申請專利範圍之目的,除非另外說明,否則表示數量、百分比或比例之所有數字,及本說明書及申請專利範圍中所使用之其他數值均應理解為在所有情況下藉由術語「約」修飾至其尚未如此修飾之程度。因此,除非相反地指示,否則以下說明書及所附申請專利範圍中所闡述之數值參數為可根據設法獲得之所需特性而變化的近似值。至少且不試圖將均等論之應用限於申請專利範圍之範疇,各數值參數至少應根據所報導之有效數位的數目且藉由應用一般捨入技術來解釋。
應注意,如本說明書及所附申請專利範圍中所使用,除非明確且肯定地限於一個參考物,否則單數形式「一(a)」、「一(an)」及「該(the)」以及任何字語之任何單數使用形式均包括複數個參考物。如本文中所使用,術語「包括」及其文法變異體意欲為非限制性的,從而使得清單中之項的敍述不排除可取代或添加至所列項中之其他類似項。
圖1A至圖1J展示在Hepa1-6細胞中10種不同siRNA對AAVR mRNA之減弱。標繪圖展示所評估之10種siRNA中之各者的10點劑量反應。圖1K提供評估中所使用之經修飾之siRNA序列的代表性結構。
圖2展示在C2C12細胞中具有基於MOE或LNA之不同ASO的AAVR mRNA之減弱。標繪圖展示AAVR mRNA含量相對於未經處理之樣品的倍數變化,如在用50 nM ASO處理之後48小時藉由qPCR所量測。虛線指示未經處理之樣品的mRNA表現量。誤差條指示標準差。在水平軸線上,「siRNA」係指靶向AAVR之siRNAVT011 (陽性對照);「lipo」係指僅RNAiMax脂染胺(陰性對照);「未經處理」係指不含脂染胺之樣品(陰性對照)。
圖3展示在Huh7細胞中具有基於LNA之不同ASO的AAVR mRNA之減弱。標繪圖展示AAVR mRNA含量相對於未經處理之樣品的倍數變化,如在用10、50、100或200 nM ASO處理之後48小時藉由qPCR所量測。虛線指示未經處理之樣品的mRNA表現量。在水平軸線上,「siRNA」係指靶向AAVR之siRNAVT011 (陽性對照);「lipo」係指僅RNAiMax脂染胺(陰性對照);「scram」係指非靶向siRNA (IDT目錄號51-01-14-03) (陰性對照);「未經處理」係指不含脂染胺之樣品(陰性對照)。對於各ASO,ASO之nM濃度指示為名稱中之數字。
圖4A至圖4D展示在ASO處理後AAV受體mRNA及蛋白質表現之時程。圖4A及圖4C展示由qPCR所量測之AAVR mRNA含量相對於未經處理之樣品的倍數變化,圖4B及圖4D為來自細胞溶解產物之AAV受體蛋白及β-肌動蛋白之西方墨點法(Western Blot)偵測結果的影像。圖4A及圖4B展示未經處理之樣品的mRNA及蛋白質小組,且圖4C及圖4D展示經處理之樣品的mRNA及蛋白質小組,其中如所指示之時間點以小時為單位。誤差條展示標準差。
圖5A至圖5B展示在AAV9-GFP (Vector Biolabs目錄號7007)感染後的72小時對照樣品及經預處理之樣品的亮視野影像。圖5A展示未經處理之對照細胞;圖5B展示用ASOVT002 (250 nM)給藥之經預處理之細胞。
圖6A至圖6B展示在Huh7細胞中之GFP轉殖基因表現。圖6A至圖6B展示在AAV9-GFP (Vector Biolabs目錄號7007)感染後的72小時對照樣品及經預處理之樣品的代表性螢光影像。圖6A展示未經處理之對照細胞;圖6B展示用LNA-1 (250 nM)給藥之經預處理之細胞。
圖7展示在以2、7或20 mg/kg劑量之AAVR靶向ASO、20 mg/kg之對照ASO,或PBS給藥後7天的AAV受體蛋白定量。資料相對於經PBS處理之樣品標準化。誤差條表示與平均值之標準差。
圖8A及圖8B展示在用20 mg/kg之AAVR ASO (ASOVT002)給藥後的7天或經PBS處理之動物的心臟及肌肉中之AAV受體蛋白含量。資料相對於經PBS處理之樣品標準化。誤差條表示與平均值之標準差。
圖9展示在用20 mg/kg之AAVR ASO (ASOVT002)給藥後的3、7及10天,或PBS處理之後的AAV受體蛋白定量。資料相對於經PBS處理之樣品標準化。誤差條表示與平均值之標準差。
圖10為活體內研究設計之圖形表示,該研究設計測試基於ASO之AAVR減弱對與實例6中之研究對應的AAV分佈的作用。
Claims (62)
- 一種組合物,其包含阻斷AAV結合至AAV受體(AAVR)之藥劑及將該藥劑遞送至肝臟之遞送分子。
- 如請求項1之組合物,其中該藥劑包含小干擾RNA (siRNA)。
- 如請求項2之組合物,其中該siRNA包含SEQ ID No: 4300至9527中之任一者的至少19個鄰接核苷酸。
- 如請求項3之組合物,其中該siRNA包含SEQ ID No: 4300至9527之序列中之任一者。
- 如請求項4之組合物,其中該siRNA之長度不超過21、25或31個核苷酸。
- 如請求項1之組合物,其中該藥劑包含抗AAVR抗體。
- 如請求項1之組合物,其中該藥劑包含小分子。
- 如請求項1之組合物,其中該藥劑包含反義寡核苷酸(ASO)。
- 如請求項8之組合物,其中該ASO包含SEQ ID No: 9600至9623之序列中之任一者,或包含SEQ ID No: 9600至9623中之任一者的至少14個連續核苷酸。
- 如請求項1至9中任一項之組合物,其中該遞送分子包含以下中之一或多者:乳糖、半乳糖、N-乙醯基半乳胺糖(GalNAc)、半乳胺糖、N-甲醯基半乳胺糖、N-乙醯基半乳胺糖、N-丙醯基半乳胺糖、N-丁醯基半乳胺糖、N-異丁醯基-半乳胺糖及膽固醇或其衍生物。
- 如請求項10之組合物,其中該遞送分子包含N-乙醯基半乳胺糖(GalNAc)。
- 如請求項1至9中任一項之組合物,其中該遞送分子包含脂質奈米粒子(LNP)。
- 如請求項1至9中任一項之組合物,其中該遞送分子包含AAV。
- 一種方法,其包含:(a)向個體投與阻斷AAV結合至肝臟中之AAV受體(AAVR)之藥劑,及隨後(b)向該個體投與AAV載體。
- 如請求項14之方法,其中該AAV載體進一步包含有效負載。
- 如請求項15之方法,其中該有效負載包含用以預防或治療疾病之治療劑。
- 如請求項15之方法,其中該有效負載包含嚮導RNA、核酸內切酶、tRNA、小分子、ASO、抗體、siRNA或RNAi藥劑。
- 一種增加個體中遞送至非肝臟標靶之AAV之百分比的方法,其包含(a)包含向該個體投與組合物之預處理步驟,該組合物包含阻斷AAV結合至肝臟中之AAV受體(AAVR)之藥劑,及隨後(b)投與靶向非肝臟組織之AAV載體。
- 如請求項14至18中任一項之方法,其中步驟(a)包含向該個體投與如請求項1至13中任一項之組合物。
- 一種降低個體中AAV向肝臟之趨性的方法,其包含(a)向該個體投與如請求項1至13中任一項之組合物,及隨後(b)投與靶向非肝臟組織之AAV載體。
- 如請求項14至20中任一項之方法,其中向該個體投與阻斷AAV結合至肝臟中之AAV受體(AAVR)的該組合物及/或藥劑暫時阻斷AAV結合至肝臟中之AAV受體。
- 如請求項14至20中任一項之方法,其中向該個體投與阻斷AAV結合至肝臟中之AAV受體(AAVR)的該組合物及/或藥劑為該預處理步驟之部分。
- 如請求項14至20中任一項之方法,其中向該個體投與阻斷AAV結合至肝臟中之AAV受體(AAVR)的該組合物及/或藥劑發生在投與該AAV載體之前約2天、約3天、約4天、約5天、約6天、約7天、約8天、約9天、約10天、約11天、約12天、約13天、約14天、約15天、約16天、約17天、約18天、約19天、約20天或約21天。
- 如請求項14至20中任一項之方法,其中向該個體投與阻斷AAV結合至肝臟中之AAV受體(AAVR)的該組合物及/或藥劑發生在投與該AAV載體之前約1天、約2天、約3天、約4天、約5天、約6天、約7天。
- 如請求項14至20中任一項之方法,其中向該個體投與阻斷AAV結合至肝臟中之AAV受體(AAVR)的該組合物及/或藥劑發生在投與該AAV載體之前約7天、約8天、約9天、約10天、約11天、約12天、約13天或約14天。
- 如請求項14至20中任一項之方法,其中向該個體投與如請求項1至13中任一項之組合物緊接在投與該AAV載體之前。
- 如請求項14至20中任一項之方法,其中共同投與如請求項1至10中任一項之組合物及該AAV載體。
- 如請求項14至20中任一項之方法,其中步驟(a)包含向該個體投與包含小干擾RNA (siRNA)或反義寡核苷酸(ASO)之組合物。
- 如請求項28之方法,其中該組合物包含與肝臟靶向部分結合之小干擾RNA (siRNA)。
- 如請求項29之方法,其中該組合物包含結合N-乙醯基半乳胺糖(GalNAc)之siRNA。
- 如請求項28之方法,其中該組合物包含囊封於脂質奈米粒子(LNP)中之小干擾RNA (siRNA)。
- 如請求項28之方法,其中該組合物包含ASO。
- 如請求項14至32中任一項之方法,其中該組合物包含醫藥學上可接受之載劑。
- 如請求項33之方法,其中該方法包含藉由腹膜內注射進行投與。
- 如請求項34之方法,其中在投與該AAV載體之前約1天、約2天、約3天、約4天、約5天、約6天、約7天投與該ASO。
- 如請求項34之方法,其中在投與該AAV載體之前約24小時與約48小時之間投與該ASO。
- 如請求項34之方法,其中在投與該AAV載體之前約24小時投與該ASO。
- 如請求項34之方法,其中在投與該AAV載體之前約48小時投與該ASO。
- 如請求項31至38中任一項之方法,其中該方法包含共同投與在肝臟中促進該siRNA或ASO之吸收增加的其他藥物。
- 如請求項14至39中任一項之方法,其中步驟(a)中對AAV結合至肝臟中之AAV受體的阻斷並非暫時的。
- 如請求項39之方法,其中該組合物包含阻斷AAV結合至AAV受體之抗AAV抗體。
- 如請求項14至41中任一項之方法,其中該AAV載體意欲用於腦;中樞神經系統;脊髓;眼;視網膜;骨;心肌、骨骼肌及/或平滑肌;肺;胰臟;心臟;及/或腎臟。
- 如請求項14至42中任一項之方法,其中該AAV載體意欲用於心肌、骨骼肌及/或平滑肌。
- 如請求項14至43中任一項之方法,其中在步驟(a)中投與該組合物增加遞送至該非肝臟標靶之AAV之百分比。
- 如請求項14至44中任一項之方法,其中與接受該AAV但未接受阻斷AAV結合至肝臟中之AAV受體(AAVR)之該藥劑的對照個體之相應組織中的該AAV相比,該方法引起大腦;中樞神經系統;脊髓;眼;視網膜;骨;心肌、骨骼肌及/或平滑肌;肺;胰臟;心臟;及/或腎臟中之AAV增加至少10%、30%、50%、75%、100%、125%、150%、200%、250%、300%、350%、400%、450%、500%、600%、700%、800%、900%或1000%。
- 如請求項45之方法,與接受該AAV但未接受該藥劑之對照個體之相應肌肉中的該AAV相比,該方法引起骨骼肌中之AAV增加至少10%、30%、50%、75%、100%、125%、150%、200%、250%、300%、350%、400%、450%、500%、600%、700%、800%、900%或1000%。
- 如請求項14至46中任一項之方法,其中該AAV載體進一步包含用於增強針對標靶宿主細胞或組織之趨性的分子。
- 如請求項14至47中任一項之方法,其中該個體為人類個體。
- 如請求項14至48中任一項之方法,其中該AAV載體包含編碼一或多個嚮導RNA及Cas9之單一核酸分子,其中該單一核酸分子包含: a.編碼選自SEQ ID NO: 1至35、1000至1078或3000至3069中之任一者的一或多個間隔子序列之第一核酸,及編碼金黃色葡萄球菌Cas9 ( Staphylococcus aureus Cas9;SaCas9)之第二核酸;或 b.編碼選自SEQ ID NO: 100至225、2000至2116或4000至4251中之任一者的一或多個間隔子序列之第一核酸,及編碼路鄧葡萄球菌( Staphylococcus lugdunensis;SluCas9)之第二核酸;或 c.編碼一或多個間隔子序列之第一核酸,該一或多個間隔子序列包含選自SEQ ID NO: 1至35、1000至1078或3000至3069中之任一者之間隔子序列的至少20個鄰接核苷酸,及編碼金黃色葡萄球菌Cas9 (SaCas9)之第二核酸;或 d.編碼一或多個間隔子序列之第一核酸,該一或多個間隔子序列包含選自SEQ ID NO: 100至225、2000至2116或4000至4251中之任一者之間隔子序列的至少20個鄰接核苷酸,及編碼路鄧葡萄球菌(SluCas9)之第二核酸;或 e.編碼一或多個間隔子序列之第一核酸,該一或多個間隔子序列與SEQ ID NO: 1至35、1000至1078或3000至3069中之任一者至少90%一致,及編碼金黃色葡萄球菌Cas9 (SaCas9)之第二核酸;或 f.編碼一或多個間隔子序列之第一核酸,該一或多個間隔子序列與SEQ ID NO: 100至225、2000至2116或4000至4251中之任一者至少90%一致,及編碼路鄧葡萄球菌(SluCas9)之第二核酸;或 g.編碼嚮導RNA對之第一核酸,該嚮導RNA對包含選自以下間隔子序列對中之任一者的第一及第二間隔子序列:SEQ ID NO: 10及15;10及16;12及16;1001及1005;1001及15;1001及16;1003及1005;16及1003;12及1010;12及1012;12及1013;10及1016;1017及1005;1017及16;1018及16;15及10;16及10;16及12;1005及1001;15及1001;16及1001;1005及1003;1003及16;1010及12;1012及12;1013及12;1016及10;1005及1017;16及1017;以及16及1018;及編碼金黃色葡萄球菌Cas9 (SaCas9)之第二核酸;或 h.編碼嚮導RNA對之第一核酸,該嚮導RNA對包含選自以下間隔子序列對中之任一者的第一及第二間隔子序列之至少17、18、19、20或21個鄰接核苷酸:SEQ ID NO: 10及15;10及16;12及16;1001及1005;1001及15;1001及16;1003及1005;16及1003;12及1010;12及1012;12及1013;10及1016;1017及1005;1017及16;1018及16;15及10;16及10;16及12;1005及1001;15及1001;16及1001;1005及1003;1003及16;1010及12;1012及12;1013及12;1016及10;1005及1017;16及1017;以及16及1018;及編碼金黃色葡萄球菌Cas9 (SaCas9)之第二核酸;或 i.編碼嚮導RNA對之第一核酸,該嚮導RNA對與選自以下間隔子序列對中之任一者的第一及第二間隔子序列至少90%一致:SEQ ID NO: 10及15;10及16;12及16;1001及1005;1001及15;1001及16;1003及1005;16及1003;12及1010;12及1012;12及1013;10及1016;1017及1005;1017及16;1018及16;15及10;16及10;16及12;1005及1001;15及1001;16及1001;1005及1003;1003及16;1010及12;1012及12;1013及12;1016及10;1005及1017;16及1017;以及16及1018;及編碼金黃色葡萄球菌Cas9 (SaCas9)之第二核酸;或 j.編碼嚮導RNA對之第一核酸,該嚮導RNA對包含選自以下間隔子序列對中之任一者的第一及第二間隔子序列:SEQ ID NO: 148及134;149及135;150及135;131及136;151及136;139及131;139及151;140及131;140及151;141及148;144及149;144及150;145及131;145及151;146及148;134及148;135及149;135及150;136及131;136及151;131及139;151及139;131及140;151及140;148及141;149及144;150及144;131及145;151及145;以及148及146;及編碼路鄧葡萄球菌(SluCas9)之第二核酸;或 k.編碼嚮導RNA對之第一核酸,該嚮導RNA對包含選自以下間隔子序列對中之任一者的第一及第二間隔子序列之至少17、18、19、20或21個鄰接核苷酸:SEQ ID NO: 148及134;149及135;150及135;131及136;151及136;139及131;139及151;140及131;140及151;141及148;144及149;144及150;145及131;145及151;146及148;134及148;135及149;135及150;136及131;136及151;131及139;151及139;131及140;151及140;148及141;149及144;150及144;131及145;151及145;以及148及146;及編碼路鄧葡萄球菌(SluCas9)之第二核酸;或 l.編碼嚮導RNA對之第一核酸,該嚮導RNA對與選自以下間隔子序列對中之任一者的第一及第二間隔子序列至少90%一致:SEQ ID NO: 148及134;149及135;150及135;131及136;151及136;139及131;139及151;140及131;140及151;141及148;144及149;144及150;145及131;145及151;146及148;134及148;135及149;135及150;136及131;136及151;131及139;151及139;131及140;151及140;148及141;149及144;150及144;131及145;151及145;以及148及146;及編碼路鄧葡萄球菌(SluCas9)之第二核酸;或 m.編碼嚮導RNA對之第一核酸,該嚮導RNA對與選自以下間隔子序列對中之任一者的第一及第二間隔子序列至少90%一致: i. SEQ ID NO: 148及134, ii. SEQ ID No: 145及131, iii. SEQ ID No: 144及149; iv. SEQ ID No: 144及150; v. SEQ ID No: 146及148; 及編碼路鄧葡萄球菌(SluCas9)之第二核酸;或 n.編碼嚮導RNA對之第一核酸,該嚮導RNA對與選自以下間隔子序列對中之任一者的第一及第二間隔子序列至少90%一致: i. SEQ ID NO: 12及1013;及 ii. SEQ ID No: 12及1016; 及編碼SaCas9-KKH之第二核酸。
- 如請求項14至49中任一項之方法,其中該AAV載體自ITR至ITR,包括兩個ITR,之尺寸在3.9至5 kb、4至5 kb、4.2至5 kb、4.4至5 kb、4.6至5 kb、4.7至5 kb、3.9至4.9 kb、4.2至4.9 kb、4.4至4.9 kb、4.7至4.9 kb、3.9至4.85 kb、4.2至4.85 kb、4.4至4.85 kb、4.6至4.85 kb、4.7至4.85 kb、4.7至4.9 kb、3.9至4.8 kb、4.2至4.8 kb、4.4至4.8 kb或4.6至4.8 kb之間。
- 如請求項14至50中任一項之方法,其中該AAV載體為AAV9載體。
- 如請求項14至51中任一項之方法,其中該藥劑為siRNA。
- 如請求項52之方法,其中該siRNA包含SEQ ID No: 4300至9527中之任一者的至少19個鄰接核苷酸。
- 如請求項52之方法,其中該siRNA包含SEQ ID No: 4300至9527之序列中之任一者。
- 如請求項52之方法,其中該siRNA包含SEQ ID No: 9508至9531中之任一者的至少19個鄰接核苷酸。
- 如請求項52之方法,其中該siRNA包含SEQ ID No: 9508至9531之序列中之任一者。
- 如請求項52至56中任一項之方法,其中該siRNA之長度不超過21、25或31個核苷酸。
- 如請求項14至51中任一項之方法,其中該藥劑包含抗AAVR抗體。
- 如請求項14至51中任一項之方法,其中該藥劑包含小分子。
- 如請求項14至51中任一項之方法,其中該藥劑包含反義寡核苷酸(ASO)。
- 如請求項60之方法,其中該ASO包含SEQ ID No: 9600至9623之序列中之任一者,或包含SEQ ID No: 9600至9623中之任一者的至少14個連續核苷酸。
- 如請求項60之方法,其中該ASO之長度在14至35、15至30或15至25個核苷酸之間。
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EP1695979B1 (en) | 1991-12-24 | 2011-07-06 | Isis Pharmaceuticals, Inc. | Gapped modified oligonucleotides |
WO1995032305A1 (en) | 1994-05-19 | 1995-11-30 | Dako A/S | Pna probes for detection of neisseria gonorrhoeae and chlamydia trachomatis |
EP1310571B1 (en) | 2001-11-13 | 2006-02-15 | The Trustees of The University of Pennsylvania | A Method of identifying unknown adeno-associated virus (AVV) sequences and a kit for the method |
US20050058982A1 (en) | 2002-07-26 | 2005-03-17 | Chiron Corporation | Modified small interfering RNA molecules and methods of use |
MXPA05004860A (es) | 2002-11-04 | 2005-08-18 | Advisys Inc | Promotores musculares sinteticos con actividades que exceden las secuencias reguladoras de origen natural en las celulas cardiacas. |
RU2653444C2 (ru) | 2012-02-17 | 2018-05-08 | Дзе Чилдрен'З Хоспитал Оф Филадельфия | Композиции вектора aav и способы переноса генов в клетки, органы и ткани |
WO2016141224A1 (en) | 2015-03-03 | 2016-09-09 | The General Hospital Corporation | Engineered crispr-cas9 nucleases with altered pam specificity |
WO2017083423A1 (en) * | 2015-11-10 | 2017-05-18 | The Board Of Trustees Of The Leland Stanford Junior University | Methods and compositions for modulating aav infection |
CA3018978A1 (en) | 2016-03-30 | 2017-10-05 | Intellia Therapeutics, Inc. | Lipid nanoparticle formulations for crispr/cas components |
US11932856B2 (en) | 2017-03-03 | 2024-03-19 | The Regents Of The University Of California | RNA targeting of mutations via suppressor tRNAs and deaminases |
US20200248149A1 (en) * | 2017-03-24 | 2020-08-06 | Ohio State Innovation Foundation | Novel recombinant adeno-associated viral vectors restricting off-target transduction in liver and uses thereof |
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