KR101036126B1 - Ｐｃｓｋ9 유전자의 발현을 억제하기 위한 조성물 및 방법 - Google Patents

Ｐｃｓｋ9 유전자의 발현을 억제하기 위한 조성물 및 방법 Download PDF

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KR101036126B1
KR101036126B1 KR1020087030164A KR20087030164A KR101036126B1 KR 101036126 B1 KR101036126 B1 KR 101036126B1 KR 1020087030164 A KR1020087030164 A KR 1020087030164A KR 20087030164 A KR20087030164 A KR 20087030164A KR 101036126 B1 KR101036126 B1 KR 101036126B1
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파멜라 탄
비르기트 브람라게
마리아 프랭크-카메네츠키
케빈 피츠제럴드
애킨 애킹크
빅터 이. 코텔리안스키
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Abstract

본 발명은 길이가 30개 뉴클레오타이드 미만, 일반적으로 길이가 19 내지 24개 뉴클레오타이드이고 PCSK9 유전자의 적어도 일부분에 대해 실질적으로 상보적인 뉴클레오타이드 서열을 갖는 안티센스 쇄를 포함하는, PCSK9 유전자(PCSK9 유전자)의 발현을 억제하기 위한 이본쇄 리보핵산(dsRNA)에 관한 것이다. 본 발명은 또한 당해 dsRNA와 약제학적으로 허용되는 담체를 포함하는 약제학적 조성물; 당해 약제학적 조성물을 사용하여 PCSK9 유전자 발현 및 PCSK9 유전자의 발현에 의해 유발되는 질환을 치료하는 방법에 관한 것이다.
Figure R1020087030164
PCSK9 유전자 발현 억제, 이본쇄 리보핵산(dsRNA), RNA 간섭(RNAi), 고지혈증, 고콜레스테롤혈증

Description

ＰＣＳＫ9 유전자의 발현을 억제하기 위한 조성물 및 방법{Compositions and methods for inhibiting expression of the PCSK9 gene}
관련 출원에 대한 상호참조
본 출원은 2006년 5월 11일자로 출원된 미국 가특허 출원 제60/799,458호; 2006년 6월 27일자로 출원된 미국 가특허 출원 제60/817,203호; 2006년 8월 25일자로 출원된 미국 가특허 출원 제60/840,089호; 2006년 10월 18일자로 출원된 미국 가특허 출원 제60/829,914호 및 2007년 2월 13일자로 출원된 미국 가특허 출원 제60/901,134호를 우선권으로 청구한다. 이들 모든 가특허 출원의 내용은 전문이 본원에서 참조로 인용된다.
본 발명은 이본쇄 리보핵산(dsRNA), 및 RNA 간섭을 매개하여 PCSK9 유전자의 발현을 억제하는데 있어서의 이의 용도 및 PCSK9을 하향 조절함에 의해 매개될 수 있는 병리학적 과정, 예를 들면, 고지혈증을 치료하기 위한 dsRNA의 용도에 관한 것이다.
프로단백질 컨버타제 서브틸리신 켁신 9(Proprotein Convertase Subtilisin Kexin 9; PCSK9)은 서브틸리신 세린 프로테아제 계열의 구성원이다. 다른 8종의 포유동물 서브틸리신 프로테아제, PCSK1 내지 PCSK8 (PC1/3, PC2, 푸린, PC4, PC5/6, PACE4, PC7 및 S1P/SKI-1로도 지칭됨)은 분비 경로에서 광범위한 단백질을 프로세싱하고 다양한 생물학적 과정에 관여하는 프로단백질 컨버타제이다[참조: Bergeron, F. (2000) J. Mol. Endocrinol. 24, 122, Gensberg, K., (1998) Semin. Cell Dev. Biol. 9, 1117, Seidah, N. G. (1999) Brain Res. 848, 4562, Taylor, N. A., (2003) FASEB J. 17, 1215-1227, 및 Zhou, A., (1999) J. Biol . Chem . 274, 20745-20748]. PCSK9는 콜레스테롤 대사작용에 관여하는 것으로 제안되었다. PCSK9 mRNA 발현은 마우스에서 식이 콜레스테롤 공급에 의해 햐향 조절되고[참조: Maxwell, K. N., (2003) J. Lipid Res . 44, 2109-2119], HepG2 세포에서 스타틴에 의해 상향 조절되고[참조: Dubuc, G., (2004) Arterioscler . Thromb . Vasc . Biol . 24, 1454-1459], 콜레스테롤 생합성 효소 및 저밀도 지단백질 수용체(LDLR)와 유사하게 스테롤 조절성 요소 결합 단백질(SREBP) 유전자이식된(transgenic) 마우스에서 상향 조절된다[참조: Horton, J. D., (2003) Proc . Natl . Acad . Sci . USA 100, 12027-12032]. 또한, PCSK9 미스센스(missense) 돌연변이는 상염색체 우성 고콜레스테롤혈증(Hchola3)과 관련된 것으로 확인되었다[참조: Abifadel, M., et al . (2003) Nat . Genet . 34, 154-156, Timms, K. M., (2004) Hum . Genet . 114, 349-353, Leren, T. P. (2004) Clin . Genet . 65, 419-422]. PCSK9는 또한, 단일 뉴클레오타이드 다형성(Single-Nucleotide Polymorphism; SNP)이 일본인 집단의 콜레스 테롤 수준과 관련되었기 때문에 총인구의 LDL 콜레스테롤 수준을 결정하는데도 관여할 수 있는 것으로 확인되었다[참조: Shioji, K., (2004) J. Hum . Genet . 49, 109-114].
상염색체 우성 고콜레스테롤혈증(ADH)은 환자가 상승된 전체 및 LDL 콜레스테롤 수준, 건 황색종 및 조기 아테롬성동맥경화증을 나타내는 단일유전자 질환이다[참조: Rader, D. J., (2003) J. Clin. Invest. 111, 1795-1803]. ADH 및 열성형, 상염색체 열성 고콜레스테롤혈증(ARH)의 발병기전[참조: Cohen, J. C., (2003) Curr. Opin. Lipidol. 14, 121-127]은 간에 의한 LDL 흡수의 결함에 기인한다. ADH는 LDL 흡수를 방지하는 LDLR 돌연변이에 의해 유발되거나 LDLR에 결합하는, LDL상의 단백질인 아포지단백질 B내의 돌연변이에 의해 유발될 수 있다. ARH는 클라트린과의 상호작용을 통한 LDLR-LDL 복합체의 세포내이입작용(endocytosis)에 필수적인 ARH 단백질내의 돌연변이에 의해 유발된다. 그러므로, PCSK9 돌연변이가 Hchola3 계열의 원인인 경우, PCSK9는 수용체-매개된 LDL 흡수와 관련이 있는 것으로 보인다.
과발현 연구는 LDLR 수준 및 이에 따른 간에 의한 LDL 흡수를 조절하는데 있어 PCSK9의 역할을 지적한다[참조: Maxwell, K. N. (2004) Proc. Natl. Acad. Sci. USA 101, 7100-7105, Benjannet, S., et al . (2004) J. Biol . Chem . 279, 48865-48875, Park, S. W., (2004) J. Biol . Chem . 279, 50630-50638]. 마우스에서 3일 또는 4일 동안의 마우스 또는 사람 PCSK9의 아데노바이러스-매개 과발현은 전체 및 LDL 콜레스테롤 수준을 상승시켰고, 이러한 효과는 LDLR 녹아웃(knockout) 동물에 서는 나타나지 않는다[참조: Maxwell, K. N. (2004) Proc . Natl . Acad . Sci . USA 101, 7100-7105, Benjannet, S., et al . (2004) J. Biol . Chem . 279, 48865-48875, Park, S. W., (2004) J. Biol . Chem . 279, 50630-50638]. 또한, PCSK9 과발현은 LDLR mRNA 수준, SREBP 단백질 수준 또는 SREBP 단백질 핵 대 세포질 비율에 영향을 주지 않으면서 간의 LDLR 단백질의 심각한 감소를 초래한다. 이러한 결과들은 PCSK9가 직접적이든 또는 간접적이든 전사후 기전에 의해 LDLR 단백질 수준을 감소시킴을 나타낸다.
PCSK9의 기능 상실 돌연변이가 마우스 모델에서 고안되었고[참조; Rashid et.al., (2005) PNAS, 102, 5374-5379], 사람 개체에서 동정되었다[참조: Cohen et al., (2005), Nature Genetics., 37, 161-165]. 두 경우 모두에서 PCSK9 기능의 상실은 전체 및 LDLc 콜레스테롤의 저하를 유도한다. 15년에 걸친 후향 결과 연구에서, PCSK9의 1개 카피의 상실은 LDLc를 보다 저하시키고 심혈관 질환의 발병으로부터의 위험-이익 보호를 증가시키는 것으로 나타났다[참조: Cohen et.al., 2006 N. Engl. J. Med., 354., 1264-1272.]. 명백하게, 현재까지의 데이터는 PCSK9의 저하가 LDLc를 저하시킬 수 있음을 나타낸다.
최근, 이본쇄 RNA 분자(dsRNA)는 RNA 간섭(RNAi)으로서 알려진 고도로 보존된 조절 기전으로 유전자 발현을 차단하는 것으로 나타났다. 국제 공개공보 제WO 99/32619호(Fire 등)에는 씨.엘레간스(C. elegans)에서 유전자 발현을 억제하기 위한, 길이가 25개 뉴클레오타이드 이상인 dsRNA의 용도가 개시되어 있다. dsRNA는 또한 식물[참조: WO 99/53050, Waterhouse et al.; 및 WO 99/61631, Heifetz et al.], 드로소필라(Drosophila)[참조: Yang, D., et al., Curr. Biol. (2000) 10:1191-1200] 및 포유동물[참조: WO 00/44895, Limmer; 및 DE 101 00 586.5, Kreutzer et al.]을 포함하는 기타 유기체에서 표적 RNA를 분해시키는 것으로 나타났다. 이러한 천연 기전은 현재 유전자의 비정상적 또는 원치않는 조절에 의해 유발되는 장애를 치료하기 위한 신규 약제 부류의 개발을 위한 초점이 되고 있다.
RNAi 분야의 상당한 진보와 PCSK9 유전자 발현을 하향 조절함에 의해 매개될 수 있는 병리학적 과정의 치료에서의 진보에도 불구하고, PCSK9 유전자 발현을 억제할 수 있고 고지혈증과 같은 PCSK9 유전자 발현과 관련된 질환을 치료할 수 있는 제제가 여전히 요구되고 있다.
발명의 개요
본 발명은 PCSK9 발현을 사일런싱(silencing)시키는 이본쇄 리보핵산(dsRNA)을 사용함으로써, 프로단백질 컨버타제 서브틸리신 켁신 9(PCSK9)을 하향 조절함에 의해 조정될 수 있는 질환을 치료하기 위한 과제에 대한 해결책을 제공한다.
본 발명은 이본쇄 리보핵산(dsRNA) 뿐만 아니라 이러한 dsRNA를 사용하여 세포 또는 포유동물에서의 PCSK9 유전자 발현을 억제하기 위한 조성물 및 방법을 제공한다. 또한, 본 발명은 PCSK9 유전자의 발현을 하향 조절함에 의해 조정될 수 있는 병리학적 상태, 예를 들면, 고지혈증을 치료하기 위한 조성물 및 방법을 제공한다. 본 발명의 dsRNA는 길이가 30개 뉴클레오타이드 미만, 일반적으로 길이가 19 내지 24개 뉴클레오타이드이고 PCSK9 유전자의 mRNA 전사체의 적어도 일부분에 대해 실질적으로 상보적인 영역을 갖는 RNA 쇄(안티센스 쇄)를 포함한다.
하나의 양태에서, 본 발명은 PCSK9 유전자의 발현을 억제하기 위한 이본쇄 리보핵산(dsRNA) 분자를 제공한다. 당해 dsRNA는 서로 상보적인 2개 이상의 서열을 포함한다. 당해 dsRNA는 제1 서열을 포함하는 센스 쇄와 제2 서열을 포함하는 안티센스 쇄를 포함한다. 안티센스 쇄는 PCSK9를 암호화하는 mRNA의 적어도 일부분에 대해 실질적으로 상보적인 뉴클레오타이드 서열을 포함하고, 상보성 영역은 길이가 30개 뉴클레오타이드 미만, 일반적으로 길이가 19 내지 24개 뉴클레오타이드이다. 당해 dsRNA는, PCSK9를 발현하는 세포와 접촉시, PCSK9 유전자의 발현을 40% 이상 억제한다.
예를 들면, 본 발명의 dsRNA 분자는 표 1 및 표 2의 센스 서열로 이루어진 그룹으로부터 선택되는 dsRNA의 제1 서열과 표 1 및 표 2의 안티센스 서열로 이루어진 그룹으로부터 선택되는 제2 서열로 이루어질 수 있다. 본 발명의 dsRNA 분자는 천연 뉴클레오타이드로 이루어질 수 있거나 하나 이상의 변형된 뉴클레오타이드, 예를 들면, 2'-O-메틸 변형된 뉴클레오타이드, 5'-포스포로티오에이트 그룹을 포함하는 뉴클레오타이드, 및 콜레스테릴 유도체에 연결된 말단 뉴클레오타이드로 이루어질 수 있다. 대안으로, 변형된 뉴클레오타이드는 2'-데옥시-2'-플루오로 변형된 뉴클레오타이드, 2'-데옥시-변형된 뉴클레오타이드, 록트(locked) 뉴클레오타이드, 무염기(abasic) 뉴클레오타이드, 2'-아미노-변형된 뉴클레오타이드, 2'-알킬-변형된 뉴클레오타이드, 모르폴리노 뉴클레오타이드, 포스포르아미데이트 및 비-천연 염기 포함 뉴클레오타이드의 그룹으로부터 선택될 수 있다. 일반적으로, 이 러한 변형된 서열은 표 1 및 표 2의 센스 서열로 이루어진 그룹으로부터 선택된 상기 dsRNA의 제1 서열과 표 1 및 표 2의 안티센스 서열로 이루어진 그룹으로부터 선택된 제2 서열에 기초할 수 있다.
다른 양태에서, 본 발명은 본 발명의 dsRNA 중 하나 이상을 포함하는 세포를 제공한다. 당해 세포는 일반적으로 사람 세포와 같은 포유동물 세포이다.
다른 양태에서, 본 발명은 본 발명의 dsRNA 하나 이상과 약제학적으로 허용되는 담체 또는 전달 비히클을 포함하는, 유기체, 일반적으로 사람 피험체에서 PCSK9 유전자의 발현을 억제하기 위한 약제학적 조성물을 제공한다.
다른 양태에서, 본 발명은 다음의 단계들을 포함하여, 세포에서 PCSK9 유전자의 발현을 억제하기 위한 방법을 제공한다:
(a) 서로 상보적인 2개 이상의 서열을 포함하는 이본쇄 리보핵산(dsRNA)을 세포 내로 도입하는 단계. 당해 dsRNA는 제1 서열을 포함하는 센스 쇄와 제2 서열을 포함하는 안티센스 쇄를 포함한다. 안티센스 쇄는 PCSK9를 암호화는 mRNA의 적어도 일부분에 대해 실질적으로 상보적인 상보성 영역을 포함하고, 당해 상보성 영역은 길이가 30개 뉴클레오타이드 미만, 일반적으로 길이가 19 내지 24개 뉴클레오타이드이며, 당해 dsRNA는, PCSK9를 발현하는 세포와 접촉시, PCSK9 유전자의 발현을 40% 이상 억제한다.
(b) 상기 단계(a)에서 생성된 세포를 PCSK9 유전자의 mRNA 전사체가 분해되는데 충분한 시간 동안 유지시켜, 당해 세포에서의 PCSK9 유전자의 발현을 억제하는 단계.
다른 양태에서, 본 발명은 PCSK9 유전자 발현을 하향 조절함에 의해 매개될 수 있는 병리학적 과정, 예를 들면, 고지혈증의 치료, 예방 또는 관리가 필요한 환자에게 본 발명의 하나 이상의 dsRNA의 치료학적 또는 예방학적 유효량을 투여함을 포함하여, 당해 병리학적 과정을 치료, 예방 또는 관리하는 방법을 제공한다.
다른 양태에서, 본 발명은 본 발명의 dsRNA 중 하나의 하나 이상의 쇄를 암호화하는 뉴클레오타이드 서열에 작동가능하게 연결된 조절 서열을 포함하는, 세포에서의 PCSK9 유전자의 발현을 억제하기 위한 벡터를 제공한다.
다른 양태에서, 본 발명은 세포에서의 PCSK9 유전자의 발현을 억제하기 위한 벡터를 포함하는 세포를 제공한다. 당해 벡터는 본 발명의 dsRNA 중 하나의 하나 이상의 쇄를 암호화하는 뉴클레오타이드 서열에 작동가능하게 연결된 조절 서열을 포함한다.
도 1은 ND-98 지질의 구조를 도시한 것이다.
도 2는 C57/BL6 마우스(5마리 동물/그룹)에서 PCSK9 mRNA의 상이한 ORF 영역(그래프에 표시된 ORF 위치에 상응하는 제1 뉴클레오타이드를 가짐)에 대해 지시된 16개의 마우스 특이적(AL-DP-9327 내지 AL-DP-9342) PCSK9 siRNA의 생체내 스크리닝의 결과를 도시한 것이다. 간 용해물 중의 GAPDH mRNA에 대한 PCSK9 mRNA의 비를 각 처리군에 걸쳐서 평균치를 구하고, PBS로 처리된 대조군 또는 비관련 siRNA(혈액 응고 인자 VII)로 처리된 대조군과 비교하였다.
도 3은 C57/BL6 마우스(5마리 동물/그룹)에서 PCSK9 mRNA의 상이한 ORF 영역(그래프에 표시된 ORF 위치에 상응하는 제1 뉴클레오타이드를 가짐)에 대해 지시된 16개의 사람/마우스/랫트 교차반응성 PCSK9 siRNA(AL-DP-9311 내지 AL-DP-9326)의 생체내 스크리닝의 결과를 도시한 것이다. 간 용해물 중의 GAPDH mRNA에 대한 PCSK9 mRNA의 비를 각 처리군에 걸쳐서 평균치를 구하고, PBS로 처리된 대조군 또는 비관련 siRNA(혈액 응고 인자 VII)로 처리된 대조군과 비교하였다.
PCSK9 mRNA의 사일런싱은 총 혈청 콜레스테롤 수준을 저하시켰다.
PCSK9 메시지를 녹다운시키는데 있어 가장 효과가 있는 siRNA는 가장 현저한 콜레스테롤 저하 효과(대략 20 내지 30%)를 나타냈다.
도 4는 C57/BL6 마우스(5마리 동물/그룹)에서 16개의 마우스 특이적 PCSK9 siRNA(AL-DP-9327 내지 AL-DP-9342)의 생체내 스크리닝의 결과를 도시한 것이다. 총 혈청 콜레스테롤 수준을 각 처리군에 걸쳐서 평균치를 구하고, PBS로 처리된 대조군 또는 비관련 siRNA(혈액 응고 인자 VII)로 처리된 대조군과 비교하였다.
도 5는 C57/BL6 마우스(5마리 동물/그룹)에서 16개의 사람/마우스/랫트 교차반응성 PCSK9 siRNA(AL-DP-9311 내지 AL-DP-9326)의 생체내 스크리닝의 결과를 도시한 것이다. 총 혈청 콜레스테롤 수준을 각 처리군에 걸쳐서 평균치를 구하고, PBS로 처리된 대조군 또는 비관련 siRNA(혈액 응고 인자 VII)로 처리된 대조군과 비교하였다.
도 6은 PCSK9의 사일런싱에 대한 시험관내 결과와 생체내 결과의 비교를 도시한 것이다.
도 7A 및 도 7B는 원숭이 1차 간세포를 사용하였을 때의 PCSK9의 사일런싱에 대한 시험관내 결과를 도시한 것이다.
도 8은 LNP-01 제형화된 siRNA의 pcsk-9에 대한 생체내 활성을 도시한 것이다.
도 9는 상이한 시간에서 LNP-01 제형화된 화학적으로 변형된 9314 및 10792 모(母) 분자의 생체내 활성을 도시한 것이다. 명백히, 10792의 변형된 버젼은 생체내 사일런싱 활성을 나타낸다.
본 발명은 PCSK9 유전자를 사일런싱시키는 이본쇄 리보핵산(dsRNA)를 사용하여 고지혈증과 같은 질환에 대한 치료법을 제공함으로써, PCSK9의 하향 조절에 의해 조정될 수 있는 질환을 치료하고자 하는 과제에 대한 해결책을 제공한다.
본 발명은 이본쇄 리보핵산(dsRNA) 뿐만 아니라 이러한 dsRNA를 사용하여 세포 또는 포유동물에서의 CSK9 유전자 발현을 억제하기 위한 조성물 및 방법을 제공한다. 또한, 본 발명은 PCSK9 유전자의 발현을 하향 조절함에 의해 조정될 수 있는 병리학적 상태 및 질환을 치료하기 위한 조성물 및 방법을 제공한다. dsRNA는 RNA 간섭(RNAi)으로서 공지된 과정을 통해서 mRNA의 서열-특이적 분해를 지시한다.
본 발명의 dsRNA는 길이가 30개 뉴클레오타이드 미만, 일반적으로 길이가 19 내지 24개 뉴클레오타이드이고 PCSK9 유전자의 mRNA 전사체의 적어도 일부분에 대해 실질적으로 상보적인 영역을 갖는 RNA 쇄(안티센스 쇄)를 포함한다. 이러한 dsRNA를 사용하여 나트륨 수송에 관여하는 mRNA의 표적화된 분해를 가능케할 수 있다. 세포-기반 분석법 및 동물 분석법을 사용하여, 본 발명의 발명자들은 이들 dsRNA의 매우 적은 용량이 RNAi를 특이적이고 효율적으로 매개하여 PCSK9 유전자 발현의 현저한 억제를 초래할 수 있음을 입증하였다. 따라서, 이들 dsRNA를 포함하는 본 발명의 방법 및 조성물은 PCSK9를 하향 조절함에 의해 매개될 수 있는 병리학적 과정의 치료, 예를 들면, 고지혈증의 치료에서 유용하다.
다음의 상세한 설명은 표적 PCSK9 유전자의 발현을 억제하는 dsRNA, 및 dsRNA를 함유하는 조성물을 제조하고 사용하는 방법 뿐만 아니라 PCSK9의 발현을 하향 조절함에 의해 조정될 수 있는 질환, 예를 들면, 고지혈증을 치료하기 위한 조성물 및 방법을 기술한다. 본 발명의 약제학적 조성물은 길이가 30개 뉴클레오타이드 미만, 일반적으로 길이가 19 내지 24개 뉴클레오타이드이고 PCSK9 유전자의 RNA 전사체의 적어도 일부분에 대해 실질적으로 상보적인 상보성 영역을 포함하는 안티센스 쇄를 갖는 dsRNA와 함께 약제학적으로 허용되는 담체를 포함한다.
따라서, 본 발명의 특정 측면은 본 발명의 dsRNA와 함께 약제학적으로 허용되는 담체를 포함하는 약제학적 조성물, 당해 조성물을 사용하여 PCSK9 유전자의 발현을 억제하는 방법 및 PCSK9 유전자의 발현을 하향 조절함에 의해 조정될 수 있는 질환을 치료하기 위한 약제학적 조성물의 사용 방법을 제공한다.
I. 정의
편의상, 본원 명세서, 실시예 및 첨부된 청구의 범위에서 사용되는 특정 용어와 어구의 의미를 하기 제공한다. 본원 명세서의 다른 부분의 용어의 용법과 본 단락에 제공된 정의 간에 명백한 차이가 있다면, 본 단락의 정의가 우선한다.
"G," "C," "A" 및 "U"는 각각 일반적으로 염기로서 구아닌, 시토신, 아데닌 및 우라실을 각각 함유하는 뉴클레오타이드를 나타낸다. 그러나, "리보뉴클레오타이드" 또는 "뉴클레오타이드"란 용어는 하기에서 추가로 설명하는 바와 같이 변형된 뉴클레오타이드 또는 대용 치환 잔기를 지칭할 수도 있다. 당업자라면 구아닌, 시토신, 아데닌 및 우라실이 이러한 치환 잔기를 보유하는 뉴클레오타이드를 포함하는 올리고뉴클레오타이드의 염기쌍 형성 특성을 실질적으로 변경하지 않으면서 다른 잔기로 치환될 수 있음을 잘 인지하고 있다. 예를 들면, 제한 없이, 이의 염기로서 이노신을 포함하는 뉴클레오타이드는 아데닌, 시토신 또는 우라실을 함유하는 뉴클레오타이드와 염기 쌍을 형성할 수 있다. 따라서, 우라실, 구아닌, 시토신 또는 아데닌을 함유하는 뉴클레오타이드는 본 발명의 뉴클레오타이드 서열내에서 예를 들면 이노신을 함유하는 뉴클레오타이드로 치환될 수 있다. 이러한 치환 잔기를 포함하는 서열은 본 발명의 양태이다.
본원에서 사용되는 바와 같이, "PCSK9"는 프로단백질 컨버타제 서브틸리신 켁신 9 유전자 또는 단백질(FH3, HCHOLA3, NARC-1, NARC1로도 공지됨)을 지칭한다. PCSK9에 대한 mRNA 서열은 사람: NM_174936; 마우스: NM_153565 및 랫트: NM_199253으로서 제공된다.
본원에서 사용되는 바와 같이, "표적 서열"은 1차 전사 생성물의 RNA 프로세싱 산물인 mRNA를 포함하여 PCSK9 유전자의 전사 동안 형성된 mRNA 분자의 뉴클레오타이드 서열의 연속적 부분을 지칭한다.
본원에서 사용되는 바와 같이, "서열을 포함하는 쇄"란 용어는 표준 뉴클레오타이드 명명법을 사용하여 언급되는 서열로서 기술되는 뉴클레오타이드의 쇄를 포함하는 올리고뉴클레오타이드를 지칭한다.
본원에서 사용되는 바와 같이, 달리 나타내지 않는 한, "상보적"이란 용어는 제1 뉴클레오타이드 서열을 제2 뉴클레오타이드 서열과 비교하여 기술하기 위해 사용되는 경우에, 당업자가 이해할 수 있는 바와 같이, 특정 조건하에 제2 뉴클레오타이드 서열을 포함하는 올리고뉴클레오타이드 또는 폴리뉴클레오타이드와 하이브리드화하여 듀플렉스(duplex) 구조를 형성할 수 있는 제1 뉴클레오타이드 서열을 포함하는 올리고뉴클레오타이드 또는 폴리뉴클레오타이드의 능력을 지칭한다. 이러한 조건은 예를 들면, 엄중한 조건(stringent condition)일 수 있으며, 여기서 엄중한 조건은 50℃ 또는 70℃에서 12시간 내지 16시간 동안 400 mM NaCl, 40 mM PIPES pH 6.4, 1 mM EDTA에 뒤이은 세척을 포함할 수 있다. 유기체 내부에서 직면할 수 있는 생리학적으로 관련된 조건과 같은 다른 조건이 적용될 수 있다. 당업자는 하이브리드화된 뉴클레오타이드의 궁극적 적용에 따라서 두 서열의 상보성 시험에 가장 적절한 조건의 세트를 결정할 수 있을 것이다.
이는 제1 및 제2 뉴클레오타이드 서열의 전체 길이에 걸친, 제2 뉴클레오타이드 서열을 포함하는 올리고뉴클레오타이드 또는 폴리뉴클레오타이드에 대한 제1 뉴클레오타이드 서열을 포함하는 올리고뉴클레오타이드 또는 폴리뉴클레오타이드의 염기쌍 형성을 포함한다. 이러한 서열들은 본원에서 서로에 대해 "완전히 상보적인" 것으로 언급될 수 있다. 그러나, 제1 서열이 본원에서 제2 서열에 대해서 "실질적으로 상보적인" 것으로 언급되는 경우에, 2개의 서열은 완전히 상보적일 수 있거나, 하이브리드화시 이들의 궁극적 적용과 가장 관련된 조건하에 하이브리드화하는 능력을 유지하면서 하나 이상, 그러나 일반적으로 4개, 3개 또는 2개 이하의 미스매치(mismatch)된 염기 쌍을 형성할 수 있다. 그러나, 2개의 올리고뉴클레오타이드를 하이브리드화시 하나 이상의 일본쇄 오버행(overhang)을 형성하도록 고안한 경우, 이러한 오버행은 상보성 결정과 관련하여 미스매치로서 간주되지 않아야 한다. 예를 들면, 길이가 21개 뉴클레오타이드인 하나의 올리고뉴클레오타이드와 길이가 23개 뉴클레오타이드인 다른 올리고뉴클레오타이드를 포함하고, 보다 긴 올리고뉴클레오타이드가 보다 짧은 올리고뉴클레오타이드와 완전히 상보적인 21개 뉴클레오타이드의 서열을 포함하는 dsRNA는 본 발명의 목적상 여전히 "완전히 상보적인" 것으로서 언급될 수 있다.
본원에서 사용되는 바와 같이, "상보적" 서열은, 하이브리드화하는 능력과 관련하여 상기한 요건이 충족되는 한, 비-왓슨-크릭 염기 쌍 및/또는 비-천연 및 변형된 뉴클레오타이드로부터 형성된 염기 쌍을 또한 포함할 수 있거나 전적으로 이러한 염기 쌍으로부터만 형성될 수 있다.
본원에서 "상보적인", "완전히 상보적인" 및 "실질적으로 상보적인"이란 용어는 이의 사용 범주로부터 이해될 수 있는 바와 같이 dsRNA의 센스 쇄와 안티센스 쇄 사이 또는 dsRNA의 안티센스 쇄와 표적 서열 사이의 염기 매칭과 관련하여 사용될 수 있다.
본원에서 사용되는 바와 같이, 메신저 RNA(mRNA)의 적어도 일부분과 "실질적으로 상보적인" 폴리뉴클레오타이드는 관심대상의 mRNA(예를 들면, PCSK9를 암호화하는 mRNA)의 연속적 부분과 실질적으로 상보적인 폴리뉴클레오타이드를 지칭한다. 예를 들면, 폴리뉴클레오타이드는 당해 서열이 PCSK9를 암호화하는 mRNA의 비-방해된 부분에 대해 실질적으로 상보적인 경우에 PCSK9 mRNA의 적어도 일부분에 대해 상보적이다.
"이본쇄 RNA" 또는 "dsRNA"란 용어는, 본원에서 사용되는 바와 같이, 상기 정의한 바와 같은 실질적으로 상보적인 2개의 역평행 핵산 쇄를 포함하는 듀플렉스 구조를 갖는 리보핵산 분자의 복합체를 지칭한다. 이러한 듀플렉스 구조를 형성하는 2개의 쇄는 하나의 큰 RNA 분자의 서로 다른 부분일 수 있거나, 별개의 RNA 분자일 수 있다. 별개의 RNA 분자인 경우, 이러한 dsRNA는 문헌에서 흔히 siRNA("짧은 간섭 RNA")로서 지칭된다. 2개의 쇄가 하나의 큰 분자의 일부분이고 따라서 듀플렉스 구조를 형성하는 하나의 쇄의 3'-말단과 각각의 다른 쇄의 5'-말단 사이에서 연속된 뉴클레오타이드 사슬에 의해 연결되어 있는 경우, 이러한 연결 RNA 사슬은 "헤어핀 루프(hairpin loop)", "짧은 헤어핀 RNA" 또는 "shRNA"로서 지칭된다. 2개의 쇄가 하나의 쇄의 3'-말단과 각각의 다른 쇄의 5'-말단 사이에서 연속된 뉴클레오타이드 사슬 이외의 수단에 의해 공유 연결되어 듀플렉스 구조를 형성하는 경우, 이러한 연결 구조는 "링커"로서 지칭된다. RNA 쇄는 동일하거나 상이한 개수의 뉴클레오타이드를 가질 수 있다. 염기쌍의 최대 개수는 dsRNA의 가장 짧은 쇄 중의 뉴클레오타이드의 개수에서 듀플렉스 중에 존재하는 임의의 오버행의 개수를 감산한 수이다. 듀플렉스 구조 이외에, dsRNA는 하나 이상의 뉴클레오타이드 오버행을 포함할 수 있다. 또한, 본원 명세서에서 사용되는 바와 같이, "dsRNA"는 다수의 뉴클레오타이드에서의 실질적 변형 및 본원에 기술되거나 당업계에 공지된 모든 종류의 변형을 포함하는 리보뉴클레오타이드에 대한 화학적 변형을 포함할 수 있다. siRNA 유형 분자에서 사용되는 바와 같이 이러한 임의의 변형은 본원 명세서 및 청구의 범위의 목적상 "dsRNA"에 포함된다.
본원에서 사용되는 바와 같이, "뉴클레오타이드 오버행"은 dsRNA의 1개 쇄의 3'-말단이 다른 쇄의 5'-말단 너머로 뻗어있거나 또는 그 반대의 경우에 dsRNA의 듀플렉스 구조로부터 돌출된, 쌍을 이루지 않은 뉴클레오타이드 또는 뉴클레오타이드들을 지칭한다. "평활한(blunt)" 또는 "평활 말단(blunt end)"은 dsRNA의 말단에 쌍을 이루지 않은 뉴클레오타이드가 없음, 즉 뉴클레오타이드 오버행이 없음을 의미한다. "평활 말단" dsRNA는 이의 전체 길이에 걸쳐서 이본쇄인, 즉 분자의 전체 말단에 뉴클레오타이드 오버행이 없는 dsRNA이다. 명확성을 위해, siRNA의 3' 말단 또는 5' 말단에 접합된 화학적 캡 또는 비-뉴클레오타이드 화학적 잔기는 siRNA가 오버행을 갖는지 또는 평활 말단인지를 결정하는데 있어 고려되지 않는다.
"안티센스 쇄"란 용어는 표적 서열에 대해 실질적으로 상보적인 영역을 포함하는 dsRNA의 쇄를 지칭한다. 본원에서 사용되는 바와 같이, "상보성 영역"이란 용어는 서열, 예를 들면, 본원에서 정의한 바와 같은 표적 서열에 대해 실질적으로 상보적인 안티센스 쇄 상의 영역을 지칭한다. 상보성 영역이 표적 서열에 대해 완전히 상보적이지 않은 경우, 미스매치는 말단 영역에서 가장 많이 허용되며, 존재하는 경우, 일반적으로 말단 영역 또는 예를 들면, 5' 및/또는 3' 말단의 6, 5, 4, 3 또는 2개 뉴클레오타이드 내의 영역에 있다.
본원에서 사용되는 바와 같이, "센스 쇄"란 용어는 안티센스 쇄의 영역에 대해 실질적으로 상보적인 영역을 포함하는 dsRNA의 쇄를 지칭한다.
"세포 내로의 도입"은 dsRNA를 지칭하는 경우에, 당업자가 이해하는 바와 같이 세포 내로의 섭취 또는 흡수를 용이하게 함을 의미한다. dsRNA의 흡수 또는 섭취는 자발적인 확산성 또는 능동적인 세포 과정을 통해 또는 보조 제제 또는 장치에 의해 일어날 수 있다. 당해 용어의 의미는 시험관내 세포로 제한되는 것은 아니며, dsRNA는 살아있는 유기체의 일부분인 "세포 내로 도입"될 수도 있다. 이러한 경우에, 세포 내로의 도입은 유기체로의 전달을 포함할 수 있다. 예를 들면, 시험관내 전달을 위해, dsRNA는 조직 부위로 주사될 수 있거나 전신 투여될 수 있다. 세포 내로의 시험관내 도입은 전기천공 및 리포펙션(lipofection)과 같은 당업계에 공지된 방법을 포함한다.
"사일런싱시키다" 또는 "~의 발현을 억제하다"란 용어는, 본원에서 이들 용어가 PCSK9 유전자를 지칭하는 한, PCSK9 유전자가 전사되고 PCSK9 유전자의 발현이 억제되도록 처리된 제1 세포 또는 세포 그룹으로부터 분리될 수 있는 PCSK9 유전자로부터 전사된 mRNA 양이 상기 제1 세포 세포 또는 세포 그룹과 실질적으로 동일하지만 이러한 처리를 받지 않은 제2 세포 또는 세포 그룹(대조군 세포)와 비교하여 감소된 것으로 나타나는 PCSK9 유전자의 발현의 적어도 부분적 억제를 지칭한다. 억제 정도는 일반적으로 다음 식으로 표현된다:
Figure 112008085095997-pct00001
대안으로, 억제 정도는 PCSK9 유전자 전사와 기능적으로 연관된 파라미터, 예를 들면, 세포에 의해 분비되는 PCSK9 유전자에 의해 암호화된 단백질의 양 또는 특정 표현형(예: 아폽토시스(apoptosis))을 나타내는 세포의 수의 감소로 표현될 수 있다. 원칙적으로, PCSK9 유전자 사일런싱은 표적을 구성적으로(constitutively) 발현하거나 게놈 조작(genomic engineering)에 의해 표적을 발현하는 어떠한 세포에서라도 어떠한 적절한 분석법에 의해서도 측정할 수 있다. 그러나, 소정의 dsRNA가 PCSK9 유전자의 발현을 어느 정도까지 억제하는지를 측정하기 위해 참조가 요구되고 따라서 이것이 본 발명에 포함되는 경우, 하기 실시예에 제공된 분석법이 이러한 참조가 될 것이다.
예를 들면, 특정 경우에 PCSK9 유전자의 발현은 본 발명의 이본쇄 올리고뉴클레오타이드의 투여에 의해 약 20%, 25%, 35% 또는 50% 이상 억제된다. 일부 양태에서, PCSK9 유전자는 본 발명의 이본쇄 올리고뉴클레오타이드의 투여에 의해 약 60%, 70% 또는 80% 이상 억제된다. 일부 양태에서, PCSK9 유전자는 이본쇄 올리고뉴클레오타이드의 투여에 의해 약 85%, 90% 또는 95% 이상 억제된다. 표 1 및 2는 다양한 농도에서 다양한 PCSK9 dsRNA 분자를 사용한 시험관내 분석법에서 수득된 발현의 억제에 대한 광범위한 값을 제공한다.
본원에서 사용되는 바와 같이 PCSK9 발현과 관련하여, "치료하다", "치료"란 용어 등은 PCSK9 유전자를 하향 조절함에 의해 매개될 수 있는 병리학적 과정의 경감 또는 완화를 지칭한다. 본 발명의 범주에서 하기에 언급된 다른 임의의 상태(PCSK9 유전자를 하향 조절함에 의해 매개될 수 있는 병리학적 과정이 아닌 과정)와 관련되는 한, "치료하다", "치료"란 용어 등은 이러한 상태와 연관된 하나 이상의 증상을 경감 또는 완화시키거나 이러한 상태의 진행을 늦추거나 역전시키는 것을 의미한다. 예를 들면, 고지혈증의 범주에서, 치료는 혈청 지질 수준의 감소와 관련될 것이다.
본원에서 사용되는 바와 같이, "치료학적 유효량" 및 "예방학적 유효량"이란 어구는 PCSK9 유전자를 하향 조절함에 의해 매개될 수 있는 병리학적 과정 또는 PCSK9 유전자를 하향 조절함에 의해 매개될 수 있는 병리학적 과정의 명백한 징후의 치료, 예방 또는 관리에 있어 치료학적 이익을 제공하는 양을 지칭한다. 치료학적으로 유효한 구체적 양은 의사에 의해 용이하게 결정될 수 있거나 당업계에 공지된 요인들, 예를 들면, PCSK9 유전자를 하향 조절함에 의해 매개될 수 있는 병리학적 과정의 종류, 환자의 병력 및 연령, PCSK9 유전자를 하향 조절함에 의해 매개될 수 있는 병리학적 과정의 병기 및 PCSK9 유전자 발현을 하향 조절함에 의해 매개될 수 있는 다른 항-병리학적 과정의 실시에 따라서 달라질 수 있다.
본원에서 사용되는 바와 같이, "약제학적 조성물"은 약리학적 유효량의 dsRNA와 약제학적으로 허용되는 담체를 포함한다. 본원에서 사용되는 바와 같이, "약리학적 유효량" "치료학적 유효량" 또는 단순히 "유효량"은 의도하는 약리학적, 치료학적 또는 예방학적 결과를 발생하기에 유효한 RNA의 양을 지칭한다. 예를 들면, 질환 또는 장애와 관련된 측정가능한 파라미터가 25% 이상 감소될 때에 소정의 임상적 치료가 유효한 것으로 고려된다면, 당해 질환 또는 장애 치료용 약물의 치료학적 유효량은 당해 파라미터의 25% 이상의 감소를 야기하는데 필요한 양이다.
"약제학적으로 허용되는 담체"란 용어는 치료제의 투여를 위한 담체를 지칭한다. 이러한 담체로는 염수, 완충 염수, 덱스트로오즈, 물, 글리세롤, 에탄올 및 이들의 배합물이 포함되나 이에 제한되는 것은 아니며, 하기에서 보다 상세히 기술된다. 당해 용어는 특별히 세포 배양 배지를 배제한다.
본원에서 사용되는 바와 같이, "형질전환된 세포"는 벡터가 도입되어 dsRNA 분자가 발현될 수 있는 세포이다.
II . 이본쇄 리보핵산 ( dsRNA )
하나의 양태에서, 본 발명은 PCSK9 유전자의 발현시에 형성된 mRNA의 적어도 일부분에 대해 상보적이고 길이가 30개 뉴클레오타이드 미만, 일반적으로 길이가 19 내지 24개 뉴클레오타이드인 상보성 영역을 포함하는 안티센스 쇄를 포함하고, 상기 PCSK9 유전자를 발현하는 세포와 접촉시, 상기 PCSK9 유전자의 발현을 40% 이상 억제하는, 세포 또는 포유동물에서 PCSK9 유전자의 발현을 억제하기 위한 이본쇄 리보핵산(dsRNA) 분자를 제공한다. 당해 dsRNA는 하이브리드화하여 듀플렉스 구조를 형성할 수 있을 정도로 충분히 상보적인 2개의 RNA 쇄를 포함한다. 당해 dsRNA의 하나의 쇄(안티센스 쇄)는 PCSK9 유전자의 발현 동안에 형성된 mRNA의 서열로부터 유래된 표적 서열에 대해 실질적으로 상보적인, 일반적으로는 완전히 상보적인 상보성 영역을 포함하고, 나머지 쇄(센스 쇄)는 당해 안티센스 쇄에 상보적인 영역을 포함하고, 이에 따라 상기 2개의 쇄는 적합한 조건하에 배합되는 경우에 하이브리드화하고 듀플렉스 구조를 형성한다. 일반적으로, 듀플렉스 구조는 길이가 15 내지 30개, 보다 일반적으로는 18개 내지 25개, 보다 더욱 일반적으로는 19 내지 24개, 가장 일반적으로는 19개 내지 21개의 염기 쌍이다. 마찬가지로, 표적 서열에 대한 상보성 영역은 길이가 15 내지 30개, 보다 일반적으로는 18개 내지 25개, 보다 더욱 일반적으로는 19개 내지 24개, 가장 일반적으로는 19개 내지 21개의 뉴클레오타이드이다. 본 발명의 dsRNA는 하나 이상의 일본쇄 뉴클레오타이드 오버행(들)을 추가로 포함할 수 있다. dsRNA는 하기에서 추가로 논의되는 바와 같이 당업게에 공지된 표준 방법, 예를 들면, 자동화 DNA 합성기(예를 들면, Biosearch, Applied Biosystems, Inc.로부터 시판)를 사용하여 합성할 수 있다. 바람직한 양태에서, PCSK9 유전자는 사람 PCSK9 유전자이다. 구체적 양태에서, dsRNA의 안티센스 쇄는 표 1 및 2의 센스 서열로부터 선택된 쇄 및 표 1 및 2의 안티센스 서열로 이루어진 그룹으로부터 선택된 제2 서열을 포함한다. 표 1 및 2에 제공된 표적 서열 내 어느 다른 곳을 표적화하는 대안적 안티센스 서열은 표적 서열 및 측면(flanking) PCSK9 서열을 사용하여 용이하게 결정될 수 있다.
추가의 양태에서, dsRNA는 표 1 및 2에 제공된 서열의 그룹으로부터 선택된 하나 이상의 뉴클레오타이드 서열을 포함한다. 다른 양태에서, dsRNA는 상기 그룹으로부터 선택된 적어도 2개의 서열을 포함하며, 이때 적어도 2개의 서열 중 하나는 적어도 2개의 서열 중 나머지 하나에 대해 상보적이며, 적어도 2개의 서열 중 하나는 PCSK9 유전자의 발현시에 생성된 mRNA의 서열에 대해 실질적으로 상보적이다. 일반적으로, dsRNA는 2개의 올리고뉴클레오타이드를 포함하며, 이때 하나의 올리고뉴클레오타이드는 표 1 및 2에서 센스 쇄로서 기술되며, 제2 올리고뉴클레오타이드는 표 1 및 2에서 안티센스 쇄로서 기술된다.
당업자는 20 내지 23개, 그러나 구체적으로는 21개의 염기쌍의 듀플렉스 구조를 포함하는 dsRNA가 RNA 간섭을 유도하는데 특히 효과적인 것으로 인식되었음을 잘 인지하고 있다[참조: Elbashir et al., EMBO 2001, 20:6877-6888]. 그러나, 다른 이들은 보다 짧거나 긴 dsRNA도 마찬가지로 효과적일 수 있음을 발견하였다. 상기한 양태에서, 표 1 및 2에 제공된 올리고뉴클레오타이드 서열의 성질 덕택에, 본 발명의 dsRNA는 길이가 최소 21nt인 하나 이상의 쇄를 포함할 수 있다. 표 1 및 2의 서열 중 하나를 포함하고 한쪽 또는 양쪽 말단에서 오직 수개의 뉴클레오타이드만이 없는 보다 짧은 dsRNA가 상기한 dsRNA와 비교해 유사하게 효과적일 수 있음이 합리적으로 예상될 수 있다. 따라서, 표 1 및 2의 서열 중 하나로부터의 적어도 15, 16, 17, 18, 19, 20개 이상의 연속적 뉴클레오타이드의 부분적 서열을 포함하고 PCSK9 유전자의 발현을 5, 10, 15, 20, 25 또는 30% 이하의 억제율로 낮게 억제하는 능력에 있어 전체 서열을 포함하는 dsRNA와 상이한 dsRNA가 본 발명에 의해 의도된다. 추가로, 표 1 및 2에 제공된 표적 서열 내부를 절단하는 dsRNA는 PCSK9 서열 및 제공된 표적 서열을 사용하여 용이하게 제조할 수 있다.
또한, 표 1 및 2에 제공된 RNAi 제제는 RNAi 기반 절단에 민감한 PCSK9 mRNA 내의 부위를 인식한다. 이와 같이 본 발명은 본 발명의 제제 중 하나에 의해 표적화되는 서열 내부를 표적화하는 RNAi 제제를 추가로 포함한다. 본원에서 사용되는 바와 같이 제2 RNAi 제제는 당해 제2 RNAi 제제가 제1 RNAi 제제의 안티센스 쇄에 대해 상보적인 mRNA 내의 어딘가에 있는 메시지라도 절단하는 경우에 제1 RNAi 제제의 서열 내부를 표적화한다고 언급된다. 이러한 제2 제제는 일반적으로 PCSK9 유전자 내의 선택된 서열에 인접한 영역으로부터 취해진 추가의 뉴클레오타이드 서열에 커플링된 표 1 및 2에 제공된 서열 중 하나로부터의 15개 이상의 연속적 뉴클레오타이드로 이루어질 수 있다. 예를 들면, 표적 PCSK9 유전자로부터의 그 다음 6개 뉴클레오타이드와 조합된 서열번호 1의 마지막 15개 뉴클레오타이드(부가된 AA 서열이 없음)는 표 1 및 2에 제공된 서열 중 하나에 기초하는 21개 뉴클레오타이드의 일본쇄 제제를 생성한다.
본 발명의 dsRNA는 표적 서열에 대한 하나 이상의 미스매치를 함유할 수 있다. 바람직한 양태에서, 본 발명의 dsRNA는 3개 이하의 미스매치를 함유한다. dsRNA의 안티센스 쇄가 표적 서열에 대한 미스매치를 함유하는 경우, 미스매치 부위가 상보성 영역의 중심에 위치하지 않는 것이 바람직하다. dsRNA의 안티센스 쇄가 표적 서열에 대한 미스매치를 함유하는 경우, 미스매치는 어느 한 말단으로부터의 5개 뉴클레오타이드, 예를 들면, 상보성 영역의 5' 또는 3' 말단으로부터의 5, 4, 3, 2 또는 1개의 뉴클레오타이드로 제한되는 것이 바람직하다. 예를 들면, PCSK9 유전자의 영역에 대해 상보적인 23개 뉴클레오타이드 dsRNA 쇄의 경우에, dsRNA는 중심의 13개 뉴클레오타이드 내에 어떠한 미스매치도 함유하지 않는다. 본 발명에서 기술되는 방법을 사용하여 표적 서열에 대한 미스매치를 함유하는 dsRNA가 PCSK9 유전자의 발현을 억제하는데 효과적인지를 결정할 수 있다. 특히 PCSK9 유전자 내의 특정 상보성 영역이 집단내에서 다형성 서열 변이를 갖는 것으로 공지되어 있는 경우에, PCSK9 유전자의 발현을 억제하는데 있어 미스매치를 함유하는 dsRNA의 효능을 고려하는 것이 중요하다.
하나의 양태에서, dsRNA의 하나 이상의 말단은 1 내지 4개, 일반적으로 1 또는 2개의 뉴클레오타이드의 일본쇄 뉴클레오타이드 오버행을 갖는다. 하나 이상의 뉴클레오타이드 오버행을 갖는 dsRNA는 이의 평활 말단 대상체보다 예상외의 우수한 억제 특성을 갖는다. 게다가, 본 발명자들은 오직 1개의 뉴클레오타이드 오버행의 존재가 dsRNA의 전반적 안정성에 영향을 주지 않으면서 dsRNA의 간섭 능력을 강화시킴을 발견하였다. 오직 1개의 오버행만을 갖는 dsRNA는 생체내 뿐만 아니라 다양한 세포, 세포 배양 배지, 혈액 및 혈청 중에서 특히 안정하고 효과적인 것으로 입증되었다. 일반적으로, 일본쇄 오버행은 안티센스 쇄의 3'-말단에 위치하거나, 또는 센스 쇄의 3'-말단에 위치한다. dsRNA는 또한 일반적으로 안티센스 쇄의 5'-말단에 위치하는 평활 말단을 가질 수도 있다. 이러한 dsRNA는 개선된 안정성 및 억제 활성을 가짐으로써 적은 용량, 즉 1일당 5mg/kg 체중 미만으로 투여할 수 있도록 한다. 일반적으로, dsRNA의 안티센스 쇄는 3'-말단에 뉴클레오타이드 오버행을 갖고 5'-말단은 평활 말단이다. 다른 양태에서, 오버행내의 하나 이상의 뉴클레오타이드는 뉴클레오사이드 티오포스페이트로 대체된다.
또 다른 양태에서, dsRNA는 안정성을 향상시키기 위해 화학적으로 변형된다. 본 발명의 핵산은 당업계에 익히 확립된 방법, 예를 들면, 문헌[참조: "Current protocols in nucleic acid chemistry", Beaucage, S.L. et al. (Edrs.), John Wiley & Sons, Inc., New York, NY, USA; 이는 본원에서 참조로 인용된다]에 기술된 방법에 의해 합성하고/하거나 변형시킬 수 있다. 화학적 변형은 2' 변형, 올리고뉴클레오타이드의 다른 당 또는 염기 부위에서의 변형, 올리고뉴클레오타이드 쇄 내로의 비-천연 염기의 도입, 리간드 또는 화학적 잔기에의 공유적 부착, 및 뉴클레오타이드내 포스페이트 연결의 티오포스페이트와 같은 다른 대안적 연결로의 대체를 포함할 수 있으나 이에 제한되는 것은 아니다. 이러한 변형 중 하나 이상이 사용될 수 있다.
2개의 개별적 dsRNA 쇄의 화학적 연결은 임의의 널리 공지된 기술, 예를 들면, 공유 결합, 이온 결합 또는 수소 결합의 도입; 소수성 상호작용, 반 데르 발스 상호작용 또는 적층 상호작용(stacking interaction); 금속-이온 배위에 의해 또는 푸린 유사체의 사용을 통해 달성할 수 있다. 일반적으로, dsRNA를 변형시키는데 사용될 수 있는 화학 그룹에는 제한없이, 메틸렌 블루; 이작용성 그룹, 일반적으로 비스-(2-클로로에틸)아민; N-아세틸-N'-(p-글리옥실벤조일)시스타민; 4-티오우라실; 및 프소랄렌이 포함된다. 하나의 양태에서, 링커는 헥사-에틸렌 글리콜 링커이다. 이러한 경우, dsRNA는 고체 상 합성에 의해 생성되며, 헥사-에틸렌 글리콜 링커는 표준 방법에 따라 혼입된다[참조: Williams, D.J., and K.B. Hall, Biochem. (1996) 35:14665-14670]. 특정한 양태에서, 안티센스 쇄의 5'-말단 및 센스 쇄의 3'-말단이 헥사에틸렌 글리콜 링커를 통해 화학적으로 연결된다. 다른 양태에서, dsRNA의 하나 이상의 뉴클레오타이드는 포스포로티오에이트 또는 포스포로디티오에이트 그룹을 포함한다. dsRNA에서의 화학 결합은 일반적으로 삼중-나선 결합에 의해 형성된다. 표 1 및 2는 본 발명의 변형된 RNAi 제제의 예를 제공한다.
또 다른 양태에서, 2개의 단일 쇄 중 하나 또는 둘다에 있는 뉴클레오타이드를 변형시켜, 예를 들면, 제한 없이 특정 뉴클레아제와 같은 세포 효소의 분해 활성을 방지 또는 억제할 수 있다. 2'-아미노 변형, 2'-아미노 당 변형, 2'-F 당 변형, 2'-F 변형, 2'-알킬 당 변형, 비하전 골격 변형, 모르폴리노 변형, 2'-O-메틸 변형 및 포스포르아미데이트를 포함하여 핵산에 대한 세포 효소의 분해 활성을 억제하기 위한 기술은 당업계에 공지되어 있다[참조: Wagner, Nat . Med. (1995) 1:1116-8]. 따라서, dsRNA 상의 뉴클레오타이드의 하나 이상의 2'-하이드록실 그룹은 화학 그룹, 일반적으로 2'-아미노 또는 2'-메틸 그룹으로 치환된다. 또한, 하나 이상의 뉴클레오타이드를 변형시켜 록트 뉴클레오타이드를 형성시킬 수 있다. 이러한 록트 뉴클레오타이드는 리보오스의 2'-산소를 리보오스의 4'-탄소와 연결시키는 메틸렌 브릿지를 함유한다. 록트 뉴클레오타이드를 함유하는 올리고뉴클레오타이드는 문헌[참조: Koshkin, A.A., et al., Tetrahedron (1998), 54: 3607-3630 및 Obika, S. et al., Tetrahedron Lett .(1998), 39: 5401-5404]에 기재되어 있다. 올리고뉴클레오타이드 내로의 록트 뉴클레오타이드의 도입은 상보적 서열에 대한 친화성을 개선시키고 융점을 몇도 정도 상승시킨다[참조: Braasch, D.A. and D.R. Corey, Chem . Biol . (2001), 8:1-7].
dsRNA에 대한 리간드의 접합은 세포 흡수 뿐만 아니라 특정 조직으로의 표적화 또는 간 세포와 같은 특정 유형의 세포에 의한 흡수를 향상시킬 수 있다. 특정한 경우에, 소수성 리간드를 dsRNA에 접합시켜 세포 막의 직접적 투과 또는 간 세포를 통과하는 흡수를 촉진시킨다. 대안으로, dsRNA에 접합된 리간드는 수용체-매개된 세포내이입작용에 대한 기질이다. 이러한 접근법은 안티센스 올리고뉴클레오타이드 뿐만 아니라 dsRNA 제제의 세포 투과를 촉진시키기 위해 사용되었다. 예를 들면, 콜레스테롤을 다양한 안티센스 올리고뉴클레오타이드에 접합시켜 비-접합된 유사체와 비교해 실질적으로 보다 활성적인 화합물을 수득하였다[참조: M. Manoharan Antisense & Nucleic Acid Drug Development 2002, 12, 103]. 올리고뉴클레오타이드에 접합된 다른 친지성 화합물에는 1-피렌 부티르산, 1,3-비스-O-(헥사데실)글리세롤 및 메탄올이 포함된다. 수용체-매개된 세포내이입작용에 대한 리간드의 한 예는 엽산이다. 엽산은 폴레이트-수용체-매개된 세포내이입작용에 의해 세포내로 진입한다. 엽산을 보유한 dsRNA 화합물은 폴레이트-수용체-매개된 세포내이입작용을 통해서 세포내로 효율적으로 수송될 수 있다. 리(Li)와 동료들은 올리고뉴클레오타이드의 3'-말단에 엽산이 부착되면 상기 올리고뉴클레오타이드의 세포성 흡수가 8배 증가함을 보고하고 있다[참조: Li, S.; Deshmukh, H. M.; Huang, L. Pharm. Res. 1998, 15, 1540]. 올리고뉴클레오타이드에 접합된 다른 리간드에는 폴리에틸렌 글리콜, 탄수화물 클러스터, 가교결합제, 포르피린 접합체, 전달 펩타이드 및 콜레스테롤과 같은 지질이 포함된다.
특정 경우에, 올리고뉴클레오타이드에 대한 양이온성 리간드의 접합은 뉴클레아제에 대한 내성을 개선시킨다. 양이온성 리간드의 대표적 예에는 프로필암모늄 및 디메틸프로필암모늄이 있다. 흥미롭게도, 안티센스 올리고뉴클레오타이드는 양이온성 리간드가 올리고뉴클레오타이드 전반에 분산되어 있는 경우에 mRNA에 대한 높은 결합 친화성을 유지하는 것으로 보고되었다[참조: M. Manoharan Antisense & Nucleic Acid Drug Development 2002, 12, 103 및 당해 문헌의 참조문헌].
본 발명의 리간드-접합된 dsRNA는 dsRNA 상으로의 연결 분자의 부착으로부터 유도된 것과 같은 펜던트(pendant) 반응성 작용기를 보유하는 dsRNA의 사용에 의해 합성할 수 있다. 이러한 반응성 올리고뉴클레오타이드는 시판되는 리간드, 다양한 보호 그룹 중 어느 하나를 보유하도록 합성된 리간드 또는 부착된 연결 잔기를 갖는 리간드와 쉽게 반응할 수 있다. 본 발명의 방법은 일부 바람직한 양태에서 리간드와 적절히 접합되었고 고체-지지체 물질에 추가로 부착될 수 있는 뉴클레오타이드 단량체의 사용에 의해 리간드-접합된 dsRNA의 합성을 촉진한다. 임의로 고체-지지체 물질에 부착된 이러한 리간드-뉴클레오사이드 접합체는 선택된 혈청-결합 리간드와 뉴클레오사이드 또는 올리고뉴클레오타이드의 5' 위치상에 위치하는 연결 잔기와의 반응을 통해서 본 발명의 방법의 일부 바람직한 양태에 따라서 제조된다. 특정 경우에, dsRNA의 3'-말단에 부착된 아르알킬 리간드를 보유하는 dsRNA는 먼저 단량체 빌딩 블록을 장쇄 아미노알킬 그룹을 통해서 제어된-기공-유리 지지체에 공유 부착시켜 제조한다. 이어서, 뉴클레오타이드를 표준 고체 상 합성 기술을 통해서 고체 지지체에 결합된 단량체 빌딩-블록에 결합시킨다. 단량체 빌딩 블록은 고체 상 합성과 상용성인 뉴클레오사이드 또는 기타 유기 화합물일 수 있다.
본 발명의 접합체에서 사용되는 dsRNA는 널리 공지된 고체-상 합성 기술을 통해서 편리하고 통상적으로 제조할 수 있다. 이러한 합성용 장치는 예를 들면, Applied Biosystems (Foster City, CA)를 포함하는 몇몇 판매사들에 의해 시판되고 있다. 당업계에 공지된 이러한 합성을 위한 임의의 기타 수단은 추가로 또는 대안적으로 사용할 수 있다. 또한, 유사한 기술을 사용하여 포스포로티오에이트 및 알킬화 유도체와 같은 기타 올리고뉴클레오타이드를 제조하는 것도 또한 공지되어 있다.
특정한 변형된 올리고뉴클레오타이드의 합성에 관한 기술은 다음 미국 특허에서 찾아볼 수 있다: 폴리아민 접합된 올리고뉴클레오타이드에 관한 미국 특허 제5,138,045호 및 제5,218,105호; 키랄 인 연결을 갖는 올리고뉴클레오타이드의 제조를 위한 단량체에 관한 미국 특허 제5,212,295호; 변형된 골격을 갖는 올리고뉴클레오타이드에 관한 미국 특허 제5,378,825호 및 제5,541,307호; 골격-변형된 올리고뉴클레오타이드 및 반응성 커플링을 통한 이의 제조에 관한 미국 특허 제5,386,023호; 3-데아자푸린 환 시스템에 기초한 변형된 뉴클레오염기 및 이의 합성방법에 미국 특허 제5,457,191호; N-2 치환된 푸린에 기초한 변형된 뉴클레오염기에 관한 미국 특허 제5,459,255호; 키랄 인 연결을 갖는 올리고뉴클레오타이드의 제조에 관한 미국 특허 제5,521,302호; 펩타이드 핵산에 관한 미국 특허 제5,539,082호; 락탐 골격을 갖는 올리고뉴클레오타이드에 관한 미국 특허 제5,554,746호; 올리고뉴클레오타이드의 합성을 위한 방법 및 물질에 관한 미국 특허 제5,571,902호; 알킬티오 그룹이 뉴클레오사이드의 다양한 위치중 어느 한 위치에 부착된 다른 잔기에 대한 링커로서 사용될 수 있는 알킬티오 그룹을 갖는 뉴클레오사이드에 관한 미국 특허 제5,578,718호; 높은 키랄 순도의 포스포로티오에이트 연결을 갖는 올리고뉴클레오타이드에 관한 미국 특허 제5,587,361호 및 제5,599,797호; 2,6-디아미노푸린 화합물을 포함하는 2'-O-알킬 구아노신 및 관련 화합물의 제조에 관한 미국 특허 제5,506,351호; N-2 치환된 푸린을 갖는 올리고뉴클레오타이드에 관한 미국 특허 제5,587,469호; 3-데아자푸린을 갖는 올리고뉴클레오타이드에 관한 미국 특허 제5,587,470호; 접합된 4'-데스메틸 뉴클레오사이드 유사체에 관한 미국 특허 제5,223,168호 및 미국 특허 제5,608,046호; 골격-변형된 올리고뉴클레오타이드 유사체에 관한 미국 특허 제5,602,240호 및 제5,610,289호; 특히 2'-플루오로-올리고뉴클레오타이드의 합성 방법에 관한 미국 특허 제6,262,241호 및 제5,459,255호.
본 발명의 서열-특이적 연결된 뉴클레오사이드를 보유한 리간드-접합된 dsRNA 및 리간드-분자에서, 올리고뉴클레오타이드 및 올리고뉴클레오사이드는 표준 뉴클레오타이드 또는 뉴클레오사이드 전구체, 또는 이미 연결 잔기를 보유하는 뉴클레오타이드 또는 뉴클레오사이드 접합체 전구체, 리간드 분자를 이미 보유하는 리간드-뉴클레오타이드 또는 뉴클레오사이드-접합체 전구체 또는 비-뉴클레오사이드 리간드-보유 빌딩 블록를 사용하여 적합한 DNA 합성기에서 어셈블리할 수 있다.
이미 연결 잔기를 보유하는 뉴클레오타이드-접합체 전구체를 사용하는 경우, 서열-특이적 연결된 뉴클레오사이드의 합성을 통상적으로 종결시키고 이어서 리간드 분자를 연결 잔기와 반응시켜 리간드-접합된 올리고뉴클레오타이드를 형성시킨다. 스테로이드, 비타민, 지질 및 리포터 분자와 같은 다양한 분자를 보유하는 올리고뉴클레오타이드 접합체는 이미 기술된 바 있다[참조: Manoharan et al., PCT 출원 제WO 93/07883호]. 바람직한 양태에서, 본 발명의 올리고뉴클레오타이드 또는 연결된 뉴클레오사이드는 시판되고 있고 올리고뉴클레오타이드 합성에서 통상적으로 사용되는 표준 포스포르아미다이트 및 비-표준 포스포르아미다이트에 추가하여 리간드-뉴클레오사이드 접합체로부터 유도된 포스포르아미다이트를 사용하여 자동화 합성기에 의해 합성한다.
올리고뉴클레오타이드의 뉴클레오사이드 내의 2'-O-메틸, 2'-O-에틸, 2'-O-프로필, 2'-O-알릴, 2'-O-아미노알킬 또는 2'-데옥시-2'-플루오로 그룹의 혼입은 올리고뉴클레오타이드에 향상된 하이브리드화 특성을 제공한다. 또한, 포스포로티오에이트 골격을 함유하는 올리고뉴클레오타이드는 향상된 뉴클레아제 안정성을 갖는다. 따라서, 본 발명의 작용화된 연결된 뉴클레오사이드를 포스포로티오에이트 골격 또는 2'-O-메틸, 2'-O-에틸, 2'-O-프로필, 2'-O-아미노알킬, 2'-O-알릴 또는 2'-데옥시-2'-플루오로 그룹중 하나 또는 둘다를 포함하도록 증대시킬 수 있다. 당업계에 공지된 올리고뉴클레오타이드 변형중 일부의 요약 목록은 예를 들면, PCT 공보 제WO 200370918호에서 찾아볼 수 있다.
일부 양태에서, 5'-말단에 아미노 그룹을 지니는 본 발명의 작용화된 뉴클레오사이드 서열은 DNA 합성기를 사용하여 제조한 다음, 선택된 리간드의 활성 에스테르 유도체와 반응시킨다. 활성 에스테르 유도체는 당업자에게 널리 공지되어 있다. 대표적 활성 에스테르에는 N-하이드로석신이미드 에스테르, 테트라플루오로페놀성 에스테르, 펜타플루오로페놀성 에스테르 및 펜타클로로페놀성 에스테르가 포함된다. 아미노 그룹과 활성 에스테르의 반응은 선택된 리간드가 연결 그룹을 통해서 5'-위치에 부착되어 있는 올리고뉴클레오타이드를 생성시킨다. 5'-말단에 있는 아미노 그룹은 5'-아미노-변형제 C6 시약을 사용하여 제조할 수 있다. 하나의 양태에서, 리간드 분자는 리간드-뉴클레오사이드 포스포로아미다이트의 사용에 의해 5'-위치에서 올리고뉴클레오타이드에 접합시킬 수 있으며, 이때 리간드는 직접적으로 또는 링커를 통해 간접적으로 5'-하이드록시 그룹에 연결된다. 이러한 리간드-뉴클레오사이드 포스포로아미다이트는 5'-말단에 리간드를 보유하는 리간드-접합된 올리고뉴클레오타이드를 제공하기 위해 통상적으로 자동화 합성 공정의 말기에 사용된다.
변형된 뉴클레오사이드내 연결 또는 골격의 예에는, 예를 들면, 포스포로티오에이트, 키랄 포스포로티오에이트, 포스포로디티오에이트, 포스포로트리에스테르, 아미노알킬포스포트리에스테르, 메틸, 및 3'-알킬렌 포스포네이트 및 키랄 포스포네이트를 포함하는 기타 알킬 포스포네이트, 포스피네이트, 3'-아미노 포스포로아미데이트 및 아미노알킬포스포르아미데이트를 포함하는 포스포르아미데이트, 티오노포스포르아미데이트, 티오노알킬포스포네이트, 티오노알킬포스포트리에스테르, 및 표준 3'-5' 연결을 갖는 보라노포스페이트, 이들의 2'-5' 연결된 유사체, 및 뉴클레오사이드 단위의 인접 쌍이 3'-5'에서 5'-3' 또는 2'-5'에서 5'-2'로 연결된 반대 극성을 갖는 것들이 포함된다. 다양한 염, 혼합 염 및 유리산 형태가 또한 포함된다.
상기 인-원자 함유 연결의 제조와 관련된 대표적 미국 특허에는 미국 특허 제3,687,808호; 제4,469,863호; 제4,476,301호; 제5,023,243호; 제5,177,196호; 제5,188,897호; 제5,264,423호; 제5,276,019호; 제5,278,302호; 제5,286,717호; 제5,321,131호; 제5,399,676호; 제5,405,939호; 제5,453,496호; 제5,455,233호; 제5,466,677호; 제5,476,925호; 제5,519,126호; 제5,536,821호; 제5,541,306호; 제5,550,111호; 제5,563,253호; 제5,571,799호; 제5,587,361호; 제5,625,050호; 및 제5,697,248호[각각 본원에서 참조로 인용된다]가 포함되나 이에 제한되는 것은 아니다.
내부에 인 원자를 포함하지 않는 변형된 뉴클레오사이드내 연결 또는 골격(즉,올리고뉴클레오사이드)의 예는 단쇄 알킬 또는 사이클로알킬 당상호간 연결, 혼합 헤테로원자 및 알킬 또는 사이클로알킬 당상호간 연결 또는 하나 이상의 단쇄 헤테로원자 또는 헤테로사이클릭 당상호간 연결에 의해 형성된 골격을 갖는다. 이들은 모르폴리노 연결(부분적으로 뉴클레오사이드의 당 부분으로부터 형성됨); 실록산 골격; 설파이드, 설폭사이드 및 설폰 골격; 포름아세틸 및 티오포름아세틸 골격; 메틸렌 포름아세틸 및 티오포름아세틸 골격; 알켄 함유 골격; 설파메이트 골격; 메틸렌이미노 및 메틸렌히드라지노 골격; 설포네이트 및 설폰아미드 골격; 아미드 골격; 및 혼합된 N, O, S 및 CH2 성분 부분을 갖는 기타 것들을 포함한다.
상기한 올리고뉴클레오타이드의 제조와 관련된 대표적 미국 특허에는 미국 특허 제5,034,506호; 제5,166,315호; 제5,185,444호; 제5,214,134호; 제5,216,141호; 제5,235,033호; 제5,264,562호; 제5,264,564호; 제5,405,938호; 제5,434,257호; 제5,466,677호; 제5,470,967호; 제5,489,677호; 제5,541,307호; 제5,561,225호; 제5,596,086호; 제5,602,240호; 제5,610,289호; 제5,602,240호; 제5,608,046호; 제5,610,289호; 제5,618,704호; 제5,623,070호; 제5,663,312호; 제5,633,360호; 제5,677,437호; 및 제5,677,439호[각각은 본원에서 참조로 인용된다]가 포함되나 이에 제한되지는 않는다.
특정한 경우에, 올리고뉴클레오타이드를 비-리간드 그룹에 의해 변형시킬 수 있다. 올리고뉴클레오타이드의 활성, 세포 분포 또는 세포 흡수를 향상시키기 위해 많은 비-리간드 분자를 올리고뉴클레오타이드에 접합시킬 수 있으며, 이러한 접합을 수행하기 위한 방법은 과학 문헌에서 입수할 수 있다. 이러한 비-리간드 잔기는 콜레스테롤[참조: Letsinger et al., Proc. Natl. Acad. Sci. USA, 1989, 86:6553], 콜산[참조: Manoharan et al., Bioorg. Med. Chem. Lett., 1994, 4:1053], 티오에테르, 예를 들면, 헥실-S-트리틸티올[참조: Manoharan et al., Ann. N.Y. Acad. Sci., 1992, 660:306; Manoharan et al., Bioorg. Med. Chem. Let., 1993, 3:2765], 티오콜레스테롤[참조: Oberhauser et al., Nucl. Acids Res., 1992, 20:533], 지방족 쇄, 예를 들면, 도데칸디올 또는 운데실 잔기[참조: Saison-Behmoaras et al., EMBO J., 1991, 10:111; Kabanov et al., FEBS Lett., 1990, 259:327; Svinarchuk et al., Biochimie, 1993, 75:49], 인지질, 예를 들면, 디-헥사데실-rac-글리세롤 또는 트리에틸암모늄 1,2-디-O-헥사데실-rac-글리세로-3-H-포스포네이트[참조: Manoharan et al., Tetrahedron Lett., 1995, 36:3651; Shea et al., Nucl. Acids Res., 1990, 18:3777], 폴리아민 또는 폴리에틸렌 글리콜 쇄[참조: Manoharan et al., Nucleosides & Nucleotides, 1995, 14:969] 또는 아다만탄 아세트산[참조: Manoharan et al., Tetrahedron Lett., 1995, 36:3651], 팔미틸 잔기[참조: Mishra et al., Biochim. Biophys. Acta, 1995, 1264:229] 또는 옥타데실아민 또는 헥실아미노-카보닐-옥시콜레스테롤 잔기[참조: Crooke et al., J. Pharmacol. Exp. Ther., 1996, 277:923]와 같은 지질 잔기를 포함하였다. 이러한 올리고뉴클레오타이드 접합체의 제조를 교시하는 대표적 미국 특허는 상기 기재한 바 있다. 통상적 접합 프로토콜은 서열의 하나 이상의 위치에 아미노링커를 보유하는 올리고뉴클레오타이드의 합성을 포함한다. 이어서, 아미노 그룹을 적절한 커플링 또는 활성화 시약을 사용하여 접합시킬 분자와 반응시킨다. 접합 반응은 여전히 고체 지지체에 결합된 올리고뉴클레오타이드를 사용하여 수행하거나 용액 상에서 올리고뉴클레오타이드를 절단한 후에 수행할 수 있다. HPLC에 의한 올리고뉴클레오타이드 접합체의 정제는 통상적으로 순수한 접합체를 제공한다. 이러한 잔기는 PCSK9의 발현 부위인 간 세포로의 표적화를 증가시킬 수 있기 때문에 콜레스테롤 접합체의 사용이 특히 바람직하다.
벡터 암호화된 RNAi 제제
본 발명의 dsRNA는 또한 재조합 바이러스 벡터로부터 생체내 세포내에서 발현시킬 수 있다. 본 발명의 재조합 바이러스 벡터는 본 발명의 dsRNA를 암호화하는 서열 및 dsRNA 서열을 발현시키기 위한 임의의 적합한 프로모터를 포함한다. 적합한 프로모터에는, 예를 들면, U6 또는 H1 RNA pol III 프로모터 서열 및 사이토메갈로바이러스 프로모터가 포함된다. 다른 적합한 프로모터의 선택은 당업계의 기술 범위내에 있다. 본 발명의 재조합 바이러스 벡터는 또한 특정한 조직 또는 특정한 세포내 환경 내에서 dsRNA를 발현시키기 위한 유도성 또는 조절가능한 프로모터를 포함할 수 있다. 본 발명의 dsRNA를 생체내 세포로 전달하기 위한 재조합 바이러스 벡터의 사용은 하기에서 보다 상세히 논의한다.
본 발명의 dsRNA는 2개의 개별적인 상보적인 RNA 분자로서 또는 2개의 상보적 영역을 갖는 단일 RNA 분자로서 재조합 바이러스 벡터로부터 발현시킬 수 있다.
발현될 dsRNA 분자(들)에 대한 암호화 서열을 수용할 수 있는 임의의 바이러스 벡터, 예를 들면, 아데노바이러스(AV); 아데노-관련된 바이러스(Adeno-Associated Virus; AAV); 레트로바이러스(예를 들면, 렌티바이러스(LV), 라브도바이러스, 쥐 백혈병 바이러스); 헤르페스 바이러스 등으로부터 유도된 벡터를 사용할 수 있다. 바이러스 벡터의 향성(tropism)은 벡터를 외피 단백질 또는 다른 바이러스로부터의 다른 표면 항원으로 슈도타이핑(pseudotyping)하거나 또는 상이한 바이러스 캡시드 단백질을 경우에 맞게 치환시킴으로써 변형시킬 수 있다.
예를 들면, 본 발명의 렌티바이러스 벡터는 수포성 구내염 바이러스(VSV), 광견병, 에볼라, 모콜라(Mokola) 등으로부터의 표면 단백질로 슈도타이핑할 수 있다. 본 발명의 AAV 벡터는 당해 벡터를 상이한 캡시드 단백질 혈청형을 발현하도록 조작하여 상이한 세포를 표적화하도록 만들 수 있다. 예를 들면, 혈청형 2 게놈상의 혈청형 2 캡시드를 발현하는 AAV 벡터는 AAV 2/2라 불린다. AAV 2/2 벡터 내의 이러한 혈청형 2 캡시드 유전자를 혈청형 5 캡시드 유전자로 대체시켜 AAV 2/5 벡터를 제조할 수 있다. 상이한 캡시드 단백질 혈청형을 발현하는 AAV 벡터를 작제하기 위한 기술은 당업계의 기술 범위내에 있다[참조: Rabinowitz J E et al. (2002), J Virol 76:791-801, 이의 전문은 본원에서 참조로 인용된다].
본 발명에서 사용하기에 적합한 재조합 바이러스 벡터의 선별, dsRNA를 발현하기 위한 핵산 서열을 벡터내로 삽입하기 위한 방법 및 바이러스 벡터를 관심대상의 세포로 전달하기 위한 방법은 당업계의 기술 범위내에 있다[참조: Dornburg R (1995), Gene Therap. 2: 301-310; Eglitis M A (1988), Biotechniques 6: 608-614; Miller A D (1990), Hum Gene Therap. 1: 5-14; Anderson W F (1998), Nature 392: 25-30; 및 Rubinson D A et al., Nat. Genet. 33: 401-406, 이의 전문은 본원에서 참조로 인용된다].
바람직한 바이러스 벡터는 AV 및 AAV로부터 유도된 벡터이다. 특히 바람직한 양태에서, 본 발명의 dsRNA는 예를 들면, U6 또는 H1 RNA 프로모터 또는 사이토메갈로바이러스(CMV) 프로모터를 포함하는 재조합 AAV 벡터로부터 2개의 개별적인 상보적 일본쇄 RNA 분자로서 발현시킨다.
본 발명의 dsRNA를 발현시키기에 적합한 AV 벡터 및 당해 벡터를 표적 세포로 전달시키는 방법은 문헌[참조: Xia H et al. (2002), Nat. Biotech. 20: 1006-1010]에 기재되어 있다.
본 발명의 dsRNA를 발현시키기에 적합한 AAV 벡터, 재조합 AV 벡터를 작제하는 방법 및 당해 벡터를 표적 세포로 전달시키는 방법은 문헌[참조: Samulski R et al. (1987), J. Virol. 61: 3096-3101; Fisher K J et al. (1996), J. Virol, 70: 520-532; Samulski R et al. (1989), J. Virol. 63: 3822-3826; 미국 특허 제5,252,479호; 미국 특허 제5,139,941호; 국제 특허출원 제WO 94/13788호; 및 국제 특허출원 제WO 93/24641호; 이들의 전문은 본원에서 참조로 인용된다]에 기재되어 있다.
III . dsRNA 를 포함하는 약제학적 조성물
하나의 양태에서, 본 발명은 본원에 기술된 dsRNA 및 약제학적으로 허용되는 담체를 포함하는 약제학적 조성물을 제공한다. 당해 dsRNA를 포함하는 약제학적 조성물은 PCSK9 유전자 발현을 하향 조절함에 의해 매개될 수 있는 병리학적 과정과 같은 PCSK9 유전자의 발현 또는 활성과 연관된 질환 또는 장애, 예를 들면, 고지혈증을 치료하는데 유용하다. 이러한 약제학적 조성물은 전달 방식에 기초하여 제형화한다. 한가지 예는 비경구 전달을 통한 간으로의 전달을 위해 제형화되는 조성물이다.
본 발명의 약제학적 조성물은 PCSK9 유전자의 발현을 억제하기에 충분한 용량으로 투여된다. 본 발명자들은, 본 발명의 dsRNA를 포함하는 조성물이, 이의 개선된 효능으로 인해서 놀랍게도 낮은 용량으로 투여될 수 있음을 발견하였다. 1일당 수용자의 체중 kg당 5mg dsRNA의 용량이 PCSK9 유전자의 발현을 억제 또는 저해하는데 충분하고 환자에게 전신 투여될 수 있다.
일반적으로, dsRNA의 적합한 용량은 1일당 수용자의 체중 kg당 0.01 내지 5.0 mg의 범위, 일반적으로 1일당 체중 1kg당 1㎍ 내지 1mg의 범위일 수 있다. 약제학적 조성물은 1일 1회 투여될 수 있거나, dsRNA는 하루 전체에 걸쳐서 적절한 간격으로 2회, 3회 또는 세부-용량으로 투여될 수 있거나, 제어된 방출 제형을 통해서 연속 주입 또는 전달을 사용하여 투여될 수 있다. 이러한 경우에, 총 1일 용량을 달성하기 위해 각 세부-용량에 함유된 dsRNA는 상응하게 보다 작아야 한다. 또한, 예를 들면, 수일에 걸쳐서 dsRNA의 서방출을 제공하는 통상의 서방형 제형을 사용하여 수일에 걸쳐서 전달하기 위해 용량 단위를 제조할 수 있다. 서방형 제형은 당업계에 널리 공지되어 있다.
당업자는 질환 또는 장애의 중증도, 이전의 치료법, 피험체의 전반적 건강 및/또는 연령 및 존재하는 기타 질환을 포함하는 특정한 요인들이 피험체를 효과적으로 치료하는데 요구되는 용량 및 시기에 영향을 줄 수 있음을 인지할 것이다. 또한, 치료학적 유효량의 조성물을 이용한 피험체의 치료는 단일 치료 또는 일련의 치료를 포함할 수 있다. 본 발명에 포함되는 개개의 dsRNA에 대한 유효량 및 생체내 반감기는 통상의 방법론을 사용하거나 본원의 다른 곳에 기재된 바와 같은 적절한 동물 모델을 사용한 생체내 시험에 기초하여 추산할 수 있다.
마우스 유전학의 진보는 PCSK9 유전자 발현을 하향 조절함에 의해 매개될 수 있는 병리학적 과정과 같은 다양한 사람 질환에 대한 연구를 위한 수많은 마우스 모델을 생성시켰다. 이러한 모델은 dsRNA의 생체내 시험 뿐만 아니라 치료학적 유효량을 측정하기 위해 사용된다.
본 발명의 dsRNA를 포유동물에게 투여하기 위해 어떠한 방법이라도 사용될 수 있다. 예를 들면, 투여는 직접; 경구; 또는 비경구 투여(예를 들면, 피하, 뇌실내, 근육내 또는 복강내 주사 또는 정맥내 점적에 의해)일 수 있다. 투여는 신속할 수 있거나(예를 들면, 주사에 의해) 시간에 걸쳐서 일어날 수 있다(예를 들면, 느린 주입 또는 서방형 제형의 투여에 의해).
통상적으로, 고지혈증을 앓는 포유동물을 치료할 경우에, 당해 dsRNA 분자는 비경구 수단을 통해서 전신 투여된다. 예를 들면, 접합되거나 비접합되거나 리포좀과 함께 또는 리포좀 없이 제형화된 dsRNA가 환자에게 정맥내 투여될 수 있다. 이를 위해, dsRNA 분자는 알코올과 같은 통상의 용매 중의 멸균 및 비-멸균 수용액, 비수성 용액 또는 액체 또는 고체 오일 기제 중의 용액과 같은 조성물로 제형화될 수 있다. 이러한 용액은 또한 완충제, 희석제 및 기타 적합한 첨가제를 함유할 수 있다. 비경구, 수막강내(intrathecal) 또는 뇌실내 투여의 경우, dsRNA 분자는 완충제, 희석제 및 기타 적합한 첨가제(예를 들면, 투과 증진제, 담체 화합물 및 기타 약제학적으로 허용되는 담체)를 또한 함유할 수 있는 멸균 수용액과 같은 조성물로 제형화될 수 있다.
또한, dsRNA 분자는 미국 특허 제6,271,359에 기재된 바와 같은 생물학적 또는 비생물학적 수단으로서 포유동물에게 투여될 수 있다. 비생물학적 전달은, 제한없이 (1) 리포좀에 본원에 제공된 dsRNA 산 분자를 로딩함 및 (2) dsRNA 분자와 지질 또는 리포좀을 복합체화시켜 핵산-지질 또는 핵산-리포좀 복합체를 형성함을 포함하는 다양한 방법으로 달성될 수 있다. 리포좀은 시험관내에서 세포를 형질감염시키는데 통상적으로 사용되는 양이온성 및 중성 지질로 이루어질 수 있다. 양이온성 지질은 음 하전된 핵산과 복합체화(예를 들면, 전하-결합)되어 리포좀을 형성할 수 있다. 양이온성 리포좀의 예에는, 제한없이, 리포펙틴, 리포펙타민, 리포펙트에이스 및 DOTAP가 포함된다. 리포좀의 형성 방법은 당업계에 널리 공지되어 있다. 리포좀 조성물은 예를 들면, 포스파티딜콜린, 디미리스토일 포스파티딜콜린, 디팔미토일 포스파티딜콜린, 디미리스토일 포스파티딜글리세롤 또는 디올레오일 포스파티딜에탄올아민으로부터 형성될 수 있다. 리포펙틴RTM(제조원: Invitrogen/Life Technologies, Carlsbad, Calif.) 및 에펙텐TM(제조원: Qiagen, Valencia, Calif.)을 포함하는 수많은 친지성 제제들이 시판되고 있다. 또한, 각각이 DOPE 또는 콜레스테롤과 같은 중성 지질과 혼합될 수 있는 DDAB 또는 DOTAP와 같은 시판되는 양이온성 지질을 사용하여 전신적 전달 방법을 최적화시킬 수 있다. 일부 경우에, 문헌[참조: Templeton et al., Nature Biotechnology, 15: 647-652 (1997)]에 기술된 바와 같은 리포좀을 사용할 수 있다. 다른 양태에서, 폴리에틸렌이민과 같은 다가양이온을 사용하여 생체내 및 생체외 전달을 달성할 수 있다[참조: Boletta et al., J. Am Soc. Nephrol. 7: 1728 (1996)]. 핵산을 전달하기 위한 리포좀의 사용에 관한 추가 정보는 미국 특허 제6,271,359호, PCT 공보 제WO 96/40964호 및 문헌[Morrissey, D. et al. 2005. Nat Biotechnol. 23(8):1002-7]에서 찾아볼 수 있다.
생물학적 전달은, 제한없이 바이러스 벡터의 사용을 포함하는 다양한 방법에 의해 달성될 수 있다. 예를 들면, 바이러스 벡터(예를 들면, 아데노바이러스 및 헤르페르바이러스 벡터)를 사용하여 dsRNA 분자를 간 세포로 전달할 수 있다. 표준 분자생물학 기술을 사용하여, 본원에 제공된 하나 이상의 dsRNA를 핵산을 세포로 전달하기 위해 이미 개발된 다수의 상이한 바이러스 벡터 중 하나로 도입시킬 수 있다. 이러한 수득된 바이러스 벡터를 사용하여, 예를 들면, 감염에 의해 하나 이상의 dsRNA를 세포로 전달하는데 사용할 수 있다.
본 발명의 dsRNA는 약제학적으로 허용되는 담체 또는 희석제 중에서 제형화할 수 있다. "약제학적으로 허용되는 담체"(본원에서 "부형제"로서도 지칭됨)는 약제학적으로 허용되는 용매, 현탁화제 또는 임의의 기타 약리학적 불활성 비히클이다. 약제학적으로 허용되는 담체는 액체 또는 고체일 수 있고 목적하는 부피, 경도 및 기타 지속적 수송 및 화학적 특성을 제공하도록 계획된 투여 방식으로 선택할 수 있다. 통상적인 약제학적으로 허용되는 담체에는, 예를 들면, 제한없이, 물; 식염 용액; 결합제(예: 폴리비닐피롤리돈 또는 하이드록시프로필 메틸셀룰로오즈); 충전재(예: 락토오즈 및 기타 당, 젤라틴 또는 황산칼슘); 윤활제(예: 전분, 폴리에틸렌 글리콜 또는 나트륨 아세테이트); 붕해제(예: 전분 또는 나트륨 전분 글리콜레이트); 및 습윤제(예: 나트륨 라우릴 설페이트)가 포함된다.
또한, PCSK9 유전자를 표적화하는 dsRNA를 다른 분자, 분자 구조 또는 핵산의 혼합물과 혼합된, 캡슐화된, 접합된 또는 그밖에 연합된 dsRNA를 함유하는 조성물로 제형화할 수 있다. 예를 들면, PCSK9 유전자를 표적화하는 하나 이상의 dsRNA 제제를 함유하는 조성물은 기타 지질 저하제(예: 스타틴)와 같은 다른 치료제를 함유할 수 있다.
PCSK9의 발현을 햐항 조절함에 의해 조정될 수 있는 질환의 치료 방법
본원에 기술된 방법 및 조성물을 사용하여, PCSK9의 발현을 햐항 조절하여 조정될 수 있는 질환 및 상태를 치료할 수 있다. 예를 들면, 본원에 기술된 조성물을 사용하여 고지혈증 및 다른 형태의 지질 불균형, 예를 들면, 고콜레스테롤혈증, 고트리글리세라이드혈증 및 이들 장애와 연관된 병리학적 상태, 예를 들면, 심장 및 순환계 질환을 치료할 수 있다.
PCSK9 유전자의 발현을 억제하는 방법
또 다른 측면에서, 본 발명은 포유동물에서 PCSK9 유전자의 발현을 억제하는 방법을 제공한다. 당해 방법은 본 발명의 조성물을 포유동물에게 투여하여, 표적 PCSK9 유전자의 발현이 사일런싱되도록 함을 포함한다. 본 발명의 dsRNA는 이의 높은 특이성으로 인하여 표적 PCSK9 유전자의 표적 RNA(1차 또는 프로세싱됨)를 특이적으로 표적화한다. dsRNA를 사용하여 이들 PCSK9 유전자의 발현을 억제하기 위한 조성물 및 방법은 본원의 다른 곳에 기술된 바와 같이 수행할 수 있다.
하나의 양태에서, 당해 방법은 치료될 포유동물의 PCSK9 유전자의 RNA 전사체의 적어도 일부분에 대해 상보적인 뉴클레오타이드 서열을 포함하는 dsRNA를 포함하는 조성물을 투여함을 포함한다. 치료될 유기체가 사람과 같은 포유동물인 경우, 당해 조성물은 정맥내, 근육내, 피하, 경피, 기도(에어로졸) 투여를 포함하는 경구 또는 비경구 경로를 포함하나 이에 제한되지 않는 당업계에 공지된 임의의 수단에 의해 투여할 수 있다. 바람직한 양태에서, 당해 조성물은 정맥내 주입 또는 주사로 투여된다.
달리 정의하지 않는 한, 본원에 사용된 모든 기술적 및 과학적 용어들은 본 발명이 속하는 분야의 숙련가들에 의해 통상적으로 이해되는 바와 동일한 의미를 갖는다. 본원에 기술된 것과 유사하거나 동등한 방법 및 물질이 본 발명을 실시하거나 시험하는데 사용될 수 있지만, 적합한 방법 및 물질을 하기 기술한다. 본원에 언급된 모든 간행물, 특허원, 특허 및 기타 참조문헌은 전문이 본원에서 참조로 인용된다. 상충되는 경우, 정의를 포함하는 본원 명세서에 의해 조정될 것이다. 또한, 물질, 방법 및 예는 단지 예시적이며 제한하기 위함이 아니다.
PCSK9 유전자의 유전자 워킹( gene walking )
siRNA 고안을 수행하여 2가지 개별적 선별물을 동정하였다.
a) PCSK9 사람 및 마우스 또는 랫트 mRNA를 표적화하는 siRNA; 및
b) 표적 유전자 PCSK9에 대한 예측된 특이성을 갖는 모든 사람 반응성 siRNA.
사람, 마우스 및 랫트 PCSK9에 대한 mRNA 서열을 사용하였다: 사람 서열 NM_174936.2를 완전한 siRNA 선별 과정 동안 참조 서열로서 사용하였다.
사람과 마우스 PCSK9 mRNA 서열 및 사람과 랫트 PCSK9 mRNA 서열에 보존된 19량체 서열을 제1 단계에서 동정하여 사람 및 마우스 표적에 대해 교차반응성인 siRNA 및 사람과 랫트 표적에 대해 교차반응성인 siRNA의 선별물을 수득하였다.
사람 PCSK9를 특이적으로 표적화하는 siRNA를 두번째 선별에서 동정하였다. 사람 PCSK9의 모든 가능한 19량체 서열을 추출하고 후보 표적 서열로서 정의하였 다. 사람 및 원숭이에 대해 교차반응성인 서열 및 마우스, 랫트, 사람 및 원숭이에 대해 교차반응성인 서열은 모두 표 1 및 2에 기재되어 있다. 이들 서열의 화학적으로 변형된 버젼 및 시험관내 및 생체내 분석법에서의 이들의 활성도 또한 표 1 및 2에 기재되어 있으며 예는 도 2 내지 8에 기재되어 있다.
후보 표적 서열 및 이의 상응하는 siRNA를 등급화하고 적절한 것을 선별하기 위해, 이들이 비관련 표적과 상호작용할 예측되는 잠재성(오프-타겟 잠재성(off-target potential))을 등급화 파라미터로서 취하였다. 오프-타겟 잠재성이 낮은 siRNA를 바람직한 것으로 정의하였으며 생체내에서 보다 특이적인 것으로 가정하였다.
siRNA-특이적 오프-타겟 잠재성을 예측하기 위해, 다음과 같이 가정하였다:
1) 쇄의 위치 2 내지 9(5'부터 3'으로 계수함)(핵심 영역(seed region))는 서열의 나머지(비-핵심 및 절단 부위 영역)보다 더욱 오프-타겟 잠재성에 기여할 수 있다.
2) 쇄의 위치 10 및 11(5'부터 3'으로 계수함)(절단 부위 영역)은 비-핵심 영역보다 더욱 오프-타겟 잠재성에 기여할 수 있다.
3) 각 쇄의 위치 1 및 19는 오프-타겟 상호작용과 관련되지 않는다.
4) 오프-타겟 스코어는 유전자의 서열 및 미스매치 위치에 대한 siRNA 쇄 서열의 상보성에 기초하여 각 유전자 및 각 쇄에 대해 계산할 수 있다.
5) 예측되는 오프-타겟의 수와 최고 오프-타겟 스코어가 오프-타겟 잠재성을 위해 고려되어야 한다.
6) 오프-타겟 스코어는 오프-타겟의 수보다 오프-타겟 잠재성과 더욱 관련되는 것으로 고려된다.
7) 내부 변형에 의한 센스 쇄 활성의 잠재적 중지를 가정할 때, 안티센스 쇄의 오프-타겟 잠재성만이 관련될 것이다.
잠재적 오프-타겟 유전자를 동정하기 위해, 19량체 후보 서열의 상동성을 공개적으로 입수가능한 사람 mRNA 서열과 대조하면서 조사하였다.
각 19량체 입력 서열에 대한 다음의 오프-타겟 특성을 각 오프-타겟 유전자에 대해 추론하여 오프-타겟 스코어를 계산하였다:
비-핵심 영액 내의 미스매치의 수
핵심-영역 내의 미스매치의 수
절단 부위 영역 내의 미스매치의 수
가정 1 내지 3을 고려하기 위해 오프-타겟 스코어를 다음과 같이 계산하였다:
오프-타겟 스코어 = 핵심 미스매치의 수 * 10
+ 절단 부위 미스매치의 수 * 1.2
+ 비-핵심 미스매치의 수 * 1
입력 19량체 서열에 상응하는 각 siRNA에 대한 가장 관련되는 오프-타겟 유전자를 오프-타겟 스코어가 최저인 유전자로서 정의하였다. 따라서, 최저 오프-타겟 스코어를 각 siRNA에 대한 관련되는 오프-타겟 스코어로서 정의하였다.
dsRNA 합성
시약 공급원
시약 공급원을 본원에서 구체적으로 기재하지 않는 경우, 이러한 시약은 분자생물학에서의 적용에 표준인 품질/순도에서 어떠한 분자생물학용 시약 공급업자로부터도 입수할 수 있다.
siRNA 합성
일본쇄 RNA를 Expedite 8909 합성기(제조원: Applied Biosystems, Applera Deutschland GmbH, Darmstadt, Germany) 및 고체 지지체로서 제어된 기공 유리(CPG, 500Å, 제조원: Proligo Biochemie GmbH, Hamburg, Germany)를 사용하여 1μmole의 규모로 고체상 합성에 의해 제조하였다. RNA 및 2'-O-메틸 뉴클레오타이드를 함유하는 RNA를 각각 상응하는 포스포르아미다이트 및 2'-O-메틸 포스포르아미다이트(제조원: Proligo Biochemie GmbH, Hamburg, Germany)를 사용하여 고체상 합성에 의해 생성시켰다. 이들 빌딩 블록을 문헌[참조: Current protocols in nucleic acid chemistry, Beaucage, S.L. et al. (Edrs.), John Wiley & Sons, Inc., New York, NY, USA]에 기재된 바와 같은 표준 뉴클레오사이드 포스포르아미다이트 화학을 사용하여 올리고리보뉴클레오타이드 사슬의 서열 내의 선별된 부위에 혼입시켰다. 요오드 산화제 용액을 아세토니트릴(1%) 중의 뷰케이지(Beaucage) 시약(판매원: Chruachem Ltd, Glasgow, UK)으로 대체시켜 포스포로티오에이트 연결을 도입시켰다. 추가의 보조 시약은 말린크로트 베이커(Mallinckrodt Baker, Griesheim, Germany)로부터 입수하였다.
조(crude) 올리고리보뉴클레오타이드를 확립된 과정에 따라서 음이온 교환 HPLC에 의해 탈보호시키고 정제하였다. 수율 및 농도를 스펙트럼 광도계(DU 640B, Beckman Coulter GmbH, Unterschleiheim, Germany)를 사용하여 260 nm의 파장에서 각각의 RNA의 용액의 UV 흡수에 의해 측정하였다. 이본쇄 RNA를 어닐링(annealing) 완충액(20mM 인산나트륨, pH 6.8; 100 mM 염화나트륨) 중의 상보적 쇄의 등몰 용액을 혼합하여 생성시키고 85 내지 90℃의 수조에서 3분 동안 가열하고 3 내지 4시간에 걸쳐서 실온으로 냉각시켰다. 어닐링된 RNA 용액을 사용할 때까지 20℃에서 저장하였다.
3'-콜레스테롤-접합된 siRNA(본원에서 -Chol-3'로서 지칭됨)의 합성을 위해, 적절히 변형된 고체 지지체를 RNA 합성을 위해 사용하였다. 변형된 고체 지지체를 다음과 같이 제조하였다:
디에틸-2-아자부탄-1,4-디카복실레이트 (화학식 AA)
Figure 112008085095997-pct00002
수산화나트륨의 4.7M 수용액(50 mL)을 물(50 mL) 중의 에틸 글리시네이트 하이드로클로라이드(32.19 g, 0.23 mole)의 교반된 빙냉 용액에 부가하였다. 이어서, 에틸 아크릴레이트(23.1 g, 0.23 mole)를 부가하고, 혼합물을 반응의 완료를 TLC로 확인할 때까지 실온에서 교반하였다. 19시간 후, 용액을 디클로로메탄(3 x 100 mL)으로 분배하였다. 유기 상을 무수 황산나트륨으로 건조시키고 여과하고 증발시켰다. 잔사를 증류시켜 AA (28.8 g, 61%)를 수득하였다.
3-{에톡시카보닐메틸-[6-(9H-플루오렌-9-일메톡시카보닐-아미노)-헥사노일]-아미노}-프로피온산 에틸 에스테르 (화학식 AB)
Figure 112008085095997-pct00003
Fmoc-6-아미노-헥산산(9.12 g, 25.83 mmol)을 디클로로메탄(50 mL)에 용해시키고 얼음으로 냉각시킨다. 디이소프로필카보디이미드(3.25 g, 3.99 mL, 25.83 mmol)를 0℃에서 용액에 부가하였다. 이어서, 여기에 디에틸-아자부탄-1,4-디카복실레이트(5 g, 24.6 mmol) 및 디메틸아미노 피리딘(0.305 g, 2.5 mmol)을 부가하였다. 용액을 실온이 되도록 하고 6시간 동안 추가로 교반하였다. 반응의 완결을 TLC로 확인하였다. 반응 혼합물을 진공하에 농축시키고 에틸 아세테이트를 부가하여 디이소프로필 우레아를 침전시켰다. 현탁액을 여과하였다. 여액을 5% 수성 염산, 5% 중탄산나트륨 및 물로 세척하였다. 합한 유기 층을 황산나트륨으로 건조시키고 농축시켜 조 생성물을 수득하고, 이를 컬럼 크로마토그래피(50% EtOAC/헥산)로 정제하여 11.87g(88%)의 AB를 수득하였다.
3-[(6-아미노-헥사노일)-에톡시카보닐메틸-아미노]-프로피온산 에틸 에스테르 (화학식 AC)
Figure 112008085095997-pct00004
3-{에톡시카보닐메틸-[6-(9H-플루오렌-9-일메톡시카보닐아미노)-헥사노일]-아미노}-프로피온산 에틸 에스테르 AB(11.5 g, 21.3 mmol)를 0℃에서 디메틸포름아미드 중의 20% 피페리딘에 용해시켰다. 용액을 1시간 동안 계속해서 교반하였다. 반응 혼합물을 진공하에 농축시키고, 물을 잔사에 부가하고, 생성물을 에틸 아세테이트로 추출하였다. 조 생성물을 이의 하이드로클로라이드 염으로 전환시켜 정제하였다.
3-({6-[17-(1,5-디메틸-헥실)-10,13-디메틸-2,3,4,7,8,9,10,11,12,13,14,15,16,17-테트라데카하이드로-1H-사이클로펜타[a]페난트렌-3-일옥시카보닐아미노]-헥사노일}에톡시카보닐메틸-아미노)-프로피온산 에틸 에스테르 (화학식 AD)
Figure 112008085095997-pct00005
3-[(6-아미노-헥사노일)-에톡시카보닐메틸-아미노]-프로피온산 에틸 에스테르 AC의 하이드로클로라이드 염(4.7 g, 14.8 mmol)을 디클로로메탄에 용해시켰다. 현탁액을 빙상에서 0℃까지 냉각시켰다. 현탁액에 디이소프로필에틸아민(3.87 g, 5.2 mL, 30 mmol)을 부가하였다. 수득된 용액에 콜레스테릴 클로로포르메이트(6.675g, 14.8 mmol)를 부가하였다. 반응 혼합물을 밤새 교반하였다. 반응 혼합물을 디클로로메탄으로 희석시키고 10% 염산으로 세척하였다. 생성물을 플래시 크로마토그래피로 정제하였다 (10.3 g, 92%).
1-{6-[17-(1,5-디메틸-헥실)-10,13-디메틸-2,3,4,7,8,9,10,11,12,13,14,15,16,17-테트라데카하이드로-1H-사이클로펜타[a]페난트렌-3-일옥시카보닐아미노]-헥사노일}-4-옥소-피롤리딘-3-카복실산 에틸 에스테르 (화학식 AE)
Figure 112008085095997-pct00006
칼륨 t-부톡사이드(1.1 g, 9.8 mmol)를 무수 톨루엔 30 mL 중에 슬러리화시켰다. 혼합물을 빙상에서 0℃까지 냉각시키고, 디에스테르 AD 5g(6.6 mmol)을 교반하면서 20분 이내에 천천히 부가하였다. 부가 동안에 온도는 5℃ 미만으로 유지하였다. 0℃에서 30분 동안 계속해서 교반하고, 빙초산 1 mL를 부가한 직후에 물 40 mL 중의 NaH2PO4·H2O 4g을 부가하였다. 수득된 생성물을 디클로로메탄 각각 100mL으로 2회 추출하고, 합한 유기 추출물을 포스페이트 완충액 각각 10mL으로 2회 세척하고, 증발 건조시켰다. 잔사를 톨루엔 60 mL에 용해시키고, 0℃까지 냉각시키고, 냉각된 pH 9.5 카보네이트 완충액의 3개의 50 mL 분획으로 추출하였다. 수성 추출물을 인산을 이용하여 pH 3으로 조정하고 클로로포름의 5개의 40 mL 분획으로 추출하고, 이를 합하고 건조시키고 증발 건조시켰다. 잔사를 25% 에틸아세테이트/헥산을 사용하여 컬럼 크로마토그래피로 정제하여 b-케토에스테르 1.9 g (39%)을 수득하였다.
[6-(3-하이드록시-4-하이드록시메틸-피롤리딘-1-일)-6-옥소-헥실]-카밤산 17-(1,5-디메틸-헥실)-10,13-디메틸-2,3,4,7,8,9,10,11,12,13,14,15,16,17-테트라데카하이드로-1H-사이클로펜타[a]페난트렌-3-일 에스테르 (화학식 AF)
Figure 112008085095997-pct00007
메탄올(2 mL)을 1시간에 걸쳐서 테트라하이드로푸란(10 mL) 중의 b-케토에스테르 AE(1.5 g, 2.2 mmol) 및 수소화붕소나트륨(0.226 g, 6 mmol)의 환류 혼합물에 적가하였다. 환류 온도에서 1시간 동안 계속해서 교반하였다. 실온으로 냉각시킨 후, 1N HCl(12.5 mL)을 부가하고, 혼합물을 에틸아세테이트(3 x 40 mL)로 추출하였다. 합한 에틸아세테이트 층을 무수 황산나트륨으로 건조시키고 진공하에 농축시켜 생성물을 수득하고, 이를 컬럼 크로마토그래피(10% MeOH/CHCl3)로 정제하였다(89%).
(6-{3-[비스-(4-메톡시-페닐)-페닐-메톡시메틸]-4-하이드록시-피롤리딘-1-일}-6-옥소-헥실)-카밤산 17-(1,5-디메틸-헥실)-10,13-디메틸-2,3,4,7,8,9,10,11,12,13,14,15,16,17-테트라데카하이드로-1H-사이클로펜타[a]페난트렌-3-일 에스테르 (화학식 AG)
Figure 112008085095997-pct00008
디올 AF(1.25 gm 1.994 mmol)를 진공하에 피리딘(2 x 5mL)으로 증발시켜 건조시켰다. 무수 피리딘(10 mL) 및 4,4'-디메톡시트리틸클로라이드(0.724 g, 2.13 mmol)를 교반하면서 부가하였다. 반응을 실온에서 밤새 수행하였다. 메탄올을 부가하여 반응을 퀀칭(quenching)시켰다. 반응 혼합물을 진공하에 농축시키고 잔류 디클로로메탄(50 mL)에 부가하였다. 유기 층을 1M 수성 중탄산나트륨으로 세척하였다. 유기 층을 무수 황산나트륨으로 건조시키고 여과하고 농축시켰다. 잔류 피리딘을 톨루엔으로 증발시켜 제거하였다. 조 생성물을 컬럼 크로마토그래피(2% MeOH/클로로포름, Rf = 5% MeOH/CHCl3 중에서 0.5)로 정제하였다 (1.75 g, 95%).
석신산 모노-(4-[비스-(4-메톡시-페닐)-페닐-메톡시메틸]-1-{6-[17-(1,5-디메틸-헥실)-10,13-디메틸 2,3,4,7,8,9,10,11,12,13,14,15,16,17-테트라데카하이드로-1H 사이클로펜타[a]페난트렌-3-일옥시카보닐아미노]-헥사노일}-피롤리딘-3-일) 에스테르 (화학식 AH)
Figure 112008085095997-pct00009
화합물 AG(1.0 g, 1.05 mmol)를 석신산 무수물(0.150 g, 1.5 mmol) 및 DMAP(0.073 g, 0.6 mmol)와 혼합하고 진공하에 40℃에서 밤새 건조시켰다. 혼합물을 무수 디클로로에탄(3 mL)에 용해시키고, 트리에틸아민(0.318 g, 0.440mL, 3.15 mmol)을 부가하고, 용액을 실온에서 아르곤 대기하에 16시간 동안 교반하였다. 이어서, 이를 디클로로메탄(40 mL)으로 희석시키고 빙냉 수성 시트르산(5중량%, 30 mL) 및 물(2 X 20 mL)로 세척하였다. 유기 상을 무수 황산나트륨으로 건조시키고 농축 건조시켰다. 잔사를 다음 단계에서 그대로 사용하였다.
콜레스테롤 유도체화된 CPG (화학식 AI)
Figure 112008085095997-pct00010
석시네이트 AH(0.254 g, 0.242 mmol)를 디클로로메탄/아세토니트릴(3:2, 3 mL)의 혼합물에 용해시켰다. 상기 용액에 아세토니트릴(1.25 mL) 중의 DMAP(0.0296 g, 0.242 mmol), 아세토니트릴/디클로로에탄(3:1, 1.25 mL) 중의 2,2'-디티오-비스(5-니트로피리딘)(0.075 g, 0.242 mmol)을 연속적으로 부가하였다. 수득된 용액에 아세토니트릴(0.6 ml) 중의 트리페닐포스핀(0.064 g, 0.242 mmol)을 부가하였다. 반응 혼합물은 색상이 밝은 오렌지색으로 변하였다. 용액을 팔 달린 진탕기(wrist-action shaker)를 사용하여 잠시동안 진탕하였다(5분). 장쇄 알킬 아민-CPG(LCAA-CPG)(1.5 g, 61mM)를 부가하였다. 현탁액을 2시간 동안 진탕하였다. CPG를 소결 깔때기를 통해 여과하고 아세토니트릴, 디클로로메탄 및 에테르로 연속적으로 세척하였다. 미반응한 아미노 그룹을 아세트산 무수물/피리딘을 사용하여 차단시켰다. 달성된 CPG의 로딩을 UV 측정(37 mM/g)을 실시하여 측정하였다.
5'-12-도데칸산 비스데실아미드 그룹(본원에서 "5'-C32-"로 지칭함) 또는 5'-콜레스테릴 유도체 그룹(본원에서 "5'-Chol-"로 지칭함)을 보유한 siRNA의 합성을 WO 2004/065601에 기술된 바와 같이 실시하되, 단 콜레스테릴 유도체의 경우, 핵산 올리고머의 5'-말단에 포스포로티오에이트 연결을 도입하기 위해 산화 단계는 뷰케이지 시약을 사용하여 실시하였다.
핵산 서열은 표준 명명법 및 구체적으로는 표 A의 약어를 사용하여 하기에 나타낸다.
Figure 112008085095997-pct00011
HuH7, HepG2, Hela 및 1차 원숭이 간세포에서의 PCSK9 siRNA 스크리닝에 의해 고도로 활성인 서열을 찾아낸다.
HuH-7 세포를 JCRB 세포 은행(Japanese Collection of Research Bioresources)(일본 신주쿠, 카탈로그 번호: JCRB0403)으로부터 입수하였다. 세포를 37℃에서 5% CO2를 함유한 대기하에 가습된 항온배양기(Heraeus HERAcell, Kendro Laboratory Products, Langenselbold, Germany) 내에서 10% 태아 송아지 혈청(FCS)(Biochrom AG, Berlin, Germany, 카탈로그 번호: S0115), 페니실린 100 U/ml, 스트렙토마이신 100㎍/ml(Biochrom AG, Berlin, Germany, 카탈로그 번호: A2213) 및 2mM L-글루타민(Biochrom AG, Berlin, Germany, 카탈로그 번호: K0282)을 함유하도록 보충된 둘베코(Dulbecco) MEM(Biochrom AG, Berlin, Germany, 카탈로그 번호: F0435)에서 배양하였다. HepG2 및 Hela 세포를 아메리칸 타입 컬쳐 컬렉션(Rockville, MD, 카탈로그 번호: HB-8065)으로부터 입수하고, 37℃에서 5% CO2를 함유한 대기하에 가습된 항온배양기(Heraeus HERAcell, Kendro Laboratory Products, Langenselbold, Germany) 내에서 10% 태아 송아지 혈청(FCS)(Biochrom AG, Berlin, Germany, 카탈로그 번호: S0115), 페니실린 100 U/ml, 스트렙토마이신 100 ㎍/ml(Biochrom AG, Berlin, Germany, 카탈로그 번호: A2213), 1x 비필수 아미노산(Biochrom AG, Berlin, Germany, 카탈로그 번호: K-0293) 및 1mM 나트륨 피루베이트(Biochrom AG, Berlin, Germany, 카탈로그 번호: L-0473)을 함유하도록 보충된 MEM(Gibco Invitrogen, Karlsruhe, Germany, 카탈로그 번호: 21090-022)에서 배양하였다.
siRNA로 형질감염시키기 위해, HuH7, HepG2 또는 Hela 세포를 96웰 플레이트에 2.0 x 104개 세포/웰의 밀도로 접종하고 직접 형질감염시켰다. siRNA(단일 용량 스크리닝의 경우 30nM)의 형질감염을 제조업자에 의해 기술된 바와 같이 리포펙타민 2000(Invitrogen GmbH, Karlsruhe, Germany, 카탈로그 번호: 11668-019)으로 실시하였다.
형질감염 24시간 후에 HuH7 및 HepG2 세포를 용해시키고 PCSK9 mRNA 수준을 프로토콜에 따라서 Quantigene Explore 키트(Genosprectra, Dumbarton Circle Fremont, USA, 카탈로그 번호: QG-000-02)로 정량하였다. PCSK9 mRNA 수준을 GAP-DH mRNA에 대해 표준화하였다. 각 siRNA에 대해 8개의 개별적 데이터포인트가 수집되었다. PCSK9 유전자와 관련되지 않은 siRNA 듀플렉스를 대조군으로서 사용하였다. 소정의 PCSK9 특이적 siRNA 듀플렉스의 활성을 대조군 siRNA 듀플렉스로 처리된 세포 내의 PCSK9 mRNA에 대한 처리된 세포 내의 % PCSK9 mRNA 농도로서 표현하였다.
1차 사이노몰거스 원숭이 간세포(냉동보존됨)를 In vitro Technologies, Inc.(Baltimore, Maryland, USA, 카탈로그 번호 M00305)로부터 입수하고 37℃에서 5% CO2를 함유한 대기하에 가습된 항온배양기 내에서 InVitroGRO CP 배지(카탈로그 번호 Z99029)에서 배양하였다.
siRNA로 형질감염시키기 위해, 1차 사이노몰거스 원숭이 세포를 96웰 플레이트내에서 3.5 x 104개 세포/웰의 밀도로 콜라겐 피복된 플레이트에 접종시키고 직접 형질감염시켰다. siRNA(30nM로부터 출발하여 8개의 2배 희석액 시리즈)를 제조업자에 의해 기술된 바와 같이 리포펙타민 2000(Invitrogen GmbH, Karlsruhe, Germany, 카탈로그 번호: 11668-019)으로 실시하였다.
형질감염 16시간 후에 배지를 Torpedo 항생제 혼합물(In vitro Technologies, Inc, 카탈로그 번호: Z99000)이 새로운 신선한 InVitroGRO CP 배지로 교환하였다.
배지 교환 24시간 후에 1차 사이노몰거스 세포를 용해시키고, PCSK9 mRNA 수준을 프로토콜에 따라서 Quantigene Explore 키트(Genosprectra, Dumbarton Circle Fremont, USA, 카탈로그 번호: QG-000-02)로 정량하였다. PCSK9 mRNA 수준을 GAPDH mRNA에 대해 표준화하였다. 이어서, 표준화된 PCSK9/GAPDH 비를 리포펙타민 2000 단독 대조군의 PCSK9/GAPDH 비와 비교하였다.
표 1 및 2(및 도 6)은 당해 결과를 요약한 것이며 상이한 용량에서 상이한 세포주에서의 시험관내 스크리닝의 예를 제공한다. PCSK9 전사체의 사일런싱은 소정의 용량에서의 잔류하는 전사체의 비율(%)로서 표현하였다. 고도로 활성인 서열은 100nm 이하의 용량에서 소정의 siRNA로 처리한 후 잔류하는 전사체가 70% 미만인 서열이다. 매우 활성인 서열은 100nM 이하의 용량으로 처리한 후 잔류하는 전사체가 60% 미만인 서열이다. 활성 서열은 높은 용량(100nM)으로 처리한 후 잔류하는 전사체가 85% 미만인 서열이다. 활성 siRNA의 예가 또한 하기 기술하는 리피도이드 제형 중에서 마우스에서 생체내 스크리닝되었다. 시험관내에서 활성인 서열은 일반적으로 생체내에서도 활성이었다(도 6 참조).
PCSK9 siRNA 의 생체내 효율 스크리닝
제형화 과정
리피도이드 LNP-01·4HCl(MW 1487)(도 1), 콜레스테롤(Sigma-Aldrich) 및 PEG-세라마이드 C16(Avanti Polar Lipids)를 사용하여 지질-siRNA 나노입자를 제조하였다. 에탄올 중의 각각의 모액을 제조하였다: LNP-01, 133 mg/mL; 콜레스테롤, 25 mg/mL, PEG-세라마이드 C16, 100 mg/mL. 이어서, LNP-01, 콜레스테롤 및 PEG-세라마이드 C16 모액을 42:48:10 몰비로 배합하였다. 배합된 지질 용액을 수성 siRNA(나트륨 아세테이트 중, pH 5)와 신속하게 혼합하여 최종 에탄올 농도가 35 내지 45%가 되도록 하고, 최종 나트륨 아세테이트 농도가 100 내지 300 mM이 되도록 하였다. 지질-siRNA 나노입자는 혼합시 자발적으로 형성되었다. 목적하는 입자 크기 분포에 따라, 수득된 나노입자 혼합물을 일부 경우에 써모배럴 압출기(thermobarrel extruder)(Lipex Extruder, Northern Lipids, Inc)를 사용하여 폴리카보네이트 막(100 nm 컷-오프)을 통해서 압출시켰다. 다른 경우에는 압출 단계가 생략되었다. 에탄올 제거 및 동시적 완충액 교환을 투석 또는 접선류(tangential flow) 여과에 의해 달성하였다. 완충액을 포스페이트 완충된 염수(PBS)(pH 7.2)로 교체하였다.
제형의 특성 규명
표준 방법 또는 비압출(extrusion-free) 방법으로 제조된 제형을 유사한 방식으로 특성 규명한다. 제형을 먼저 육안 조사로 특성 규명한다. 제형은 응집물 또는 침강물이 없는 담백색의 반투명 용액이여야 한다. 지질-나노입자의 입자 크기 및 입자 크기 분포는 Malvern Zetasizer Nano ZS(Malvern, USA)를 사용하여 동적광산란법으로 측정한다. 입자는 크기가 20 내지 300 nm이고, 이상적으로는 40 내지 100 nm여야 한다. 입자 크기 분포는 단봉형이여야 한다. 제형 중의 총 siRNA 농도 뿐만 아니라 포획된 분획을 염료 배제 분석법으로 추산한다. 제형화된 siRNA의 샘플을 제형 붕괴 계면활성제 0.5% Triton-X100의 존재 또는 부재하에 RNA-결합 염료 리보그린(Ribogreen)(Molecular Probes)과 함께 항온처리한다. 제형 중의 총 siRNA를 표준 곡선과 비교하여, 계면활성제를 함유하는 샘플로부터의 시그날로 측정한다. 포획된 분획을 총 siRNA 함량으로부터 "유리" siRNA 함량(계면활성제의 부재하의 시그날로 측정됨)을 감산하여 측정한다. 포획된 siRNA %는 통상적으로 85% 초과이다.
일시 주사 투약
C57/BL6 마우스(5마리/그룹, 8 내지 10주령, Charles River Laboratories, MA)에서의 제형화된 siRNA의 일시 주사 투약을 27G 바늘을 사용하여 꼬리 정맥에 주사하여 실시하였다. siRNA를 0.5 mg/ml 농도로 LNP-01 중에 제형화하여(이어서 PBS에 대해 투석한다) 10㎕/체중g 중에 5mg/kg 용량이 전달될 수 있도록 한다. 주사를 용이하게 하기 위해, 마우스를 투여 전 약 3분 동안 적외선 램프하에 유지시켰다.
투여한지 48시간 후에 마우스를 CO2-질식에 의해 희생시켰다. 혈액 0.2ml를 안와후 출혈에 의해 채혈하고 간을 수거하여 액체 질소 중에서 동결시켰다. 혈청 및 간을 -80℃에서 저장하였다.
동결된 간을 6850 Freezer/Mill Cryogenic Grinder(SPEX CentriPrep, Inc)를 사용하여 분쇄시키고 분말을 분석할 때까지 80℃에서 저장하였다.
PCSK9 mRNA 수준을 프로토콜에 따라서 QuantiGene Reagent System (Genospectra)로부터의 키트에 기초하는 분지-DNA 기술을 사용하여 검출하였다. 동결된 간 분말 10 내지 20mg을 65℃에서 3시간 동안 조직 및 세포 용해 용액(Epicentre, #MTC096H) 중의 600㎕의 0.16㎍/ml 프로테이나제 K(Epicentre, #MPRK092) 중에 용해시켰다. 이어서, 용해물 10㎕을 용해 작업 시약(Lysis Working Reagent) 90㎕(물 2용적 중의 스톡 용해 혼합물 1용적)에 부가하고 마우스 PCSK9 및 마우스 GAPDH 또는 사이클로필린 B에 대해 특이적인 프로브 셋트를 갖는 Genospectra 포획 플레이트상에서 52℃에서 밤새 항온처리하였다. 캡처 익스텐더(CE; Capture Extender), 라벨 익스텐더(LE; Label Extender) 및 블로킹(BL; blocking) 프로브에 대한 핵산 서열을 QuantiGene ProbeDesigner 소프트웨어 2.0(Genospectra, Fremont, CA, USA, 카탈로그 번호: QG-002-02)을 사용하여 PCSK9, GAPDH 및 사이클로필린 B의 핵산 서열로부터 선별하였다. 화학발광을 Victor2-Light(Perkin Elmer)에서 상대적 광 단위로서 판독하였다. 간 용해물 중의 PCSK9 mRNA 대 GAPDH 또는 사이클로필린 B mRNA의 비를 각 처리군에 대해서 평균치를 구하고 PBS로 처리된 대조군 또는 비관련 siRNA(혈액 응고 인자 VII)로 처리된 대조군과 비교하였다.
마우스 혈청 중의 총 혈청 콜레스테롤을 제조업자의 지시에 따라서 StanBio Cholesterol LiquiColor 키트(StanBio Laboratoriy, Boerne, Texas, USA)를 사용하여 측정하였다. 측정은 495 nm에서 Victor2 1420 Multilabel 계수기(Perkin Elmer)에서 수행하였다.
실시예
LNP-01 리포좀에 제형화된 32개의 PCSK9 siRNA를 마우스 모델에서 생체내 시험하였다. 실험은 5mg/kg siRNA 용량에서 실시하였으며, 10개 이상의 PCSK9 siRNA는 PBS로 처리된 대조군과 비교한 경우 40% 초과의 PCSK9 mRNA 녹다운(knock down)을 나타낸 반면에, 비관련 siRNA(혈액 응고 인자 VII)로 처리된 대조군은 효과가 없었다(도 2 내지 5). PCSK9 전사체의 사일런싱은 이들 동물에서 콜레스테롤의 저하와도 상관관계가 있었다(도 4 및 5). 또한, 시험관내에서 활성인 분자와 생체내에서 활성인 분자 사이에 강력한 상관관계가 있었다(도 6). 상이한 화학적 변형을 함유하는 서열을 또한 시험관내(표 1 및 2) 및 생체내에서 스크리닝하였다. 예로서, 덜 변형된 서열 9314 및 9318, 및 서열 9314-(10792, 10793 및 10796); 9318-(10794, 10795, 10797)의 보다 변형된 버젼을 LNP-01 중에서 제형화하여 시험관내(1차 원숭 간세포에서) 또는 생체내(9314 및 10792) 둘다에서 시험하였다. 도 7(표 1 및 2를 또한 참조)은 모 분자 9314 및 9318와 변형된 버젼이 모두 시험관내에서 활성임을 보여준다. 예로서 도 8은 모 9314 및 보다 고도로 변형된 10792 서열 둘다가 생체내에서 활성이며 마우스에서 내인성 PCSK9의 50 내지 60% 사일런싱을 나타냄을 보여준다. 도 9는 추가로 모 9314 및 10792의 다른 화학적으로 변형된 버젼의 활성을 예시한다.
dsRNA 발현 벡터
본 발명의 다른 측면에서, PCSK9 유전자 발현 활성을 조정하는 PCSK9 특이적 dsRNA 분자는 DNA 또는 RNA 벡터 내로 삽입된 전사 단위로부터 발현된다[참조: Couture, A, et al., TIG. (1996), 12:5-10; Skillern, A., et al., 국제 PCT, 공보 제WO 00/22113호, Conrad, 국제 PCT 공보 제WO 00/22114호, 및 Conrad, 미국 특허 제6,054,299호]. 이들 전이유전자(transgene)는 선형 작제물, 환형 플라스미드 또는 바이러스 벡터로서 도입시킬 수 있으며, 이는 숙주 게놈내로 통합된 전이유전자로서 혼입되고 유전될 수 있다. 전이유전자는 또한 이것이 염색체외 플라스미드로서 유전될 수 있도록 작제할 수도 있다[참조: Gassmann, et al., Proc. Natl. Acad. Sci. USA (1995) 92:1292].
dsRNA의 개별적 쇄는 2개의 별도의 발현 벡터상에서 프로모터에 의해 전사되어 표적 세포로 공동 형질감염될 수 있다. 또는, dsRNA의 각 개별적 쇄는 이와 동일한 발현 플라스미드상에 위치하는 프로모터에 의해 전사될 수 있다. 바람직한 양태에서, dsRNA는 링커 폴리뉴클레오타이드 서열에 의해 연결된 역 반복체로서 발현되어, 당해 dsRNA는 스템-루프(stem and loop) 구조를 갖게 된다.
재조합 dsRNA 발현 벡터는 일반적으로 DNA 플라스미드 또는 바이러스 벡터이다. dsRNA 발현 바이러스 벡터는 아데노-관련 바이러스[참조: Muzyczka, et al., Curr. Topics Micro . Immunol . (1992) 158:97-129)]; 아데노바이러스[참조: 예를 들면, Berkner, et al., BioTechniques (1998) 6:616, Rosenfeld et al., 1991, Science 252:431-434, 및 Rosenfeld et al. (1992), Cell 68:143-155]; 또는 알파바이러스 및 당업계에 공지된 기타 바이러스에 기초하여 작제할 수 있으나, 이에 제한되는 것은 아니다. 레트로바이러스는 시험관내 및/또는 생체내에서 상피 세포를 포함하는 많은 상이한 세포 유형 내로 다양한 유전자를 도입시키는데 사용되어 왔다[참조: Eglitis, et al., Science (1985) 230:1395-1398; Danos and Mulligan, Proc. NatI. Acad. Sci. USA (1998) 85:6460-6464; Wilson et al., 1988, Proc. NatI. Acad. Sci. USA 85:3014-3018; Armentano et al., 1990, Proc. NatI. Acad. Sci. USA 87:61416145; Huber et al., 1991, Proc. NatI. Acad. Sci. USA 88:8039-8043; Ferryet al., 1991, Proc. NatI. Acad. Sci. USA 88:8377-8381; Chowdhury et al., 1991, Science 254:1802-1805; van Beusechem. et al., 1992, Proc. Nad. Acad. Sci. USA 89:7640-19 ; Kay et al., 1992, Human Gene Therapy 3:641-647; Dai et al., 1992, Proc. Natl.Acad. Sci. USA 89:10892-10895; Hwu et al., 1993, J. Immunol. 150:4104-4115; 미국 특허 제4,868,116호; 미국 특허 제4,980,286호; PCT 출원 제WO 89/07136호; PCT 출원 제WO 89/02468호; PCT 출원 제WO 89/05345호; 및 PCT 출원 제WO 92/07573호]. 세포의 게놈내로 삽입된 유전자를 형질도입하고 발현할 수 있는 재조합 레트로바이러스 벡터는 재조합 레트로바이러스 게놈을 PA317 및 Psi-CRIP와 같은 적합한 패키징 세포주 내로 형질감염시켜 생산할 수 있다[참조: Comette et al., 1991, Human Gene Therapy 2:5-10; Cone et al., 1984, Proc. Natl. Acad. Sci. USA 81:6349]. 재조합 아데노바이러스 벡터는 감수성 숙주(예: 랫트, 햄스터, 개 및 침팬지)에서 광범위한 세포 및 조직을 감염시키는데 사용될 수 있고[참조: Hsu et al., 1992, J. Infectious Disease, 166:769], 또한 감염을 위해 유사분열 면에서 활성인 세포를 요구하지 않는다는 이점을 갖고 있다.
본 발명의 DNA 플라스미드 또는 바이러스 벡터에서의 dsRNA 발현을 구동하는 프로모터는 진핵성 RNA 폴리머라제 I(예: 리보솜 RNA 프로모터), RNA 폴리머라제 II(예: CMV 조기발현 프로모터 또는 액틴 프로모터 또는 U1 snRNA 프로모터) 또는 일반적으로 RNA 폴리머라제 III 프로모터(예: U6 snRNA 또는 7SK RNA 프로모터) 또는 원핵성 프로모터, 예를 들면, T7 프로모터일 수 있으며, 단 발현 플라스미드는 T7 프로모터로부터의 전사를 위해 요구되는 T7 RNA 폴리머라제를 암호화한다. 프로모터는 또한 전이유전자 발현을 췌장으로 지시할 수도 있다[예를 들면, 췌장에 대한 인슐린 조절성 서열 (참조: Bucchini et al., 1986, Proc. Natl. Acad. Sci. USA 83:2511-2515)].
또한, 전이유전자의 발현은 예를 들면, 특정 생리학적 조절인자, 예를 들면, 순환 글루코오즈 수준 또는 호르몬에 대해 민감성인 조절 서열과 같은 유도성 조절 서열 및 발현 시스템을 사용하여 정확하게 조절할 수 있다[참조: Docherty et al., 1994, FASEB J. 8:20-24]. 세포 또는 포유동물에서의 전이유전자 발현의 조절에 적합한 이러한 유도성 발현 시스템은 엑디손, 에스트로겐, 프로게스테론, 테트라사이클린, 이량체화의 화학적 유도제 및 이소프로필-베타-D1-티오갈락토피라노사이드(EPTG)에 의한 조절을 포함한다. 당업자라면 dsRNA 전이유전자의 의도된 사용에 기초하여 적절한 조절/프로모터 서열을 선택할 수 있을 것이다.
일반적으로, dsRNA 분자를 발현할 수 있는 재조합 벡터는 하기와 같이 전달되며 표적 세포에서 유지된다. 또는, dsRNA 분자의 일시적 발현을 제공하는 바이러스 벡터가 사용될 수 있다. 이러한 벡터는 필요에 따라 반복 투여될 수 있다. 일단 발현되면, dsRNA는 표적 RNA에 결합하고 이의 기능 또는 발현을 조정한다. dsRNA 발현 벡터의 전달은 정맥내 또는 근육내 투여, 환자로부터 체외이식된 표적 세포로 투여한 후의 환자로의 재도입 또는 목적 표적 세포로 도입되도록 하는 임의의 다른 수단에 의한 것과 같은 전신적 전달일 수 있다.
dsRNA 발현 DNA 플라스미드는 통상적으로 양이온성 지질 담체(예: 올리고펙타민) 또는 비양이온성 지질-기반 담체(예: Transit-TKOTM)와의 복합체로서 표적 세포내로 형질감염된다. 1주 이상의 기간에 걸쳐서 단일 PCSK9 유전자 또는 다수의 PCSK9 유전자의 상이한 영역을 표적화하는 dsRNA-매개된 녹다운을 위한 다수의 지질 형질감염도 또한 본 발명에서 고려된다. 숙주 세포내로의 본 발명의 벡터의 성공적 도입은 다양한 공지된 방법을 사용하여 모니터할 수 있다. 예를 들면, 일시적 형질감염은 리포터, 예를 들면, 녹색 형광 단백질(GFP)과 같은 형광 마커를 사용하여 감지할 수 있다. 생체외 세포의 안정한 형질감염은 형질감염된 세포에 하이그로마이신 B 내성과 같이 특이적 환경 인자(예: 항생제 및 약물)에 대한 내성을 제공하는 마커를 사용하여 확인할 수 있다.
PCSK9 특이적 dsRNA 분자는 또한 벡터내로 삽입되어 사람 환자용 유전자 요법 벡터로서 사용될 수도 있다. 유전자 요법 벡터는 예를 들면, 정맥내 주사, 국소 투여[참조: 미국 특허 제5,328,470호] 또는 정위 주사(stereotactic injection)[참조: Chen et al. (1994) Proc. Natl. Acad. Sci. USA 91:3054-3057]에 의해 피험체에게 전달될 수 있다. 유전자 요법 벡터의 약제학적 제제는 허용되는 희석제 중에 유전자 요법 벡터를 포함할 수 있거나, 유전자 요법 비히클이 매립되어진 서방출 매트릭스를 포함할 수 있다. 또는, 완전한 유전자 전달 벡터, 예를 들면, 레트로바이러스 벡터가 재조합 세포로부터 온전한 상태로 생산될 수 있는 경우, 약제학적 제제는 유전자 전달 시스템을 생산하는 하나 이상의 세포를 포함할 수 있다.
당업자는 본원 명세서에서 구체적으로 제시한 것들 이외에 이하 첨부된 전체 청구의 범위까지 본 발명을 실시할 수 있도록 하는 방법 및 조성물을 잘 알고 있다.
Figure 112008085095997-pct00012
Figure 112008085095997-pct00013
Figure 112008085095997-pct00014
Figure 112008085095997-pct00015
Figure 112008085095997-pct00016
Figure 112008085095997-pct00017
Figure 112008085095997-pct00018
Figure 112008085095997-pct00019
Figure 112008085095997-pct00020
Figure 112008085095997-pct00021
Figure 112008085095997-pct00022
Figure 112008085095997-pct00023
Figure 112008085095997-pct00024
Figure 112008085095997-pct00025
Figure 112008085095997-pct00026
Figure 112008085095997-pct00027
Figure 112008085095997-pct00028
Figure 112008085095997-pct00029
Figure 112008085095997-pct00030
Figure 112008085095997-pct00031
Figure 112008085095997-pct00032
Figure 112008085095997-pct00033
Figure 112008085095997-pct00034
Figure 112008085095997-pct00035
Figure 112008085095997-pct00036
Figure 112008085095997-pct00037
Figure 112008085095997-pct00038
Figure 112008085095997-pct00039
Figure 112008085095997-pct00040
Figure 112008085095997-pct00041
Figure 112008085095997-pct00042
Figure 112008085095997-pct00043
Figure 112008085095997-pct00044
Figure 112008085095997-pct00045
Figure 112008085095997-pct00046
Figure 112008085095997-pct00047
<110> Alnylam Pharmaceuticals, Inc. <120> Compositions and methods for inhibiting expression of the PCSK9 gene <130> 14174-135WO1 <150> US 60/799,458 <151> 2006-05-11 <150> US 60/817,203 <151> 2006-06-27 <150> US 60/840,089 <151> 2006-08-25 <150> US 60/829,914 <151> 2006-10-18 <150> US 60/901,134 <151> 2007-02-13 <160> 1504 <170> KopatentIn 1.71 <210> 1 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1 agcgacgucg aggcgcucat t 21 <210> 2 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 2 ugagcgccuc gacgucgcut t 21 <210> 3 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 3 cgcucauggu ugcaggcggt t 21 <210> 4 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 4 ccgccugcaa ccaugagcgt t 21 <210> 5 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 5 gcucaugguu gcaggcgggt t 21 <210> 6 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 6 cccgccugca accaugagct t 21 <210> 7 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 7 gcgggcgccg ccguucagut t 21 <210> 8 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 8 acugaacggc ggcgcccgct t 21 <210> 9 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 9 cgggcgccgc cguucaguut t 21 <210> 10 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 10 aacugaacgg cggcgcccgt t 21 <210> 11 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 11 gggcgccgcc guucaguuct t 21 <210> 12 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 12 gaacugaacg gcggcgccct t 21 <210> 13 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 13 ccguucaguu cagggucugt t 21 <210> 14 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 14 cagacccuga acugaacggt t 21 <210> 15 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 15 uucaguucag ggucugagct t 21 <210> 16 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 16 gcucagaccc ugaacugaat t 21 <210> 17 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 17 gugagacugg cucgggcggt t 21 <210> 18 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 18 ccgcccgagc cagucucact t 21 <210> 19 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 19 ggccgggacg cgucguugct t 21 <210> 20 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 20 gcaacgacgc gucccggcct t 21 <210> 21 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 21 gccgggacgc gucguugcat t 21 <210> 22 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 22 ugcaacgacg cgucccggct t 21 <210> 23 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 23 ccgggacgcg ucguugcagt t 21 <210> 24 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 24 cugcaacgac gcgucccggt t 21 <210> 25 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 25 ggacgcgucg uugcagcagt t 21 <210> 26 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 26 cugcugcaac gacgcgucct t 21 <210> 27 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 27 ucccagccag gauuccgcgt t 21 <210> 28 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 28 cgcggaaucc uggcugggat t 21 <210> 29 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1, 2, 3, 4, 7, 8, 13, 14, 15, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 5, 6, 9, 10, 11, 12, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 29 ucccagccag gauuccgcgt t 21 <210> 30 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 30 cgcggaaucc uggcugggat t 21 <210> 31 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 31 cccagccagg auuccgcgct t 21 <210> 32 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 32 gcgcggaauc cuggcugggt t 21 <210> 33 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1, 2, 3, 6, 7, 12, 13, 14, 15, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 4, 5, 8, 9, 10, 11, 16, 18 <223> /mod_base = "2'-hydroxy corresponding base" <400> 33 cccagccagg auuccgcgct t 21 <210> 34 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 34 gcgcggaauc cuggcugggt t 21 <210> 35 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 35 cagccaggau uccgcgcgct t 21 <210> 36 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 36 gcgcgcggaa uccuggcugt t 21 <210> 37 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1, 4, 5, 10, 11, 12, 13, 15, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 3, 6, 7, 8, 9, 14, 16, 18 <223> /mod_base = "2'-hydroxy corresponding base" <400> 37 cagccaggau uccgcgcgct t 21 <210> 38 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 38 gcgcgcggaa uccuggcugt t 21 <210> 39 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 39 agcuccugca caguccucct t 21 <210> 40 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 40 ggaggacugu gcaggagcut t 21 <210> 41 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 3, 4, 5, 6, 7, 9, 11, 14, 15, 16, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 8, 10, 12, 13 <223> /mod_base = "2'-hydroxy corresponding base" <400> 41 agcuccugca caguccucct t 21 <210> 42 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 12 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 13, 14, 15, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 42 ggaggacugu gcaggagcut t 21 <210> 43 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 43 caccgcaagg cucaaggcgt t 21 <210> 44 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 44 cgccuugagc cuugcggugt t 21 <210> 45 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 45 cgcaaggcuc aaggcgccgt t 21 <210> 46 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 46 cggcgccuug agccuugcgt t 21 <210> 47 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 47 caaggcucaa ggcgccgcct t 21 <210> 48 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 48 ggcggcgccu ugagccuugt t 21 <210> 49 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 49 guggaccgcg cacggccuct t 21 <210> 50 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 50 gaggccgugc gcgguccact t 21 <210> 51 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 51 uggaccgcgc acggccucut t 21 <210> 52 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 52 agaggccgug cgcgguccat t 21 <210> 53 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 53 ggaccgcgca cggccucuat t 21 <210> 54 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 54 uagaggccgu gcgcggucct t 21 <210> 55 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 55 gaccgcgcac ggccucuagt t 21 <210> 56 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 56 cuagaggccg ugcgcgguct t 21 <210> 57 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 57 accgcgcacg gccucuaggt t 21 <210> 58 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 58 ccuagaggcc gugcgcggut t 21 <210> 59 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 59 ccgcgcacgg ccucuaggut t 21 <210> 60 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 60 accuagaggc cgugcgcggt t 21 <210> 61 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 61 cgcgcacggc cucuagguct t 21 <210> 62 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 62 gaccuagagg ccgugcgcgt t 21 <210> 63 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 63 gcgcacggcc ucuaggucut t 21 <210> 64 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 64 agaccuagag gccgugcgct t 21 <210> 65 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 65 cgcacggccu cuaggucuct t 21 <210> 66 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 66 gagaccuaga ggccgugcgt t 21 <210> 67 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 67 cucuaggucu ccucgccagt t 21 <210> 68 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 68 cuggcgagga gaccuagagt t 21 <210> 69 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 69 ucuaggucuc cucgccaggt t 21 <210> 70 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 70 ccuggcgagg agaccuagat t 21 <210> 71 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 71 cuaggucucc ucgccaggat t 21 <210> 72 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 72 uccuggcgag gagaccuagt t 21 <210> 73 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 73 aggucuccuc gccaggacat t 21 <210> 74 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 74 uguccuggcg aggagaccut t 21 <210> 75 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 75 ccucgccagg acagcaacct t 21 <210> 76 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 76 gguugcuguc cuggcgaggt t 21 <210> 77 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 77 cgucagcucc aggcggucct t 21 <210> 78 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 78 ggaccgccug gagcugacgt t 21 <210> 79 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1, 3, 4, 7, 8, 9, 10, 14, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 5, 6, 11, 12, 13, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 79 cgucagcucc aggcggucct t 21 <210> 80 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 80 ggaccgccug gagcugacgt t 21 <210> 81 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 81 gucagcucca ggcgguccut t 21 <210> 82 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 82 aggaccgccu ggagcugact t 21 <210> 83 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 2, 3, 6, 7, 8, 9, 13, 16, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 4, 5, 10, 11, 12, 14, 15 <223> /mod_base = "2'-hydroxy corresponding base" <400> 83 gucagcucca ggcgguccut t 21 <210> 84 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 84 aggaccgccu ggagcugact t 21 <210> 85 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 85 ggcgcccgug cgcaggaggt t 21 <210> 86 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 86 ccuccugcgc acgggcgcct t 21 <210> 87 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 87 ggagcuggug cuagccuugt t 21 <210> 88 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 88 caaggcuagc accagcucct t 21 <210> 89 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 5, 6, 9, 11, 12, 15, 16, 17, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 7, 8, 10, 13, 14, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 89 ggagcuggug cuagccuugt t 21 <210> 90 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1, 7, 10, 13 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 3, 4, 5, 6, 8, 9, 11, 12, 14, 15, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 90 caaggcuagc accagcucct t 21 <210> 91 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 91 gcuggugcua gccuugcgut t 21 <210> 92 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 92 acgcaaggcu agcaccagct t 21 <210> 93 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 2, 3, 6, 8, 9, 12, 13, 14, 15, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 4, 5, 7, 10, 11, 16, 18 <223> /mod_base = "2'-hydroxy corresponding base" <400> 93 gcuggugcua gccuugcgut t 21 <210> 94 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 4, 10, 13, 16 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 5, 6, 7, 8, 9, 11, 12, 14, 15, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 94 acgcaaggcu agcaccagct t 21 <210> 95 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 95 cuggugcuag ccuugcguut t 21 <210> 96 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 96 aacgcaaggc uagcaccagt t 21 <210> 97 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 97 cuggugcuag ccuugcguut t 21 <210> 98 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 98 aacgcaaggc uagcaccagt t 21 <210> 99 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1, 2, 5, 7, 8, 11, 12, 13, 14, 16, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 3, 4, 6, 9, 10, 15, 17 <223> /mod_base = "2'-hydroxy corresponding base" <400> 99 cuggugcuag ccuugcguut t 21 <210> 100 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 5, 11, 14, 17 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 6, 7, 8, 9, 10, 12, 13, 15, 16, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 100 aacgcaaggc uagcaccagt t 21 <210> 101 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 101 ugcuagccuu gcguuccgat t 21 <210> 102 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 102 ucggaacgca aggcuagcat t 21 <210> 103 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1, 3, 4, 7, 8, 9, 10, 12, 14, 15, 16, 17 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 5, 6, 11, 13, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 103 ugcuagccuu gcguuccgat t 21 <210> 104 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 9, 15, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 6, 7, 8, 10, 11, 12, 13, 14, 16, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 104 ucggaacgca aggcuagcat t 21 <210> 105 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 105 uagccuugcg uuccgaggat t 21 <210> 106 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 106 uccucggaac gcaaggcuat t 21 <210> 107 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1, 4, 5, 6, 7, 9, 11, 12, 13, 14 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 3, 8, 10, 15, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 107 uagccuugcg uuccgaggat t 21 <210> 108 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 12, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 13, 14, 15, 16, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 108 uccucggaac gcaaggcuat t 21 <210> 109 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 109 gacggccugg ccgaagcact t 21 <210> 110 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 110 gugcuucggc caggccguct t 21 <210> 111 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 111 ggccgaagca cccgagcact t 21 <210> 112 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 112 gugcucgggu gcuucggcct t 21 <210> 113 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 113 gccgaagcac ccgagcacgt t 21 <210> 114 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 114 cgugcucggg ugcuucggct t 21 <210> 115 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 115 ccgaagcacc cgagcacggt t 21 <210> 116 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 116 ccgugcucgg gugcuucggt t 21 <210> 117 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 117 ccgagcacgg aaccacagct t 21 <210> 118 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 118 gcugugguuc cgugcucggt t 21 <210> 119 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 119 caccgcugcg ccaaggauct t 21 <210> 120 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 120 gauccuuggc gcagcggugt t 21 <210> 121 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 121 ccgcugcgcc aaggauccgt t 21 <210> 122 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 122 cggauccuug gcgcagcggt t 21 <210> 123 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 123 cgcugcgcca aggauccgut t 21 <210> 124 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 124 acggauccuu ggcgcagcgt t 21 <210> 125 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 125 cugcgccaag gauccguggt t 21 <210> 126 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 126 ccacggaucc uuggcgcagt t 21 <210> 127 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 127 auccguggag guugccuggt t 21 <210> 128 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 128 ccaggcaacc uccacggaut t 21 <210> 129 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 129 gguugccugg caccuacgut t 21 <210> 130 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 130 acguaggugc caggcaacct t 21 <210> 131 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 131 aggagaccca ccucucgcat t 21 <210> 132 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 132 ugcgagaggu gggucuccut t 21 <210> 133 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 133 ggagacccac cucucgcagt t 21 <210> 134 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 134 cugcgagagg ugggucucct t 21 <210> 135 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 135 gagacccacc ucucgcagut t 21 <210> 136 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 136 acugcgagag gugggucuct t 21 <210> 137 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 137 ccaccucucg cagucagagt t 21 <210> 138 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 138 cucugacugc gagagguggt t 21 <210> 139 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 139 ccucucgcag ucagagcgct t 21 <210> 140 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 140 gcgcucugac ugcgagaggt t 21 <210> 141 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 141 cucucgcagu cagagcgcat t 21 <210> 142 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 142 ugcgcucuga cugcgagagt t 21 <210> 143 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 143 ucucgcaguc agagcgcact t 21 <210> 144 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 144 gugcgcucug acugcgagat t 21 <210> 145 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 145 cucgcaguca gagcgcacut t 21 <210> 146 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 146 agugcgcucu gacugcgagt t 21 <210> 147 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1, 2, 3, 5, 8, 9, 14, 16, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 4, 6, 7, 10, 11, 12, 13, 15, 17 <223> /mod_base = "2'-hydroxy corresponding base" <400> 147 cucgcaguca gagcgcacut t 21 <210> 148 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 148 agugcgcucu gacugcgagt t 21 <210> 149 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 149 gcagucagag cgcacugcct t 21 <210> 150 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 150 ggcagugcgc ucugacugct t 21 <210> 151 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 2, 5, 6, 11, 13, 15, 16, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 4, 7, 8, 9, 10, 12, 14, 17 <223> /mod_base = "2'-hydroxy corresponding base" <400> 151 gcagucagag cgcacugcct t 21 <210> 152 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 3 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 152 ggcagugcgc ucugacugct t 21 <210> 153 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 153 gggauaccuc accaagauct t 21 <210> 154 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 154 gaucuuggug agguauccct t 21 <210> 155 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 5, 7, 8, 9, 10, 12, 13, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 6, 11, 14, 15, 16, 17 <223> /mod_base = "2'-hydroxy corresponding base" <400> 155 gggauaccuc accaagauct t 21 <210> 156 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 14 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 156 gaucuuggug agguauccct t 21 <210> 157 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 157 uggugaagau gaguggcgat t 21 <210> 158 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 158 ucgccacuca ucuucaccat t 21 <210> 159 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1, 4, 10, 14, 17 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 3, 5, 6, 7, 8, 9, 11, 12, 13, 15, 16, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 159 uggugaagau gaguggcgat t 21 <210> 160 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 5, 9, 15, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 6, 7, 8, 10, 11, 12, 13, 14, 16, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 160 ucgccacuca ucuucaccat t 21 <210> 161 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 161 gaagaugagu ggcgaccugt t 21 <210> 162 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 162 caggucgcca cucaucuuct t 21 <210> 163 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 6, 10, 13, 16, 17, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 7, 8, 9, 11, 12, 14, 15, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 163 gaagaugagu ggcgaccugt t 21 <210> 164 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1, 9, 13 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 3, 4, 5, 6, 7, 8, 10, 11, 12, 14, 15, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 164 caggucgcca cucaucuuct t 21 <210> 165 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 165 cccaugucga cuacaucgat t 21 <210> 166 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 166 ucgauguagu cgacaugggt t 21 <210> 167 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1, 2, 3, 5, 7, 8, 11, 12, 14, 16, 17 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 4, 6, 9, 10, 13, 15, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 167 cccaugucga cuacaucgat t 21 <210> 168 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 7, 14 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 6, 8, 9, 10, 11, 12, 13, 15, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 168 ucgauguagu cgacaugggt t 21 <210> 169 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 169 aucgaggagg acuccucugt t 21 <210> 170 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 170 cagaggaguc cuccucgaut t 21 <210> 171 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 2, 3, 12, 13, 14, 15, 16, 17, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 4, 5, 6, 7, 8, 9, 10, 11, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 171 aucgaggagg acuccucugt t 21 <210> 172 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 172 cagaggaguc cuccucgaut t 21 <210> 173 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 173 ggaaccugga gcggauuact t 21 <210> 174 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 174 guaauccgcu ccagguucct t 21 <210> 175 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 175 gaaccuggag cggauuacct t 21 <210> 176 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 176 gguaauccgc uccagguuct t 21 <210> 177 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 177 aaccuggagc ggauuaccct t 21 <210> 178 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 178 ggguaauccg cuccagguut t 21 <210> 179 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 179 cccuccacgg uaccgggcgt t 21 <210> 180 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 180 cgcccgguac cguggagggt t 21 <210> 181 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 181 cacgguaccg ggcggaugat t 21 <210> 182 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 182 ucauccgccc gguaccgugt t 21 <210> 183 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1, 3, 6, 8, 9, 13, 17 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 4, 5, 7, 10, 11, 12, 14, 15, 16, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 183 cacgguaccg ggcggaugat t 21 <210> 184 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 2, 13 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 15, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 184 ucauccgccc gguaccgugt t 21 <210> 185 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 185 acgguaccgg gcggaugaat t 21 <210> 186 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 186 uucauccgcc cgguaccgut t 21 <210> 187 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 2, 5, 7, 8, 12, 16 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 4, 6, 9, 10, 11, 13, 14, 15, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 187 acgguaccgg gcggaugaat t 21 <210> 188 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 3, 14 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 188 uucauccgcc cgguaccgut t 21 <210> 189 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 189 cgguaccggg cggaugaaut t 21 <210> 190 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 190 auucauccgc ccgguaccgt t 21 <210> 191 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1, 4, 6, 7, 11, 15, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 3, 5, 8, 9, 10, 12, 13, 14, 16, 17, 18 <223> /mod_base = "2'-hydroxy corresponding base" <400> 191 cgguaccggg cggaugaaut t 21 <210> 192 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 4, 15 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 192 auucauccgc ccgguaccgt t 21 <210> 193 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 193 gguaccgggc ggaugaauat t 21 <210> 194 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 194 uauucauccg cccgguacct t 21 <210> 195 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 3, 5, 6, 10, 14, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 4, 7, 8, 9, 11, 12, 13, 15, 16, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 195 gguaccgggc ggaugaauat t 21 <210> 196 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1, 5, 16 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 3, 4, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 196 uauucauccg cccgguacct t 21 <210> 197 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 197 guaccgggcg gaugaauact t 21 <210> 198 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 198 guauucaucc gcccgguact t 21 <210> 199 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 2, 4, 5, 9, 13, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 6, 7, 8, 10, 11, 12, 14, 15, 16, 18 <223> /mod_base = "2'-hydroxy corresponding base" <400> 199 guaccgggcg gaugaauact t 21 <210> 200 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 2, 6, 17 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 4, 5, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 200 guauucaucc gcccgguact t 21 <210> 201 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 201 accgggcgga ugaauaccat t 21 <210> 202 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 202 ugguauucau ccgcccggut t 21 <210> 203 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 2, 3, 7, 11, 15, 17, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 4, 5, 6, 8, 9, 10, 12, 13, 14, 16, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 203 accgggcgga ugaauaccat t 21 <210> 204 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 4, 8 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 5, 6, 7, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 204 ugguauucau ccgcccggut t 21 <210> 205 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 205 ccgggcggau gaauaccagt t 21 <210> 206 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 206 cugguauuca uccgcccggt t 21 <210> 207 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1, 2, 6, 10, 14, 16, 17 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 3, 4, 5, 7, 8, 9, 11, 12, 13, 15, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 207 ccgggcggau gaauaccagt t 21 <210> 208 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 5, 9 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 6, 7, 8, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 208 cugguauuca uccgcccggt t 21 <210> 209 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 209 ccugguggag guguaucuct t 21 <210> 210 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 210 gagauacacc uccaccaggt t 21 <210> 211 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1, 2, 3, 6, 12, 14, 16, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 4, 5, 7, 8, 9, 10, 11, 13, 15 <223> /mod_base = "2'-hydroxy corresponding base" <400> 211 ccugguggag guguaucuct t 21 <210> 212 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 5, 7, 13, 16 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 6, 8, 9, 10, 11, 12, 14, 15, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 212 gagauacacc uccaccaggt t 21 <210> 213 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 213 cugguggagg uguaucucct t 21 <210> 214 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 214 ggagauacac cuccaccagt t 21 <210> 215 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1, 2, 5, 11, 13, 15, 16, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 3, 4, 6, 7, 8, 9, 10, 12, 14 <223> /mod_base = "2'-hydroxy corresponding base" <400> 215 cugguggagg uguaucucct t 21 <210> 216 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 6, 8, 14, 17 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 7, 9, 10, 11, 12, 13, 15, 16, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 216 ggagauacac cuccaccagt t 21 <210> 217 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 217 ugguggaggu guaucuccut t 21 <210> 218 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 218 aggagauaca ccuccaccat t 21 <210> 219 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1, 4, 10, 12, 14, 15, 16, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 3, 5, 6, 7, 8, 9, 11, 13 <223> /mod_base = "2'-hydroxy corresponding base" <400> 219 ugguggaggu guaucuccut t 21 <210> 220 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 7, 9, 15, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 6, 8, 10, 11, 12, 13, 14, 16, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 220 aggagauaca ccuccaccat t 21 <210> 221 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 221 gguggaggug uaucuccuat t 21 <210> 222 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 222 uaggagauac accuccacct t 21 <210> 223 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 3, 9, 11, 13, 14, 15, 16, 17, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 4, 5, 6, 7, 8, 10, 12, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 223 gguggaggug uaucuccuat t 21 <210> 224 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1, 8, 10, 16 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 3, 4, 5, 6, 7, 9, 11, 12, 13, 14, 15, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 224 uaggagauac accuccacct t 21 <210> 225 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 225 ggagguguau cuccuagact t 21 <210> 226 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 226 gucuaggaga uacaccucct t 21 <210> 227 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 6, 8, 10, 11, 12, 13, 14, 15, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 7, 9, 16, 17, 18 <223> /mod_base = "2'-hydroxy corresponding base" <400> 227 ggagguguau cuccuagact t 21 <210> 228 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 4, 11, 13 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 5, 6, 7, 8, 9, 10, 12, 14, 15, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 228 gucuaggaga uacaccucct t 21 <210> 229 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 229 agguguaucu ccuagacact t 21 <210> 230 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 230 gugucuagga gauacaccut t 21 <210> 231 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 4, 6, 8, 9, 10, 11, 12, 13, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 5, 7, 14, 15, 16, 18 <223> /mod_base = "2'-hydroxy corresponding base" <400> 231 agguguaucu ccuagacact t 21 <210> 232 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 6, 13, 15 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, 14, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 232 gugucuagga gauacaccut t 21 <210> 233 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 233 agguguaucu ccuagacact t 21 <210> 234 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 234 gugucuagga gauacaccut t 21 <210> 235 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 4, 6, 8, 9, 10, 11, 12, 13, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 5, 7, 14, 15, 16, 18 <223> /mod_base = "2'-hydroxy corresponding base" <400> 235 agguguaucu ccuagacact t 21 <210> 236 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 5, 6, 13, 15, 17, 18, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 7, 8, 9, 10, 11, 12, 14, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 236 gugucuagga gauacaccut t 21 <210> 237 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 237 agguguaucu ccuagacact t 21 <210> 238 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 238 gugucuagga gauacaccut t 21 <210> 239 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 239 agguguaucu ccuagacact t 21 <210> 240 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 5, 6, 13, 15, 17, 18, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 7, 8, 9, 10, 11, 12, 14, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 240 gugucuagga gauacaccut t 21 <210> 241 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 241 agguguaucu ccuagacact t 21 <210> 242 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 8, 9, 12, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 242 gugucuagga gauacaccut t 21 <210> 243 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 4, 6, 8, 9, 10, 11, 12, 13, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 5, 7, 14, 15, 16, 18 <223> /mod_base = "2'-hydroxy corresponding base" <400> 243 agguguaucu ccuagacact t 21 <210> 244 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 8, 9, 12, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 244 gugucuagga gauacaccut t 21 <210> 245 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 245 agguguaucu ccuagacact t 21 <210> 246 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 8, 9, 12, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 246 gugucuagga gauacaccut t 21 <210> 247 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 247 gcacccucau aggccuggat t 21 <210> 248 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 248 uccaggccua ugagggugct t 21 <210> 249 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 5, 6, 7, 8, 10, 14, 15, 16 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 9, 11, 12, 13, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 249 gcacccucau aggccuggat t 21 <210> 250 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 2, 3, 7, 8, 9, 11, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 4, 5, 6, 10, 12, 13, 14, 15, 16, 18 <223> /mod_base = "2'-hydroxy corresponding base" <400> 250 uccaggccua ugagggugct t 21 <210> 251 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 251 gcacccucau aggccuggat t 21 <210> 252 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 252 uccaggccua ugagggugct t 21 <210> 253 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 253 gcacccucau aggccuggat t 21 <210> 254 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 2, 3, 7, 8, 9, 11, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 4, 5, 6, 10, 12, 13, 14, 15, 16, 18 <223> /mod_base = "2'-hydroxy corresponding base" <400> 254 uccaggccua ugagggugct t 21 <210> 255 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 255 gcacccucau aggccuggat t 21 <210> 256 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 8, 9, 12, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 256 uccaggccua ugagggugct t 21 <210> 257 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 5, 6, 7, 8, 10, 14, 15, 16 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 9, 11, 12, 13, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 257 gcacccucau aggccuggat t 21 <210> 258 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 8, 9, 12, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 258 uccaggccua ugagggugct t 21 <210> 259 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 259 gcacccucau aggccuggat t 21 <210> 260 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 8, 9, 12, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 260 uccaggccua ugagggugct t 21 <210> 261 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 261 uguaucuccu agacaccagt t 21 <210> 262 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 262 cuggugucua ggagauacat t 21 <210> 263 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 5, 6, 7, 8, 9, 10, 14, 16, 17 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 4, 11, 12, 13, 15, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 263 uguaucuccu agacaccagt t 21 <210> 264 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 9, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 6, 7, 8, 10, 11, 12, 13, 14, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 264 cuggugucua ggagauacat t 21 <210> 265 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 265 ucuccuagac accagcauat t 21 <210> 266 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 266 uaugcuggug ucuaggagat t 21 <210> 267 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 2, 3, 4, 5, 6, 10, 12, 13, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 7, 8, 9, 11, 14, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 267 ucuccuagac accagcauat t 21 <210> 268 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 13 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 15, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 268 uaugcuggug ucuaggagat t 21 <210> 269 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 269 ucuccuagac accagcauat t 21 <210> 270 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 270 uaugcuggug ucuaggagat t 21 <210> 271 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 2, 3, 4, 5, 6, 10, 12, 13, 16, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 7, 8, 9, 11, 14, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 271 ucuccuagac accagcauat t 21 <210> 272 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 5, 6, 9, 11, 12, 13 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 4, 7, 8, 10, 14, 15, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 272 uaugcuggug ucuaggagat t 21 <210> 273 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 273 ucuccuagac accagcauat t 21 <210> 274 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 274 uaugcuggug ucuaggagat t 21 <210> 275 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 275 ucuccuagac accagcauat t 21 <210> 276 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 5, 6, 9, 11, 12, 13 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 4, 7, 8, 10, 14, 15, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 276 uaugcuggug ucuaggagat t 21 <210> 277 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 1, 3, 5, 8, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 7 <223> /mod_base = "2'-hydroxy corresponding base" <400> 277 ucuccuaaac accagcauat t 21 <210> 278 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 8, 9, 12, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 278 uaugcuggug ucuaggagat t 21 <210> 279 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 2, 3, 4, 5, 6, 10, 12, 13, 16, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 7, 8, 9, 11, 14, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 279 ucuccuagac accagcauat t 21 <210> 280 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 8, 9, 12, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 280 uaugcuggug ucuaggagat t 21 <210> 281 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 281 ucuccuagac accagcauat t 21 <210> 282 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 8, 9, 12, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 282 uaugcuggug ucuaggagat t 21 <210> 283 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 283 aggccuggag uuuauucggt t 21 <210> 284 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 284 ccgaauaaac uccaggccut t 21 <210> 285 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 4, 5, 6, 11, 12, 13, 15, 16, 17 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 7, 8, 9, 10, 14, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 285 aggccuggag uuuauucggt t 21 <210> 286 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 2, 6, 10, 11, 12, 13, 17, 18, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 3, 4, 5, 7, 8, 9, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 286 ccgaauaaac uccaggccut t 21 <210> 287 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 287 aggccuggag uuuauucggt t 21 <210> 288 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 288 ccgaauaaac uccaggccut t 21 <210> 289 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 289 aggccuggag uuuauucggt t 21 <210> 290 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 2, 6, 10, 11, 12, 13, 17, 18, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 3, 4, 5, 7, 8, 9, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 290 ccgaauaaac uccaggccut t 21 <210> 291 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 291 aggccuggag uuuauucggt t 21 <210> 292 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 8, 9, 12, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 292 ccgaauaaac uccaggccut t 21 <210> 293 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 4, 5, 6, 11, 12, 13, 15, 16, 17 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 7, 8, 9, 10, 14, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 293 aggccuggag uuuauucggt t 21 <210> 294 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 8, 9, 12, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 294 ccgaauaaac uccaggccut t 21 <210> 295 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 295 aggccuggag uuuauucggt t 21 <210> 296 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 8, 9, 12, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 296 ccgaauaaac uccaggccut t 21 <210> 297 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 297 cuccuagaca ccagcauact t 21 <210> 298 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 298 guaugcuggu gucuaggagt t 21 <210> 299 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 2, 3, 4, 5, 9, 11, 12, 15, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 6, 7, 8, 10, 13, 14, 16, 18 <223> /mod_base = "2'-hydroxy corresponding base" <400> 299 cuccuagaca ccagcauact t 21 <210> 300 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 14 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 300 guaugcuggu gucuaggagt t 21 <210> 301 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 301 uccuagacac cagcauacat t 21 <210> 302 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 302 uguaugcugg ugucuaggat t 21 <210> 303 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 2, 3, 4, 8, 10, 11, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 5, 6, 7, 9, 12, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 303 uccuagacac cagcauacat t 21 <210> 304 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 3, 15 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 304 uguaugcugg ugucuaggat t 21 <210> 305 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 305 ccuagacacc agcauacagt t 21 <210> 306 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 306 cuguaugcug gugucuaggt t 21 <210> 307 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 2, 3, 7, 9, 10, 13, 15, 17 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 4, 5, 6, 8, 11, 12, 14, 16, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 307 ccuagacacc agcauacagt t 21 <210> 308 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 4, 16 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 308 cuguaugcug gugucuaggt t 21 <210> 309 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 309 gacaccagca uacagagugt t 21 <210> 310 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 310 cacucuguau gcugguguct t 21 <210> 311 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 3, 5, 6, 9, 11, 13, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 4, 7, 8, 10, 12, 14, 15, 16, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 311 gacaccagca uacagagugt t 21 <210> 312 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 8 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 312 cacucuguau gcugguguct t 21 <210> 313 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 313 cauacagagu gaccaccggt t 21 <210> 314 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 314 ccggugguca cucuguaugt t 21 <210> 315 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 5, 10, 13, 14, 16, 17 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 4, 6, 7, 8, 9, 11, 12, 15, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 315 cauacagagu gaccaccggt t 21 <210> 316 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 9, 16 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 6, 7, 8, 10, 11, 12, 13, 14, 15, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 316 ccggugguca cucuguaugt t 21 <210> 317 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 317 agagugacca ccgggaaaut t 21 <210> 318 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 318 auuucccggu ggucacucut t 21 <210> 319 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 5, 8, 9, 11, 12, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 6, 7, 10, 13, 14, 15, 16, 17, 18 <223> /mod_base = "2'-hydroxy corresponding base" <400> 319 agagugacca ccgggaaaut t 21 <210> 320 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 14 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 320 auuucccggu ggucacucut t 21 <210> 321 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 321 gagugaccac cgggaaauct t 21 <210> 322 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 322 gauuucccgg uggucacuct t 21 <210> 323 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 4, 7, 8, 10, 11, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 5, 6, 9, 12, 13, 14, 15, 16, 17 <223> /mod_base = "2'-hydroxy corresponding base" <400> 323 gagugaccac cgggaaauct t 21 <210> 324 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 15 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 324 gauuucccgg uggucacuct t 21 <210> 325 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 325 gugaccaccg ggaaaucgat t 21 <210> 326 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 326 ucgauuuccc gguggucact t 21 <210> 327 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 5, 6, 8, 9, 16, 17 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 4, 7, 10, 11, 12, 13, 14, 15, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 327 gugaccaccg ggaaaucgat t 21 <210> 328 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 17 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 328 ucgauuuccc gguggucact t 21 <210> 329 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 329 gaccaccggg aaaucgaggt t 21 <210> 330 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 330 ccucgauuuc ccggugguct t 21 <210> 331 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 3, 4, 6, 7, 14, 15 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 5, 8, 9, 10, 11, 12, 13, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 331 gaccaccggg aaaucgaggt t 21 <210> 332 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 332 ccucgauuuc ccggugguct t 21 <210> 333 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 333 accaccggga aaucgagggt t 21 <210> 334 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 334 cccucgauuu cccgguggut t 21 <210> 335 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 3, 5, 6, 13, 14 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 4, 7, 8, 9, 10, 11, 12, 15, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 335 accaccggga aaucgagggt t 21 <210> 336 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 336 cccucgauuu cccgguggut t 21 <210> 337 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 337 ccaccgggaa aucgagggct t 21 <210> 338 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 338 gcccucgauu ucccgguggt t 21 <210> 339 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 2, 4, 5, 12, 13, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 3, 6, 7, 8, 9, 10, 11, 14, 15, 16, 17, 18 <223> /mod_base = "2'-hydroxy corresponding base" <400> 339 ccaccgggaa aucgagggct t 21 <210> 340 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 340 gcccucgauu ucccgguggt t 21 <210> 341 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 341 aaaucgaggg cagggucaut t 21 <210> 342 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 342 augacccugc ccucgauuut t 21 <210> 343 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 4, 5, 11, 16, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 6, 7, 8, 9, 10, 12, 13, 14, 15, 18 <223> /mod_base = "2'-hydroxy corresponding base" <400> 343 aaaucgaggg cagggucaut t 21 <210> 344 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 344 augacccugc ccucgauuut t 21 <210> 345 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 345 aaaucgaggg cagggucaut t 21 <210> 346 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 346 augacccugc ccucgauuut t 21 <210> 347 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 4, 5, 11, 16, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 6, 7, 8, 9, 10, 12, 13, 14, 15, 18 <223> /mod_base = "2'-hydroxy corresponding base" <400> 347 aaaucgaggg cagggucaut t 21 <210> 348 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 5, 6, 7, 8, 10, 11, 12, 13, 14, 17, 18, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 4, 9, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 348 augacccugc ccucgauuut t 21 <210> 349 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 349 aaaucgaggg cagggucaut t 21 <210> 350 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 350 augacccugc ccucgauuut t 21 <210> 351 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 351 aaaucgaggg cagggucaut t 21 <210> 352 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 5, 6, 7, 8, 10, 11, 12, 13, 14, 17, 18, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 4, 9, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 352 augacccugc ccucgauuut t 21 <210> 353 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 353 aaaucgaggg cagggucaut t 21 <210> 354 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 8, 9, 12, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 354 augacccugc ccucgauuut t 21 <210> 355 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 4, 5, 11, 16, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 6, 7, 8, 9, 10, 12, 13, 14, 15, 18 <223> /mod_base = "2'-hydroxy corresponding base" <400> 355 aaaucgaggg cagggucaut t 21 <210> 356 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 8, 9, 12, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 356 augacccugc ccucgauuut t 21 <210> 357 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 357 aaaucgaggg cagggucaut t 21 <210> 358 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 8, 9, 12, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 358 augacccugc ccucgauuut t 21 <210> 359 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 359 cggcacccuc auaggccugt t 21 <210> 360 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 360 caggccuaug agggugccgt t 21 <210> 361 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 4, 6, 7, 8, 9, 10, 12, 16, 17, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 3, 5, 11, 13, 14, 15, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 361 cggcacccuc auaggccugt t 21 <210> 362 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 5, 6, 7, 9, 15, 17, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 3, 4, 8, 10, 11, 12, 13, 14, 16, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 362 caggccuaug agggugccgt t 21 <210> 363 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 363 cggcacccuc auaggccugt t 21 <210> 364 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 364 caggccuaug agggugccgt t 21 <210> 365 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 365 cggcacccuc auaggccugt t 21 <210> 366 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 5, 6, 7, 9, 15, 17, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 3, 4, 8, 10, 11, 12, 13, 14, 16, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 366 caggccuaug agggugccgt t 21 <210> 367 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 367 cggcacccuc auaggccugt t 21 <210> 368 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 8, 9, 12, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 368 caggccuaug agggugccgt t 21 <210> 369 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 4, 6, 7, 8, 9, 10, 12, 16, 17, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 3, 5, 11, 13, 14, 15, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 369 cggcacccuc auaggccugt t 21 <210> 370 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 8, 9, 12, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 370 caggccuaug agggugccgt t 21 <210> 371 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 371 cggcacccuc auaggccugt t 21 <210> 372 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 8, 9, 12, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 372 caggccuaug agggugccgt t 21 <210> 373 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 373 aucgagggca gggucauggt t 21 <210> 374 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 374 ccaugacccu gcccucgaut t 21 <210> 375 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 3, 9, 14, 15, 17 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 4, 5, 6, 7, 8, 10, 11, 12, 13, 16, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 375 aucgagggca gggucauggt t 21 <210> 376 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 376 ccaugacccu gcccucgaut t 21 <210> 377 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 7, 12, 13, 15, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 3, 4, 5, 6, 8, 9, 10, 11, 14, 16, 17 <223> /mod_base = "2'-hydroxy corresponding base" <400> 377 cgagggcagg gucaugguct t 21 <210> 378 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 4 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 378 gaccaugacc cugcccucgt t 21 <210> 379 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 379 gagggcaggg ucauggucat t 21 <210> 380 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 380 ugaccaugac ccugcccuct t 21 <210> 381 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 11, 12, 14, 17, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 7, 8, 9, 10, 13, 15, 16, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 381 gagggcaggg ucauggucat t 21 <210> 382 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 5 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 382 ugaccaugac ccugcccuct t 21 <210> 383 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 383 gggcaggguc auggucacct t 21 <210> 384 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 384 ggugaccaug acccugccct t 21 <210> 385 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 4, 9, 10, 12, 15, 16, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 5, 6, 7, 8, 11, 13, 14, 17 <223> /mod_base = "2'-hydroxy corresponding base" <400> 385 gggcaggguc auggucacct t 21 <210> 386 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 7 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 6, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 386 ggugaccaug acccugccct t 21 <210> 387 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 387 cagggucaug gucaccgact t 21 <210> 388 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 388 gucggugacc augacccugt t 21 <210> 389 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 6, 7, 9, 12, 13, 15, 16, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 3, 4, 5, 8, 10, 11, 14, 17, 18 <223> /mod_base = "2'-hydroxy corresponding base" <400> 389 cagggucaug gucaccgact t 21 <210> 390 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 10 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14, 15, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 390 gucggugacc augacccugt t 21 <210> 391 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 391 agggucaugg ucaccgacut t 21 <210> 392 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 392 agucggugac caugacccut t 21 <210> 393 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 5, 6, 8, 11, 12, 14, 15, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 7, 9, 10, 13, 16, 17 <223> /mod_base = "2'-hydroxy corresponding base" <400> 393 agggucaugg ucaccgacut t 21 <210> 394 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 11 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14, 15, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 394 agucggugac caugacccut t 21 <210> 395 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 395 auggucaccg acuucgagat t 21 <210> 396 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 396 ucucgaaguc ggugaccaut t 21 <210> 397 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 5, 6, 8, 9, 12, 13, 14, 15 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 4, 7, 10, 11, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 397 auggucaccg acuucgagat t 21 <210> 398 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 17 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 398 ucucgaaguc ggugaccaut t 21 <210> 399 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 399 ccgacuucga gaaugugcct t 21 <210> 400 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 400 ggcacauucu cgaagucggt t 21 <210> 401 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 401 ggaggacggg acccgcuuct t 21 <210> 402 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 402 gaagcggguc ccguccucct t 21 <210> 403 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 403 cagcggccgg gaugccggct t 21 <210> 404 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 404 gccggcaucc cggccgcugt t 21 <210> 405 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 4, 7, 8, 13, 15, 16, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 3, 5, 6, 9, 10, 11, 12, 14, 17, 18 <223> /mod_base = "2'-hydroxy corresponding base" <400> 405 cagcggccgg gaugccggct t 21 <210> 406 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 406 gccggcaucc cggccgcugt t 21 <210> 407 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 407 gggugccagc augcgcagct t 21 <210> 408 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 408 gcugcgcaug cuggcaccct t 21 <210> 409 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 409 ccugcgcgug cucaacugct t 21 <210> 410 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 410 gcaguugagc acgcgcaggt t 21 <210> 411 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 2, 3, 5, 7, 9, 11, 12, 13, 16, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 4, 6, 8, 10, 14, 15, 18 <223> /mod_base = "2'-hydroxy corresponding base" <400> 411 ccugcgcgug cucaacugct t 21 <210> 412 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 10, 16 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14, 15, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 412 gcaguugagc acgcgcaggt t 21 <210> 413 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 413 ugcgcgugcu caacugccat t 21 <210> 414 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 414 uggcaguuga gcacgcgcat t 21 <210> 415 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 5, 7, 9, 10, 11, 14, 15, 17, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 4, 6, 8, 12, 13, 16, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 415 ugcgcgugcu caacugccat t 21 <210> 416 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 4, 12, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 13, 14, 15, 16, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 416 uggcaguuga gcacgcgcat t 21 <210> 417 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 417 cgcgugcuca acugccaagt t 21 <210> 418 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 418 cuuggcaguu gagcacgcgt t 21 <210> 419 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 5, 7, 8, 9, 12, 13, 15, 16 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 4, 6, 10, 11, 14, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 419 cgcgugcuca acugccaagt t 21 <210> 420 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 14 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, 13, 15, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 420 cuuggcaguu gagcacgcgt t 21 <210> 421 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 421 cugccaaggg aagggcacgt t 21 <210> 422 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 422 cgugcccuuc ccuuggcagt t 21 <210> 423 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 2, 4, 5, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 3, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 423 cugccaaggg aagggcacgt t 21 <210> 424 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 17 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 424 cgugcccuuc ccuuggcagt t 21 <210> 425 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 425 caagggaagg gcacgguuat t 21 <210> 426 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 426 uaaccgugcc cuucccuugt t 21 <210> 427 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 427 aagggaaggg cacgguuagt t 21 <210> 428 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 428 cuaaccgugc ccuucccuut t 21 <210> 429 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 429 agggaagggc acgguuagct t 21 <210> 430 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 430 gcuaaccgug cccuucccut t 21 <210> 431 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 431 gggaagggca cgguuagcgt t 21 <210> 432 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 432 cgcuaaccgu gcccuuccct t 21 <210> 433 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 433 ggaagggcac gguuagcggt t 21 <210> 434 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 434 ccgcuaaccg ugcccuucct t 21 <210> 435 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 435 gaagggcacg guuagcggct t 21 <210> 436 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 436 gccgcuaacc gugcccuuct t 21 <210> 437 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 437 aagggcacgg uuagcggcat t 21 <210> 438 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 438 ugccgcuaac cgugcccuut t 21 <210> 439 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 439 agggcacggu uagcggcact t 21 <210> 440 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 440 gugccgcuaa ccgugcccut t 21 <210> 441 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 441 cacgguuagc ggcacccuct t 21 <210> 442 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 442 gagggugccg cuaaccgugt t 21 <210> 443 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 443 acgguuagcg gcacccucat t 21 <210> 444 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 444 ugagggugcc gcuaaccgut t 21 <210> 445 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 445 guuagcggca cccucauagt t 21 <210> 446 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 446 cuaugagggu gccgcuaact t 21 <210> 447 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 447 uuagcggcac ccucauaggt t 21 <210> 448 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 448 ccuaugaggg ugccgcuaat t 21 <210> 449 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 449 gcggcacccu cauaggccut t 21 <210> 450 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 450 aggccuauga gggugccgct t 21 <210> 451 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 451 gcacccucau aggccuggat t 21 <210> 452 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 452 uccaggccua ugagggugct t 21 <210> 453 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 453 ucauaggccu ggaguuuaut t 21 <210> 454 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 454 auaaacucca ggccuaugat t 21 <210> 455 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 455 ggccuggagu uuauucggat t 21 <210> 456 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 456 uccgaauaaa cuccaggcct t 21 <210> 457 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 457 gccuggaguu uauucggaat t 21 <210> 458 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 458 uuccgaauaa acuccaggct t 21 <210> 459 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 3, 4, 9, 10, 11, 13, 14, 15 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 5, 6, 7, 8, 12, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 459 gccuggaguu uauucggaat t 21 <210> 460 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 8, 15 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 460 uuccgaauaa acuccaggct t 21 <210> 461 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 3, 4, 9, 10, 11, 13, 14, 15 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 5, 6, 7, 8, 12, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 461 gccuggaguu uauucggaat t 21 <210> 462 <211> 20 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 20 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..18 <223> /mod_base = "2'-hydroxy corresponding base" <400> 462 uuccgaauaa cuccaggctt 20 <210> 463 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 463 cuggaguuua uucggaaaat t 21 <210> 464 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 464 uuuuccgaau aaacuccagt t 21 <210> 465 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 2, 7, 8, 9, 11, 12, 13 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 3, 4, 5, 6, 10, 14, 15, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 465 cuggaguuua uucggaaaat t 21 <210> 466 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 10, 17 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14, 15, 16, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 466 uuuuccgaau aaacuccagt t 21 <210> 467 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 467 ggaguuuauu cggaaaagct t 21 <210> 468 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 468 gcuuuuccga auaaacucct t 21 <210> 469 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 5, 6, 7, 9, 10, 11, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 8, 12, 13, 14, 15, 16, 17, 18 <223> /mod_base = "2'-hydroxy corresponding base" <400> 469 ggaguuuauu cggaaaagct t 21 <210> 470 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 12 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 13, 14, 15, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 470 gcuuuuccga auaaacucct t 21 <210> 471 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 471 gaguuuauuc ggaaaagcct t 21 <210> 472 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 472 ggcuuuuccg aauaaacuct t 21 <210> 473 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 4, 5, 6, 8, 9, 10, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 7, 11, 12, 13, 14, 15, 16, 17 <223> /mod_base = "2'-hydroxy corresponding base" <400> 473 gaguuuauuc ggaaaagcct t 21 <210> 474 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 13 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 15, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 474 ggcuuuuccg aauaaacuct t 21 <210> 475 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 475 uuauucggaa aagccagcut t 21 <210> 476 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 476 agcuggcuuu uccgaauaat t 21 <210> 477 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 2, 4, 5, 6, 14, 15, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 3, 7, 8, 9, 10, 11, 12, 13, 16, 17 <223> /mod_base = "2'-hydroxy corresponding base" <400> 477 uuauucggaa aagccagcut t 21 <210> 478 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 17 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 478 agcuggcuuu uccgaauaat t 21 <210> 479 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 479 cccuggcggg uggguacagt t 21 <210> 480 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 480 cuguacccac ccgccagggt t 21 <210> 481 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 2, 3, 4, 7, 11, 15, 17 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 5, 6, 8, 9, 10, 12, 13, 14, 16, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 481 cccuggcggg uggguacagt t 21 <210> 482 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 4, 8, 15 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 5, 6, 7, 9, 10, 11, 12, 13, 14, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 482 cuguacccac ccgccagggt t 21 <210> 483 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 483 ccuggcgggu ggguacagct t 21 <210> 484 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 484 gcuguaccca cccgccaggt t 21 <210> 485 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 485 uggcgggugg guacagccgt t 21 <210> 486 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 486 cggcuguacc cacccgccat t 21 <210> 487 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 4, 8, 12, 14, 17, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 3, 5, 6, 7, 9, 10, 11, 13, 15, 16, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 487 uggcgggugg guacagccgt t 21 <210> 488 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 7, 11, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 6, 8, 9, 10, 12, 13, 14, 15, 16, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 488 cggcuguacc cacccgccat t 21 <210> 489 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 489 ggcggguggg uacagccgct t 21 <210> 490 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 490 gcggcuguac ccacccgcct t 21 <210> 491 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 491 gguggguaca gccgcgucct t 21 <210> 492 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 492 ggacgcggcu guacccacct t 21 <210> 493 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 493 uggguacagc cgcguccuct t 21 <210> 494 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 494 gaggacgcgg cuguacccat t 21 <210> 495 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 495 gccgcguccu caacgccgct t 21 <210> 496 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 496 gcggcguuga ggacgcggct t 21 <210> 497 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 497 ccgcguccuc aacgccgcct t 21 <210> 498 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 498 ggcggcguug aggacgcggt t 21 <210> 499 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 499 gucgugcugg ucaccgcugt t 21 <210> 500 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 500 cagcggugac cagcacgact t 21 <210> 501 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 3, 5, 7, 8, 11, 12, 14, 15, 17, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 4, 6, 9, 10, 13, 16, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 501 gucgugcugg ucaccgcugt t 21 <210> 502 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 11, 14 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 15, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 502 cagcggugac cagcacgact t 21 <210> 503 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 503 ucgugcuggu caccgcugct t 21 <210> 504 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 504 gcagcgguga ccagcacgat t 21 <210> 505 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 2, 4, 6, 7, 10, 11, 13, 14, 16, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 3, 5, 8, 9, 12, 15, 18 <223> /mod_base = "2'-hydroxy corresponding base" <400> 505 ucgugcuggu caccgcugct t 21 <210> 506 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 12, 15 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 4, 5, 6, 7, 8, 9, 10, 11, 13, 14, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 506 gcagcgguga ccagcacgat t 21 <210> 507 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 507 uggucaccgc ugccggcaat t 21 <210> 508 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 508 uugccggcag cggugaccat t 21 <210> 509 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 4, 5, 7, 8, 10, 11, 13, 14, 17 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 3, 6, 9, 12, 15, 16, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 509 uggucaccgc ugccggcaat t 21 <210> 510 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 8, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, 15, 16, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 510 uugccggcag cggugaccat t 21 <210> 511 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 511 ggucaccgcu gccggcaact t 21 <210> 512 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 512 guugccggca gcggugacct t 21 <210> 513 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 3, 4, 6, 7, 9, 10, 12, 13, 16, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 5, 8, 11, 14, 15, 17, 18 <223> /mod_base = "2'-hydroxy corresponding base" <400> 513 ggucaccgcu gccggcaact t 21 <210> 514 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 9 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 6, 7, 8, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 514 guugccggca gcggugacct t 21 <210> 515 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 515 caccgcugcc ggcaacuuct t 21 <210> 516 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 516 gaaguugccg gcagcggugt t 21 <210> 517 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 4, 6, 7, 9, 10, 13, 16, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 5, 8, 11, 12, 14, 15 <223> /mod_base = "2'-hydroxy corresponding base" <400> 517 caccgcugcc ggcaacuuct t 21 <210> 518 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 12 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 13, 14, 15, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 518 gaaguugccg gcagcggugt t 21 <210> 519 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 519 ccgcugccgg caacuuccgt t 21 <210> 520 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 520 cggaaguugc cggcagcggt t 21 <210> 521 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 2, 4, 5, 7, 8, 11, 14, 15, 16, 17, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 3, 6, 9, 10, 12, 13, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 521 ccgcugccgg caacuuccgt t 21 <210> 522 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 14 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 522 cggaaguugc cggcagcggt t 21 <210> 523 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 523 cgcugccggc aacuuccggt t 21 <210> 524 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 524 ccggaaguug ccggcagcgt t 21 <210> 525 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 4, 6, 7, 10, 13, 14, 15, 16, 17 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 5, 8, 9, 11, 12, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 525 cgcugccggc aacuuccggt t 21 <210> 526 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 15 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 526 ccggaaguug ccggcagcgt t 21 <210> 527 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 527 gcugccggca acuuccgggt t 21 <210> 528 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 528 cccggaaguu gccggcagct t 21 <210> 529 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 3, 5, 6, 9, 12, 13, 14, 15, 16 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 4, 7, 8, 10, 11, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 529 gcugccggca acuuccgggt t 21 <210> 530 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 16 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 530 cccggaaguu gccggcagct t 21 <210> 531 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 531 cggcaacuuc cgggacgaut t 21 <210> 532 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 532 aucgucccgg aaguugccgt t 21 <210> 533 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 4, 7, 8, 9, 10, 11, 16, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 3, 5, 6, 12, 13, 14, 15, 17, 18 <223> /mod_base = "2'-hydroxy corresponding base" <400> 533 cggcaacuuc cgggacgaut t 21 <210> 534 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 534 aucgucccgg aaguugccgt t 21 <210> 535 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 535 ggcaacuucc gggacgaugt t 21 <210> 536 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 536 caucgucccg gaaguugcct t 21 <210> 537 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 3, 6, 7, 8, 9, 10, 15, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 4, 5, 11, 12, 13, 14, 16, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 537 ggcaacuucc gggacgaugt t 21 <210> 538 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 538 caucgucccg gaaguugcct t 21 <210> 539 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 539 uuccgggacg augccugcct t 21 <210> 540 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 540 ggcaggcauc gucccggaat t 21 <210> 541 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 2, 3, 4, 9, 12, 14, 15, 16, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 5, 6, 7, 8, 10, 11, 13, 17 <223> /mod_base = "2'-hydroxy corresponding base" <400> 541 uuccgggacg augccugcct t 21 <210> 542 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 3, 7 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 4, 5, 6, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 542 ggcaggcauc gucccggaat t 21 <210> 543 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 543 ggacgaugcc ugccucuact t 21 <210> 544 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 544 guagaggcag gcaucgucct t 21 <210> 545 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 545 ggacgaugcc ugccucuact t 21 <210> 546 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 546 guagaggcag gcaucgucct t 21 <210> 547 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 4, 7, 9, 10, 11, 13, 14, 15, 16, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 5, 6, 8, 12, 18 <223> /mod_base = "2'-hydroxy corresponding base" <400> 547 ggacgaugcc ugccucuact t 21 <210> 548 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 8, 12 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 4, 5, 6, 7, 9, 10, 11, 13, 14, 15, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 548 guagaggcag gcaucgucct t 21 <210> 549 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 549 gcucccgagg ucaucacagt t 21 <210> 550 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 550 cugugaugac cucgggagct t 21 <210> 551 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 551 cucccgaggu caucacagut t 21 <210> 552 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 552 acugugauga ccucgggagt t 21 <210> 553 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 553 ucccgagguc aucacaguut t 21 <210> 554 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 554 aacugugaug accucgggat t 21 <210> 555 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 555 ccaagaccag ccggugacct t 21 <210> 556 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 556 ggucaccggc uggucuuggt t 21 <210> 557 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 557 caagaccagc cggugaccct t 21 <210> 558 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 558 gggucaccgg cuggucuugt t 21 <210> 559 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 559 accaacuuug gccgcugugt t 21 <210> 560 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 560 cacagcggcc aaaguuggut t 21 <210> 561 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 3, 6, 7, 8, 9, 12, 13, 15, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 4, 5, 10, 11, 14, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 561 accaacuuug gccgcugugt t 21 <210> 562 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 10 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14, 15, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 562 cacagcggcc aaaguuggut t 21 <210> 563 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 563 caacuuuggc cgcugugugt t 21 <210> 564 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 564 cacacagcgg ccaaaguugt t 21 <210> 565 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 4, 5, 6, 7, 10, 11, 13, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 3, 8, 9, 12, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 565 caacuuuggc cgcugugugt t 21 <210> 566 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 5, 12 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 4, 6, 7, 8, 9, 10, 11, 13, 14, 15, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 566 cacacagcgg ccaaaguugt t 21 <210> 567 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 567 cgcugugugg accucuuugt t 21 <210> 568 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 568 caaagagguc cacacagcgt t 21 <210> 569 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 4, 6, 8, 12, 13, 14, 15, 16, 17, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 5, 7, 9, 10, 11, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 569 cgcugugugg accucuuugt t 21 <210> 570 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 11, 13, 15 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 570 caaagagguc cacacagcgt t 21 <210> 571 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 571 gacaucauug gugccuccat t 21 <210> 572 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 572 uggaggcacc aaugauguct t 21 <210> 573 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 3, 5, 6, 8, 9, 12, 14, 15, 16, 17, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 4, 7, 10, 11, 13, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 573 gacaucauug gugccuccat t 21 <210> 574 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 7, 10 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 6, 8, 9, 11, 12, 13, 14, 15, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 574 uggaggcacc aaugauguct t 21 <210> 575 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 575 ucauuggugc cuccagcgat t 21 <210> 576 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 576 ucgcuggagg caccaaugat t 21 <210> 577 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 2, 4, 5, 8, 10, 11, 12, 13, 14, 17 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 3, 6, 7, 9, 15, 16, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 577 ucauuggugc cuccagcgat t 21 <210> 578 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 11, 14 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 15, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 578 ucgcuggagg caccaaugat t 21 <210> 579 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 579 agcaccugcu uugugucact t 21 <210> 580 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 580 gugacacaaa gcaggugcut t 21 <210> 581 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 3, 5, 6, 7, 9, 10, 11, 12, 14, 16, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 4, 8, 13, 15, 18 <223> /mod_base = "2'-hydroxy corresponding base" <400> 581 agcaccugcu uugugucact t 21 <210> 582 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 5, 7, 12 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 6, 8, 9, 10, 11, 13, 14, 15, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 582 gugacacaaa gcaggugcut t 21 <210> 583 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 583 cacagagugg gacaucacat t 21 <210> 584 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 584 ugugaugucc cacucugugt t 21 <210> 585 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 585 augcugucug ccgagccggt t 21 <210> 586 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 586 ccggcucggc agacagcaut t 21 <210> 587 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 5, 7, 8, 9, 11, 12, 16, 17 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 6, 10, 13, 14, 15, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 587 augcugucug ccgagccggt t 21 <210> 588 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 10, 14, 17 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 15, 16, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 588 ccggcucggc agacagcaut t 21 <210> 589 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 589 gucugccgag ccggagcuct t 21 <210> 590 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 590 gagcuccggc ucggcagact t 21 <210> 591 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 3, 4, 6, 7, 11, 12, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 5, 8, 9, 10, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 591 gucugccgag ccggagcuct t 21 <210> 592 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 15 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 592 gagcuccggc ucggcagact t 21 <210> 593 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 593 guugaggcag agacugauct t 21 <210> 594 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 594 gaucagucuc ugccucaact t 21 <210> 595 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 3, 8, 14, 15, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 4, 5, 6, 7, 9, 10, 11, 12, 13, 16, 17 <223> /mod_base = "2'-hydroxy corresponding base" <400> 595 guugaggcag agacugauct t 21 <210> 596 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 4, 16 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 596 gaucagucuc ugccucaact t 21 <210> 597 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 597 gcagagacug auccacuuct t 21 <210> 598 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 598 gaaguggauc agucucugct t 21 <210> 599 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 8, 9, 12, 13, 14, 16, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 4, 5, 6, 7, 10, 11, 15 <223> /mod_base = "2'-hydroxy corresponding base" <400> 599 gcagagacug auccacuuct t 21 <210> 600 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 10 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14, 15, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 600 gaaguggauc agucucugct t 21 <210> 601 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 601 agagacugau ccacuucuct t 21 <210> 602 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 602 gagaagugga ucagucucut t 21 <210> 603 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 7, 10, 11, 12, 14, 15, 16, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 8, 9, 13 <223> /mod_base = "2'-hydroxy corresponding base" <400> 603 agagacugau ccacuucuct t 21 <210> 604 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 12 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 13, 14, 15, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 604 gagaagugga ucagucucut t 21 <210> 605 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 605 uucucugcca aagaugucat t 21 <210> 606 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 606 ugacaucuuu ggcagagaat t 21 <210> 607 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 2, 3, 4, 5, 6, 8, 9, 15, 17, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 7, 10, 11, 12, 13, 14, 16, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 607 uucucugcca aagaugucat t 21 <210> 608 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 4, 13 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 14, 15, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 608 ugacaucuuu ggcagagaat t 21 <210> 609 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 609 cucugccaaa gaugucauct t 21 <210> 610 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 610 gaugacaucu uuggcagagt t 21 <210> 611 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 2, 3, 4, 6, 7, 13, 15, 16, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 5, 8, 9, 10, 11, 12, 14, 17 <223> /mod_base = "2'-hydroxy corresponding base" <400> 611 cucugccaaa gaugucauct t 21 <210> 612 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 15 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, 13, 14, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 612 gaugacaucu uuggcagagt t 21 <210> 613 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 613 cugaggacca gcggguacut t 21 <210> 614 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 614 aguacccgcu gguccucagt t 21 <210> 615 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 2, 8, 9, 12, 16, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 3, 4, 5, 6, 7, 10, 11, 13, 14, 15, 17 <223> /mod_base = "2'-hydroxy corresponding base" <400> 615 cugaggacca gcggguacut t 21 <210> 616 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 3, 17 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 616 aguacccgcu gguccucagt t 21 <210> 617 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 617 ugaggaccag cggguacugt t 21 <210> 618 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 618 caguacccgc ugguccucat t 21 <210> 619 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 7, 8, 11, 15, 17, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 3, 4, 5, 6, 9, 10, 12, 13, 14, 16, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 619 ugaggaccag cggguacugt t 21 <210> 620 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 4, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 620 caguacccgc ugguccucat t 21 <210> 621 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 621 acuguauggu cagcacacut t 21 <210> 622 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 622 agugugcuga ccauacagut t 21 <210> 623 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 623 uguaugguca gcacacucgt t 21 <210> 624 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 624 cgagugugcu gaccauacat t 21 <210> 625 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 625 guauggucag cacacucggt t 21 <210> 626 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 626 ccgagugugc ugaccauact t 21 <210> 627 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 627 ggauggccac agccgucgct t 21 <210> 628 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 628 gcgacggcug uggccaucct t 21 <210> 629 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 629 gauggccaca gccgucgcct t 21 <210> 630 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 630 ggcgacggcu guggccauct t 21 <210> 631 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 631 caagcugguc ugccgggcct t 21 <210> 632 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 632 ggcccggcag accagcuugt t 21 <210> 633 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 633 cugccgggcc cacaacgcut t 21 <210> 634 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 634 agcguugugg gcccggcagt t 21 <210> 635 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 2, 4, 5, 9, 10, 11, 13, 16, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 3, 6, 7, 8, 12, 14, 15, 17 <223> /mod_base = "2'-hydroxy corresponding base" <400> 635 cugccgggcc cacaacgcut t 21 <210> 636 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 17 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 636 agcguugugg gcccggcagt t 21 <210> 637 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 637 ugccgggccc acaacgcuut t 21 <210> 638 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 638 aagcguugug ggcccggcat t 21 <210> 639 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 4, 8, 9, 10, 12, 15, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 5, 6, 7, 11, 13, 14, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 639 ugccgggccc acaacgcuut t 21 <210> 640 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 640 aagcguugug ggcccggcat t 21 <210> 641 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 641 ccgggcccac aacgcuuuut t 21 <210> 642 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 642 aaaagcguug ugggcccggt t 21 <210> 643 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 2, 6, 7, 8, 10, 13, 15, 16, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 3, 4, 5, 9, 11, 12, 14 <223> /mod_base = "2'-hydroxy corresponding base" <400> 643 ccgggcccac aacgcuuuut t 21 <210> 644 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 644 aaaagcguug ugggcccggt t 21 <210> 645 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 645 gggcccacaa cgcuuuuggt t 21 <210> 646 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 646 ccaaaagcgu ugugggccct t 21 <210> 647 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 4, 5, 6, 8, 11, 13, 14, 15, 16, 17 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 7, 9, 10, 12, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 647 gggcccacaa cgcuuuuggt t 21 <210> 648 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 648 ccaaaagcgu ugugggccct t 21 <210> 649 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 649 ggugagggug ucuacgccat t 21 <210> 650 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 650 uggcguagac acccucacct t 21 <210> 651 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 3, 9, 11, 12, 13, 15, 17, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 4, 5, 6, 7, 8, 10, 14, 16, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 651 ggugagggug ucuacgccat t 21 <210> 652 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 10, 16 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 7, 8, 9, 11, 12, 13, 14, 15, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 652 uggcguagac acccucacct t 21 <210> 653 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 653 gagggugucu acgccauugt t 21 <210> 654 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 654 caauggcgua gacacccuct t 21 <210> 655 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 8, 9, 10, 12, 14, 15, 17, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 7, 11, 13, 16, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 655 gagggugucu acgccauugt t 21 <210> 656 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 9, 13 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 3, 4, 5, 6, 7, 8, 10, 11, 12, 14, 15, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 656 caauggcgua gacacccuct t 21 <210> 657 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 657 gccaggugcu gccugcuact t 21 <210> 658 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 658 guagcaggca gcaccuggct t 21 <210> 659 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 3, 7, 9, 10, 12, 13, 14, 16, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 4, 5, 6, 8, 11, 15, 18 <223> /mod_base = "2'-hydroxy corresponding base" <400> 659 gccaggugcu gccugcuact t 21 <210> 660 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 5, 9, 12 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 4, 6, 7, 8, 10, 11, 13, 14, 15, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 660 guagcaggca gcaccuggct t 21 <210> 661 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 661 ccaggugcug ccugcuacct t 21 <210> 662 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 662 gguagcaggc agcaccuggt t 21 <210> 663 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 2, 6, 8, 9, 11, 12, 13, 15, 16, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 3, 4, 5, 7, 10, 14, 17 <223> /mod_base = "2'-hydroxy corresponding base" <400> 663 ccaggugcug ccugcuacct t 21 <210> 664 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 3, 6, 10, 13 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 4, 5, 7, 8, 9, 11, 12, 14, 15, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 664 gguagcaggc agcaccuggt t 21 <210> 665 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 665 acccacaagc cgccugugct t 21 <210> 666 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 666 gcacaggcgg cuugugggut t 21 <210> 667 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 667 gugcugaggc cacgagguct t 21 <210> 668 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 668 gaccucgugg ccucagcact t 21 <210> 669 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 5, 10, 11, 13, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 6, 7, 8, 9, 12, 14, 15, 16, 17 <223> /mod_base = "2'-hydroxy corresponding base" <400> 669 gugcugaggc cacgagguct t 21 <210> 670 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 14, 17 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15, 16, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 670 gaccucgugg ccucagcact t 21 <210> 671 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 671 ugcugaggcc acgaggucat t 21 <210> 672 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 672 ugaccucgug gccucagcat t 21 <210> 673 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 673 ugcugaggcc acgaggucat t 21 <210> 674 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 674 ugaccucgug gccucagcat t 21 <210> 675 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 4, 9, 10, 12, 17, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 5, 6, 7, 8, 11, 13, 14, 15, 16, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 675 ugcugaggcc acgaggucat t 21 <210> 676 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 15, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 676 ugaccucgug gccucagcat t 21 <210> 677 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 677 ugcugaggcc acgaggucat t 21 <210> 678 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 678 ugaccucgug gccucagcat t 21 <210> 679 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 4, 9, 10, 12, 17, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 5, 6, 7, 8, 11, 13, 14, 15, 16, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 679 ugcugaggcc acgaggucat t 21 <210> 680 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 4, 5, 6, 7, 9, 12, 13, 14, 15, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 3, 8, 10, 11, 16, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 680 ugaccucgug gccucagcat t 21 <210> 681 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 681 ugcugaggcc acgaggucat t 21 <210> 682 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 682 ugaccucgug gccucagcat t 21 <210> 683 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 683 ugcugaggcc acgaggucat t 21 <210> 684 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 4, 5, 6, 7, 9, 12, 13, 14, 15, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 3, 8, 10, 11, 16, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 684 ugaccucgug gccucagcat t 21 <210> 685 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 685 ugcugaggcc acgaggucat t 21 <210> 686 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 8, 9, 12, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 686 ugaccucgug gccucagcat t 21 <210> 687 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 4, 9, 10, 12, 17, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 5, 6, 7, 8, 11, 13, 14, 15, 16, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 687 ugcugaggcc acgaggucat t 21 <210> 688 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 8, 9, 12, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 688 ugaccucgug gccucagcat t 21 <210> 689 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 689 ugcugaggcc acgaggucat t 21 <210> 690 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 8, 9, 12, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 690 ugaccucgug gccucagcat t 21 <210> 691 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 691 guggucagcg gccgggaugt t 21 <210> 692 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 692 caucccggcc gcugaccact t 21 <210> 693 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 5, 6, 9, 12, 13, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 4, 7, 8, 10, 11, 14, 15, 16, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 693 guggucagcg gccgggaugt t 21 <210> 694 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 4, 5, 6, 9, 10, 12, 13, 16, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 7, 8, 11, 14, 15, 18 <223> /mod_base = "2'-hydroxy corresponding base" <400> 694 caucccggcc gcugaccact t 21 <210> 695 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 695 guggucagcg gccgggaugt t 21 <210> 696 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 696 caucccggcc gcugaccact t 21 <210> 697 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 697 guggucagcg gccgggaugt t 21 <210> 698 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 4, 5, 6, 9, 10, 12, 13, 16, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 7, 8, 11, 14, 15, 18 <223> /mod_base = "2'-hydroxy corresponding base" <400> 698 caucccggcc gcugaccact t 21 <210> 699 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 699 guggucagcg gccgggaugt t 21 <210> 700 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 8, 9, 12, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 700 caucccggcc gcugaccact t 21 <210> 701 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 5, 6, 9, 12, 13, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 4, 7, 8, 10, 11, 14, 15, 16, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 701 guggucagcg gccgggaugt t 21 <210> 702 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 8, 9, 12, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 702 caucccggcc gcugaccact t 21 <210> 703 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 703 guggucagcg gccgggaugt t 21 <210> 704 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 8, 9, 12, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 704 caucccggcc gcugaccact t 21 <210> 705 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 705 ggccacgagg ucagcccaat t 21 <210> 706 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 706 uugggcugac cucguggcct t 21 <210> 707 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 707 cgaggucagc ccaaccagut t 21 <210> 708 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 708 acugguuggg cugaccucgt t 21 <210> 709 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 709 gucagcccaa ccagugcgut t 21 <210> 710 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 710 acgcacuggu ugggcugact t 21 <210> 711 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 711 cagcccaacc agugcguggt t 21 <210> 712 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 712 ccacgcacug guugggcugt t 21 <210> 713 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 713 cacagggagg ccagcaucct t 21 <210> 714 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 714 ggaugcuggc cucccugugt t 21 <210> 715 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 715 ccagcaucca cgcuuccugt t 21 <210> 716 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 716 caggaagcgu ggaugcuggt t 21 <210> 717 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 2, 5, 7, 8, 9, 11, 13, 14, 15, 16, 17, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 3, 4, 6, 10, 12, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 717 ccagcaucca cgcuuccugt t 21 <210> 718 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 718 caggaagcgu ggaugcuggt t 21 <210> 719 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 719 agucaaggag cauggaauct t 21 <210> 720 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 720 gauuccaugc uccuugacut t 21 <210> 721 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 3, 4, 11, 13, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 5, 6, 7, 8, 9, 10, 12, 14, 15, 16, 17 <223> /mod_base = "2'-hydroxy corresponding base" <400> 721 agucaaggag cauggaauct t 21 <210> 722 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 722 gauuccaugc uccuugacut t 21 <210> 723 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 723 agucaaggag cauggaauct t 21 <210> 724 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 724 gauuccaugc uccuugacut t 21 <210> 725 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 3, 4, 11, 13, 18, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 5, 6, 7, 8, 9, 10, 12, 14, 15, 16, 17 <223> /mod_base = "2'-hydroxy corresponding base" <400> 725 agucaaggag cauggaauct t 21 <210> 726 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 3, 4, 5, 6, 8, 10, 11, 12, 13, 14, 15, 18, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 7, 9, 16, 17 <223> /mod_base = "2'-hydroxy corresponding base" <400> 726 gauuccaugc uccuugacut t 21 <210> 727 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 727 agucaaggag cauggaauct t 21 <210> 728 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 728 gauuccaugc uccuugacut t 21 <210> 729 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 729 agucaaggag cauggaauct t 21 <210> 730 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 3, 4, 5, 6, 8, 10, 11, 12, 13, 14, 15, 18, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 7, 9, 16, 17 <223> /mod_base = "2'-hydroxy corresponding base" <400> 730 gauuccaugc uccuugacut t 21 <210> 731 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 731 agucaaggag cauggaauct t 21 <210> 732 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 8, 9, 12, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 732 gauuccaugc uccuugacut t 21 <210> 733 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 3, 4, 11, 13, 18, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 5, 6, 7, 8, 9, 10, 12, 14, 15, 16, 17 <223> /mod_base = "2'-hydroxy corresponding base" <400> 733 agucaaggag cauggaauct t 21 <210> 734 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 8, 9, 12, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 734 gauuccaugc uccuugacut t 21 <210> 735 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 735 agucaaggag cauggaauct t 21 <210> 736 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 8, 9, 12, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 736 gauuccaugc uccuugacut t 21 <210> 737 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 737 gcggcacccu cauaggccut t 21 <210> 738 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 738 aggccuauga gggugccgct t 21 <210> 739 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 5, 7, 8, 9, 10, 11, 13, 17, 18, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 4, 6, 12, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 739 gcggcacccu cauaggccut t 21 <210> 740 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 4, 5, 6, 8, 14, 16, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 7, 9, 10, 11, 12, 13, 15, 18 <223> /mod_base = "2'-hydroxy corresponding base" <400> 740 aggccuauga gggugccgct t 21 <210> 741 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 741 gcggcacccu cauaggccut t 21 <210> 742 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 742 aggccuauga gggugccgct t 21 <210> 743 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 743 gcggcacccu cauaggccut t 21 <210> 744 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 4, 5, 6, 8, 14, 16, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 7, 9, 10, 11, 12, 13, 15, 18 <223> /mod_base = "2'-hydroxy corresponding base" <400> 744 aggccuauga gggugccgct t 21 <210> 745 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 745 gcggcacccu cauaggccut t 21 <210> 746 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 8, 9, 12, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 746 aggccuauga gggugccgct t 21 <210> 747 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 5, 7, 8, 9, 10, 11, 13, 17, 18, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 4, 6, 12, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 747 gcggcacccu cauaggccut t 21 <210> 748 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 8, 9, 12, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 748 aggccuauga gggugccgct t 21 <210> 749 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 749 gcggcacccu cauaggccut t 21 <210> 750 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 8, 9, 12, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 750 aggccuauga gggugccgct t 21 <210> 751 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 751 aaggagcaug gaaucccggt t 21 <210> 752 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 752 ccgggauucc augcuccuut t 21 <210> 753 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 7, 9, 14, 15, 16, 17 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 6, 8, 10, 11, 12, 13, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 753 aaggagcaug gaaucccggt t 21 <210> 754 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 10 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14, 15, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 754 ccgggauucc augcuccuut t 21 <210> 755 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 755 aggagcaugg aaucccggct t 21 <210> 756 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 756 gccgggauuc caugcuccut t 21 <210> 757 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 8, 13, 14, 15, 16, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 7, 9, 10, 11, 12, 17, 18 <223> /mod_base = "2'-hydroxy corresponding base" <400> 757 aggagcaugg aaucccggct t 21 <210> 758 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 11 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14, 15, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 758 gccgggauuc caugcuccut t 21 <210> 759 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 759 gagcauggaa ucccggccct t 21 <210> 760 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 760 gggccgggau uccaugcuct t 21 <210> 761 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 4, 6, 11, 12, 13, 14, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 5, 7, 8, 9, 10, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 761 gagcauggaa ucccggccct t 21 <210> 762 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 13 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 15, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 762 gggccgggau uccaugcuct t 21 <210> 763 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 763 gccuacgccg uagacaacat t 21 <210> 764 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 764 uguugucuac ggcguaggct t 21 <210> 765 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 765 ccuacgccgu agacaacact t 21 <210> 766 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 766 guguugucua cggcguaggt t 21 <210> 767 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 767 cuacgccgua gacaacacgt t 21 <210> 768 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 768 cguguugucu acggcguagt t 21 <210> 769 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 769 uacgccguag acaacacgut t 21 <210> 770 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 770 acguguuguc uacggcguat t 21 <210> 771 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 771 cgccguagac aacacgugut t 21 <210> 772 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 772 acacguguug ucuacggcgt t 21 <210> 773 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 773 gccguagaca acacgugugt t 21 <210> 774 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 774 cacacguguu gucuacggct t 21 <210> 775 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 775 ccguagacaa cacgugugut t 21 <210> 776 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 776 acacacgugu ugucuacggt t 21 <210> 777 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 777 cguagacaac acguguguat t 21 <210> 778 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 778 uacacacgug uugucuacgt t 21 <210> 779 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 779 uagacaacac guguguagut t 21 <210> 780 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 780 acuacacacg uguugucuat t 21 <210> 781 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 781 agacaacacg uguguaguct t 21 <210> 782 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 782 gacuacacac guguugucut t 21 <210> 783 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 783 gacaacacgu guguagucat t 21 <210> 784 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 784 ugacuacaca cguguuguct t 21 <210> 785 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 785 acaacacgug uguagucagt t 21 <210> 786 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 786 cugacuacac acguguugut t 21 <210> 787 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 787 caacacgugu guagucaggt t 21 <210> 788 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 788 ccugacuaca cacguguugt t 21 <210> 789 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 789 cacgugugua gucaggagct t 21 <210> 790 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 790 gcuccugacu acacacgugt t 21 <210> 791 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 791 acguguguag ucaggagcct t 21 <210> 792 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 792 ggcuccugac uacacacgut t 21 <210> 793 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 793 cguguguagu caggagccgt t 21 <210> 794 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 794 cggcuccuga cuacacacgt t 21 <210> 795 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 795 uguguaguca ggagccgggt t 21 <210> 796 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 796 cccggcuccu gacuacacat t 21 <210> 797 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 797 gucaggagcc gggacgucat t 21 <210> 798 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 798 ugacgucccg gcuccugact t 21 <210> 799 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 3, 9, 10, 15, 17, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 4, 5, 6, 7, 8, 11, 12, 13, 14, 16, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 799 gucaggagcc gggacgucat t 21 <210> 800 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 800 ugacgucccg gcuccugact t 21 <210> 801 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 801 ucaggagccg ggacgucagt t 21 <210> 802 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 802 cugacguccc ggcuccugat t 21 <210> 803 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 2, 8, 9, 14, 16, 17 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 3, 4, 5, 6, 7, 10, 11, 12, 13, 15, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 803 ucaggagccg ggacgucagt t 21 <210> 804 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 804 cugacguccc ggcuccugat t 21 <210> 805 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 805 caggagccgg gacgucagct t 21 <210> 806 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 806 gcugacgucc cggcuccugt t 21 <210> 807 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 7, 8, 13, 15, 16, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 3, 4, 5, 6, 9, 10, 11, 12, 14, 17, 18 <223> /mod_base = "2'-hydroxy corresponding base" <400> 807 caggagccgg gacgucagct t 21 <210> 808 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 808 gcugacgucc cggcuccugt t 21 <210> 809 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 809 agccgggacg ucagcacuat t 21 <210> 810 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 810 uagugcugac gucccggcut t 21 <210> 811 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 811 ccgggacguc agcacuacat t 21 <210> 812 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 812 uguagugcug acgucccggt t 21 <210> 813 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 813 ccgugacagc cguugccaut t 21 <210> 814 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 814 auggcaacgg cugucacggt t 21 <210> 815 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 815 gccaucugcu gccggagcct t 21 <210> 816 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 816 ggcuccggca gcagauggct t 21 <210> 817 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 817 cccaucccag gaugggugut t 21 <210> 818 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 818 acacccaucc ugggaugggt t 21 <210> 819 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 819 caucccagga ugggugucut t 21 <210> 820 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 820 agacacccau ccugggaugt t 21 <210> 821 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 821 agcuuuaaaa ugguuccgat t 21 <210> 822 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 822 ucggaaccau uuuaaagcut t 21 <210> 823 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 823 gcuuuaaaau gguuccgact t 21 <210> 824 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 824 gucggaacca uuuuaaagct t 21 <210> 825 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 825 cuuuaaaaug guuccgacut t 21 <210> 826 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 826 agucggaacc auuuuaaagt t 21 <210> 827 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 827 uuuaaaaugg uuccgacuut t 21 <210> 828 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 828 aagucggaac cauuuuaaat t 21 <210> 829 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 829 uuaaaauggu uccgacuugt t 21 <210> 830 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 830 caagucggaa ccauuuuaat t 21 <210> 831 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 831 uaaaaugguu ccgacuugut t 21 <210> 832 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 832 acaagucgga accauuuuat t 21 <210> 833 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 833 aaaaugguuc cgacuuguct t 21 <210> 834 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 834 gacaagucgg aaccauuuut t 21 <210> 835 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 835 aaaugguucc gacuugucct t 21 <210> 836 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 836 ggacaagucg gaaccauuut t 21 <210> 837 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 837 aaugguuccg acuuguccct t 21 <210> 838 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 838 gggacaaguc ggaaccauut t 21 <210> 839 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 839 gguuccgacu ugucccucut t 21 <210> 840 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 840 agagggacaa gucggaacct t 21 <210> 841 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 841 cuccauggcc uggcacgagt t 21 <210> 842 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 842 cucgugccag gccauggagt t 21 <210> 843 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 843 ccauggccug gcacgagggt t 21 <210> 844 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 844 cccucgugcc aggccauggt t 21 <210> 845 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 845 gaacucacuc acucugggut t 21 <210> 846 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 846 acccagagug agugaguuct t 21 <210> 847 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 847 ucacucacuc ugggugccut t 21 <210> 848 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 848 aggcacccag agugagugat t 21 <210> 849 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 849 uuucaccauu caaacaggut t 21 <210> 850 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 850 accuguuuga auggugaaat t 21 <210> 851 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 851 cauucaaaca ggucgagcut t 21 <210> 852 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 852 agcucgaccu guuugaaugt t 21 <210> 853 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 853 auucaaacag gucgagcugt t 21 <210> 854 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 854 cagcucgacc uguuugaaut t 21 <210> 855 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 855 uucaaacagg ucgagcugut t 21 <210> 856 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 856 acagcucgac cuguuugaat t 21 <210> 857 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 857 ucaaacaggu cgagcugugt t 21 <210> 858 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 858 cacagcucga ccuguuugat t 21 <210> 859 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 859 caaacagguc gagcugugct t 21 <210> 860 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 860 gcacagcucg accuguuugt t 21 <210> 861 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 861 aaacaggucg agcugugcut t 21 <210> 862 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 862 agcacagcuc gaccuguuut t 21 <210> 863 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 863 aacaggucga gcugugcuct t 21 <210> 864 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 864 gagcacagcu cgaccuguut t 21 <210> 865 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 865 caggucgagc ugugcucggt t 21 <210> 866 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 866 ccgagcacag cucgaccugt t 21 <210> 867 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 867 aggucgagcu gugcucgggt t 21 <210> 868 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 868 cccgagcaca gcucgaccut t 21 <210> 869 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 869 gucgagcugu gcucgggugt t 21 <210> 870 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 870 cacccgagca cagcucgact t 21 <210> 871 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 871 ucgagcugug cucgggugct t 21 <210> 872 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 872 gcacccgagc acagcucgat t 21 <210> 873 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 873 agcugcuccc aaugugccgt t 21 <210> 874 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 874 cggcacauug ggagcagcut t 21 <210> 875 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 875 gcugcuccca augugccgat t 21 <210> 876 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 876 ucggcacauu gggagcagct t 21 <210> 877 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 877 ugcucccaau gugccgaugt t 21 <210> 878 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 878 caucggcaca uugggagcat t 21 <210> 879 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 879 ucccaaugug ccgaugucct t 21 <210> 880 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 880 ggacaucggc acauugggat t 21 <210> 881 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 881 ccaaugugcc gauguccgut t 21 <210> 882 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 882 acggacaucg gcacauuggt t 21 <210> 883 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 883 caaugugccg auguccgugt t 21 <210> 884 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 884 cacggacauc ggcacauugt t 21 <210> 885 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 885 aaugugccga uguccguggt t 21 <210> 886 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 886 ccacggacau cggcacauut t 21 <210> 887 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 887 ccgauguccg ugggcagaat t 21 <210> 888 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 888 uucugcccac ggacaucggt t 21 <210> 889 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 889 gauguccgug ggcagaaugt t 21 <210> 890 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 890 cauucugccc acggacauct t 21 <210> 891 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 891 guccgugggc agaaugacut t 21 <210> 892 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 892 agucauucug cccacggact t 21 <210> 893 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 893 uccgugggca gaaugacuut t 21 <210> 894 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 894 aagucauucu gcccacggat t 21 <210> 895 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 895 ugggcagaau gacuuuuaut t 21 <210> 896 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 896 auaaaaguca uucugcccat t 21 <210> 897 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 897 acuuuuauug agcucuugut t 21 <210> 898 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 898 acaagagcuc aauaaaagut t 21 <210> 899 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 899 auugagcucu uguuccgugt t 21 <210> 900 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 900 cacggaacaa gagcucaaut t 21 <210> 901 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 901 agcucuuguu ccgugccagt t 21 <210> 902 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 902 cuggcacgga acaagagcut t 21 <210> 903 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 903 gcucuuguuc cgugccaggt t 21 <210> 904 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 904 ccuggcacgg aacaagagct t 21 <210> 905 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 905 uguuccgugc caggcauuct t 21 <210> 906 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 906 gaaugccugg cacggaacat t 21 <210> 907 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 907 guuccgugcc aggcauucat t 21 <210> 908 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 908 ugaaugccug gcacggaact t 21 <210> 909 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 909 uuccgugcca ggcauucaat t 21 <210> 910 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 910 uugaaugccu ggcacggaat t 21 <210> 911 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 911 cgugccaggc auucaaucct t 21 <210> 912 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 912 ggauugaaug ccuggcacgt t 21 <210> 913 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 913 gugccaggca uucaauccut t 21 <210> 914 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 914 aggauugaau gccuggcact t 21 <210> 915 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 915 caauccucag gucuccacct t 21 <210> 916 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 916 gguggagacc ugaggauugt t 21 <210> 917 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 917 caccaaggag gcaggauuct t 21 <210> 918 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 918 gaauccugcc uccuuggugt t 21 <210> 919 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 4, 12, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 5, 6, 7, 8, 9, 10, 11, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 919 caccaaggag gcaggauuct t 21 <210> 920 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 920 gaauccugcc uccuuggugt t 21 <210> 921 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 921 caccaaggag gcaggauuct t 21 <210> 922 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 922 gaauccugcc uccuuggugt t 21 <210> 923 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 4, 12, 17, 18, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 5, 6, 7, 8, 9, 10, 11, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 923 caccaaggag gcaggauuct t 21 <210> 924 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, 15, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 8, 16, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 924 gaauccugcc uccuuggugt t 21 <210> 925 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 925 caccaaggag gcaggauuct t 21 <210> 926 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 926 gaauccugcc uccuuggugt t 21 <210> 927 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 927 caccaaggag gcaggauuct t 21 <210> 928 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, 15, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 8, 16, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 928 gaauccugcc uccuuggugt t 21 <210> 929 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 929 caccaaggag gcaggauuct t 21 <210> 930 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 8, 9, 12, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 930 gaauccugcc uccuuggugt t 21 <210> 931 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 4, 12, 17, 18, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 5, 6, 7, 8, 9, 10, 11, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 931 caccaaggag gcaggauuct t 21 <210> 932 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 8, 9, 12, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 932 gaauccugcc uccuuggugt t 21 <210> 933 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 933 caccaaggag gcaggauuct t 21 <210> 934 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 8, 9, 12, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 934 gaauccugcc uccuuggugt t 21 <210> 935 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 935 ggccuggagu uuauucggat t 21 <210> 936 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 936 uccgaauaaa cuccaggcct t 21 <210> 937 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 3, 4, 5, 10, 11, 12, 14, 15, 16 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 6, 7, 8, 9, 13, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 937 ggccuggagu uuauucggat t 21 <210> 938 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 2, 3, 7, 11, 12, 13, 14, 18, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 4, 5, 6, 8, 9, 10, 15, 16, 17 <223> /mod_base = "2'-hydroxy corresponding base" <400> 938 uccgaauaaa cuccaggcct t 21 <210> 939 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 939 ggccuggagu uuauucggat t 21 <210> 940 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 940 uccgaauaaa cuccaggcct t 21 <210> 941 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 941 ggccuggagu uuauucggat t 21 <210> 942 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 2, 3, 7, 11, 12, 13, 14, 18, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 4, 5, 6, 8, 9, 10, 15, 16, 17 <223> /mod_base = "2'-hydroxy corresponding base" <400> 942 uccgaauaaa cuccaggcct t 21 <210> 943 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 943 ggccuggagu uuauucggat t 21 <210> 944 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 8, 9, 12, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 944 uccgaauaaa cuccaggcct t 21 <210> 945 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 3, 4, 5, 10, 11, 12, 14, 15, 16 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 6, 7, 8, 9, 13, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 945 ggccuggagu uuauucggat t 21 <210> 946 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 8, 9, 12, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 946 uccgaauaaa cuccaggcct t 21 <210> 947 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 947 ggccuggagu uuauucggat t 21 <210> 948 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 8, 9, 12, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 948 uccgaauaaa cuccaggcct t 21 <210> 949 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 949 gcaggauucu ucccauggat t 21 <210> 950 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 950 uccaugggaa gaauccugct t 21 <210> 951 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 951 ugcagggaca aacaucguut t 21 <210> 952 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 952 aacgauguuu gucccugcat t 21 <210> 953 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 953 gcagggacaa acaucguugt t 21 <210> 954 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 954 caacgauguu ugucccugct t 21 <210> 955 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 955 agggacaaac aucguugggt t 21 <210> 956 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 956 cccaacgaug uuugucccut t 21 <210> 957 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 957 cccucaucuc cagcuaacut t 21 <210> 958 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 958 aguuagcugg agaugagggt t 21 <210> 959 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 959 caucuccagc uaacuguggt t 21 <210> 960 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 960 ccacaguuag cuggagaugt t 21 <210> 961 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 961 gcucccugau uaauggaggt t 21 <210> 962 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 962 ccuccauuaa ucagggagct t 21 <210> 963 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 963 cccugauuaa uggaggcuut t 21 <210> 964 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 964 aagccuccau uaaucagggt t 21 <210> 965 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 965 ccugauuaau ggaggcuuat t 21 <210> 966 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 966 uaagccucca uuaaucaggt t 21 <210> 967 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 967 ugauuaaugg aggcuuagct t 21 <210> 968 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 968 gcuaagccuc cauuaaucat t 21 <210> 969 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 969 gauuaaugga ggcuuagcut t 21 <210> 970 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 970 agcuaagccu ccauuaauct t 21 <210> 971 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 971 auuaauggag gcuuagcuut t 21 <210> 972 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 972 aagcuaagcc uccauuaaut t 21 <210> 973 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 973 uuaauggagg cuuagcuuut t 21 <210> 974 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 974 aaagcuaagc cuccauuaat t 21 <210> 975 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 975 uuucuggaug gcaucuagct t 21 <210> 976 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 976 gcuagaugcc auccagaaat t 21 <210> 977 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 2, 3, 4, 5, 9, 12, 14, 15, 16, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 6, 7, 8, 10, 11, 13, 17, 18 <223> /mod_base = "2'-hydroxy corresponding base" <400> 977 uuucuggaug gcaucuagct t 21 <210> 978 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 3, 10, 14 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 4, 5, 6, 7, 8, 9, 11, 12, 13, 15, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 978 gcuagaugcc auccagaaat t 21 <210> 979 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 979 uucuggaugg caucuagcct t 21 <210> 980 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 980 ggcuagaugc cauccagaat t 21 <210> 981 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 2, 3, 4, 8, 11, 13, 14, 15, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 5, 6, 7, 9, 10, 12, 16, 17 <223> /mod_base = "2'-hydroxy corresponding base" <400> 981 uucuggaugg caucuagcct t 21 <210> 982 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 4, 11, 15 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 5, 6, 7, 8, 9, 10, 12, 13, 14, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 982 ggcuagaugc cauccagaat t 21 <210> 983 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 983 ucuggauggc aucuagccat t 21 <210> 984 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 984 uggcuagaug ccauccagat t 21 <210> 985 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 2, 3, 7, 10, 12, 13, 14, 17, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 4, 5, 6, 8, 9, 11, 15, 16, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 985 ucuggauggc aucuagccat t 21 <210> 986 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 5, 12, 16 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 6, 7, 8, 9, 10, 11, 13, 14, 15, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 986 uggcuagaug ccauccagat t 21 <210> 987 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 987 aggcuggaga caggugcgct t 21 <210> 988 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 988 gcgcaccugu cuccagccut t 21 <210> 989 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 989 ggcuggagac aggugcgcct t 21 <210> 990 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 990 ggcgcaccug ucuccagcct t 21 <210> 991 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 991 gcuggagaca ggugcgccct t 21 <210> 992 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 992 gggcgcaccu gucuccagct t 21 <210> 993 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 993 uuccugagcc accuuuacut t 21 <210> 994 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 994 aguaaaggug gcucaggaat t 21 <210> 995 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 995 uccugagcca ccuuuacuct t 21 <210> 996 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 996 gaguaaaggu ggcucaggat t 21 <210> 997 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 997 ccugagccac cuuuacucut t 21 <210> 998 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 998 agaguaaagg uggcucaggt t 21 <210> 999 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 999 ugagccaccu uuacucugct t 21 <210> 1000 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1000 gcagaguaaa gguggcucat t 21 <210> 1001 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1001 agccaccuuu acucugcuct t 21 <210> 1002 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1002 gagcagagua aagguggcut t 21 <210> 1003 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1003 caccuuuacu cugcucuaut t 21 <210> 1004 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1004 auagagcaga guaaaggugt t 21 <210> 1005 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1005 uacucugcuc uaugccaggt t 21 <210> 1006 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1006 ccuggcauag agcagaguat t 21 <210> 1007 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 4, 5, 6, 8, 9, 10, 11, 13, 15, 16 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 7, 12, 14, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1007 uacucugcuc uaugccaggt t 21 <210> 1008 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 8, 13, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 7, 9, 10, 11, 12, 14, 15, 16, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1008 ccuggcauag agcagaguat t 21 <210> 1009 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1009 augccaggcu gugcuagcat t 21 <210> 1010 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1010 ugcuagcaca gccuggcaut t 21 <210> 1011 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1011 aggcugugcu agcaacacct t 21 <210> 1012 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1012 gguguugcua gcacagccut t 21 <210> 1013 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1013 cugugcuagc aacacccaat t 21 <210> 1014 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1014 uuggguguug cuagcacagt t 21 <210> 1015 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1015 gcuagcaaca cccaaaggut t 21 <210> 1016 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1016 accuuugggu guugcuagct t 21 <210> 1017 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1017 ggagccauca ccuaggacut t 21 <210> 1018 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1018 aguccuaggu gauggcucct t 21 <210> 1019 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1019 caccuaggac ugacucggct t 21 <210> 1020 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1020 gccgagucag uccuaggugt t 21 <210> 1021 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1021 aggacugacu cggcagugut t 21 <210> 1022 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1022 acacugccga gucaguccut t 21 <210> 1023 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1023 ggacugacuc ggcagugugt t 21 <210> 1024 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1024 cacacugccg agucagucct t 21 <210> 1025 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1025 uggugcaugc acugucucat t 21 <210> 1026 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1026 ugagacagug caugcaccat t 21 <210> 1027 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1027 augcacuguc ucagccaact t 21 <210> 1028 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1028 guuggcugag acagugcaut t 21 <210> 1029 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1029 cugucucagc caacccgcut t 21 <210> 1030 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1030 agcggguugg cugagacagt t 21 <210> 1031 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1031 cucagccaac ccgcuccact t 21 <210> 1032 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1032 guggagcggg uuggcugagt t 21 <210> 1033 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 2, 3, 6, 7, 10, 11, 12, 14, 15, 16, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 4, 5, 8, 9, 13, 18 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1033 cucagccaac ccgcuccact t 21 <210> 1034 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1034 guggagcggg uuggcugagt t 21 <210> 1035 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1035 gccaacccgc uccacuacct t 21 <210> 1036 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1036 gguaguggag cggguuggct t 21 <210> 1037 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 3, 6, 7, 8, 10, 11, 12, 13, 15, 16, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 4, 5, 9, 14, 17 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1037 gccaacccgc uccacuacct t 21 <210> 1038 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 3 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1038 gguaguggag cggguuggct t 21 <210> 1039 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1039 aacccgcucc acuacccggt t 21 <210> 1040 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1040 ccggguagug gagcggguut t 21 <210> 1041 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1041 ccgcuccacu acccggcagt t 21 <210> 1042 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1042 cugccgggua guggagcggt t 21 <210> 1043 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1043 cuacccggca ggguacacat t 21 <210> 1044 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1044 uguguacccu gccggguagt t 21 <210> 1045 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1045 uacccggcag gguacacaut t 21 <210> 1046 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1046 auguguaccc ugccggguat t 21 <210> 1047 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1047 acccggcagg guacacauut t 21 <210> 1048 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1048 aauguguacc cugccgggut t 21 <210> 1049 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1049 cccggcaggg uacacauuct t 21 <210> 1050 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1050 gaauguguac ccugccgggt t 21 <210> 1051 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1051 cggcagggua cacauucgct t 21 <210> 1052 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1052 gcgaaugugu acccugccgt t 21 <210> 1053 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1053 gcaggguaca cauucgcact t 21 <210> 1054 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1054 gugcgaaugu guacccugct t 21 <210> 1055 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1055 caggguacac auucgcacct t 21 <210> 1056 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1056 ggugcgaaug uguacccugt t 21 <210> 1057 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1057 aggguacaca uucgcaccct t 21 <210> 1058 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1058 gggugcgaau guguacccut t 21 <210> 1059 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1059 ggaacugagc cagaaacgct t 21 <210> 1060 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1060 gcguuucugg cucaguucct t 21 <210> 1061 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1061 gaacugagcc agaaacgcat t 21 <210> 1062 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1062 ugcguuucug gcucaguuct t 21 <210> 1063 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1063 aacugagcca gaaacgcagt t 21 <210> 1064 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1064 cugcguuucu ggcucaguut t 21 <210> 1065 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1065 ugagccagaa acgcagauut t 21 <210> 1066 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1066 aaucugcguu ucuggcucat t 21 <210> 1067 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1067 agaaacgcag auugggcugt t 21 <210> 1068 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1068 cagcccaauc ugcguuucut t 21 <210> 1069 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1069 aacgcagauu gggcuggcut t 21 <210> 1070 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1070 agccagccca aucugcguut t 21 <210> 1071 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1071 agccaagccu cuucuuacut t 21 <210> 1072 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1072 aguaagaaga ggcuuggcut t 21 <210> 1073 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 3, 4, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 5, 6, 7, 17 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1073 agccaagccu cuucuuacut t 21 <210> 1074 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 3 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1074 aguaagaaga ggcuuggcut t 21 <210> 1075 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 1075 agccaagccu cuucuuacut t 21 <210> 1076 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 1076 aguaagaaga ggcuuggcut t 21 <210> 1077 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 3, 4, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 5, 6, 7, 17 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1077 agccaagccu cuucuuacut t 21 <210> 1078 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 3, 13, 14, 15, 18, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 4, 5, 6, 7, 8, 9, 10, 11, 12, 16, 17 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1078 aguaagaaga ggcuuggcut t 21 <210> 1079 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1079 agccaagccu cuucuuacut t 21 <210> 1080 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 1080 aguaagaaga ggcuuggcut t 21 <210> 1081 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1081 agccaagccu cuucuuacut t 21 <210> 1082 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 3, 13, 14, 15, 18, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 4, 5, 6, 7, 8, 9, 10, 11, 12, 16, 17 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1082 aguaagaaga ggcuuggcut t 21 <210> 1083 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 1083 agccaagccu cuucuuacut t 21 <210> 1084 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 8, 9, 12, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1084 aguaagaaga ggcuuggcut t 21 <210> 1085 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 3, 4, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 5, 6, 7, 17 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1085 agccaagccu cuucuuacut t 21 <210> 1086 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 8, 9, 12, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1086 aguaagaaga ggcuuggcut t 21 <210> 1087 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1087 agccaagccu cuucuuacut t 21 <210> 1088 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 8, 9, 12, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1088 aguaagaaga ggcuuggcut t 21 <210> 1089 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 1089 ugguucccug aggaccagct t 21 <210> 1090 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 1090 gcugguccuc agggaaccat t 21 <210> 1091 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 4, 5, 6, 7, 8, 9, 15, 16, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 3, 10, 11, 12, 13, 14, 17, 18 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1091 ugguucccug aggaccagct t 21 <210> 1092 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 3, 6, 7, 8, 9, 10, 17, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 4, 5, 11, 12, 13, 14, 15, 16, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1092 gcugguccuc agggaaccat t 21 <210> 1093 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1093 ugguucccug aggaccagct t 21 <210> 1094 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 1094 gcugguccuc agggaaccat t 21 <210> 1095 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1095 ugguucccug aggaccagct t 21 <210> 1096 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 3, 6, 7, 8, 9, 10, 17, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 4, 5, 11, 12, 13, 14, 15, 16, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1096 gcugguccuc agggaaccat t 21 <210> 1097 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 1097 ugguucccug aggaccagct t 21 <210> 1098 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 8, 9, 12, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1098 gcugguccuc agggaaccat t 21 <210> 1099 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 4, 5, 6, 7, 8, 9, 15, 16, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 3, 10, 11, 12, 13, 14, 17, 18 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1099 ugguucccug aggaccagct t 21 <210> 1100 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 8, 9, 12, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1100 gcugguccuc agggaaccat t 21 <210> 1101 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1101 ugguucccug aggaccagct t 21 <210> 1102 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 8, 9, 12, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1102 gcugguccuc agggaaccat t 21 <210> 1103 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1103 ucuucuuacu ucacccggct t 21 <210> 1104 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1104 gccgggugaa guaagaagat t 21 <210> 1105 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1105 cuucuuacuu cacccggcut t 21 <210> 1106 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1106 agccggguga aguaagaagt t 21 <210> 1107 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1107 uucuuacuuc acccggcugt t 21 <210> 1108 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1108 cagccgggug aaguaagaat t 21 <210> 1109 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1109 gggcuccuca uuuuuacggt t 21 <210> 1110 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1110 ccguaaaaau gaggagccct t 21 <210> 1111 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1111 ggcuccucau uuuuacgggt t 21 <210> 1112 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1112 cccguaaaaa ugaggagcct t 21 <210> 1113 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1113 gcuccucauu uuuacgggut t 21 <210> 1114 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1114 acccguaaaa augaggagct t 21 <210> 1115 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1115 cuccucauuu uuacggguat t 21 <210> 1116 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1116 uacccguaaa aaugaggagt t 21 <210> 1117 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1117 uccucauuuu uacggguaat t 21 <210> 1118 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1118 uuacccguaa aaaugaggat t 21 <210> 1119 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1119 ccucauuuuu acggguaact t 21 <210> 1120 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1120 guuacccgua aaaaugaggt t 21 <210> 1121 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1121 cucauuuuua cggguaacat t 21 <210> 1122 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1122 uguuacccgu aaaaaugagt t 21 <210> 1123 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1123 cauuuuuacg gguaacagut t 21 <210> 1124 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1124 acuguuaccc guaaaaaugt t 21 <210> 1125 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1125 auuuuuacgg guaacagugt t 21 <210> 1126 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1126 cacuguuacc cguaaaaaut t 21 <210> 1127 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1127 uuuacgggua acagugaggt t 21 <210> 1128 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1128 ccucacuguu acccguaaat t 21 <210> 1129 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1129 cagaccagga agcucggugt t 21 <210> 1130 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1130 caccgagcuu ccuggucugt t 21 <210> 1131 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1131 gaccaggaag cucggugagt t 21 <210> 1132 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1132 cucaccgagc uuccugguct t 21 <210> 1133 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1133 ccaggaagcu cggugagugt t 21 <210> 1134 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1134 cacucaccga gcuuccuggt t 21 <210> 1135 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1135 ggaagcucgg ugagugaugt t 21 <210> 1136 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1136 caucacucac cgagcuucct t 21 <210> 1137 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1137 gugagugaug gcagaacgat t 21 <210> 1138 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1138 ucguucugcc aucacucact t 21 <210> 1139 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1139 gagugauggc agaacgaugt t 21 <210> 1140 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1140 caucguucug ccaucacuct t 21 <210> 1141 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1141 gauggcagaa cgaugccugt t 21 <210> 1142 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1142 caggcaucgu ucugccauct t 21 <210> 1143 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1143 agaacgaugc cugcaggcat t 21 <210> 1144 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1144 ugccugcagg caucguucut t 21 <210> 1145 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1145 acgaugccug caggcauggt t 21 <210> 1146 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1146 ccaugccugc aggcaucgut t 21 <210> 1147 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1147 gcaggcaugg aacuuuuuct t 21 <210> 1148 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1148 gaaaaaguuc caugccugct t 21 <210> 1149 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1149 ggaacuuuuu ccguuaucat t 21 <210> 1150 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1150 ugauaacgga aaaaguucct t 21 <210> 1151 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1151 gaacuuuuuc cguuaucact t 21 <210> 1152 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1152 gugauaacgg aaaaaguuct t 21 <210> 1153 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1153 aacuuuuucc guuaucacct t 21 <210> 1154 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1154 ggugauaacg gaaaaaguut t 21 <210> 1155 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1155 uaucacccag gccugauuct t 21 <210> 1156 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1156 gaaucaggcc ugggugauat t 21 <210> 1157 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1157 aggccugauu cacuggccut t 21 <210> 1158 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1158 aggccaguga aucaggccut t 21 <210> 1159 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1159 ugauucacug gccuggcggt t 21 <210> 1160 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1160 ccgccaggcc agugaaucat t 21 <210> 1161 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1161 auucacuggc cuggcggagt t 21 <210> 1162 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1162 cuccgccagg ccagugaaut t 21 <210> 1163 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1163 gcuucuaagg cauggucggt t 21 <210> 1164 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1164 ccgaccaugc cuuagaagct t 21 <210> 1165 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1165 cuucuaaggc auggucgggt t 21 <210> 1166 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1166 cccgaccaug ccuuagaagt t 21 <210> 1167 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1167 gagggccaac aacuguccct t 21 <210> 1168 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1168 gggacaguug uuggcccuct t 21 <210> 1169 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1169 acugucccuc cuugagcact t 21 <210> 1170 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1170 gugcucaagg agggacagut t 21 <210> 1171 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 4, 14, 15, 16, 18 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1171 acugucccuc cuugagcact t 21 <210> 1172 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 16 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, 13, 14, 15, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1172 gugcucaagg agggacagut t 21 <210> 1173 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1173 cugucccucc uugagcacct t 21 <210> 1174 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1174 ggugcucaag gagggacagt t 21 <210> 1175 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 2, 4, 5, 6, 7, 8, 9, 10, 11, 12, 16, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 3, 13, 14, 15, 17 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1175 cugucccucc uugagcacct t 21 <210> 1176 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 7, 17 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 6, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1176 ggugcucaag gagggacagt t 21 <210> 1177 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1177 acauuuaucu uuugggucut t 21 <210> 1178 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1178 agacccaaaa gauaaaugut t 21 <210> 1179 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 5, 6, 8, 9, 10, 11, 12, 13, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 7, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1179 acauuuaucu uuugggucut t 21 <210> 1180 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 13 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, 14, 15, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1180 agacccaaaa gauaaaugut t 21 <210> 1181 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 1181 acauuuaucu uuugggucut t 21 <210> 1182 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 1182 agacccaaaa gauaaaugut t 21 <210> 1183 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 5, 6, 8, 9, 10, 11, 12, 13, 17, 18, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 7, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1183 acauuuaucu uuugggucut t 21 <210> 1184 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 4, 5, 6, 13, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 7, 8, 9, 10, 11, 12, 14, 15, 16, 18 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1184 agacccaaaa gauaaaugut t 21 <210> 1185 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1185 acauuuaucu uuugggucut t 21 <210> 1186 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 1186 agacccaaaa gauaaaugut t 21 <210> 1187 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1187 acauuuaucu uuugggucut t 21 <210> 1188 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 4, 5, 6, 13, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 7, 8, 9, 10, 11, 12, 14, 15, 16, 18 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1188 agacccaaaa gauaaaugut t 21 <210> 1189 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 1189 acauuuaucu uuugggucut t 21 <210> 1190 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 8, 9, 12, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1190 agacccaaaa gauaaaugut t 21 <210> 1191 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 5, 6, 8, 9, 10, 11, 12, 13, 17, 18, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 7, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1191 acauuuaucu uuugggucut t 21 <210> 1192 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 8, 9, 12, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1192 agacccaaaa gauaaaugut t 21 <210> 1193 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1193 acauuuaucu uuugggucut t 21 <210> 1194 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 8, 9, 12, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1194 agacccaaaa gauaaaugut t 21 <210> 1195 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 1195 gccaucugcu gccggagcct t 21 <210> 1196 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 1196 ggcuccggca gcagauggct t 21 <210> 1197 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 3, 5, 6, 7, 9, 10, 12, 13, 18, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 4, 8, 11, 14, 15, 16, 17 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1197 gccaucugcu gccggagcct t 21 <210> 1198 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 3, 4, 5, 6, 9, 12, 16, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 7, 8, 10, 11, 13, 14, 15, 17, 18 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1198 ggcuccggca gcagauggct t 21 <210> 1199 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1199 gccaucugcu gccggagcct t 21 <210> 1200 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 1200 ggcuccggca gcagauggct t 21 <210> 1201 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1201 gccaucugcu gccggagcct t 21 <210> 1202 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 3, 4, 5, 6, 9, 12, 16, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 7, 8, 10, 11, 13, 14, 15, 17, 18 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1202 ggcuccggca gcagauggct t 21 <210> 1203 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 1203 gccaucugcu gccggagcct t 21 <210> 1204 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 8, 9, 12, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1204 ggcucaugca gcagauggct t 21 <210> 1205 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 3, 5, 6, 7, 9, 10, 12, 13, 18, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 4, 8, 11, 14, 15, 16, 17 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1205 gccaucugcu gccggagcct t 21 <210> 1206 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 8, 9, 12, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1206 ggcucaugca gcagauggct t 21 <210> 1207 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1207 gccaucugcu gccggagcct t 21 <210> 1208 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 8, 9, 12, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1208 ggcucaugca gcagauggct t 21 <210> 1209 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1209 cauuuaucuu uugggucugt t 21 <210> 1210 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1210 cagacccaaa agauaaaugt t 21 <210> 1211 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 4, 5, 7, 8, 9, 10, 11, 12, 16, 17, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 6, 13, 14, 15, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1211 cauuuaucuu uugggucugt t 21 <210> 1212 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 7, 14 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 3, 4, 5, 6, 8, 9, 10, 11, 12, 13, 15, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1212 cagacccaaa agauaaaugt t 21 <210> 1213 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1213 uaucuuuugg gucuguccut t 21 <210> 1214 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1214 aggacagacc caaaagauat t 21 <210> 1215 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 4, 5, 6, 7, 8, 12, 13, 14, 16, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 9, 10, 11, 15 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1215 uaucuuuugg gucuguccut t 21 <210> 1216 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 5, 11, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 6, 7, 8, 9, 10, 12, 13, 14, 15, 16, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1216 aggacagacc caaaagauat t 21 <210> 1217 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1217 cucuguugcc uuuuuacagt t 21 <210> 1218 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1218 cuguaaaaag gcaacagagt t 21 <210> 1219 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 2, 3, 4, 6, 7, 9, 10, 11, 12, 13, 14, 15, 17 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 5, 8, 16, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1219 cucuguugcc uuuuuacagt t 21 <210> 1220 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 4, 12, 15 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 13, 14, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1220 cuguaaaaag gcaacagagt t 21 <210> 1221 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1221 ccuuuuuaca gccaacuuut t 21 <210> 1222 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1222 aaaguuggcu guaaaaaggt t 21 <210> 1223 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1223 agccaacuuu ucuagaccut t 21 <210> 1224 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1224 aggucuagaa aaguuggcut t 21 <210> 1225 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1225 acuuuucuag accuguuuut t 21 <210> 1226 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1226 aaaacagguc uagaaaagut t 21 <210> 1227 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1227 uucuagaccu guuuugcuut t 21 <210> 1228 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1228 aagcaaaaca ggucuagaat t 21 <210> 1229 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 2, 3, 4, 8, 9, 10, 12, 13, 14, 15, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 5, 6, 7, 11, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1229 uucuagaccu guuuugcuut t 21 <210> 1230 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 4, 9, 15 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 5, 6, 7, 8, 10, 11, 12, 13, 14, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1230 aagcaaaaca ggucuagaat t 21 <210> 1231 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 1231 uucuagaccu guuuugcuut t 21 <210> 1232 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 1232 aagcaaaaca ggucuagaat t 21 <210> 1233 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 2, 3, 4, 8, 9, 10, 12, 13, 14, 15, 17, 18, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 5, 6, 7, 11, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1233 uucuagaccu guuuugcuut t 21 <210> 1234 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 4, 9, 13, 14, 15 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 5, 6, 7, 8, 10, 11, 12, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1234 aagcaaaaca ggucuagaat t 21 <210> 1235 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1235 uucuagaccu guuuugcuut t 21 <210> 1236 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 1236 aagcaaaaca ggucuagaat t 21 <210> 1237 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1237 uucuagaccu guuuugcuut t 21 <210> 1238 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 4, 9, 13, 14, 15 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 5, 6, 7, 8, 10, 11, 12, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1238 aagcaaaaca ggucuagaat t 21 <210> 1239 <211> 20 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 1239 uucuagaccu guuuucuutt 20 <210> 1240 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 4, 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 5, 8, 9, 12, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1240 aagcaaaaca ggucuagaat t 21 <210> 1241 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 2, 3, 4, 8, 9, 10, 12, 13, 14, 15, 17, 18, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 5, 6, 7, 11, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1241 uucuagaccu guuuugcuut t 21 <210> 1242 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 4, 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 5, 8, 9, 12, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1242 aagcaaaaca ggucuagaat t 21 <210> 1243 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1243 uucuagaccu guuuugcuut t 21 <210> 1244 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 4, 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 5, 8, 9, 12, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1244 aagcaaaaca ggucuagaat t 21 <210> 1245 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 1245 cauaggccug gaguuuauut t 21 <210> 1246 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 1246 aauaaacucc aggccuaugt t 21 <210> 1247 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 7, 8, 9, 14, 15, 16, 18, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 4, 5, 6, 10, 11, 12, 13, 17 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1247 cauaggccug gaguuuauut t 21 <210> 1248 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 3, 7, 8, 9, 10, 14, 15, 16, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 4, 5, 6, 11, 12, 13, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1248 aauaaacucc aggccuaugt t 21 <210> 1249 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1249 cauaggccug gaguuuauut t 21 <210> 1250 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 1250 aauaaacucc aggccuaugt t 21 <210> 1251 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1251 cauaggccug gaguuuauut t 21 <210> 1252 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 3, 7, 8, 9, 10, 14, 15, 16, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 4, 5, 6, 11, 12, 13, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1252 aauaaacucc aggccuaugt t 21 <210> 1253 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 1253 cauaggccug gaguuuauut t 21 <210> 1254 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 8, 9, 12, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1254 aauaaacucc aggccuaugt t 21 <210> 1255 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 7, 8, 9, 14, 15, 16, 18, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 4, 5, 6, 10, 11, 12, 13, 17 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1255 cauaggccug gaguuuauut t 21 <210> 1256 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 8, 9, 12, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1256 aauaaacucc aggccuaugt t 21 <210> 1257 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1257 cauaggccug gaguuuauut t 21 <210> 1258 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 8, 9, 12, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1258 aauaaacucc aggccuaugt t 21 <210> 1259 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1259 ucuagaccug uuuugcuuut t 21 <210> 1260 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1260 aaagcaaaac aggucuagat t 21 <210> 1261 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 2, 3, 7, 8, 9, 11, 12, 13, 14, 16, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 4, 5, 6, 10, 15 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1261 ucuagaccug uuuugcuuut t 21 <210> 1262 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 5, 10, 16 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 6, 7, 8, 9, 11, 12, 13, 14, 15, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1262 aaagcaaaac aggucuagat t 21 <210> 1263 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 1263 ucuagaccug uuuugcuuut t 21 <210> 1264 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 1264 aaagcaaaac aggucuagat t 21 <210> 1265 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 2, 3, 7, 8, 9, 11, 12, 13, 14, 16, 17, 18, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 4, 5, 6, 10, 15 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1265 ucuagaccug uuuugcuuut t 21 <210> 1266 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 5, 10, 14, 15, 16 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 6, 7, 8, 9, 11, 12, 13, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1266 aaagcaaaac aggucuagat t 21 <210> 1267 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1267 ucuagaccug uuuugcuuut t 21 <210> 1268 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 1268 aaagcaaaac aggucuagat t 21 <210> 1269 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1269 ucuagaccug uuuugcuuut t 21 <210> 1270 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 5, 10, 14, 15, 16 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 6, 7, 8, 9, 11, 12, 13, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1270 aaagcaaaac aggucuagat t 21 <210> 1271 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 1271 ucuagaccug uuuugcuuut t 21 <210> 1272 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 8, 9, 12, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1272 aaagcaaaac aggucuagat t 21 <210> 1273 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 2, 3, 7, 8, 9, 11, 12, 13, 14, 16, 17, 18, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 4, 5, 6, 10, 15 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1273 ucuagaccug uuuugcuuut t 21 <210> 1274 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 8, 9, 12, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1274 aaagcaaaac aggucuagat t 21 <210> 1275 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1275 ucuagaccug uuuugcuuut t 21 <210> 1276 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 8, 9, 12, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1276 aaagcaaaac aggucuagat t 21 <210> 1277 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 1277 ucauaggccu ggaguuuaut t 21 <210> 1278 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 1278 auaaacucca ggccuaugat t 21 <210> 1279 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 2, 4, 8, 9, 10, 15, 16, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 3, 5, 6, 7, 11, 12, 13, 14, 18 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1279 ucauaggccu ggaguuuaut t 21 <210> 1280 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 6, 7, 8, 9, 13, 14, 15, 17 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 4, 5, 10, 11, 12, 16, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1280 auaaacucca ggccuaugat t 21 <210> 1281 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1281 ucauaggccu ggaguuuaut t 21 <210> 1282 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 1282 auaaacucca ggccuaugat t 21 <210> 1283 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1283 ucauaggccu ggaguuuaut t 21 <210> 1284 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 6, 7, 8, 9, 13, 14, 15, 17 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 4, 5, 10, 11, 12, 16, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1284 auaaacucca ggccuaugat t 21 <210> 1285 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 1285 ucauaggccu ggaguuuaut t 21 <210> 1286 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 8, 9, 12, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1286 auaaacucca ggccuaugat t 21 <210> 1287 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 2, 4, 8, 9, 10, 15, 16, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 3, 5, 6, 7, 11, 12, 13, 14, 18 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1287 ucauaggccu ggaguuuaut t 21 <210> 1288 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 8, 9, 12, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1288 auaaacucca ggccuaugat t 21 <210> 1289 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1289 ucauaggccu ggaguuuaut t 21 <210> 1290 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 8, 9, 12, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1290 auaaacucca ggccuaugat t 21 <210> 1291 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1291 ugaagauauu uauucugggt t 21 <210> 1292 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1292 cccagaauaa auaucuucat t 21 <210> 1293 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 7, 9, 10, 11, 13, 14, 15, 16 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 3, 4, 5, 6, 8, 12, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1293 ugaagauauu uauucugggt t 21 <210> 1294 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 3, 8, 12, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 4, 5, 6, 7, 9, 10, 11, 13, 14, 15, 16, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1294 cccagaauaa auaucuucat t 21 <210> 1295 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1295 ucuggguuuu guagcauuut t 21 <210> 1296 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1296 aaaugcuaca aaacccagat t 21 <210> 1297 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 2, 3, 7, 8, 9, 10, 12, 15, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 4, 5, 6, 11, 13, 14, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1297 ucuggguuuu guagcauuut t 21 <210> 1298 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 7, 9, 16 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 6, 8, 10, 11, 12, 13, 14, 15, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1298 aaaugcuaca aaacccagat t 21 <210> 1299 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1299 auaaaaacaa acaaacguut t 21 <210> 1300 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1300 aacguuuguu uguuuuuaut t 21 <210> 1301 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1301 aaacaaacaa acguugucct t 21 <210> 1302 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1302 ggacaacguu uguuuguuut t 21 <210> 1303 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1303 aacaaacaaa cguuguccut t 21 <210> 1304 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1304 aggacaacgu uuguuuguut t 21 <210> 1305 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 2, 3, 4, 9, 10, 11, 13, 14, 15 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 5, 6, 7, 8, 12, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1305 gccuggaguu uauucggaat t 21 <210> 1306 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 8, 15 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1306 uuccgaauaa acuccaggct t 21 <210> 1307 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 2, 3, 4, 9, 10, 11, 13, 14, 15 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 5, 6, 7, 8, 12, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1307 gccuggaguu uauucggaat t 21 <210> 1308 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1, 3, 8, 14, 15 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 4, 5, 6, 7, 9, 10, 11, 12, 13, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1308 uuccgaauaa acuccaggct t 21 <210> 1309 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 2, 3, 4, 9, 10, 11, 13, 14, 15 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 5, 6, 7, 8, 12, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1309 gccuggaguu uauucggaat t 21 <210> 1310 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1310 uuccgaauaa acuccaggct t 21 <210> 1311 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 2, 3, 4, 9, 10, 11, 13, 14, 15 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 5, 6, 7, 8, 12, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1311 gccuggaguu uauucggaat t 21 <210> 1312 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1312 uuccgaauaa acuccaggct t 21 <210> 1313 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 2, 3, 4, 9, 10, 11, 13, 14, 15 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 5, 6, 7, 8, 12, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1313 gccuggaguu uauucggaat t 21 <210> 1314 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 2 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1314 uuccgaauaa acuccaggct t 21 <210> 1315 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 2, 3, 4, 9, 10, 11, 13, 14, 15 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 5, 6, 7, 8, 12, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1315 gccuggaguu uauucggaat t 21 <210> 1316 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 3 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1316 uuccgaauaa acuccaggct t 21 <210> 1317 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 2, 3, 4, 9, 10, 11, 13, 14, 15 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 5, 6, 7, 8, 12, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1317 gccuggaguu uauucggaat t 21 <210> 1318 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 4 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1318 uuccgaauaa acuccaggct t 21 <210> 1319 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1319 gccuggaguu uauucggaat t 21 <210> 1320 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1320 uuccgaauaa acuccaggct t 21 <210> 1321 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1321 gccuggaguu uauucggaat t 21 <210> 1322 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 2 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1322 uuccgaauaa acuccaggct t 21 <210> 1323 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1323 gccuggaguu uauucggaat t 21 <210> 1324 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 3 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1324 uuccgaauaa acuccaggct t 21 <210> 1325 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1325 gccuggaguu uauucggaat t 21 <210> 1326 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 4 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1326 uuccgaauaa acuccaggct t 21 <210> 1327 <211> 19 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 2, 3, 4, 9, 10, 11, 13, 14, 15 <223> /mod_base = "2'-O-methyl corresponding base" <400> 1327 gccuggaguu uauucggaa 19 <210> 1328 <211> 21 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 20, 21 <223> /mod_base = "2'-O-methyl corresponding base 5'-monophosphorothioate" <400> 1328 uuccgaauaa acuccaggcc u 21 <210> 1329 <211> 20 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 2, 3, 4, 9, 10, 11, 13, 14, 15 <223> /mod_base = "2'-O-methyl corresponding base" <400> 1329 gccuggaguu uauucggaaa 20 <210> 1330 <211> 22 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21, 22 <223> /mod_base = "2'-O-methyl corresponding base 5'-monophosphorothioate" <400> 1330 uuuccgaaua aacuccaggc cu 22 <210> 1331 <211> 21 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 2, 3, 4, 9, 10, 11, 13, 14, 15 <223> /mod_base = "2'-O-methyl corresponding base" <400> 1331 gccuggaguu uauucggaaa a 21 <210> 1332 <211> 23 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 22, 23 <223> /mod_base = "2'-O-methyl corresponding base 5'-monophosphorothioate" <400> 1332 uuuuccgaau aaacuccagg ccu 23 <210> 1333 <211> 22 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 2, 3, 4, 9, 10, 11, 13, 14, 15 <223> /mod_base = "2'-O-methyl corresponding base" <400> 1333 gccuggaguu uauucggaaa ag 22 <210> 1334 <211> 24 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 23, 24 <223> /mod_base = "2'-O-methyl corresponding base 5'-monophosphorothioate" <400> 1334 cuuuuccgaa uaaacuccag gccu 24 <210> 1335 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 2, 3, 4, 9, 10, 11, 13, 14, 15 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "thymidine with 3'-abasic nucleotide" <220> <221> modified_base <222> 1, 5, 6, 7, 8, 12, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1335 gccuggaguu uauucggaat t 21 <210> 1336 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 22 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1336 uuccgaauaa acuccaggct t 21 <210> 1337 <211> 22 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 2, 3, 4, 9, 10, 11, 13, 14, 15 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 22 <223> /mod_base = "thymidine with 3'-abasic nucleotide" <220> <221> modified_base <222> 1, 5, 6, 7, 8, 12, 16, 17, 18, 19, 20 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1337 gccuggaguu uauucggaaa tt 22 <210> 1338 <211> 22 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 9, 23 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 6, 7, 8, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1338 uuuccgaaua aacuccaggc tt 22 <210> 1339 <211> 23 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 2, 3, 4, 9, 10, 11, 13, 14, 15 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 23 <223> /mod_base = "thymidine with 3'-abasic nucleotide" <220> <221> modified_base <222> 1, 5, 6, 7, 8, 12, 16, 17, 18, 19, 20, 21 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1339 gccuggaguu uauucggaaa att 23 <210> 1340 <211> 23 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 24 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 1..21 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1340 uuuuccgaau aaacuccagg ctt 23 <210> 1341 <211> 24 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 2, 3, 4, 9, 10, 11, 13, 14, 15 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 24 <223> /mod_base = "thymidine with 3'-abasic nucleotide" <220> <221> modified_base <222> 1, 5, 6, 7, 8, 12, 16, 17, 18, 19, 20, 21, 22 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1341 gccuggaguu uauucggaaa agtt 24 <210> 1342 <211> 24 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 25 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 1..22 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1342 cuuuuccgaa uaaacuccag gctt 24 <210> 1343 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1343 gccuggaguu uauucggaat t 21 <210> 1344 <211> 21 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 20, 21 <223> /mod_base = "2'-O-methyl corresponding base 5'-monophosphorothioate" <400> 1344 uuccgaauaa acuccaggcc u 21 <210> 1345 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 2, 3, 4, 9, 10, 11, 13, 14, 15 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 5, 6, 7, 8, 12, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1345 gccuggaguu uauucggaat t 21 <210> 1346 <211> 21 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 20, 21 <223> /mod_base = "2'-O-methyl corresponding base 5'-monophosphorothioate" <400> 1346 uuccgaauaa acuccaggcc u 21 <210> 1347 <211> 19 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <400> 1347 gccuggaguu uauucggaa 19 <210> 1348 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 22 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1348 uuccgaauaa acuccaggct t 21 <210> 1349 <211> 19 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <400> 1349 gccuggaguu uauucggaa 19 <210> 1350 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1350 uuccgaauaa acuccaggct t 21 <210> 1351 <211> 19 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <400> 1351 gccuggaguu uauucggaa 19 <210> 1352 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 8, 15 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1352 uuccgaauaa acuccaggct t 21 <210> 1353 <211> 19 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <400> 1353 gccuggaguu uauucggaa 19 <210> 1354 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 1, 3, 8, 14, 15 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 4, 5, 6, 7, 9, 10, 11, 12, 13, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1354 uuccgaauaa acuccaggct t 21 <210> 1355 <211> 19 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <400> 1355 gccuggaguu uauucggaa 19 <210> 1356 <211> 19 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <400> 1356 uuccgaauaa acuccaggc 19 <210> 1357 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 2, 4, 6, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 22 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 8, 10, 12, 14, 16, 18, 20 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1357 gccuggaguu uauucggaat t 21 <210> 1358 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 8, 9, 12, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1358 uuccgaauaa acuccaggct t 21 <210> 1359 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "thymidine with 3'-abasic nucleotide" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1359 gccuggaguu uauucggaat t 21 <210> 1360 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19, 22 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 8, 9, 12, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1360 uuccgaauaa acuccaggct t 21 <210> 1361 <211> 19 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <400> 1361 gccuggaguu uauucggaa 19 <210> 1362 <211> 21 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 20, 21 <223> /mod_base = "2'-O-methyl corresponding base 5'-monophosphorothioate" <400> 1362 uuccgaauaa acuccaggcc u 21 <210> 1363 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 2, 4, 6, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 22 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 8, 10, 12, 14, 16, 18, 20 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1363 gccuggaguu uauucggaat t 21 <210> 1364 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 8, 15 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1364 uuccgaauaa acuccaggct t 21 <210> 1365 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "thymidine with 3'-abasic nucleotide" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1365 gccuggaguu uauucggaat t 21 <210> 1366 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 8, 15, 22 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1366 uuccgaauaa acuccaggct t 21 <210> 1367 <211> 19 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <400> 1367 gccuggaguu uauucggaa 19 <210> 1368 <211> 21 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 8, 15 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 20, 21 <223> /mod_base = "2'-O-methyl corresponding base 5'-monophosphorothioate" <400> 1368 uuccgaauaa acuccaggcc u 21 <210> 1369 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 2, 4, 6, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 22 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 8, 10, 12, 14, 16, 18, 20 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1369 gccuggaguu uauucggaat t 21 <210> 1370 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1370 uuccgaauaa acuccaggct t 21 <210> 1371 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "thymidine with 3'-abasic nucleotide" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1371 gccuggaguu uauucggaat t 21 <210> 1372 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 22 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1372 uuccgaauaa acuccaggct t 21 <210> 1373 <211> 19 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <400> 1373 gccuggaguu uauucggaa 19 <210> 1374 <211> 21 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 20, 21 <223> /mod_base = "2'-O-methyl corresponding base 5'-monophosphorothioate" <400> 1374 uuccgaauaa acuccaggcc u 21 <210> 1375 <211> 19 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <223> 5'-terminal nucleic acid is a nucleoside, i.e. base + sugar but lacking 5'-phosphate <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <400> 1375 gccuggaguu uauucggaa 19 <210> 1376 <211> 19 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <400> 1376 uuccgaauaa acuccaggc 19 <210> 1377 <211> 19 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <400> 1377 gccuggaguu uauucggaa 19 <210> 1378 <211> 19 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <400> 1378 uuccgaauaa acuccaggc 19 <210> 1379 <211> 19 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 3, 4, 9, 10, 11, 13, 14, 15 <223> /mod_base = "2'-O-methyl corresponding base" <400> 1379 gccuggaguu uauucggaa 19 <210> 1380 <211> 19 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <400> 1380 uuccgaauaa acuccaggc 19 <210> 1381 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 1381 gccuggaguu uauucggaat t 21 <210> 1382 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 1382 uuccgaauaa acuccaggct t 21 <210> 1383 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 1383 gccuggaguu uauucggaat t 21 <210> 1384 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 8, 15 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1384 uuccgaauaa acuccaggct t 21 <210> 1385 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 1385 gccuggaguu uauucggaat t 21 <210> 1386 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 8, 14, 15 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 4, 5, 6, 7, 9, 10, 11, 12, 13, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1386 uuccgaauaa acuccaggct t 21 <210> 1387 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 1387 gccuggaguu uauucggaat t 21 <210> 1388 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1388 uuccgaauaa acuccaggct t 21 <210> 1389 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 1389 gccuggaguu uauucggaat t 21 <210> 1390 <211> 21 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 20, 21 <223> /mod_base = "2'-O-methyl corresponding base 5'-monophosphorothioate" <400> 1390 uuccgaauaa acuccaggcc u 21 <210> 1391 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 1391 gccuggaguu uauucggaat t 21 <210> 1392 <211> 21 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 20, 21 <223> /mod_base = "2'-O-methyl corresponding base 5'-monophosphorothioate" <400> 1392 uuccgaauaa acuccaggcc u 21 <210> 1393 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1393 gccuggaguu uauucggaat t 21 <210> 1394 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 1394 uuccgaauaa acuccaggct t 21 <210> 1395 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 3, 4, 9, 10, 11, 13, 14, 15 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 5, 6, 7, 8, 12, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1395 gccuggaguu uauucggaat t 21 <210> 1396 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 1396 uuccgaauaa acuccaggct t 21 <210> 1397 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 22 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 8, 10, 12, 14, 16, 18, 20 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1397 gccuggaguu uauucggaat t 21 <210> 1398 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 1398 uuccgaauaa acuccaggct t 21 <210> 1399 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "thymidine with 3'-abasic nucleotide" <400> 1399 gccuggaguu uauucggaat t 21 <210> 1400 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 22 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <400> 1400 uuccgaauaa acuccaggct t 21 <210> 1401 <211> 19 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <400> 1401 gccuggaguu uauucggaa 19 <210> 1402 <211> 21 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "2'-O-methyl corresponding base 5'-monophosphorothioate" <220> <221> modified_base <222> 20 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base 5'-monophosphorothioate" <400> 1402 uuccgaauaa acuccaggcc u 21 <210> 1403 <211> 19 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <400> 1403 gccuggaguu uauucggaa 19 <210> 1404 <211> 21 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 20, 21 <223> /mod_base = "2'-O-methyl corresponding base 5'-monophosphorothioate" <400> 1404 uuccgaauaa acuccaggcc u 21 <210> 1405 <211> 19 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <400> 1405 gccuggaguu uauucggaa 19 <210> 1406 <211> 21 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 20, 21 <223> /mod_base = "2'-O-methyl corresponding base 5'-monophosphorothioate" <400> 1406 uuccgaauaa acuccaggcc u 21 <210> 1407 <211> 19 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <400> 1407 gccuggaguu uauucggaa 19 <210> 1408 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 8, 15 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1408 uuccgaauaa acuccaggct t 21 <210> 1409 <211> 19 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <400> 1409 gccuggaguu uauucggaa 19 <210> 1410 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 8, 14, 15 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 4, 5, 6, 7, 9, 10, 11, 12, 13, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1410 uuccgaauaa acuccaggct t 21 <210> 1411 <211> 19 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methoxyethyl corresponding base" <400> 1411 gccuggaguu uauucggaa 19 <210> 1412 <211> 19 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <400> 1412 uuccgaauaa acuccaggc 19 <210> 1413 <211> 19 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methoxyethyl corresponding base" <400> 1413 gccuggaguu uauucggaa 19 <210> 1414 <211> 19 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <400> 1414 uuccgaauaa acuccaggc 19 <210> 1415 <211> 19 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methoxyethyl corresponding base" <400> 1415 gccuggaguu uauucggaa 19 <210> 1416 <211> 21 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 20 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base 5'-monophosphorothioate" <220> <221> modified_base <222> 21 <223> /mod_base = "2'-O-methyl corresponding base 5'-monophosphorothioate" <400> 1416 uuccgaauaa acuccaggcc u 21 <210> 1417 <211> 19 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methoxyethyl corresponding base" <400> 1417 gccuggaguu uauucggaa 19 <210> 1418 <211> 21 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 20, 21 <223> /mod_base = "2'-O-methyl corresponding base 5'-monophosphorothioate" <400> 1418 uuccgaauaa acuccaggcc u 21 <210> 1419 <211> 19 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methoxyethyl corresponding base" <400> 1419 gccuggaguu uauucggaa 19 <210> 1420 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 8, 15 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1420 uuccgaauaa acuccaggct t 21 <210> 1421 <211> 19 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methoxyethyl corresponding base" <400> 1421 gccuggaguu uauucggaa 19 <210> 1422 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 8, 14, 15 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 4, 5, 6, 7, 9, 10, 11, 12, 13, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1422 uuccgaauaa acuccaggct t 21 <210> 1423 <211> 19 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methoxyethyl corresponding base" <400> 1423 gccuggaguu uauucggaa 19 <210> 1424 <211> 21 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 20, 21 <223> /mod_base = "2'-O-methyl corresponding base 5'-monophosphorothioate" <400> 1424 uuccgaauaa acuccaggcc u 21 <210> 1425 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methoxyethyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1425 gccuggaguu uauucggaat t 21 <210> 1426 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 8, 9, 12, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1426 uuccgaauaa acuccaggct t 21 <210> 1427 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methoxyethyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1427 gccuggaguu uauucggaat t 21 <210> 1428 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 8, 15 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1428 uuccgaauaa acuccaggct t 21 <210> 1429 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methoxyethyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1429 gccuggaguu uauucggaat t 21 <210> 1430 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1430 uuccgaauaa acuccaggct t 21 <210> 1431 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 3, 4, 9, 10, 11, 13, 14, 15 <223> /mod_base = "2'-O-methoxyethyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 5, 6, 7, 8, 12, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1431 gccuggaguu uauucggaat t 21 <210> 1432 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 8, 9, 12, 13, 14, 15, 16 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1432 uuccgaauaa acuccaggct t 21 <210> 1433 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 3, 4, 9, 10, 11, 13, 14, 15 <223> /mod_base = "2'-O-methoxyethyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 5, 6, 7, 8, 12, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1433 gccuggaguu uauucggaat t 21 <210> 1434 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 8, 15 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1434 uuccgaauaa acuccaggct t 21 <210> 1435 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 3, 4, 9, 10, 11, 13, 14, 15 <223> /mod_base = "2'-O-methoxyethyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 5, 6, 7, 8, 12, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1435 gccuggaguu uauucggaat t 21 <210> 1436 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1436 uuccgaauaa acuccaggct t 21 <210> 1437 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 3, 4, 9, 10, 11, 13, 14, 15 <223> /mod_base = "2'-O-methoxyethyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 5, 6, 7, 8, 12, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1437 gccuggaguu uauucggaat t 21 <210> 1438 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 2, 3, 4, 8, 12, 13, 14, 15, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 5, 6, 7, 9, 10, 11, 16, 17, 18 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1438 uuccgaauaa acuccaggct t 21 <210> 1439 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 3, 4, 9, 10, 11, 13, 14, 15 <223> /mod_base = "2'-O-methoxyethyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 5, 6, 7, 8, 12, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1439 gccuggaguu uauucggaat t 21 <210> 1440 <211> 21 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 2, 3, 4, 8, 12, 13, 14, 15, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 20, 21 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base 5'-monophosphorothioate" <400> 1440 uuccgaauaa acuccaggcc u 21 <210> 1441 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 3, 4, 9, 10, 11, 13, 14, 15 <223> /mod_base = "2'-O-methoxyethyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 5, 6, 7, 8, 12, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1441 gccuggaguu uauucggaat t 21 <210> 1442 <211> 21 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "2'-O-methyl corresponding base 5'-monophosphorothioate" <220> <221> modified_base <222> 20 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base 5'-monophosphorothioate" <400> 1442 uuccgaauaa acuccaggcc u 21 <210> 1443 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 3, 4, 9, 10, 11, 13, 14, 15 <223> /mod_base = "2'-O-methoxyethyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 5, 6, 7, 8, 12, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1443 gccuggaguu uauucggaat t 21 <210> 1444 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1444 uuccgaauaa acuccaggct t 21 <210> 1445 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 3, 4, 9, 10, 11, 13, 14, 15 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 5, 6, 7, 8, 12, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1445 gccuggaguu uauucggaat t 21 <210> 1446 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 2, 3, 4, 8, 12, 13, 14, 15, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 5, 6, 7, 9, 10, 11, 16, 17, 18 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1446 uuccgaauaa acuccaggct t 21 <210> 1447 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 3, 4, 9, 10, 11, 13, 14, 15 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 5, 6, 7, 8, 12, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1447 gccuggaguu uauucggaat t 21 <210> 1448 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1448 uuccgaauaa acuccaggct t 21 <210> 1449 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 3, 4, 9, 10, 11, 13, 14, 15 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 5, 6, 7, 8, 12, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1449 gccuggaguu uauucggaat t 21 <210> 1450 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 8, 14, 15 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 4, 5, 6, 7, 9, 10, 11, 12, 13, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1450 uuccgaauaa acuccaggct t 21 <210> 1451 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 3, 4, 9, 10, 11, 13, 14, 15 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 5, 6, 7, 8, 12, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1451 gccuggaguu uauucggaat t 21 <210> 1452 <211> 21 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 20, 21 <223> /mod_base = "2'-O-methyl corresponding base 5'-monophosphorothioate" <400> 1452 uuccgaauaa acuccaggcc u 21 <210> 1453 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 3, 4, 9, 10, 11, 13, 14, 15 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 5, 6, 7, 8, 12, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1453 gccuggaguu uauucggaat t 21 <210> 1454 <211> 21 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 20, 21 <223> /mod_base = "2'-O-methyl corresponding base 5'-monophosphorothioate" <400> 1454 uuccgaauaa acuccaggcc u 21 <210> 1455 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 3, 4, 9, 10, 11, 13, 14, 15 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 5, 6, 7, 8, 12, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1455 gccuggaguu uauucggaat t 21 <210> 1456 <211> 21 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "2'-O-methyl corresponding base 5'-monophosphorothioate" <220> <221> modified_base <222> 20 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base 5'-monophosphorothioate" <400> 1456 uuccgaauaa acuccaggcc u 21 <210> 1457 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 3, 4, 9, 10, 11, 13, 14, 15 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 5, 6, 7, 8, 12, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1457 gccuggaguu uauucggaat t 21 <210> 1458 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 1458 uuccgaauaa acuccaggct t 21 <210> 1459 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 3, 4, 9, 10, 11, 13, 14, 15 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 5, 6, 7, 8, 12, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1459 gccuggaguu uauucggaat t 21 <210> 1460 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 2, 3, 4, 8, 12, 13, 14, 15, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 5, 6, 7, 9, 10, 11, 16, 17, 18 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1460 uuccgaauaa acuccaggct t 21 <210> 1461 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1461 gccuggaguu uauucggaat t 21 <210> 1462 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 2, 3, 4, 8, 12, 13, 14, 15, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 5, 6, 7, 9, 10, 11, 16, 17, 18 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1462 uuccgaauaa acuccaggct t 21 <210> 1463 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 3, 4, 9, 10, 11, 13, 14, 15 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 5, 6, 7, 8, 12, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1463 gccuggaguu uauucggaat t 21 <210> 1464 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 2, 3, 4, 8, 12, 13, 14, 15, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 5, 6, 7, 9, 10, 11, 16, 17, 18 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1464 uuccgaauaa acuccaggct t 21 <210> 1465 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 22 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 8, 10, 12, 14, 16, 18, 20 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1465 gccuggaguu uauucggaat t 21 <210> 1466 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 2, 3, 4, 8, 12, 13, 14, 15, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 5, 6, 7, 9, 10, 11, 16, 17, 18 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1466 uuccgaauaa acuccaggct t 21 <210> 1467 <211> 19 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <400> 1467 gccuggaguu uauucggaa 19 <210> 1468 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 2, 3, 4, 8, 12, 13, 14, 15, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 5, 6, 7, 9, 10, 11, 16, 17, 18 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1468 uuccgaauaa acuccaggct t 21 <210> 1469 <211> 20 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 3, 4, 10, 11, 12, 14, 15, 16 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <400> 1469 gccuggaggu uuauucggaa 20 <210> 1470 <211> 21 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 2, 3, 4, 8, 12, 13, 14, 15, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 20, 21 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base 5'-monophosphorothioate" <400> 1470 uuccgaauaa acuccaggcc u 21 <210> 1471 <211> 20 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 3, 4, 10, 11, 12, 14, 15, 16 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <400> 1471 gccuggaggu uuauucggaa 20 <210> 1472 <211> 19 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <400> 1472 uuccgaauaa acuccaggc 19 <210> 1473 <211> 20 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 3, 4, 10, 11, 12, 14, 15, 16 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <400> 1473 gccuggaggu uuauucggaa 20 <210> 1474 <211> 21 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "2'-O-methyl corresponding base 5'-monophosphorothioate" <220> <221> modified_base <222> 20 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base 5'-monophosphorothioate" <400> 1474 uuccgaauaa acuccaggcc u 21 <210> 1475 <211> 20 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 3, 4, 10, 11, 12, 14, 15, 16 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <400> 1475 gccuggaggu uuauucggaa 20 <210> 1476 <211> 21 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 20, 21 <223> /mod_base = "2'-O-methyl corresponding base 5'-monophosphorothioate" <400> 1476 uuccgaauaa acuccaggcc u 21 <210> 1477 <211> 20 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 3, 4, 10, 11, 12, 14, 15, 16 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <400> 1477 gccuggaggu uuauucggaa 20 <210> 1478 <211> 19 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 6, 7, 10, 11, 17, 18, 19 <223> /mod_base = "2'-O-methyl corresponding base" <400> 1478 uuccgaauaa acuccaggc 19 <210> 1479 <211> 20 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 3, 4, 10, 11, 12, 14, 15, 16 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <400> 1479 gccuggaggu uuauucggaa 20 <210> 1480 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1480 uuccgaauaa acuccaggct t 21 <210> 1481 <211> 20 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 3, 4, 10, 11, 12, 14, 15, 16 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <400> 1481 gccuggaggu uuauucggaa 20 <210> 1482 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 8, 15 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1482 uuccgaauaa acuccaggct t 21 <210> 1483 <211> 20 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 3, 4, 10, 11, 12, 14, 15, 16 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <400> 1483 gccuggaggu uuauucggaa 20 <210> 1484 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 3, 8, 14, 15 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 2, 4, 5, 6, 7, 9, 10, 11, 12, 13, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1484 uuccgaauaa acuccaggct t 21 <210> 1485 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methoxyethyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1485 gccuggaguu uauucggaat t 21 <210> 1486 <211> 21 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 2, 3, 4, 8, 12, 13, 14, 15, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 20, 21 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base 5'-monophosphorothioate" <400> 1486 uuccgaauaa acuccaggcc u 21 <210> 1487 <211> 19 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methoxyethyl corresponding base" <400> 1487 gccuggaguu uauucggaa 19 <210> 1488 <211> 21 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 2, 3, 4, 8, 12, 13, 14, 15, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 20, 21 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base 5'-monophosphorothioate" <400> 1488 uuccgaauaa acuccaggcc u 21 <210> 1489 <211> 19 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <400> 1489 gccuggaguu uauucggaa 19 <210> 1490 <211> 21 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 2, 3, 4, 8, 12, 13, 14, 15, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 20, 21 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base 5'-monophosphorothioate" <400> 1490 uuccgaauaa acuccaggcc u 21 <210> 1491 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 8, 10, 12, 14, 16, 18 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 1, 3, 5, 7, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <400> 1491 gccuggaguu uauucggaat t 21 <210> 1492 <211> 21 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 2, 3, 4, 8, 12, 13, 14, 15, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 20, 21 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base 5'-monophosphorothioate" <400> 1492 uuccgaauaa acuccaggcc u 21 <210> 1493 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 4, 6, 9, 11, 13, 15, 17, 19 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 22 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 3, 5, 8, 10, 12, 14, 16, 18, 20 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1493 gccuggaguu uauucggaat t 21 <210> 1494 <211> 21 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 2, 3, 4, 8, 12, 13, 14, 15, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 20, 21 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base 5'-monophosphorothioate" <400> 1494 uuccgaauaa acuccaggcc u 21 <210> 1495 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1495 gccuggaguu uauucggaat t 21 <210> 1496 <211> 21 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 2, 3, 4, 8, 12, 13, 14, 15, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 20, 21 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base 5'-monophosphorothioate" <400> 1496 uuccgaauaa acuccaggcc u 21 <210> 1497 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 3, 4, 9, 10, 11, 13, 14, 15 <223> /mod_base = "2'-O-methyl corresponding base" <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1, 5, 6, 7, 8, 12, 16, 17, 18, 19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1497 gccuggaguu uauucggaat t 21 <210> 1498 <211> 21 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 2, 3, 4, 8, 12, 13, 14, 15, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 20, 21 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base 5'-monophosphorothioate" <400> 1498 uuccgaauaa acuccaggcc u 21 <210> 1499 <211> 19 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 3, 4, 9, 10, 11, 13, 14, 15 <223> /mod_base = "2'-O-methyl corresponding base" <400> 1499 gccuggaguu uauucggaa 19 <210> 1500 <211> 21 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 2, 3, 4, 8, 12, 13, 14, 15, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 20, 21 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base 5'-monophosphorothioate" <400> 1500 uuccgaauaa acuccaggcc u 21 <210> 1501 <211> 20 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 2, 3, 4, 10, 11, 12, 14, 15, 16 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <400> 1501 gccuggaggu uuauucggaa 20 <210> 1502 <211> 21 <212> RNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 1, 2, 3, 4, 8, 12, 13, 14, 15, 19 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base" <220> <221> modified_base <222> 20, 21 <223> /mod_base = "2'-deoxy-2'-fluoro corresponding base 5'-monophosphorothioate" <400> 1502 uuccgaauaa acuccaggcc u 21 <210> 1503 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1503 gccuggaguu uauucggaat t 21 <210> 1504 <211> 21 <212> DNA <213> Artificial sequence <220> <223> siRNAs to PCSK9 <220> <221> modified_base <222> 21 <223> /mod_base = "5'-thio thymidine" <220> <221> modified_base <222> 1..19 <223> /mod_base = "2'-hydroxy corresponding base" <400> 1504 uuccgaauaa acuccaggct t 21

Claims (22)

  1. 세포에서 사람 프로단백질 컨버타제 서브틸리신 켁신 9(PCSK9) 유전자의 발현을 억제하기 위한 이본쇄 리보핵산(dsRNA)으로서,
    상기 dsRNA가 서로 상보적인 적어도 2개의 서열로 이루어지고, 센스 쇄가 제1 서열이고, 안티센스 쇄가 서열번호 1230의 15개 이상의 연속 뉴클레오타이드로 이루어진 제2 서열인,
    세포에서 사람 PCSK9 유전자의 발현을 억제하기 위한 이본쇄 리보핵산(dsRNA).
  2. 제1항에 있어서, 제1 서열이 서열번호 1229로 이루어지고, 제2 서열이 서열번호 1230으로 이루어진 이본쇄 리보핵산(dsRNA).
  3. 제1항에 있어서, 하나 이상의 변형된 뉴클레오타이드를 포함하는 이본쇄 리보핵산(dsRNA).
  4. 제2항에 있어서, 하나 이상의 변형된 뉴클레오타이드를 포함하는 이본쇄 리보핵산(dsRNA).
  5. 제3항에 있어서, 변형된 뉴클레오타이드가 2'-O-메틸 변형된 뉴클레오타이드, 5'-포스포로티오에이트 그룹을 포함하는 뉴클레오타이드, 및 콜레스테릴 유도체 또는 도데칸산 비스데실아미드 그룹에 연결된 말단 뉴클레오타이드로 이루어진 그룹으로부터 선택되는 이본쇄 리보핵산(dsRNA).
  6. 제3항에 있어서, 변형된 뉴클레오타이드가 2'-데옥시-2'-플루오로 변형된 뉴클레오타이드, 2'-데옥시-변형된 뉴클레오타이드, 록트(locked) 뉴클레오타이드, 무염기(abasic) 뉴클레오타이드, 2'-아미노-변형된 뉴클레오타이드, 2'-알킬-변형된 뉴클레오타이드, 모르폴리노 뉴클레오타이드, 포스포르아미데이트 및 비-천연 염기 포함 뉴클레오타이드로 이루어진 그룹으로부터 선택되는 이본쇄 리보핵산(dsRNA).
  7. 삭제
  8. 제6항에 있어서, 제1 서열이 서열번호 1229로 이루어지고, 제2 서열이 서열번호 1230으로 이루어진 이본쇄 리보핵산(dsRNA).
  9. 제1항에 따른 dsRNA를 포함하는 세포.
  10. dsRNA 및 약제학적으로 허용되는 담체를 포함하는, 유기체에서 고지혈증을 치료 또는 억제하기 위한 약제학적 조성물로서,
    상기 dsRNA가 서로 상보적인 적어도 2개의 서열로 이루어지고, 센스 쇄가 제1 서열이고, 안티센스 쇄가 서열번호 1230의 15개 이상의 연속 뉴클레오타이드로 이루어진 제2 서열이며, 상기 dsRNA가 혈청 지질 수준을 감소시킬 수 있는,
    유기체에서 고지혈증을 치료 또는 예방하기 위한 약제학적 조성물.
  11. 삭제
  12. 제1항에 따른 dsRNA의 하나 이상의 쇄를 암호화하는 뉴클레오타이드 서열에 작동가능하게 연결된 조절 서열을 포함하는, 세포에서 프로단백질 컨버타제 서브틸리신 켁신 9(PCSK9) 유전자의 발현을 억제하기 위한 벡터.
  13. 제12항에 따른 벡터를 포함하는 세포.
  14. 제1항에 있어서, PSCK9 유전자를 발현하는 세포와 접촉시 상기 PCSK9 유전자의 발현을 억제하는 이본쇄 리보핵산(dsRNA).
  15. 제14항에 있어서, 상기 접촉이 시험관내에서 30 nM 이하에서 수행되는 이본쇄 리보핵산(dsRNA).
  16. 제1항에 있어서, PCSK9을 발현하는 HepG2 세포와 접촉시 상기 PCSK9 유전자의 발현을 20% 이상 억제하는 이본쇄 리보핵산(dsRNA).
  17. 제10항에 있어서, dsRNA가 PCSK9을 발현하는 세포와 접촉시 상기 PCSK9 유전자의 발현을 억제하는 약제학적 조성물.
  18. 제1항에 있어서, 동물에게 투여시 총 혈청 콜레스테롤을 감소시키는 이본쇄 리보핵산(dsRNA).
  19. 제10항에 있어서, 동물에게 투여시 총 혈청 콜레스테롤을 감소시키는 약제학적 조성물.
  20. 제10항에 있어서, dsRNA의 센스 쇄가 서열번호 1229로 이루어지고 dsRNA의 안티센스 쇄가 서열번호 1230으로 이루어진, 약제학적 조성물.
  21. 삭제
  22. 삭제
KR1020087030164A 2006-05-11 2007-05-10 Ｐｃｓｋ9 유전자의 발현을 억제하기 위한 조성물 및 방법 KR101036126B1 (ko)

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