TW201730341A - Antisense oligonucleotide for suppressing expression of complement b factor - Google Patents

Antisense oligonucleotide for suppressing expression of complement b factor Download PDF

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TW201730341A
TW201730341A TW106103617A TW106103617A TW201730341A TW 201730341 A TW201730341 A TW 201730341A TW 106103617 A TW106103617 A TW 106103617A TW 106103617 A TW106103617 A TW 106103617A TW 201730341 A TW201730341 A TW 201730341A
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methylene
modified base
dna
antisense oligonucleotide
linked bicyclic
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Yoji Yamada
Kiyoshi Shimizu
Hiroto Iwai
Asana Makino
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Kyowa Hakko Kirin Co Ltd
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Abstract

The present invention provides: an antisense oligonucleotide having CFB expression-suppressing activity; a pharmaceutical composition including the antisense oligonucleotide; and a drug that suppresses the expression of CFB including the antisense oligonucleotide, the drug preventing or treating disorders mediated by abnormalities of the complement alternative pathway such as atypical hemolytic uremic syndrome, paroxysmal nocturnal hemoglobinuria, age-related macular degeneration, membranous-proliferative glomerulonephritis, C3 nephritis, membranous nephropathy, rapid progressive glomerulonephritis (RPGN), acute kidney injury (AKI), asthma, or autoimmune diseases.

Description

抑制補體B因子之表現之反義寡核苷酸 Antisense oligonucleotides that inhibit the expression of complement factor B

本發明係關於一種用於補體B因子之表現抑制之反義寡核苷酸或含有該反義寡核苷酸之醫藥組合物。 The present invention relates to an antisense oligonucleotide for inhibiting the expression of complement factor B or a pharmaceutical composition comprising the same.

補體係介導免疫反應之血中蛋白質之一類物質，作為補體之作用，可列舉：促進吞噬細胞之吞噬病原菌之作用或對具有外膜之病毒產生傷害而使其失去感染力等。補體中，C3於血清中之存在量最多，於補體旁路途徑，藉由利用補體B因子(complement factor B；CFB)等進行活化，而抑制其作用(非專利文獻1)。 The function of complement as a complement to the immune system is to promote the action of the phagocytic pathogen of the phagocytic cells or to damage the virus having the outer membrane and to lose the infectivity. Among the complements, C3 is most abundant in the serum, and is activated by activation of complement factor B (CFB) or the like in the complement alternative pathway (Non-Patent Document 1).

已知若因與補體旁路途徑相關之控制因子之異常、或利用針對C3轉化酶之自體抗體所進行之穩定化等，而繼續使C3活化，則非典型溶血性***症候群(aHUS)、陣發性夜間血紅素尿症(PNH)、老年性黃斑變性症(AMD)、膜性增殖性腎小球腎炎(MPGN)、C3腎炎、膜性腎病、急進性腎小球腎炎(RPGN)、急性腎損傷(AKI)、全身性紅斑狼瘡(SLE)、哮喘、牛皮癬、視神經脊髓炎、重症肌無力症、自體免疫疾病等疾病會發病(非專利文獻2)。雖然可期待藉由特異性地抑制補體B因子之作用而能夠預防或治療上述疾病，但補體B因子於血中以300μg/mL之相對高濃度存在(非專利文獻3)，不易利用例如普通之抗體醫藥繼續抑制該等全部補體B因子。 It is known that atypical hemolytic uremic syndrome (aHUS) is known to continue to activate C3 due to abnormalities in control factors associated with the complement alternative pathway or stabilization by autoantibodies against C3 convertase. , paroxysmal nocturnal hemoglobinuria (PNH), age-related macular degeneration (AMD), membranous proliferative glomerulonephritis (MPGN), C3 nephritis, membranous nephropathy, progressive glomerulonephritis (RPGN) Diseases such as acute kidney injury (AKI), systemic lupus erythematosus (SLE), asthma, psoriasis, optic neuromyelitis, myasthenia gravis, and autoimmune diseases may occur (Non-Patent Document 2). Although it is expected that the above-mentioned diseases can be prevented or treated by specifically inhibiting the action of the complement factor B, the complement factor B is present in the blood at a relatively high concentration of 300 μg/mL (Non-Patent Document 3), and it is difficult to use, for example, ordinary ones. Antibody medicine continues to inhibit these all complement B factors.

另一方面，作為抑制基因表現本身之方法，已知有例如反義法(專利文獻1)。具體而言，與靶基因之mRNA或mRNA前驅物等互補之寡核苷酸 (反義寡核苷酸)若導入至細胞內，則能夠與靶基因之mRNA或mRNA前驅物形成雙鏈，而特異性地抑制該靶基因之表現。又，作為反義法以外之抑制基因表現之方法，亦已知有利用RNA干擾(RNA interference，以下稱為RNAi)之方法。該方法能夠藉由導入具有與靶基因相同之序列的雙鏈RNA(siRNA)，而特異性地抑制該靶基因之表現(專利文獻2)。 On the other hand, as a method of suppressing gene expression itself, for example, an antisense method is known (Patent Document 1). Specifically, an oligonucleotide complementary to the mRNA or mRNA precursor of the target gene or the like When the (antisense oligonucleotide) is introduced into a cell, it can form a double strand with the mRNA or mRNA precursor of the target gene, and specifically suppress the expression of the target gene. Further, as a method for suppressing gene expression other than the antisense method, a method using RNA interference (hereinafter referred to as RNAi) is also known. This method can specifically inhibit the expression of the target gene by introducing a double-stranded RNA (siRNA) having the same sequence as the target gene (Patent Document 2).

揭示有以人類補體B因子基因作為靶之siRNA序列之一部分(專利文獻3)。又，揭示有以該基因作為靶之反義序列之一部分(專利文獻4)，但本發明係與該等序列不同之序列。 A part of the siRNA sequence targeting the human complement B factor gene is disclosed (Patent Document 3). Further, a part of the antisense sequence targeting the gene is disclosed (Patent Document 4), but the present invention is a sequence different from the sequences.

[先前技術文獻] [Previous Technical Literature] [專利文獻] [Patent Literature]

[專利文獻1]國際公開第98/56905號說明書 [Patent Document 1] International Publication No. 98/56905

[專利文獻2]國際公開第2001/75164號說明書 [Patent Document 2] International Publication No. 2001/75164

[專利文獻3]國際公開第2015/089368號說明書 [Patent Document 3] International Publication No. 2015/089368

[專利文獻4]國際公開第2015/038939號說明書 [Patent Document 4] International Publication No. 2015/038939

[非專利文獻] [Non-patent literature]

[非專利文獻1]Proc Natl Acad Sci USA,, 94, 8720-8725(1997) [Non-Patent Document 1] Proc Natl Acad Sci USA,, 94, 8720-8725 (1997)

[非專利文獻2]J Am Soc Nephrol. Jul 16. pii：ASN.2015020184(2015) [Non-Patent Document 2] J Am Soc Nephrol. Jul 16. pii: ASN.2015020184 (2015)

[非專利文獻3]邀請補體，Medical View出版社，p.18(2011) [Non-Patent Document 3] Inviting Complement, Medical View Press, p. 18 (2011)

本發明之目的在於提供一種能夠抑制補體B因子之表現之新穎反義寡核苷酸。又，本發明之目的在於提供一種用於預防或治療與補體B因子之表現相關之疾病之醫藥組合物。 It is an object of the present invention to provide a novel antisense oligonucleotide capable of inhibiting the expression of the complement B factor. Further, it is an object of the present invention to provide a pharmaceutical composition for preventing or treating a disease associated with the expression of complement factor B.

本發明係關於以下之(1)~(13)。 The present invention relates to the following (1) to (13).

(1)一種鹼基長度8~80之反義寡核苷酸，其係抑制補體B因子之表現者，並且能夠於嚴格之條件下與包含序列編號53~103中之任一個所表示之靶鹼基序列的核酸進行雜交。 (1) An antisense oligonucleotide having a base length of 8 to 80 which inhibits expression of a complement B factor and which is capable of expressing a target represented by any one of SEQ ID NO: 53 to 103 under stringent conditions The nucleic acid of the base sequence is hybridized.

(2)一種鹼基長度8~80之反義寡核苷酸，其係抑制補體B因子之表現者，並且含有序列編號2~52中之任一個所表示之反義鹼基序列之連續之至少8個鹼基。 (2) An antisense oligonucleotide having a base length of 8 to 80 which inhibits the expression of the complement B factor and which comprises the contiguous sequence of the antisense base represented by any one of SEQ ID NOs: 2 to 52. At least 8 bases.

(3)一種鹼基長度8~80之反義寡核苷酸，其含有與序列編號53~103中之任一個所表示之鹼基序列互補之鹼基序列。 (3) An antisense oligonucleotide having a base length of 8 to 80, which comprises a base sequence complementary to the nucleotide sequence represented by any one of SEQ ID NOs: 53 to 103.

(4)如(3)所記載之反義寡核苷酸，其含有序列編號2~52中之任一個所表示之鹼基序列。 (4) The antisense oligonucleotide according to (3), which comprises the nucleotide sequence represented by any one of SEQ ID NOs: 2 to 52.

(5)如(4)所記載之反義寡核苷酸，其含有於序列編號2~52中之任一個所表示之鹼基序列中有1個乃至複數個鹼基經缺失、取代、***或附加之序列。 (5) The antisense oligonucleotide according to (4), wherein one or more of the base sequences represented by any one of SEQ ID NO: 2 to 52 are deleted, substituted, or inserted. Or a sequence attached.

(6)一種反義寡核苷酸，其包含序列編號2~52中之任一個所表示之鹼基序列。 (6) An antisense oligonucleotide comprising the base sequence represented by any one of SEQ ID NO: 2 to 52.

(7)如(1)至(6)中任一項所記載之反義寡核苷酸，其中5'末端附近及/或3'末端附近由糖部修飾核苷酸所構成。 (7) The antisense oligonucleotide according to any one of (1) to (6) wherein the vicinity of the 5' end and/or the vicinity of the 3' end is composed of a sugar-modified nucleotide.

(8)一種反義寡核苷酸，其包含序列編號104~154及155中之任一個所表示之核苷酸序列。 (8) An antisense oligonucleotide comprising the nucleotide sequence represented by any one of SEQ ID NOs: 104 to 154 and 155.

(9)一種反義寡核苷酸，其包含序列編號118、125、150及155中之任一個所表示之核苷酸序列。 (9) An antisense oligonucleotide comprising the nucleotide sequence represented by any one of SEQ ID NO: 118, 125, 150 and 155.

(10)如(1)至(9)中任一項所記載之反義寡核苷酸，其含有配位子。 (10) The antisense oligonucleotide according to any one of (1) to (9) which contains a ligand.

(11)一種醫藥組合物，其含有如(1)至(10)中任一項所記載之反義寡核苷酸。 (11) A pharmaceutical composition comprising the antisense oligonucleotide according to any one of (1) to (10).

(12)一種治療由補體旁路途徑之異常所介導之障礙的方法，其包括將治療上有效量之如(1)至(10)中任一項所記載之反義寡核苷酸或如(11)所記載之醫藥組合物投予需要此種治療之人的步驟。 (12) A method of treating a disorder mediated by an abnormality of the complement alternative pathway, comprising administering a therapeutically effective amount of the antisense oligonucleotide of any one of (1) to (10) or The pharmaceutical composition according to (11) is administered to a person in need of such treatment.

(13)如(12)所記載之方法，其中上述疾病為非典型溶血性***症候群、陣發性夜間血紅素尿症、老年性黃斑變性症、膜性增殖性腎小球腎炎、C3腎炎、膜性腎病、急進性腎小球腎炎(RPGN)、急性腎損傷(AKI)、哮喘或自體免疫疾病。 (13) The method according to (12), wherein the disease is atypical hemolytic uremic syndrome, paroxysmal nocturnal hemoglobinuria, age-related macular degeneration, membranous proliferative glomerulonephritis, C3 nephritis Membranous nephropathy, acute glomerulonephritis (RPGN), acute kidney injury (AKI), asthma or autoimmune disease.

藉由投予本發明之反義寡核苷酸或含有該反義寡核苷酸之醫藥組合物，能夠抑制補體B因子之表現。本發明之反義寡核苷酸或含有該反義寡核苷酸之醫藥組合物於由補體旁路途徑之異常所介導之障礙之治療或預防方面有用。 By administering the antisense oligonucleotide of the present invention or a pharmaceutical composition containing the antisense oligonucleotide, the expression of the complement B factor can be suppressed. The antisense oligonucleotide of the present invention or a pharmaceutical composition containing the same is useful for the treatment or prevention of a disorder mediated by an abnormality of the complement alternative pathway.

圖1表示投予有序列編號118、125及150中之任一個所表示之反義寡核苷酸之小鼠之活體內減弱之結果。縱軸表示將對照群之補體B因子(CFB)之mRNA之準定量值設為1之情形時之各反義寡核苷酸投予群之CFB mRNA之相對表現率。 Figure 1 shows the results of in vivo attenuation of mice administered with antisense oligonucleotides represented by any of SEQ ID NO: 118, 125 and 150. The vertical axis indicates the relative expression rate of CFB mRNA of each antisense oligonucleotide administration group when the quasi-quantitative value of the mRNA of the complement B factor (CFB) of the control group was set to 1.

圖2表示投予有序列編號155所表示之反義寡核苷酸之小鼠之活體內減弱之結果。縱軸表示將對照群之CFB之mRNA之準定量值設為1之情形時之上述反義寡核苷酸投予群之CFB mRNA之相對表現率。 Fig. 2 shows the results of in vivo attenuation of mice administered with the antisense oligonucleotide represented by SEQ ID NO: 155. The vertical axis indicates the relative expression rate of CFB mRNA of the antisense oligonucleotide administration group when the quasi-quantitative value of the CFB of the control group is set to 1.

1.本發明之反義寡核苷酸 1. Antisense oligonucleotide of the present invention

本發明提供一種抑制補體B因子(CFB)之表現之反義寡核苷酸(本說明書中，亦稱為「本發明之反義寡核苷酸」)。 The present invention provides an antisense oligonucleotide (also referred to as "antisense oligonucleotide of the present invention" which inhibits the expression of complement B factor (CFB).

於本說明書中，所謂「反義寡核苷酸」係與構成靶基因之DNA、自此種DNA轉錄之mRNA前驅物及mRNA互補之寡核苷酸，該反義寡核苷酸藉由與作為靶之DNA、mRNA前驅物或mRNA形成雙鏈或三鏈而抑制DNA、mRNA前驅物或mRNA之功能(轉錄、轉錄後編輯、轉譯等)。 In the present specification, the "antisense oligonucleotide" is an oligonucleotide complementary to the DNA constituting the target gene, the mRNA precursor transcribed from the DNA, and the mRNA, and the antisense oligonucleotide is The target DNA, mRNA precursor or mRNA forms a double strand or a triple strand to inhibit the function of DNA, mRNA precursor or mRNA (transcription, post-transcription editing, translation, etc.).

作為編碼本發明之反義寡核苷酸之標靶之CFB的基因(以下，亦稱為CFB基因)，可列舉具有登記為Genbank登記編號NM_001710之與人類CFB之全長mRNA對應之cDNA鹼基序列(序列編號1)者，當然天然存在之其變異體(例如參照Hum.Mutat.31：E1445-E1460(2010)，refsnp No.rs12614、rs641153等)亦能夠成為本發明之反義寡核苷酸之靶基因。 As a gene encoding CFB which is a target of the antisense oligonucleotide of the present invention (hereinafter also referred to as CFB gene), a cDNA base sequence corresponding to the full-length mRNA of human CFB registered as Genbank Accession No. NM_001710 can be cited. (SEQ ID NO: 1), of course, naturally occurring variants thereof (for example, refer to Hum. Mutat. 31: E1445-E1460 (2010), refsnp No. rs12614, rs641153, etc.) can also be an antisense oligonucleotide of the present invention. Target gene.

於本說明書中，所謂「互補」意指例如腺嘌呤與胸腺嘧啶或尿嘧啶之關係、及鳥嘌呤與胞嘧啶之關係般，能夠經由寬鬆之氫鍵於2個鹼基間進行鹼基配對之關係。 In the present specification, the term "complementary" means, for example, the relationship between adenine and thymine or uracil, and the relationship between guanine and cytosine, and base pairing between two bases via a loose hydrogen bond. relationship.

又，所謂「互補」不僅包括2個核苷酸序列於雙鏈區域(於使兩序列對準之情形時重疊之區域)完全互補之情形，只要該雙鏈區域整體形成雙螺旋結構、即於嚴格之條件下兩序列只要能夠進行雜交，則存在1個乃至複數個錯配之情形亦包括在內。 Further, the term "complementarity" includes not only a case where two nucleotide sequences are completely complementary in a double-stranded region (a region overlapping when the two sequences are aligned), as long as the double-stranded region integrally forms a double helix structure, that is, Under strict conditions, as long as the two sequences are capable of hybridization, one or even multiple mismatches are also included.

因此，本發明之反義寡核苷酸係能夠於嚴格之條件下與包含編碼CFB之DNA、mRNA前驅物或mRNA中之靶鹼基序列之核酸進行雜交之核酸分子。 Thus, the antisense oligonucleotide of the present invention is capable of hybridizing to a nucleic acid molecule comprising a nucleic acid encoding a CFB DNA, an mRNA precursor or a target base sequence in mRNA under stringent conditions.

於本說明書中，所謂「嚴格之條件」意指雖然本發明之反義寡核苷酸與CFB基因之靶鹼基序列進行雜交，但與其他序列不雜交，或即便雜交亦大幅度少於與靶鹼基序列雜交之量，而僅有相對可忽略之程度之微量進行雜交之條件。藉由使雜交反應及洗淨時之溫度、或雜交反應液及洗淨液之鹽濃度等變化，能夠容易地選擇此種條件。具體而言，作為嚴格之條件之一例，可列舉於6×SSC(0.9M NaCl,0.09M檸檬酸三鈉)或6×SSPE(3M NaCl,0.2M NaH2PO4,20mM EDTA‧2Na,pH值7.4)中，於42℃下進行雜交，進而於42℃下利用0.5×SSC進行洗淨之條件，但不限定於此。作為雜交之方法，例如可使用南方墨點雜交法等。具體而言，可依據Molecular Cloning：A Laboratory Mannual,Second Edition(1989)(Cold Spring Harbor Laboratory Press),Current Protocols in Molecular Biology(1994)(Wiley-Interscience)等所記載之方法進行。 In the present specification, the term "stringent conditions" means that although the antisense oligonucleotide of the present invention hybridizes with the target base sequence of the CFB gene, it does not hybridize with other sequences, or even if the hybridization is substantially less than The amount of hybridization of the target base sequence, and only a relatively negligible degree of hybridization. Such a condition can be easily selected by changing the temperature at the time of the hybridization reaction and washing, or the salt concentration of the hybridization reaction solution and the washing liquid, and the like. Specifically, as an example of stringent conditions, it can be exemplified by 6×SSC (0.9 M NaCl, 0.09 M trisodium citrate) or 6×SSPE (3 M NaCl, 0.2 M NaH 2 PO 4 , 20 mM EDTA‧2Na, pH). In the value 7.4), the hybridization was carried out at 42 ° C, and further washed at 0.5 ° C with a concentration of 0.5 × SSC, but the present invention is not limited thereto. As a method of hybridization, for example, a Southern blot hybridization method or the like can be used. Specifically, it can be carried out according to the method described in Molecular Cloning: A Laboratory Manual, Second Edition (1989) (Cold Spring Harbor Laboratory Press), Current Protocols in Molecular Biology (1994) (Wiley-Interscience).

作為本發明之反義寡核苷酸，只要為由核苷酸或具有與該核苷酸同等功能之分子聚合而成之分子，則可為任何分子，例如可列舉作為脫氧核糖核苷酸之聚合物之DNA、作為核糖核苷酸之聚合物之RNA、包含DNA與RNA之嵌合核酸及該等核酸中之至少一種核苷酸經具有與該核苷酸同等之功能之分子取代之核苷酸聚合物。又，RNA中之尿嘧啶(U)於DNA中可以同一含義換稱為胸腺嘧啶(T)。 The antisense oligonucleotide of the present invention may be any molecule as long as it is a molecule obtained by polymerizing a nucleotide or a molecule having the same function as the nucleotide, and for example, it can be exemplified as a deoxyribonucleotide. a DNA of a polymer, an RNA as a polymer of ribonucleotides, a chimeric nucleic acid comprising DNA and RNA, and a core substituted with at least one of the nucleic acids having the same function as the nucleotide Glycosylate polymer. Further, uracil (U) in RNA can be referred to as thymine (T) in the same meaning in DNA.

作為具有與核苷酸同等之功能之分子，例如可列舉核苷酸衍生物等。作為核苷酸衍生物，只要為對核苷酸實施修飾之分子，則可為任何分子，但適宜為使用例如與DNA或RNA相比，為了提高核酸酶耐性或使分子穩定化、為了提高與互補鏈核酸之親和性、為了提高細胞透過性、或為了可見化，而對脫氧核糖核苷酸或核糖核苷酸實施修飾之分子等。 Examples of the molecule having a function equivalent to a nucleotide include a nucleotide derivative and the like. The nucleotide derivative may be any molecule as long as it is a molecule that modifies a nucleotide, but it is preferably used to increase nuclease resistance or stabilize a molecule, for example, in comparison with DNA or RNA. A molecule that modifies a deoxyribonucleotide or a ribonucleotide, or the like, for affinity of a complementary strand nucleic acid, or for improving cell permeability or for visualization.

作為對核苷酸實施修飾之分子，例如可列舉：糖部修飾核苷酸、磷酸二酯鍵修飾核苷酸、鹼基修飾核苷酸、以及糖部、磷酸二酯鍵及鹼基中之2種以上經修飾之核苷酸等。 Examples of the molecule which modifies a nucleotide include a sugar moiety modified nucleotide, a phosphodiester bond modified nucleotide, a base modified nucleotide, and a saccharide moiety, a phosphodiester bond, and a base. Two or more modified nucleotides and the like.

作為糖部修飾核苷酸，只要為對核苷酸之糖之化學結構之一部分或全部利用任意之取代基進行修飾或取代者、或利用任意之原子進行置換者，則可為任何者，較佳為使用2'-修飾核苷酸。 The saccharide-modified nucleotide may be any one that is modified or substituted with a part or all of a chemical structure of a sugar of a nucleotide, or substituted by an arbitrary atom. It is preferred to use 2'-modified nucleotides.

作為2'-修飾核苷酸，例如可列舉核糖之2'-OH基被取代為選自由OR、R、R'OR、SH、SR、NH2、NHR、NR2、N3、CN、F、Cl、Br及I所組成之群(R為烷基或芳基，較佳為碳數為1~6之烷基，R'為伸烷基，較佳為碳數為1~6之伸烷基)中之取代基的2'-修飾核苷酸，較佳可列舉糖之2'-OH基被取代為F或甲氧基之2'-修飾核苷酸。又，亦可列舉核糖之2'-OH基被取代為選自由2-(甲氧基)乙氧基、3-胺基丙氧基、2-[(N,N-二甲基胺基)氧基]乙氧基、3-(N,N-二甲基胺基)丙氧基、2-[2-(N,N-二甲基胺基)乙氧基]乙氧基、2-(甲胺基)-2-側氧基乙氧基、2-(N-甲基胺甲醯基)乙氧基及2-氰基乙氧基所組成之群中之取代基的2'-修飾核苷酸等。更佳可列舉核糖之2'-OH基被取代為選自由甲氧基及2-(甲氧基)乙氧基所組成之群中之取代基的2'-修飾核苷酸等。 Examples of the 2'-modified nucleotide include, for example, a 2'-OH group of ribose substituted with OR, R, R'OR, SH, SR, NH 2 , NHR, NR 2 , N 3 , CN, F. a group consisting of Cl, Br and I (R is an alkyl group or an aryl group, preferably an alkyl group having 1 to 6 carbon atoms, and R' is an alkylene group, preferably having a carbon number of 1 to 6 The 2'-modified nucleotide of the substituent in the alkyl group is preferably a 2'-modified nucleotide in which the 2'-OH group of the sugar is substituted with F or a methoxy group. Further, it is also possible to exemplify that the 2'-OH group of ribose is substituted from 2-(methoxy)ethoxy, 3-aminopropoxy, 2-[(N,N-dimethylamino) Oxy]ethoxy, 3-(N,N-dimethylamino)propoxy, 2-[2-(N,N-dimethylamino)ethoxy]ethoxy, 2- 2'- of the substituents in the group consisting of (methylamino)-2-oxoethoxyethoxy, 2-(N-methylaminecarbamyl)ethoxy and 2-cyanoethoxy Modify nucleotides and the like. More preferably, the 2'-modified nucleotide of the ribose is substituted with a 2'-modified nucleotide selected from the group consisting of a methoxy group and a 2-(methoxy)ethoxy group.

又，作為糖部修飾核苷酸，亦適宜地使用藉由對糖部導入交聯結構而具有2個環狀結構的交聯結構型人工核酸(Bridged Nucleic Acid)(BNA)。具體而言，可列舉2'位之氧原子及4'位之碳原子經由亞甲基而交聯之鎖人工核酸(Locked Nucleic Acid)(LNA)[Tetrahedron Letters,38,8735,(1997)及Tetrahedron,54,3607,(1998)]、乙烯交聯結構型人工核酸(Ethylene bridged nucleic acid)(ENA)[Nucleic Acid Research,32, e175(2004)]、限制性乙基(cEt)[The Journal of Organic Chemistry 75,1569(2010)]、醯胺基-交聯人工核酸(AmNA)[Chem Bio Chem 13,2513(2012)]及2'-O,4'-C-螺環丙烯交聯核酸(scpBNA)[Chem.Commun.,51,9737(2015)]等。 Further, as the saccharide-modified nucleotide, a bridged-nuclear acid (BNA) having two cyclic structures by introducing a cross-linking structure into a saccharide moiety is also suitably used. Specifically, a Locked Nucleic Acid (LNA) which crosslinks an oxygen atom at the 2' position and a carbon atom at the 4' position via a methylene group can be cited [Tetrahedron Letters, 38, 8735, (1997) and Tetrahedron, 54, 3607, (1998)], Ethylene bridged nucleic acid (ENA) [Nucleic Acid Research, 32, E175 (2004)], a restricted ethyl group (cEt) [The Journal of Organic Chemistry 75, 1569 (2010)], amidino-crosslinked artificial nucleic acid (AmNA) [Chem Bio Chem 13, 2513 (2012)] and 2'-O, 4'-C-spirocyclopropene cross-linked nucleic acid (scpBNA) [Chem. Commun., 51, 9737 (2015)] and the like.

進而，作為糖部修飾核苷酸，亦可列舉肽核酸(PNA)[Acc.Chem.Res.,32,624(1999)]、氧基肽核酸(OPNA)[J.Am.Chem.Soc.,123,4653(2001)]、肽核糖核酸(PRNA)[J.Am.Chem.Soc.,122,6900(2000)]等。 Further, examples of the sugar-modified nucleotide include peptide nucleic acid (PNA) [Acc. Chem. Res., 32, 624 (1999)], and oxypeptide nucleic acid (OPNA) [J. Am. Chem. Soc., 123 , 4653 (2001)], peptide ribonucleic acid (PRNA) [J. Am. Chem. Soc., 122, 6900 (2000)] and the like.

作為磷酸二酯鍵修飾核苷酸，只要為針對核苷酸之磷酸二酯鍵之化學結構之一部分或全部，利用任意之取代基進行修飾或取代者或利用任意之原子進行置換者，則可為任何者，例如可列舉：磷酸二酯鍵被取代為硫代磷酸酯鍵之核苷酸、磷酸二酯鍵被取代為二硫代磷酸酯鍵之核苷酸、磷酸二酯鍵被取代為膦酸烷基酯鍵之核苷酸、磷酸二酯鍵被取代為亞磷醯胺鍵之核苷酸等，較佳可列舉磷酸二酯鍵被取代為硫代磷酸酯鍵之核苷酸。 The phosphodiester bond-modified nucleotide may be a part or all of a chemical structure of a phosphodiester bond to a nucleotide, and may be modified or substituted with an arbitrary substituent or replaced with an arbitrary atom. For example, a nucleotide in which a phosphodiester bond is substituted with a phosphorothioate bond, a nucleotide in which a phosphodiester bond is substituted with a phosphorodithioate bond, and a phosphodiester bond are substituted The nucleotide of the alkyl phosphonate bond, the nucleotide of the phosphodiester bond are substituted with a nucleotide of a phosphonium amide bond, etc., and a nucleotide in which a phosphodiester bond is substituted with a phosphorothioate bond is preferable.

作為鹼基修飾核苷酸，只要為針對核苷酸之鹼基之化學結構之一部分或全部，利用任意之取代基進行修飾或取代者或利用任意之原子進行置換者，則可為任何者，例如可列舉：鹼基內之氧原子被取代為硫原子者，氫原子被取代為碳數1~6之烷基、鹵基者，甲基被取代為氫、羥甲基、碳數2~6之烷基者，胺基被取代為碳數1~6之烷基、碳數1~6之烷醯基、側氧基、羥基等者。再者，使用5-甲基胞嘧啶(5-mC)代替胞嘧啶(C)作為鹼基修飾核苷酸之情形亦為本發明之較佳形態之一。 The base-modified nucleotide may be any one or all of the chemical structures of the bases of the nucleotides, and may be modified by any substituent or by substitution with any atom. For example, when an oxygen atom in a base is substituted with a sulfur atom, a hydrogen atom is substituted with an alkyl group having 1 to 6 carbon atoms, a halogen group, and a methyl group is substituted with hydrogen, a hydroxymethyl group, and a carbon number of 2~. In the case of the alkyl group of 6, the amine group is substituted with an alkyl group having 1 to 6 carbon atoms, an alkyl fluorenyl group having 1 to 6 carbon atoms, a pendant oxy group, a hydroxyl group and the like. Further, the case of using 5-methylcytosine (5-mC) instead of cytosine (C) as a base-modified nucleotide is also one of preferred embodiments of the present invention.

作為核苷酸衍生物，可列舉對於核苷酸或糖部、磷酸二酯鍵或鹼基中之至少一者經修飾之核苷酸衍生物，直接或經由連接子附加配位子而成 者，該配位子例如為：膽固醇、脂肪酸、生育酚、視黃醇等脂質類，N-乙醯半乳糖胺(GalNAc)、半乳糖(Gal)、甘露糖(Man)等糖類，完整抗體、Fab、scFv、VHH等片段抗體，低密度脂蛋白(LDL)、人類血清白蛋白等蛋白質，RGD、NGR、R9、CPP等肽類，啡、啡啶、蒽醌、葉酸等低分子，合成聚胺基酸等合成聚合物，核酸適體、吖啶、螢光素、若丹明、香豆素等色素，Cy3系列、Alexa系列、黑洞淬滅劑(black hole quenchers)等螢光團等其他化學物質。具體而言，可列舉：多胺加成核苷酸衍生物、膽固醇加成核苷酸衍生物、類固醇加成核苷酸衍生物、GalNAc加成核苷酸衍生物、膽汁酸加成核苷酸衍生物、脂肪酸加成核苷酸衍生物、維生素加成核苷酸衍生物、Cy5加成核苷酸衍生物、Cy3加成核苷酸衍生物、6-FAM加成核苷酸衍生物及生物素加成核苷酸衍生物等，較佳可列舉GalNAc加成核苷酸衍生物。該等可藉由在固相上之延伸反應時使能夠在固相上反應之修飾劑進行反應，而於5'末端、3'末端及/或序列內部實施修飾。又，亦可藉由預先合成及精製導入有胺基、巰基、疊氮基或三鍵等官能基之核酸，並使修飾劑作用於該等而獲得。 Examples of the nucleotide derivative include nucleotide derivatives modified with at least one of a nucleotide or a saccharide moiety, a phosphodiester bond, or a base, and a ligand is added directly or via a linker. The ligands are, for example, lipids such as cholesterol, fatty acids, tocopherols, and retinol, and sugars such as N-acetylgalactosamine (GalNAc), galactose (Gal), and mannose (Man), intact antibodies, Fab, scFv, VHH and other fragment antibodies, low density lipoprotein (LDL), human serum albumin and other proteins, RGD, NGR, R9, CPP and other peptides, brown , low molecular weight such as pyridine, guanidine, folic acid, synthetic polymer such as polyamino acid, aptamer, acridine, luciferin, rhodamine, coumarin, etc., Cy3 series, Alexa series, black hole Other chemicals such as fluorescent groups such as black hole quenchers. Specific examples thereof include polyamine addition nucleotide derivatives, cholesterol addition nucleotide derivatives, steroid addition nucleotide derivatives, GalNAc addition nucleotide derivatives, and bile acid addition nucleosides Acid derivative, fatty acid addition nucleotide derivative, vitamin addition nucleotide derivative, Cy5 addition nucleotide derivative, Cy3 addition nucleotide derivative, 6-FAM addition nucleotide derivative Further, a biotin addition nucleotide derivative or the like is preferably a GalNAc addition nucleotide derivative. These may be modified at the 5' end, the 3' end, and/or the inside of the sequence by reacting a modifying agent capable of reacting on a solid phase upon extension reaction on a solid phase. Further, it is also possible to obtain a nucleic acid having a functional group such as an amino group, a thiol group, an azide group or a triple bond introduced and purified in advance, and to apply a modifying agent to the above.

核苷酸衍生物亦可與核酸內之其他核苷酸或核苷酸衍生物形成伸烷基結構、肽結構、核苷酸結構、醚結構、酯結構及將該等中之至少一種組合而成之結構等交聯結構。 The nucleotide derivative may also form an alkylene structure, a peptide structure, a nucleotide structure, an ether structure, an ester structure, and at least one of the other nucleotides or nucleotide derivatives in the nucleic acid. A cross-linked structure such as a structure.

本發明之反義寡核苷酸亦包含其分子中之一部分或全部原子被取代為質量數不同之原子(同位素)者。 The antisense oligonucleotide of the present invention also includes those in which one or all of the atoms in the molecule are substituted with atoms (isotopes) having different mass numbers.

本發明之反義寡核苷酸只要為於嚴格之條件下與CFB基因之靶鹼基序列進行雜交之核酸，則可導入至髮夾低聚物、環狀低聚物之形態中，亦可含有內部或末端之凸出或環等結構要素。 The antisense oligonucleotide of the present invention may be introduced into a hairpin oligomer or a cyclic oligomer as long as it is a nucleic acid that hybridizes to a target base sequence of a CFB gene under stringent conditions. Contains structural elements such as protrusions or rings at the inner or end.

本發明之反義寡核苷酸之長度為8~80個鹼基，較佳為8~30個鹼基。例如，可為8~20個鹼基、10~20個鹼基、13~20個鹼基、13~16個鹼基、13個鹼基、14個鹼基、15個鹼基、16個鹼基、17個鹼基、18個鹼基、19個鹼基、20個鹼基。 The antisense oligonucleotide of the present invention has a length of 8 to 80 bases, preferably 8 to 30 bases. For example, it can be 8 to 20 bases, 10 to 20 bases, 13 to 20 bases, 13 to 16 bases, 13 bases, 14 bases, 15 bases, and 16 bases. Base, 17 bases, 18 bases, 19 bases, 20 bases.

作為本發明之反義寡核苷酸之具體之靶鹼基序列，可列舉表1所記載之序列編號53~103所表示之CFB mRNA(cDNA)之部分鹼基序列。因此，本發明之反義寡核苷酸係於嚴格之條件下能夠與序列編號53~103中之任一個所表示之靶鹼基序列進行雜交之寡核苷酸。本發明之反義寡核苷酸只要於嚴格之條件下能夠與上述任一靶鹼基序列進行雜交，則不僅包括與該靶鹼基序列完全互補之序列，亦包括含有相對於該靶鹼基序列有1個乃至複數個、較佳為1~3個、更佳為1或2個、尤佳為1個錯配之序列者。因此，作為本發明之反義寡核苷酸，可使用含有與序列編號53~103中之任一個所表示之靶鹼基序列互補之鹼基序列，且於與該靶鹼基序列完全互補之序列中有1~3個鹼基、較佳為1~2個鹼基、更佳為1個鹼基經缺失、取代、***或附加者。 Specific target base sequences of the antisense oligonucleotide of the present invention include a partial base sequence of CFB mRNA (cDNA) represented by SEQ ID NO: 53 to 103 shown in Table 1. Therefore, the antisense oligonucleotide of the present invention is an oligonucleotide which can hybridize to a target base sequence represented by any one of SEQ ID NOs: 53 to 103 under stringent conditions. The antisense oligonucleotide of the present invention can hybridize to any of the above target base sequences under stringent conditions, and includes not only a sequence that is completely complementary to the target base sequence, but also includes a base relative to the target base. The sequence has one or even plural, preferably 1 to 3, more preferably 1 or 2, and particularly preferably one mismatched sequence. Therefore, as the antisense oligonucleotide of the present invention, a base sequence complementary to the target base sequence represented by any one of SEQ ID NOS: 53 to 103 can be used, and is completely complementary to the target base sequence. The sequence has 1 to 3 bases, preferably 1 to 2 bases, more preferably 1 base, which is deleted, substituted, inserted or added.

特定之較佳之具體鹼基序列記載於本說明書中，但可認為含有選自表1所記載之序列編號2~52中之任一個所表示之反義鹼基序列中之至少8個連續鹼基的長度8~80個鹼基之反義寡核苷酸亦係較佳之反義寡核苷酸。可認為含有選自表1所記載之各反義鹼基序列中之更佳為9個以上、進而較佳為10個以上、更進一步較佳為11個以上、尤佳為12個以上、最佳為13個之連續鹼基的長度8~80個鹼基、較佳為8~30個鹼基之反義寡核苷酸亦係較佳之反義寡核苷酸。 The specific preferred specific base sequence is described in the present specification, but it is considered to contain at least 8 consecutive bases selected from the antisense base sequences represented by any one of SEQ ID NOs: 2 to 52 described in Table 1. Antisense oligonucleotides of 8 to 80 bases in length are also preferred antisense oligonucleotides. It is considered that it is more preferably 9 or more, more preferably 10 or more, still more preferably 11 or more, particularly preferably 12 or more, and most preferably each of the antisense base sequences selected from Table 1. An antisense oligonucleotide having a length of 8 to 80 bases, preferably 8 to 30 bases, which is preferably 13 consecutive bases, is also a preferred antisense oligonucleotide.

典型之較佳之反義寡核苷酸包括含有自表1所記載之各反義鹼基序列之5'末端起至少8個、更佳為9個以上、進而較佳為10個以上、更進一步較佳為11個以上、尤佳為12個以上之連續之核酸鹼基的寡核苷酸。同樣地，較佳之反義寡核苷酸包括含有自表1所記載之各反義鹼基序列之3'末端起至少8個以上、更佳為9個以上、進而較佳為10個以上、更進一步較佳為11個以上、尤佳為12個以上之連續之核酸鹼基的寡核苷酸。最佳為含有表1所記載之各反義鹼基序列之寡核苷酸。 A typical preferred antisense oligonucleotide comprises at least 8, more preferably 9 or more, still more preferably 10 or more, further from the 5' end of each antisense base sequence described in Table 1. Preferred are 11 or more, and more preferably 12 or more consecutive nucleobase oligonucleotides. Similarly, preferred antisense oligonucleotides include at least 8 or more, more preferably 9 or more, and still more preferably 10 or more, from the 3' end of each antisense base sequence described in Table 1. Further, it is more preferably 11 or more, and more preferably 12 or more consecutive nucleobase oligonucleotides. The oligonucleotides containing the respective antisense base sequences described in Table 1 are preferred.

作為本發明之反義寡核苷酸，亦可使用含有表1所記載之各反義鹼基序列，且於該反義鹼基序列中有1~3個鹼基、較佳為1~2個鹼基、更佳為1個鹼基經缺失、取代、***或附加者。 As the antisense oligonucleotide of the present invention, each antisense base sequence described in Table 1 may be used, and 1 to 3 bases, preferably 1 to 2, in the antisense base sequence. One base, more preferably one base, is deleted, substituted, inserted or added.

作為本發明之反義寡核苷酸，較佳為使用包含表2所記載之序列編號104~154及155中之任一個所表示之核苷酸序列的反義寡核苷酸。其中，較佳為使用包含序列編號118、125、150及155中之任一個所表示之核苷酸序列的反義寡核苷酸。 As the antisense oligonucleotide of the present invention, an antisense oligonucleotide comprising the nucleotide sequence represented by any one of SEQ ID NO: 104 to 154 and 155 shown in Table 2 is preferably used. Among them, an antisense oligonucleotide comprising a nucleotide sequence represented by any one of SEQ ID NO: 118, 125, 150, and 155 is preferably used.

作為本發明之反義寡核苷酸，可使用表2及表3所記載之反義寡核苷酸，更佳為使用含有該表所記載之CFB相對表現量為0.5以下之反義寡核苷酸序列的反義寡核苷酸，進而較佳為CFB相對表現量為0.3以下之反義寡核苷酸，尤佳為CFB相對表現量為0.1以下之反義寡核苷酸。 As the antisense oligonucleotide of the present invention, the antisense oligonucleotides described in Tables 2 and 3 can be used, and it is more preferred to use an antisense oligonucleotide having a relative amount of CFB of 0.5 or less as described in the table. The antisense oligonucleotide of the nucleotide sequence is preferably an antisense oligonucleotide having a CFB relative expression of 0.3 or less, and more preferably an antisense oligonucleotide having a CFB relative expression of 0.1 or less.

若將本發明之反義寡核苷酸導入至細胞內，則會與互補之mRNA及mRNA前驅物結合，立體地阻礙mRNA及mRNA前驅物向蛋白質之轉譯，而能夠抑制CFB基因之表現。 When the antisense oligonucleotide of the present invention is introduced into a cell, it binds to the complementary mRNA and the mRNA precursor, and stereoscopically blocks the translation of the mRNA and the mRNA precursor into the protein, thereby suppressing the expression of the CFB gene.

又，導入至細胞內之本發明之反義寡核苷酸亦有如下情形，即，於細胞內與互補之mRNA及mRNA前驅物結合，而切斷mRNA及mRNA前驅 物。作為此種例，已知有經由將RNA與DNA之雙鏈之RNA鏈切斷之核酸內切酶即RNaseH(Ribonuclease H)之作用。若本發明之反義寡核苷酸於細胞內與mRNA及mRNA前驅物形成雙鏈，則會被內在性之RNaseH所識別，而能夠酶促地(enzymatically)分解互補之mRNA鏈。 Further, the antisense oligonucleotide of the present invention introduced into a cell also has a case where it binds to a complementary mRNA and an mRNA precursor in a cell, and cleaves mRNA and mRNA precursors. Things. As such an example, an action of RNaseH (Ribonuclease H), which is an endonuclease that cleaves a double-stranded RNA strand of RNA and DNA, is known. When the antisense oligonucleotide of the present invention forms a double strand with the mRNA and the mRNA precursor in the cell, it is recognized by the intrinsic RNaseH, and the complementary mRNA strand can be enzymatically decomposed.

為了誘導利用RNaseH所進行之mRNA及mRNA前驅物之切斷，較佳為具有4~80個連續之DNA區域的反義寡核苷酸。於該情形時，反義寡核苷酸較佳為具有0~80%之糖部修飾核苷酸，更佳為10~60%，進而較佳為20~50%。又，具有糖部修飾核苷酸之情形時之連續之DNA區域更佳為4~20個，進而較佳為4~15個，最佳為5~10個。進而，反義寡核苷酸中之糖部修飾核苷酸之位置較佳為配置於5'末端附近及/或3'末端附近，更佳為配置於自5'末端起全長之長度之30%以內之位置及/或自3'末端起全長之長度之30%以內之位置，糖部修飾核苷酸進而較佳為配置於自反義寡核苷酸之5'末端起全長之長度之25%以內之位置及/或自3'末端起全長之長度之25%以內之位置。 In order to induce the cleavage of mRNA and mRNA precursor by RNaseH, an antisense oligonucleotide having 4 to 80 contiguous DNA regions is preferred. In this case, the antisense oligonucleotide preferably has a sugar-modified nucleotide of 0 to 80%, more preferably 10 to 60%, still more preferably 20 to 50%. Further, in the case of having a saccharide-modified nucleotide, the continuous DNA region is preferably 4 to 20, more preferably 4 to 15, and most preferably 5 to 10. Further, the position of the sugar-modified nucleotide in the antisense oligonucleotide is preferably arranged near the 5' end and/or near the 3' end, and more preferably 30 times the length from the 5' end. The position of the inside of the % and/or the 30% of the length of the entire length from the 3' end, the sugar-modified nucleotide is preferably disposed at a length of the entire length from the 5' end of the antisense oligonucleotide. The position within 25% and/or within 25% of the length of the full length from the 3' end.

又，若將本發明之反義寡核苷酸導入至細胞內，則會與編碼互補之CFB之基因組DNA結合，抑制自該DNA向mRNA前驅物之轉錄，而能夠抑制CFB基因之表現。 Further, when the antisense oligonucleotide of the present invention is introduced into a cell, it binds to genomic DNA encoding a complementary CFB, and inhibits transcription from the DNA to the mRNA precursor, thereby suppressing the expression of the CFB gene.

本發明之反義寡核苷酸尤佳為5'末端附近及/或3'末端附近為糖部修飾核苷酸。於本說明書中，5'末端附近為糖部修飾核苷酸意指自5'末端起1~4個、較佳為2~4個連續之核苷酸為糖部修飾核苷酸，3'末端附近為糖部修飾核苷酸意指自3'末端起1~4個、較佳為2~4個連續之核苷酸為糖部修飾核苷酸。即，本發明之反義寡核苷酸可較佳地使用作為自其5'末端起1~4個核苷酸為糖部修飾核苷酸的反義寡核苷酸，可更佳地使用作為自5' 末端起2~4個核苷酸為糖部修飾核苷酸的反義寡核苷酸。本發明之反義寡核苷酸可較佳地使用作為自其3'末端起1~4個核苷酸為糖部修飾核苷酸的反義寡核苷酸，可更佳地使用作為自3'末端2~4個核苷酸為糖部修飾核苷酸的反義寡核苷酸。 The antisense oligonucleotide of the present invention is preferably a saccharide-modified nucleotide in the vicinity of the 5' end and/or in the vicinity of the 3' end. In the present specification, the saccharide-modified nucleotide in the vicinity of the 5' end means that 1 to 4, preferably 2 to 4 consecutive nucleotides from the 5' end are saccharide-modified nucleotides, 3' The saccharide-modified nucleotide near the end means that 1 to 4, preferably 2 to 4, contiguous nucleotides from the 3' end are saccharide-modified nucleotides. That is, the antisense oligonucleotide of the present invention can be preferably used as an antisense oligonucleotide having 1 to 4 nucleotides from the 5' end thereof as a sugar-modified nucleotide, and can be more preferably used. As since 5' An antisense oligonucleotide having 2 to 4 nucleotides at the end of the saccharide-modified nucleotide. The antisense oligonucleotide of the present invention can be preferably used as an antisense oligonucleotide having 1 to 4 nucleotides from the 3' end thereof as a sugar-modified nucleotide, and can be more preferably used as a self. An antisense oligonucleotide having 2 to 4 nucleotides at the 3' end is a sugar-modified nucleotide.

作為製造本發明之反義寡核苷酸之方法，並無特別限定，可列舉使用公知之使用化學之方法，或酶轉錄法等。作為使用公知之化學合成之方法，可列舉：亞磷醯胺法、硫代磷酸酯法、磷酸三酯法、CEM法[Nucleic Acid Research,35,3287(2007)]等，例如可利用ABI3900高通量核酸合成機(Applied Biosystems公司製造)進行合成。合成結束後，進行自固相之脫附、保護基之脫保護及目標物之精製等。較理想為藉由精製而獲得純度為90%以上、較佳為95%以上之反義寡核苷酸。作為製造本發明之反義寡核苷酸之酶轉錄法，可列舉藉由以具有目標鹼基序列之質體或DNA作為模板且使用噬菌體RNA聚合酶、例如T7、T3、或SP6RNA聚合酶之轉錄所進行之方法。 The method for producing the antisense oligonucleotide of the present invention is not particularly limited, and examples thereof include a method using a known chemical method, an enzyme transcription method, and the like. Examples of the method of using known chemical synthesis include a phosphorous amide method, a phosphorothioate method, a phosphotriester method, and a CEM method [Nucleic Acid Research, 35, 3287 (2007)], and the like, for example, ABI3900 can be used. A synthesis was carried out using a flux nucleic acid synthesizer (manufactured by Applied Biosystems). After the completion of the synthesis, desorption from the solid phase, deprotection of the protecting group, and purification of the target are performed. It is preferred to obtain an antisense oligonucleotide having a purity of 90% or more, preferably 95% or more by purification. The enzyme transcription method for producing the antisense oligonucleotide of the present invention may be exemplified by using a plastid or DNA having a target base sequence as a template and using a bacteriophage RNA polymerase such as T7, T3, or SP6 RNA polymerase. The method by which transcription is performed.

本發明之反義寡核苷酸可使用轉染用之載體，較佳為使用陽離子性脂質體等陽離子性載體而導入至細胞內。又，亦可藉由磷酸鈣法、電穿孔法或顯微注射法等而直接導入至細胞內。 The antisense oligonucleotide of the present invention can be introduced into a cell by using a carrier for transfection, preferably a cationic carrier such as a cationic liposome. Further, it may be directly introduced into a cell by a calcium phosphate method, an electroporation method, a microinjection method, or the like.

本發明之反義寡核苷酸亦可藉由與互補之寡核酸形成雙鏈，以雙鏈核酸之形式導入至細胞內，而誘導靶基因之表現抑制(國際公開第2005/113571號)。該情形時利用配位子對雙鏈核酸進行修飾之位置較佳為互補之寡核酸之5'末端或3'末端。 The antisense oligonucleotide of the present invention can also induce expression inhibition of a target gene by forming a double strand with a complementary oligonucleic acid and introducing it into a cell as a double-stranded nucleic acid (International Publication No. 2005/113571). In this case, the position at which the double-stranded nucleic acid is modified by the ligand is preferably the 5' end or the 3' end of the complementary oligo.

2.利用本發明之反義寡核苷酸所進行之CFB之表現抑制 2. Inhibition of CFB expression by the antisense oligonucleotide of the present invention

本發明之反義寡核苷酸可根據與人類CFB之全長mRNA對應之cDNA 鹼基序列(序列編號1)或與mRNA前驅物對應之基因組序列而設計。人類CFB之全長mRNA之cDNA例如登記為Genbank登記編號NM_001710，又，含有人類CFB之mRNA前驅物之基因組序列例如登記為Genbank登記編號NC_000006.12(31945944..31952084)。 The antisense oligonucleotide of the present invention can be based on cDNA corresponding to the full length mRNA of human CFB The base sequence (SEQ ID NO: 1) or a genomic sequence corresponding to the mRNA precursor is designed. The cDNA of the full-length mRNA of human CFB is, for example, registered as Genbank Accession No. NM_001710, and the genomic sequence containing the mRNA precursor of human CFB is, for example, registered as Genbank Accession No. NC_000006.12 (31945944.. 31952084).

包含與CFB基因之一部分之靶鹼基序列互補之鹼基序列的核酸中，作為具有CFB之表現抑制活性之反義寡核苷酸，例如可列舉：包含選自表1或表2所記載之群中之反義鹼基序列之反義寡核苷酸。反義寡核苷酸之長度為8~80個鹼基，較佳為8~30個鹼基。例如，可為8~20個鹼基、10~20個鹼基、13~20個鹼基、13~16個鹼基、13個鹼基、14個鹼基、15個鹼基、16個鹼基、17個鹼基、18個鹼基、19個鹼基、20個鹼基。 In the nucleic acid having a nucleotide sequence complementary to the target base sequence of a part of the CFB gene, the antisense oligonucleotide having the inhibitory activity of CFB can be, for example, selected from those described in Table 1 or Table 2. Antisense oligonucleotides of antisense base sequences in the population. The length of the antisense oligonucleotide is 8 to 80 bases, preferably 8 to 30 bases. For example, it can be 8 to 20 bases, 10 to 20 bases, 13 to 20 bases, 13 to 16 bases, 13 bases, 14 bases, 15 bases, and 16 bases. Base, 17 bases, 18 bases, 19 bases, 20 bases.

藉由將該等反義寡核苷酸導入至細胞，而能夠抑制CFB之表現。例如本發明之反義寡核苷酸於以數nM~數μM之濃度導入至細胞後，於培養24小時以上、例如48小時之階段時能夠抑制CFB之mRNA之表現。 By introducing these antisense oligonucleotides into cells, the expression of CFB can be suppressed. For example, the antisense oligonucleotide of the present invention can be introduced into a cell at a concentration of several nM to several μM, and can inhibit the expression of CFB mRNA when cultured for 24 hours or longer, for example, 48 hours.

又，本發明之反義寡核苷酸之CFB之mRNA之表現抑制活性之評估可藉由以下方式進行：將該反義寡核苷酸使用陽離子性脂質體等導入至人類細胞株等中，或者直接將該反義寡核苷酸導入至人類細胞株等中，或者使該反義寡核苷酸與任一配位子結合並導入至人類細胞株等中，培養一定時間後，測定該人類細胞株中之CFB之mRNA之表現量。 Further, the evaluation of the expression inhibitory activity of the CFB mRNA of the antisense oligonucleotide of the present invention can be carried out by introducing the antisense oligonucleotide into a human cell strain or the like using a cationic liposome or the like. Alternatively, the antisense oligonucleotide is directly introduced into a human cell strain or the like, or the antisense oligonucleotide is bound to any of the ligands and introduced into a human cell strain or the like, and after the culture for a certain period of time, the measurement is performed. The amount of mRNA of CFB in human cell lines.

本發明之反義寡核苷酸亦可含有配位子。該配位子可為對本發明之反義寡核苷酸之5'末端、3'末端及/或序列內部直接進行修飾者。 The antisense oligonucleotide of the present invention may also contain a ligand. The ligand may be a direct modification of the 5' end, the 3' end and/or the inside of the sequence of the antisense oligonucleotide of the present invention.

作為本發明之反義寡核苷酸所含之配位子，只要為與生物體分子具有親和性之分子即可，例如可列舉膽固醇、脂肪酸、生育酚、視黃醇等脂質類，N-乙醯半乳糖胺(GalNAc)、半乳糖(Gal)、甘露糖(Man)等糖類， 完整抗體、Fab、scFV、VHH等片段抗體，低密度脂蛋白(LDL)、人類血清白蛋白等蛋白質，RGD、NGR、R9、CPP等肽類，葉酸等低分子，合成聚胺基酸等合成聚合物，或核酸適體等，但不限定於該等，亦可將該等適宜地組合而使用。 The ligand contained in the antisense oligonucleotide of the present invention may be a molecule having affinity with a biomolecule, and examples thereof include lipids such as cholesterol, fatty acid, tocopherol, and retinol, and N- Carbohydrates such as galactosamine (GalNAc), galactose (Gal), and mannose (Man), Intact antibodies, Fab, scFV, VHH and other fragment antibodies, low density lipoprotein (LDL), human serum albumin and other proteins, RGD, NGR, R9, CPP and other peptides, folic acid and other low molecules, synthetic polyamino acids, etc. The polymer, the aptamer or the like is not limited thereto, and these may be used in combination as appropriate.

作為對本發明之反義寡核苷酸附加配位子之方法，例如可藉由在固相上之延伸反應時使能夠於固相上反應之修飾劑進行反應，而對5'末端、3'末端及/或序列內部實施修飾，但不限定於此。又，亦可藉由預先合成導入有胺基、巰基、疊氮基或三鍵等官能基之核酸並進行精製，使修飾劑作用於該等，而獲得複合核酸。 As a method of adding a ligand to the antisense oligonucleotide of the present invention, for example, a modification agent capable of reacting on a solid phase can be reacted by an extension reaction on a solid phase, and the 5' end, 3' The modification is carried out inside the terminal and/or the sequence, but is not limited thereto. Further, a nucleic acid having a functional group such as an amine group, a thiol group, an azide group or a triple bond may be synthesized in advance and purified, and a modifying agent may be allowed to act on the compound to obtain a composite nucleic acid.

3.本發明之醫藥組合物 3. The pharmaceutical composition of the present invention

本發明係關於一種含有本發明之反義寡核苷酸作為有效成分之醫藥組合物(於本說明書中，亦稱為本發明之醫藥組合物)。 The present invention relates to a pharmaceutical composition (in the present specification, also referred to as a pharmaceutical composition of the present invention) comprising the antisense oligonucleotide of the present invention as an active ingredient.

該醫藥組合物可進而含有對於使反義寡核苷酸移動至細胞內而言有效之載體。本發明之醫藥組合物可用作非典型溶血性***症候群(aHUS)、陣發性夜間血紅素尿症(PNH)、老年性黃斑變性症(AMD)、膜性增殖性腎小球腎炎(MPGN)、C3腎炎、膜性腎病、急進性腎小球腎炎(RPGN)、急性腎損傷(AKI)、哮喘、自體免疫疾病(例如全身性紅斑狼瘡(SLE)、牛皮癬、視神經脊髓炎、重症肌無力症等)等之治療劑或預防劑。 The pharmaceutical composition may further comprise a carrier effective for moving the antisense oligonucleotide into the cell. The pharmaceutical composition of the present invention can be used as atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), age-related macular degeneration (AMD), membranous proliferative glomerulonephritis ( MPGN), C3 nephritis, membranous nephropathy, acute glomerulonephritis (RPGN), acute kidney injury (AKI), asthma, autoimmune diseases (eg systemic lupus erythematosus (SLE), psoriasis, optic neuromyelitis, severe disease A therapeutic or prophylactic agent such as myasthenia gravis or the like.

作為對於使反義寡核苷酸移動至細胞內而言有效之載體，例如可列舉陽離子性載體。作為陽離子性載體，可列舉陽離子性脂質體及陽離子性聚合物等。又，作為對於使反義寡核苷酸移動至細胞內而言有效之載體，亦可使用利用病毒包膜之載體。作為陽離子性脂質體，較佳為使用含有2-O-(2-二乙基胺基乙基)胺甲醯基-1,3-O-二油醯基甘油之脂質體(以下亦稱 為脂質體A)、Oligofectamine(Invitrogen公司)、Lipofectin(Invitrogen公司)、Lipofectamine(Invitrogen公司)、Lipofectamine 2000(Invitrogen公司)、DMRIE-C(Invitrogen公司)、GeneSilencer(Gene Therapy Systems公司)、TransMessenger(QIAGEN公司)、TransIT TKO(Mirus公司)等。作為陽離子性聚合物，較佳為使用JetSI(Qbiogene公司)、Jet-PEI(聚伸乙基亞胺，Qbiogene公司)等。作為利用病毒包膜之載體，較佳為使用GenomeOne(HVJ-E脂質體，石原產業公司)等。 As a carrier which is effective for moving an antisense oligonucleotide into a cell, a cationic carrier is mentioned, for example. Examples of the cationic carrier include cationic liposomes and cationic polymers. Further, as a carrier which is effective for moving the antisense oligonucleotide into the cell, a vector using a viral envelope can also be used. As the cationic liposome, it is preferred to use a liposome containing 2-O-(2-diethylaminoethyl)amine-mercapto-1,3-O-dioleyl glycerin (hereinafter also referred to as Liposome A), Oligofectamine (Invitrogen), Lipofectin (Invitrogen), Lipofectamine (Invitrogen), Lipofectamine 2000 (Invitrogen), DMRIE-C (Invitrogen), GeneSilencer (Gene Therapy Systems), TransMessenger (QIAGEN) Company), TransIT TKO (Mirus) and so on. As the cationic polymer, JetSI (Qbiogene Co., Ltd.), Jet-PEI (polyethylenimine, Qbiogene Co., Ltd.) or the like is preferably used. As a carrier using a viral envelope, GenomeOne (HVJ-E liposome, Ishihara Sangyo Co., Ltd.) or the like is preferably used.

於本發明之反義寡核苷酸含有上述載體之本發明之醫藥組合物可藉由從業者已知之方法而製備。例如，可將適當濃度之載體分散液與反義寡核苷酸溶液加以混合而製備。於使用陽離子性載體之情形時，由於反義寡核苷酸於水溶液中帶負電荷，因此可藉由利用常規方法於水溶液中進行混合而容易地製備。作為為了製備該組合物而使用之水性溶劑，可列舉：注射用水、注射用蒸餾水、生理試驗水等電解質液，葡萄糖液、麥芽糖液等糖液等。又，製備該組合物時之pH值及溫度等條件可由從業者適當選擇。例如於為脂質體A之情形時，可將10%麥芽糖水溶液中之反義寡核苷酸於pH值7.4、25℃之條件下一面進行攪拌，一面緩緩地添加至10%麥芽糖水溶液中之16mg/ml之脂質體分散液中而製備。 The pharmaceutical composition of the present invention containing the above carrier in the antisense oligonucleotide of the present invention can be produced by a method known to a practitioner. For example, a carrier dispersion of an appropriate concentration can be prepared by mixing an antisense oligonucleotide solution. In the case of using a cationic carrier, since the antisense oligonucleotide is negatively charged in an aqueous solution, it can be easily prepared by mixing in an aqueous solution by a conventional method. Examples of the aqueous solvent used for the preparation of the composition include an aqueous solution such as water for injection, distilled water for injection, physiological test water, a sugar liquid such as glucose solution or maltose solution, and the like. Further, conditions such as pH and temperature at the time of preparing the composition can be appropriately selected by a practitioner. For example, in the case of liposome A, the antisense oligonucleotide in a 10% aqueous solution of maltose can be gradually added to a 10% aqueous solution of maltose while stirring at pH 7.4 and 25 °C. Prepared in a 16 mg/ml liposome dispersion.

關於該組合物，若有必要，亦可藉由使用超音波分散裝置或高壓乳化裝置等進行分散處理，而製成均一之組合物。對於含有載體與反義寡核苷酸之組合物之製備而言最佳之方法及條件取決於所使用之載體，因此從業者可不侷限於上述方法而選擇對於所使用之載體而言最佳之方法。 The composition may be subjected to dispersion treatment by using an ultrasonic dispersing device or a high-pressure emulsification device, if necessary, to prepare a uniform composition. The method and conditions optimum for the preparation of the composition comprising the vector and the antisense oligonucleotide depend on the carrier used, and thus the practitioner is not limited to the above method and is selected to be optimal for the carrier used. method.

作為本發明之醫藥組合物，亦適宜地使用如下之脂質體，該脂質體包含以反義寡核苷酸及引導粒子作為構成成分之複合粒子及被覆該複合粒 子之脂質膜，且該脂質膜之構成成分能夠分散至含有可溶解該脂質膜之構成成分之極性有機溶劑的液體中，且該複合粒子亦以能夠分散之濃度存在於含有該極性有機溶劑之液體中，但不限定於此。作為引導粒子，例如可列舉：脂質集合體、脂質體、乳液粒子、高分子、金屬膠體、微粒子製劑等，較佳為使用脂質體。本發明之引導粒子可以將脂質集合體、脂質體、乳液粒子、高分子、金屬膠體、微粒子製劑等中之2種以上組合而成之複合體作為構成成分，亦可以將脂質集合體、脂質體、乳液粒子、高分子、金屬膠體、微粒子製劑等與其他化合物(例如糖、脂質、無機化合物等)組合而成之複合體作為構成成分。 As the pharmaceutical composition of the present invention, a liposome comprising a composite particle having an antisense oligonucleotide and a guide particle as a constituent component and coating the composite particle is also suitably used. a lipid film, wherein the constituent component of the lipid film can be dispersed in a liquid containing a polar organic solvent capable of dissolving a constituent component of the lipid film, and the composite particle is also present in a concentration capable of being dispersed in the polar organic solvent. In the liquid, it is not limited to this. Examples of the guiding particles include a lipid aggregate, a liposome, an emulsion particle, a polymer, a metal colloid, and a microparticle preparation. Preferably, a liposome is used. The guide particle of the present invention may be a composite of a combination of two or more of a lipid aggregate, a liposome, an emulsion particle, a polymer, a metal colloid, and a microparticle preparation, and may also be a lipid aggregate or a liposome. A composite in which an emulsion particle, a polymer, a metal colloid, or a microparticle preparation is combined with another compound (for example, a sugar, a lipid, an inorganic compound, or the like) is used as a constituent component.

作為被覆該複合粒子之脂質膜，例如可列舉將中性脂質及聚乙二醇-磷脂醯乙醇胺等作為構成成分者。 Examples of the lipid film covering the composite particles include a neutral lipid and polyethylene glycol-phospholipid oxime ethanolamine as constituent components.

該脂質體可依據例如WO2006/080118等所記載之方法而製備。 The liposome can be produced according to, for example, the method described in WO2006/080118 or the like.

關於本發明之醫藥組合物所含之反義寡核苷酸與載體之調配比，相對於反義寡核苷酸之1重量份，載體適宜為1~200重量份。較佳為相對於反義寡核苷酸之1重量份，載體為2.5~100重量份，進而較佳為載體為10~20重量份。 The ratio of the antisense oligonucleotide contained in the pharmaceutical composition of the present invention to the carrier is preferably from 1 to 200 parts by weight based on 1 part by weight of the antisense oligonucleotide. Preferably, the carrier is from 2.5 to 100 parts by weight, more preferably from 10 to 20 parts by weight, based on 1 part by weight of the antisense oligonucleotide.

於本發明之醫藥組合物中，除上述載體以外，亦可含有醫藥上可容許之載體或稀釋劑等。醫藥上可容許之載體或稀釋劑等係本質上在化學上為惰性及無毒之組合物，且對本發明之醫藥組合物之生物學上之活性完全無影響者。此種載體或稀釋劑之例子有鹽溶液、糖溶液、甘油溶液、乙醇等，但不限定於該等。 The pharmaceutical composition of the present invention may contain, in addition to the above carrier, a pharmaceutically acceptable carrier or diluent. The pharmaceutically acceptable carrier or diluent, etc., is a chemically inert and non-toxic composition, and has no effect on the biological activity of the pharmaceutical composition of the present invention. Examples of such a carrier or diluent are, but are not limited to, a salt solution, a sugar solution, a glycerin solution, ethanol, and the like.

本發明之醫藥組合物可較佳用於由補體旁路途徑之異常所介導之障礙之治療或預防用途。於本說明書中，由補體旁路途徑之異常所介導之障 礙係指非典型溶血性***症候群(aHUS)、陣發性夜間血紅素尿症(PNH)、老年性黃斑變性症(AMD)、膜性增殖性腎小球腎炎(MPGN)、C3腎炎、膜性腎病、急進性腎小球腎炎(RPGN)、急性腎損傷(AKI)、哮喘、自體免疫疾病(例如，全身性紅斑狼瘡(SLE)、牛皮癬、視神經脊髓炎、重症肌無力症等)等。因此，本發明之醫藥組合物可用作非典型溶血性***症候群(aHUS)、陣發性夜間血紅素尿症(PNH)、老年性黃斑變性症(AMD)、膜性增殖性腎小球腎炎(MPGN)、C3腎炎、膜性腎病、急進性腎小球腎炎(RPGN)、急性腎損傷(AKI)、哮喘、自體免疫疾病(例如全身性紅斑狼瘡(SLE)、牛皮癬、視神經脊髓炎、重症肌無力症等)等之治療劑或預防劑。 The pharmaceutical compositions of the present invention are preferably used for the therapeutic or prophylactic use of disorders mediated by abnormalities in the complement alternative pathway. In this specification, a barrier mediated by an abnormality in the complement alternative pathway Affiliation refers to atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), age-related macular degeneration (AMD), membranous proliferative glomerulonephritis (MPGN), C3 nephritis, Membranous nephropathy, acute glomerulonephritis (RPGN), acute kidney injury (AKI), asthma, autoimmune diseases (eg, systemic lupus erythematosus (SLE), psoriasis, optic neuromyelitis, myasthenia gravis, etc.) Wait. Therefore, the pharmaceutical composition of the present invention can be used as atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), age-related macular degeneration (AMD), membranous proliferative glomerulus Nephritis (MPGN), C3 nephritis, membranous nephropathy, acute glomerulonephritis (RPGN), acute kidney injury (AKI), asthma, autoimmune diseases (eg systemic lupus erythematosus (SLE), psoriasis, optic neuromyelitis) , a therapeutic or prophylactic agent such as myasthenia gravis, etc.).

本發明之醫藥組合物可以含有對於疾病之治療或預防而言有效量之該複合體，且能夠恰當地對患者投予之形態提供。本發明之醫藥組合物之製劑形態可為例如注射劑、滴眼劑、吸入用等液劑，例如軟膏、洗劑等外用劑等。 The pharmaceutical composition of the present invention may contain an effective amount of the complex for the treatment or prevention of the disease, and can be provided in a form suitable for administration to a patient. The preparation form of the pharmaceutical composition of the present invention may be, for example, an injection preparation, an eye drop, or a liquid preparation for inhalation, for example, an external preparation such as an ointment or a lotion.

於為液劑之情形時，本發明之醫藥組合物之濃度範圍通常為0.001~25%(w/v)，較佳為0.01~5%(w/v)，更佳為0.1~2%(w/v)。本發明之醫藥組合物可以適當量含有醫藥上容許之任意之添加劑，例如乳化輔助劑、穩定化劑、等張劑、pH值調整劑等。醫藥上容許之任意之添加劑無論於該複合體之分散前或分散後均可於適當之步驟中添加。 In the case of a liquid preparation, the concentration of the pharmaceutical composition of the present invention is usually in the range of 0.001 to 25% (w/v), preferably 0.01 to 5% (w/v), more preferably 0.1 to 2% ( w/v). The pharmaceutical composition of the present invention may contain any additives pharmaceutically acceptable, such as an emulsification aid, a stabilizer, an isotonic agent, a pH adjuster, and the like, in an appropriate amount. Any pharmaceutically acceptable additive may be added in an appropriate step before or after dispersion of the composite.

本發明之醫藥組合物亦可以冷凍乾燥製劑之形式提供。冷凍乾燥製劑可於將反義寡核苷酸及載體進行分散處理後，利用冷凍乾燥處理而製備。冷凍乾燥處理可藉由常規方法而進行。例如，可將上述之分散處理後之複合體溶液於無菌狀態下以特定量分注至小瓶中，於約-40~-20℃之條 件下預乾燥約2小時左右，於約0~10℃下於減壓下進行一次乾燥，繼而於約15~25℃下於減壓下進行二次乾燥而據以進行冷凍乾燥。然後，例如利用氮氣對小瓶內部進行置換，並封蓋，藉此可獲得本發明之醫藥組合物之冷凍乾燥製劑。 The pharmaceutical compositions of the invention may also be provided in the form of a lyophilized formulation. The lyophilized preparation can be prepared by subjecting the antisense oligonucleotide and the carrier to a dispersion treatment, followed by freeze-drying treatment. The freeze-drying treatment can be carried out by a conventional method. For example, the above-mentioned dispersion-treated complex solution can be dispensed into a vial in a specific amount under aseptic conditions at a temperature of about -40 to -20 ° C. The material was pre-dried for about 2 hours, dried once at a reduced pressure of about 0 to 10 ° C, and then subjected to secondary drying under reduced pressure at about 15 to 25 ° C to freeze-dry it. Then, the inside of the vial is replaced with, for example, nitrogen gas, and capped, whereby a freeze-dried preparation of the pharmaceutical composition of the present invention can be obtained.

於將本發明之醫藥組合物以冷凍乾燥製劑之形式提供之情形時，本發明之醫藥組合物可藉由任意之適當之溶液之添加進行再溶解而使用。作為此種溶液，可列舉注射用水、生理試驗水等電解質液、葡萄糖液、其他一般輸送液等。該溶液之液量根據用途等而異，雖無特別限定，但較佳為冷凍乾燥前之液量之0.5~2倍量、或500ml以下。 In the case where the pharmaceutical composition of the present invention is provided in the form of a lyophilized preparation, the pharmaceutical composition of the present invention can be used by re-dissolving by adding any appropriate solution. Examples of such a solution include an electrolyte solution such as water for injection and physiological test water, a glucose solution, and another general transport liquid. The amount of the solution varies depending on the use and the like, and is not particularly limited, but is preferably 0.5 to 2 times the amount of the liquid before freeze-drying or 500 ml or less.

本發明之醫藥組合物可對於包括人類在內之動物進行例如靜脈內投予、動脈內投予、經口投予、組織內投予、經皮投予、經黏膜投予或經直腸投予，較佳為藉由適合於患者症狀之適當方法進行投予。尤其較佳為使用靜脈投予、經皮投予、經黏膜投予。又，亦可進行癌內局部投予等局部投予。作為符合該等投予方法之劑型，例如可列舉各種注射劑、經口劑、點滴劑、吸收劑、滴眼劑、軟膏劑、洗劑、栓劑等。 The pharmaceutical composition of the present invention can be administered to an animal including a human, for example, intravenous, intraarterial, oral, intra-tissue, transdermal, transmucosal or rectal administration. Preferably, the administration is by an appropriate method suitable for the symptoms of the patient. In particular, intravenous administration, transdermal administration, and transmucosal administration are preferred. Further, local administration such as intra-cancer local administration can also be performed. Examples of the dosage form that conforms to the administration methods include various injections, oral preparations, drips, absorbents, eye drops, ointments, lotions, suppositories, and the like.

本發明之醫藥組合物之用量較理想為於考慮藥物、劑型、年齡或體重等患者之狀態、投予途徑、疾病之特性及程度等之基礎上決定，通常作為反義寡核苷酸之質量，對於成人而言每天為0.1mg~10g/天，較佳為1mg~500mg/天。視情況，亦有即為該用量以下亦足夠，或相反地需要該用量以上之情形。又，可1天投予1次~數次，亦可每隔1天~數天進行投予。 The dosage of the pharmaceutical composition of the present invention is preferably determined based on the state of the patient such as the drug, the dosage form, the age or the body weight, the route of administration, the nature and degree of the disease, etc., usually as the quality of the antisense oligonucleotide. For adults, 0.1 mg to 10 g per day, preferably 1 mg to 500 mg per day. Depending on the situation, it is sufficient that the amount below is sufficient, or vice versa. In addition, it can be administered once or several times a day, or every other day to several days.

4.治療方法 4. Treatment

本發明進而提供一種治療由補體旁路途徑之異常所介導之障礙之方 法(本發明之治療方法)，其包括將治療上有效量之本發明之反義寡核苷酸或本發明之醫藥組合物投予需要此種治療之人之步驟。 The invention further provides a method for treating a disorder mediated by an abnormality of the complement alternative pathway The method (the method of treatment of the present invention) comprises the step of administering a therapeutically effective amount of the antisense oligonucleotide of the present invention or the pharmaceutical composition of the present invention to a person in need of such treatment.

本發明之治療方法之特徵在於：其較佳為治療非典型溶血性***症候群、陣發性夜間血紅素尿症、老年性黃斑變性症、膜性增殖性腎小球腎炎、C3腎炎、膜性腎病、急進性腎小球腎炎(RPGN)、急性腎損傷(AKI)、哮喘、自體免疫疾病(例如，全身性紅斑狼瘡(SLE)、牛皮癬、視神經脊髓炎、重症肌無力症等)等疾病，並且將治療上有效量之本發明之反義寡核苷酸或本發明之醫藥組合物投予需要該治療之人。其他步驟及條件並無任何限定。 The treatment method of the present invention is characterized in that it is preferably for treating atypical hemolytic uremic syndrome, paroxysmal nocturnal hemoglobinuria, age-related macular degeneration, membranous proliferative glomerulonephritis, C3 nephritis, membrane Nephropathy, acute glomerulonephritis (RPGN), acute kidney injury (AKI), asthma, autoimmune diseases (eg, systemic lupus erythematosus (SLE), psoriasis, optic neuromyelitis, myasthenia gravis, etc.) The disease, and a therapeutically effective amount of an antisense oligonucleotide of the invention or a pharmaceutical composition of the invention is administered to a human in need of such treatment. Other steps and conditions are not limited.

本發明之治療方法可援用例如上述本發明之醫藥組合物之投予方法、用量、製備方法等。 For the treatment method of the present invention, for example, the administration method, the amount, the preparation method, and the like of the pharmaceutical composition of the present invention described above can be used.

以下，藉由實施例而說明本發明。但是，本發明並不限定於該等實施例。 Hereinafter, the present invention will be described by way of examples. However, the invention is not limited to the embodiments.

[實施例1] [Example 1] 人類細胞中之CFB mRNA之減弱活性之測定 Determination of the attenuating activity of CFB mRNA in human cells

將作為源自人類肝癌之細胞株的Huh7細胞(自國立研究開發法人醫藥基盤-健康-營養研究所JCRB細胞庫取得)以成為20,000細胞/80μL/孔之方式接種至96孔之培養盤中。培養基係使用包含10%胎牛血清(FBS)之DMEM培養基(Life Technologies公司製造，目錄編號11095-098)。反義寡核苷酸係利用GeneDesign合成表2所記載者而利用。於表2之反義寡核苷酸中，小寫字母表示DNA，大寫字母表示LNA，C(M)表示5-甲基胞嘧啶LNA。再者，關於任一反義寡核苷酸，各核苷酸均利用硫代磷酸酯鍵取代磷酸二酯鍵。將該反義寡核苷酸與Lipofectamine LTX & Plus試劑(Life Technologies公司製造，目錄編號15338)利用Opti-MEM培養基(Life Technologies公司製造，目錄編號11058-021)加以稀釋，以反義寡核苷酸之最終濃度成為30nM之方式將20μL之反義寡核苷酸/Lipofectamine LTX混合液添加至各96孔之培養盤中，於37℃、5%CO2條件下培養24小時。其後，將細胞利用PBS(Phosphate buffered saline)洗淨，使用Cells-to-Ct套組(Applied Biosystems公司製造，目錄編號：AM1728)依據製品隨附之說明書所記載之方法自各培養盤合成cDNA。將該cDNA 5μL添加至MicroAmpOptical 96孔培養盤(Applied Biosystems公司製造，目錄編號4326659)中，進而添加10μL之TaqMan Gene Expression Master Mix(Applied Biosystems公司製造，目錄編號4369016)、3μL之超純蒸餾水(Life Technologies公司製造，目錄編號：10977-015)、1μL之人類CFB探針、1μL之人類β-肌動蛋白探針。使用ABI7900 HT即時PCR(polymerase chain reaction，聚合酶鏈反應)系統，進行人類CFB基因及人類β-肌動蛋白之即時PCR。β-肌動蛋白係結構性之表現基因，作為內部對照進行測定，而修正CFB表現量。將不添加反義寡核苷酸而僅利用轉染試劑處理Huh7細胞時之CFB mRNA量設為1.0，計算導入有各反義寡核苷酸時之CFB mRNA相對表現量。將本實驗進行複數次，將CFB mRNA相對表現量之平均值示於表2。 Huh7 cells (obtained from the JCRB cell bank of the National Research and Development Laboratory) were 20,000 cells/80 μL/well in a 96-well culture dish. The medium was DMEM medium (manufactured by Life Technologies, catalog number 11095-098) containing 10% fetal calf serum (FBS). Antisense oligonucleotides were used as described in GeneDesign Synthesis Table 2. In the antisense oligonucleotides of Table 2, lower case letters indicate DNA, upper case letters indicate LNA, and C (M) indicates 5-methylcytosine LNA. Furthermore, with respect to any of the antisense oligonucleotides, each nucleotide is substituted with a phosphorothioate linkage for a phosphodiester bond. The antisense oligonucleotide was diluted with Lipofectamine LTX & Plus reagent (manufactured by Life Technologies, catalog number 15338) using Opti-MEM medium (manufactured by Life Technologies, catalog number 11058-021) to antisense oligonucleoside 20 μL of the antisense oligonucleotide/Lipofectamine LTX mixture was added to each 96-well culture dish at a final concentration of the acid of 30 nM, and cultured at 37 ° C under 5% CO 2 for 24 hours. Thereafter, the cells were washed with PBS (Phosphate buffered saline), and cDNA was synthesized from each culture plate using a Cell-to-Ct kit (Applied Biosystems, catalog number: AM1728) according to the method described in the specification attached to the product. 5 μL of the cDNA was added to a MicroAmpOptical 96-well culture plate (manufactured by Applied Biosystems, catalog number 4326659), and 10 μL of TaqMan Gene Expression Master Mix (manufactured by Applied Biosystems, catalog No. 4369016) and 3 μL of ultrapure distilled water (Life) were added. Manufactured by Technologies, catalog number: 10977-015), 1 μL of human CFB probe, 1 μL of human β-actin probe. Real-time PCR of human CFB gene and human β-actin was performed using the ABI7900 HT polymerase chain reaction (PCR) system. The structural expression gene of β-actin was measured as an internal control, and the amount of CFB expression was corrected. The amount of CFB mRNA when Huh7 cells were treated with only the transfection reagent without using the antisense oligonucleotide was set to 1.0, and the relative expression amount of CFB mRNA when each antisense oligonucleotide was introduced was calculated. This experiment was performed plural times, and the average value of the relative amount of CFB mRNA was shown in Table 2.

[實施例2] [Embodiment 2] 反義寡核苷酸之小鼠中之活體內減弱活性 In vivo attenuating activity in mice with antisense oligonucleotides

針對實施例1中所獲得之各反義寡核苷酸中之序列編號118、125、 150，分別藉由以下之方法測定活體內減弱活性。再者，各反義寡核苷酸係利用磷酸鹽緩衝液(DPBS)(Nacalai Tesque公司製造)加以稀釋而使用。 For the sequence numbers 118, 125 in each of the antisense oligonucleotides obtained in Example 1, 150. The in vivo attenuating activity was measured by the following method, respectively. Further, each antisense oligonucleotide was diluted and used in a phosphate buffer solution (DPBS) (manufactured by Nacalai Tesque Co., Ltd.).

將小鼠(BALB/cA，自CLEA Japan取得)進行馴化飼養後，將各反義寡核苷酸以3mg/kg逐個皮下注射投予小鼠。又，作為對照群，僅將DPBS皮下注射投予小鼠。各反義寡核苷酸或對照群分別投予3隻小鼠。 After the mice (BALB/cA, obtained from CLEA Japan) were domesticated, each antisense oligonucleotide was administered subcutaneously at 3 mg/kg to the mice. Further, as a control group, only DPBS was subcutaneously administered to mice. Three mice were administered to each of the antisense oligonucleotides or the control group.

自投予3天後使動物安樂死，摘取肝臟並於液氮中進行冷凍保存。對於肝臟冷凍樣本，使用TRIzol(註冊商標)RNA提取試劑(Isolation Regent)(Life Technologies公司製造，目錄編號15596026)及MagNA Pure 96 Cellular RNA大容量套組(Large Volume Kit)(Roche公司製造，目錄編號05467535001)，依據製品隨附之說明書所記載之方法，進行總RNA之回收。進而，使用Transcriptor第一鏈cDNA合成套組(First Strand cDNA Synthesis Kit)(Roche公司製造，目錄編號04897030001)，依據製品隨附之說明書所記載之方法，以所獲得之總RNA作為模板之逆轉錄反應而製作cDNA。以所獲得之cDNA作為模板，以TaqMan(註冊商標)基因表現分析探針(Gene Expression Assay probe)(Applied Biosystems公司製造)作為探針，使用Quant Studio 12 K-flex即時PCR系統(Real-time PCR System)(ABI公司製造)，依據隨附之使用說明書所記載之方法進行PCR反應，藉此使CFB基因及作為構成性表現基因的甘油醛3-磷酸脫氫酶(D-glyceraldehyde-3-phosphate dehydrogenase，以下記為Gapdh)基因進行PCR反應，並分別測定mRNA擴增量，以Gapdh之mRNA擴增量作為內部對照，算出CFB之mRNA之準定量值。將同樣地測得之對照群之CFB之mRNA之準定量值設為1，由CFB之mRNA之準定量值求出CFB之mRNA之表現率。將所獲得之CFB之mRNA之相對表現率示於圖1。 The animals were euthanized 3 days after the administration, and the liver was removed and stored frozen in liquid nitrogen. For liver frozen samples, TRIzol (registered trademark) RNA extraction reagent (Isolation Regent) (manufactured by Life Technologies, catalog number 15596026) and MagNA Pure 96 Cellular RNA Large Volume Kit (Roche), catalog number 05467535001), recovery of total RNA according to the method described in the instructions accompanying the product. Further, using the Transcriptor First Strand cDNA Synthesis Kit (manufactured by Roche, catalog number 04897030001), reverse transcription was performed using the obtained total RNA as a template according to the method described in the specification attached to the product. The reaction was carried out to prepare cDNA. Using the obtained cDNA as a template, a TaqMan (registered trademark) Gene Expression Assay probe (Applied Biosystems) was used as a probe, and a Quant Studio 12 K-flex real-time PCR system (Real-time PCR) was used. System) (manufactured by ABI), the PCR reaction was carried out according to the method described in the accompanying instruction manual, thereby making the CFB gene and glyceraldehyde 3-phosphate dehydrogenase (D-glyceraldehyde-3-phosphate as a constitutive gene) The dehydrogenase (hereinafter referred to as Gapdh) gene was subjected to a PCR reaction, and the amount of mRNA amplification was measured, and the amount of mRNA amplification of Gapdh was used as an internal control to calculate a quasi-quantitative value of CFB mRNA. The quasi-quantitative value of the CFB mRNA of the control group measured in the same manner was set to 1, and the expression rate of the CFB mRNA was determined from the quasi-quantitative value of the CFB mRNA. The relative expression rate of the obtained CFB mRNA is shown in Fig. 1.

[實施例3] [Example 3] 修飾核酸不同之反義寡核苷酸(序列編號155)之活體外及活體內減弱活性 In vitro and in vivo attenuating activities of antisense oligonucleotides (SEQ ID NO: 155) with different modified nucleic acids

利用GeneDesign而新合成修飾有實施例1中所獲得之反義鹼基序列(序列編號23)的C(M)C(M)AtgttgtgC(M)AA(序列編號155)，並測定活體外及活體內減弱活性。其中，小寫字母表示DNA，大寫字母表示LNA，C(M)表示5-甲基胞嘧啶LNA。再者，關於任一反義寡核苷酸，各核苷酸均利用硫代磷酸酯鍵取代磷酸二酯鍵。 C(M)C(M)AtgttgtgC(M)AA (SEQ ID NO: 155) modified with the antisense base sequence (SEQ ID NO: 23) obtained in Example 1 was newly synthesized by GeneDesign, and assayed in vitro and live. Attenuate activity in vivo. Among them, lowercase letters indicate DNA, uppercase letters indicate LNA, and C(M) indicates 5-methylcytosine LNA. Furthermore, with respect to any of the antisense oligonucleotides, each nucleotide is substituted with a phosphorothioate linkage for a phosphodiester bond.

活體外減弱活性係將以反義寡核苷酸(序列編號155)之最終濃度分別成為30nM、10nM、3nM、1nM、0.3nM之方式進行調整，並藉由與實施例1相同之方法測定3次之結果之平均值示於表3。關於活體內減弱活性，將反義寡核苷酸(序列編號155)以10mg/kg逐個皮下注射投予小鼠，將藉由與實施例2相同之方法所測得之結果示於圖2。 The in vitro weakening activity was adjusted so that the final concentration of the antisense oligonucleotide (SEQ ID NO: 155) was 30 nM, 10 nM, 3 nM, 1 nM, and 0.3 nM, respectively, and was measured by the same method as in Example 1. The average of the results of the second time is shown in Table 3. With respect to the attenuating activity in vivo, an antisense oligonucleotide (SEQ ID NO: 155) was administered subcutaneously at a dose of 10 mg/kg to the mice, and the results obtained by the same method as in Example 2 are shown in Fig. 2 .

本申請案係以於日本所申請之日本專利特願2016-21128(申請日：2016年2月5日)為基礎，藉由在此提及而將其內容全部包含於本說明書中。 The present application is based on Japanese Patent Application No. 2016-21128 (filed on Feb. 5, 2016), the entire contents of which are hereby incorporated by reference.

[產業上之可利用性] [Industrial availability]

本發明提供具有CFB之表現抑制活性之反義寡核苷酸、及以該反義寡核苷酸作為有效成分之醫藥組合物等。本發明之反義寡核苷酸及醫藥組 合物抑制CFB之表現，對於非典型溶血性***症候群、陣發性夜間血紅素尿症、老年性黃斑變性症、膜性增殖性腎小球腎炎、C3腎炎、膜性腎病、急進性腎小球腎炎(RPGN)、急性腎損傷(AKI)、哮喘、自體免疫疾病(例如，全身性紅斑狼瘡(SLE)、牛皮癬、視神經脊髓炎、重症肌無力症等)等由補體旁路途徑之異常所介導之障礙之治療、預防有用。 The present invention provides an antisense oligonucleotide having an inhibitory activity of CFB, a pharmaceutical composition containing the antisense oligonucleotide as an active ingredient, and the like. Antisense oligonucleotides and pharmaceutical groups of the invention Compound inhibits the performance of CFB, for atypical hemolytic uremic syndrome, paroxysmal nocturnal hemoglobinuria, age-related macular degeneration, membranous proliferative glomerulonephritis, C3 nephritis, membranous nephropathy, rapid progressive kidney Small ball nephritis (RPGN), acute kidney injury (AKI), asthma, autoimmune diseases (eg, systemic lupus erythematosus (SLE), psoriasis, optic neuromyelitis, myasthenia gravis, etc.) by the complement bypass pathway It is useful for the treatment and prevention of disorders mediated by abnormalities.

<110> 協和醱酵麒麟有限公司 <110> Concord Yeast Kylin Co., Ltd.

<120> 抑制補體B因子之表現之反義寡核苷酸 <120> Antisense oligonucleotides that inhibit the expression of complement factor B

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<210> 41 <210> 41

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成寡核苷酸 <223> Synthetic oligonucleotide

<400> 41 <400> 41

<210> 42 <210> 42

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成寡核苷酸 <223> Synthetic oligonucleotide

<400> 42 <400> 42

<210> 43 <210> 43

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成寡核苷酸 <223> Synthetic oligonucleotide

<400> 43 <400> 43

<210> 44 <210> 44

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成寡核苷酸 <223> Synthetic oligonucleotide

<400> 44 <400> 44

<210> 45 <210> 45

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成寡核苷酸 <223> Synthetic oligonucleotide

<400> 45 <400> 45

<210> 46 <210> 46

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成寡核苷酸 <223> Synthetic oligonucleotide

<400> 46 <400> 46

<210> 47 <210> 47

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成寡核苷酸 <223> Synthetic oligonucleotide

<400> 47 <400> 47

<210> 48 <210> 48

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成寡核苷酸 <223> Synthetic oligonucleotide

<400> 48 <400> 48

<210> 49 <210> 49

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成寡核苷酸 <223> Synthetic oligonucleotide

<400> 49 <400> 49

<210> 50 <210> 50

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成寡核苷酸 <223> Synthetic oligonucleotide

<400> 50 <400> 50

<210> 51 <210> 51

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成寡核苷酸 <223> Synthetic oligonucleotide

<400> 51 <400> 51

<210> 52 <210> 52

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成寡核苷酸 <223> Synthetic oligonucleotide

<400> 52 <400> 52

<210> 53 <210> 53

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<400> 53 <400> 53

<210> 54 <210> 54

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<400> 54 <400> 54

<210> 55 <210> 55

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<400> 55 <400> 55

<210> 56 <210> 56

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<400> 56 <400> 56

<210> 57 <210> 57

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<400> 57 <400> 57

<210> 58 <210> 58

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<400> 58 <400> 58

<210> 59 <210> 59

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<400> 59 <400> 59

<210> 60 <210> 60

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<400> 60 <400> 60

<210> 61 <210> 61

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<400> 61 <400> 61

<210> 62 <210> 62

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<400> 62 <400> 62

<210> 63 <210> 63

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<400> 63 <400> 63

<210> 64 <210> 64

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<400> 64 <400> 64

<210> 65 <210> 65

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<400> 65 <400> 65

<210> 66 <210> 66

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<400> 66 <400> 66

<210> 67 <210> 67

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<400> 67 <400> 67

<210> 68 <210> 68

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<400> 68 <400> 68

<210> 69 <210> 69

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<400> 69 <400> 69

<210> 70 <210> 70

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<400> 70 <400> 70

<210> 71 <210> 71

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<400> 71 <400> 71

<210> 72 <210> 72

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<400> 72 <400> 72

<210> 73 <210> 73

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<400> 73 <400> 73

<210> 74 <210> 74

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<400> 74 <400> 74

<210> 75 <210> 75

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<400> 75 <400> 75

<210> 76 <210> 76

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<400> 76 <400> 76

<210> 77 <210> 77

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<400> 77 <400> 77

<210> 78 <210> 78

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<400> 78 <400> 78

<210> 79 <210> 79

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<400> 79 <400> 79

<210> 80 <210> 80

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<400> 80 <400> 80

<210> 81 <210> 81

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<400> 81 <400> 81

<210> 82 <210> 82

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<400> 82 <400> 82

<210> 83 <210> 83

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<400> 83 <400> 83

<210> 84 <210> 84

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<400> 84 <400> 84

<210> 85 <210> 85

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<400> 85 <400> 85

<210> 86 <210> 86

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<400> 86 <400> 86

<210> 87 <210> 87

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<400> 87 <400> 87

<210> 88 <210> 88

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<400> 88 <400> 88

<210> 89 <210> 89

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<400> 89 <400> 89

<210> 90 <210> 90

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<400> 90 <400> 90

<210> 91 <210> 91

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<400> 91 <400> 91

<210> 92 <210> 92

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<400> 92 <400> 92

<210> 93 <210> 93

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<400> 93 <400> 93

<210> 94 <210> 94

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<400> 94 <400> 94

<210> 95 <210> 95

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<400> 95 <400> 95

<210> 96 <210> 96

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<400> 96 <400> 96

<210> 97 <210> 97

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<400> 97 <400> 97

<210> 98 <210> 98

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<400> 98 <400> 98

<210> 99 <210> 99

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<400> 99 <400> 99

<210> 100 <210> 100

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<400> 100 <400> 100

<210> 101 <210> 101

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<400> 101 <400> 101

<210> 102 <210> 102

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<400> 102 <400> 102

<210> 103 <210> 103

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 智人 <213> Homo sapiens

<400> 103 <400> 103

<210> 104 <210> 104

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成寡核苷酸：結合DNA/RNA分子：核苷酸3至10為脫氧核糖核苷酸，其餘核苷酸為核糖核苷酸 <223> Synthetic oligonucleotide: binding DNA/RNA molecule: nucleotides 3 to 10 are deoxyribonucleotides, and the remaining nucleotides are ribonucleotides

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (1)..(1) <222> (1)..(1)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 未歸類特徵 <221> Uncategorized features

<222> (1)..(13) <222> (1)..(13)

<223> 硫代磷酸酯-核苷酸間鍵結 <223> Phosphorothioate-internucleotide linkage

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (2)..(2) <222> (2)..(2)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (11)..(11) <222> (11)..(11)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (12)..(12) <222> (12)..(12)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (13)..(13) <222> (13)..(13)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<400> 104 <400> 104

<210> 105 <210> 105

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成寡核苷酸：結合DNA/RNA分子：核苷酸3至10為脫氧核糖核苷酸，其餘核苷酸為核糖核苷酸 <223> Synthetic oligonucleotide: binding DNA/RNA molecule: nucleotides 3 to 10 are deoxyribonucleotides, and the remaining nucleotides are ribonucleotides

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (1)..(1) <222> (1)..(1)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 未歸類特徵 <221> Uncategorized features

<222> (1)..(13) <222> (1)..(13)

<223> 硫代磷酸酯-核苷酸間鍵結 <223> Phosphorothioate-internucleotide linkage

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (2)..(2) <222> (2)..(2)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (11)..(11) <222> (11)..(11)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (12)..(12) <222> (12)..(12)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (13)..(13) <222> (13)..(13)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<400> 105 <400> 105

<210> 106 <210> 106

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成寡核苷酸：結合DNA/RNA分子：核苷酸3至10為脫氧核糖核苷酸，其餘核苷酸為核糖核苷酸 <223> Synthetic oligonucleotide: binding DNA/RNA molecule: nucleotides 3 to 10 are deoxyribonucleotides, and the remaining nucleotides are ribonucleotides

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (1)..(1) <222> (1)..(1)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 未歸類特徵 <221> Uncategorized features

<222> (1)..(13) <222> (1)..(13)

<223> 硫代磷酸酯-核苷酸間鍵結 <223> Phosphorothioate-internucleotide linkage

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (2)..(2) <222> (2)..(2)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (11)..(11) <222> (11)..(11)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (12)..(12) <222> (12)..(12)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (13)..(13) <222> (13)..(13)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<400> 106 <400> 106

<210> 107 <210> 107

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成寡核苷酸：結合DNA/RNA分子：核苷酸3至10為脫氧核糖核苷酸，其餘核苷酸為核糖核苷酸 <223> Synthetic oligonucleotide: binding DNA/RNA molecule: nucleotides 3 to 10 are deoxyribonucleotides, and the remaining nucleotides are ribonucleotides

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (1)..(1) <222> (1)..(1)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 未歸類特徵 <221> Uncategorized features

<222> (1)..(13) <222> (1)..(13)

<223> 硫代磷酸酯-核苷酸間鍵結 <223> Phosphorothioate-internucleotide linkage

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (2)..(2) <222> (2)..(2)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (11)..(11) <222> (11)..(11)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (12)..(12) <222> (12)..(12)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (13)..(13) <222> (13)..(13)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<400> 107 <400> 107

<210> 108 <210> 108

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成寡核苷酸：結合DNA/RNA分子：核苷酸3至10為脫氧核糖核苷酸，其餘核苷酸為核糖核苷酸 <223> Synthetic oligonucleotide: binding DNA/RNA molecule: nucleotides 3 to 10 are deoxyribonucleotides, and the remaining nucleotides are ribonucleotides

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (1)..(1) <222> (1)..(1)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 未歸類特徵 <221> Uncategorized features

<222> (1)..(13) <222> (1)..(13)

<223> 硫代磷酸酯-核苷酸間鍵結 <223> Phosphorothioate-internucleotide linkage

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (2)..(2) <222> (2)..(2)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (11)..(11) <222> (11)..(11)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (12)..(12) <222> (12)..(12)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (13)..(13) <222> (13)..(13)

<223> 2'-O,4'-C-亞甲基連接雙環核苷鹼 <223> 2'-O, 4'-C-methylene-linked bicyclic nucleobase

<400> 108 <400> 108

<210> 109 <210> 109

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成寡核苷酸：結合DNA/RNA分子：核苷酸3至10為脫氧核糖核苷酸，其餘核苷酸為核糖核苷酸 <223> Synthetic oligonucleotide: binding DNA/RNA molecule: nucleotides 3 to 10 are deoxyribonucleotides, and the remaining nucleotides are ribonucleotides

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (1)..(1) <222> (1)..(1)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 未歸類特徵 <221> Uncategorized features

<222> (1)..(13) <222> (1)..(13)

<223> 硫代磷酸酯-核苷酸間鍵結 <223> Phosphorothioate-internucleotide linkage

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (2)..(2) <222> (2)..(2)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (11)..(11) <222> (11)..(11)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (12)..(12) <222> (12)..(12)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (13)..(13) <222> (13)..(13)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<400> 109 <400> 109

<210> 110 <210> 110

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成寡核苷酸：結合DNA/RNA分子：核苷酸3至10為脫氧核糖核苷酸，其餘核苷酸為核糖核苷酸 <223> Synthetic oligonucleotide: binding DNA/RNA molecule: nucleotides 3 to 10 are deoxyribonucleotides, and the remaining nucleotides are ribonucleotides

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (1)..(1) <222> (1)..(1)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 未歸類特徵 <221> Uncategorized features

<222> (1)..(13) <222> (1)..(13)

<223> 硫代磷酸酯-核苷酸間鍵結 <223> Phosphorothioate-internucleotide linkage

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (2)..(2) <222> (2)..(2)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (11)..(11) <222> (11)..(11)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (12)..(12) <222> (12)..(12)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (13)..(13) <222> (13)..(13)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<400> 110 <400> 110

<210> 111 <210> 111

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成寡核苷酸：結合DNA/RNA分子：核苷酸3至10為脫氧核糖核苷酸，其餘核苷酸為核糖核苷酸 <223> Synthetic oligonucleotide: binding DNA/RNA molecule: nucleotides 3 to 10 are deoxyribonucleotides, and the remaining nucleotides are ribonucleotides

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (1)..(1) <222> (1)..(1)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 未歸類特徵 <221> Uncategorized features

<222> (1)..(13) <222> (1)..(13)

<223> 硫代磷酸酯-核苷酸間鍵結 <223> Phosphorothioate-internucleotide linkage

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (2)..(2) <222> (2)..(2)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (11)..(11) <222> (11)..(11)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (12)..(12) <222> (12)..(12)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (13)..(13) <222> (13)..(13)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<400> 111 <400> 111

<210> 112 <210> 112

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成寡核苷酸：結合DNA/RNA分子：核苷酸3至10為脫氧核糖核苷酸，其餘核苷酸為核糖核苷酸 <223> Synthetic oligonucleotide: binding DNA/RNA molecule: nucleotides 3 to 10 are deoxyribonucleotides, and the remaining nucleotides are ribonucleotides

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (1)..(1) <222> (1)..(1)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 未歸類特徵 <221> Uncategorized features

<222> (1)..(13) <222> (1)..(13)

<223> 硫代磷酸酯-核苷酸間鍵結 <223> Phosphorothioate-internucleotide linkage

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (2)..(2) <222> (2)..(2)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (11)..(11) <222> (11)..(11)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (12)..(12) <222> (12)..(12)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (13)..(13) <222> (13)..(13)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<400> 112 <400> 112

<210> 113 <210> 113

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成寡核苷酸：結合DNA/RNA分子：核苷酸3至10為脫氧核糖核苷酸，其餘核苷酸為核糖核苷酸 <223> Synthetic oligonucleotide: binding DNA/RNA molecule: nucleotides 3 to 10 are deoxyribonucleotides, and the remaining nucleotides are ribonucleotides

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (1)..(1) <222> (1)..(1)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 未歸類特徵 <221> Uncategorized features

<222> (1)..(13) <222> (1)..(13)

<223> 硫代磷酸酯-核苷酸間鍵結 <223> Phosphorothioate-internucleotide linkage

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (2)..(2) <222> (2)..(2)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (11)..(11) <222> (11)..(11)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (12)..(12) <222> (12)..(12)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (13)..(13) <222> (13)..(13)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<400> 113 <400> 113

<210> 114 <210> 114

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成寡核苷酸：結合DNA/RNA分子：核苷酸3至10為脫氧核糖核苷酸，其餘核苷酸為核糖核苷酸 <223> Synthetic oligonucleotide: binding DNA/RNA molecule: nucleotides 3 to 10 are deoxyribonucleotides, and the remaining nucleotides are ribonucleotides

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (1)..(1) <222> (1)..(1)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 未歸類特徵 <221> Uncategorized features

<222> (1)..(13) <222> (1)..(13)

<223> 硫代磷酸酯-核苷酸間鍵結 <223> Phosphorothioate-internucleotide linkage

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (2)..(2) <222> (2)..(2)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (11)..(11) <222> (11)..(11)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (12)..(12) <222> (12)..(12)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (13)..(13) <222> (13)..(13)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<400> 114 <400> 114

<210> 115 <210> 115

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成寡核苷酸：結合DNA/RNA分子：核苷酸3至10為脫氧核糖核苷酸，其餘核苷酸為核糖核苷酸 <223> Synthetic oligonucleotide: binding DNA/RNA molecule: nucleotides 3 to 10 are deoxyribonucleotides, and the remaining nucleotides are ribonucleotides

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (1)..(1) <222> (1)..(1)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 未歸類特徵 <221> Uncategorized features

<222> (1)..(13) <222> (1)..(13)

<223> 硫代磷酸酯-核苷酸間鍵結 <223> Phosphorothioate-internucleotide linkage

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (2)..(2) <222> (2)..(2)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (11)..(11) <222> (11)..(11)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (12)..(12) <222> (12)..(12)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (13)..(13) <222> (13)..(13)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<400> 115 <400> 115

<210> 116 <210> 116

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成寡核苷酸：結合DNA/RNA分子：核苷酸3至10為脫氧核酸核苷酸，其餘核苷酸為核糖核苷酸 <223> Synthetic oligonucleotide: binding DNA/RNA molecule: nucleotides 3 to 10 are deoxynucleic acid nucleotides, and the remaining nucleotides are ribonucleotides

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (1)..(1) <222> (1)..(1)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 未歸類特徵 <221> Uncategorized features

<222> (1)..(13) <222> (1)..(13)

<223> 硫代磷酸酯-核苷酸間鍵結 <223> Phosphorothioate-internucleotide linkage

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (2)..(2) <222> (2)..(2)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (11)..(11) <222> (11)..(11)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (12)..(12) <222> (12)..(12)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (13)..(13) <222> (13)..(13)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<400> 116 <400> 116

<210> 117 <210> 117

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成寡核苷酸：結合DNA/RNA分子：核苷酸3至10為脫氧核糖核苷酸，其餘核苷酸為核糖核苷酸 <223> Synthetic oligonucleotide: binding DNA/RNA molecule: nucleotides 3 to 10 are deoxyribonucleotides, and the remaining nucleotides are ribonucleotides

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (1)..(1) <222> (1)..(1)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 未歸類特徵 <221> Uncategorized features

<222> (1)..(13) <222> (1)..(13)

<223> 硫代磷酸酯-核苷酸間鍵結 <223> Phosphorothioate-internucleotide linkage

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (2)..(2) <222> (2)..(2)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (11)..(11) <222> (11)..(11)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (12)..(12) <222> (12)..(12)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (13)..(13) <222> (13)..(13)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<400> 117 <400> 117

<210> 118 <210> 118

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成寡核苷酸：結合DNA/RNA分子：核苷酸3至10為脫氧核糖核苷酸，其餘核苷酸為核糖核苷酸 <223> Synthetic oligonucleotide: binding DNA/RNA molecule: nucleotides 3 to 10 are deoxyribonucleotides, and the remaining nucleotides are ribonucleotides

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (1)..(1) <222> (1)..(1)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 未歸類特徵 <221> Uncategorized features

<222> (1)..(13) <222> (1)..(13)

<223> 硫代磷酸酯-核苷酸間鍵結 <223> Phosphorothioate-internucleotide linkage

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (2)..(2) <222> (2)..(2)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (11)..(11) <222> (11)..(11)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (12)..(12) <222> (12)..(12)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (13)..(13) <222> (13)..(13)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<400> 118 <400> 118

<210> 119 <210> 119

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成寡核苷酸：結合DNA/RNA分子：核苷酸3至10為脫氧核糖核苷酸，其餘核苷酸為核糖核苷酸 <223> Synthetic oligonucleotide: binding DNA/RNA molecule: nucleotides 3 to 10 are deoxyribonucleotides, and the remaining nucleotides are ribonucleotides

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (1)..(1) <222> (1)..(1)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 未歸類特徵 <221> Uncategorized features

<222> (1)..(13) <222> (1)..(13)

<223> 硫代磷酸酯-核苷酸間鍵結 <223> Phosphorothioate-internucleotide linkage

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (2)..(2) <222> (2)..(2)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (11)..(11) <222> (11)..(11)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (12)..(12) <222> (12)..(12)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (13)..(13) <222> (13)..(13)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<400> 119 <400> 119

<210> 120 <210> 120

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成寡核苷酸：結合DNA/RNA分子：核苷酸3至10為脫氧核糖核苷酸，其餘核苷酸為核糖核苷酸 <223> Synthetic oligonucleotide: binding DNA/RNA molecule: nucleotides 3 to 10 are deoxyribonucleotides, and the remaining nucleotides are ribonucleotides

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (1)..(1) <222> (1)..(1)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 未歸類特徵 <221> Uncategorized features

<222> (1)..(13) <222> (1)..(13)

<223> 硫代磷酸酯-核苷酸間鍵結 <223> Phosphorothioate-internucleotide linkage

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (2)..(2) <222> (2)..(2)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (11)..(11) <222> (11)..(11)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (12)..(12) <222> (12)..(12)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (13)..(13) <222> (13)..(13)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<400> 120 <400> 120

<210> 121 <210> 121

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成寡核苷酸：結合DNA/RNA分子：核苷酸3至10為脫氧核糖核苷酸，其餘核苷酸為核糖核苷酸 <223> Synthetic oligonucleotide: binding DNA/RNA molecule: nucleotides 3 to 10 are deoxyribonucleotides, and the remaining nucleotides are ribonucleotides

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (1)..(1) <222> (1)..(1)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 未歸類特徵 <221> Uncategorized features

<222> (1)..(13) <222> (1)..(13)

<223> 硫代磷酸酯-核苷酸間鍵結 <223> Phosphorothioate-internucleotide linkage

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (2)..(2) <222> (2)..(2)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (11)..(11) <222> (11)..(11)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (12)..(12) <222> (12)..(12)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (13)..(13) <222> (13)..(13)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<400> 121 <400> 121

<210> 122 <210> 122

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成寡核苷酸：結合DNA/RNA分子：核苷酸3至10為脫氧核糖核苷酸，其餘核苷酸為核糖核苷酸 <223> Synthetic oligonucleotide: binding DNA/RNA molecule: nucleotides 3 to 10 are deoxyribonucleotides, and the remaining nucleotides are ribonucleotides

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (1)..(1) <222> (1)..(1)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 未歸類特徵 <221> Uncategorized features

<222> (1)..(13) <222> (1)..(13)

<223> 硫代磷酸酯-核苷酸間鍵結 <223> Phosphorothioate-internucleotide linkage

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (2)..(2) <222> (2)..(2)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (11)..(11) <222> (11)..(11)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (12)-(12) <222> (12)-(12)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (13)..(13) <222> (13)..(13)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<400> 122 <400> 122

<210> 123 <210> 123

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成寡核苷酸：結合DNA/RNA分子：核苷酸3至10為脫氧核糖核苷酸，其餘核苷酸為核糖核苷酸 <223> Synthetic oligonucleotide: binding DNA/RNA molecule: nucleotides 3 to 10 are deoxyribonucleotides, and the remaining nucleotides are ribonucleotides

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (1)..(1) <222> (1)..(1)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 未歸類特徵 <221> Uncategorized features

<222> (1)..(13) <222> (1)..(13)

<223> 硫代磷酸酯-核苷酸間鍵結 <223> Phosphorothioate-internucleotide linkage

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (2)..(2) <222> (2)..(2)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (11)..(11) <222> (11)..(11)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (12)..(12) <222> (12)..(12)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (13)..(13) <222> (13)..(13)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<400> 123 <400> 123

<210> 124 <210> 124

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成寡核苷酸：結合DNA/RNA分子：核苷酸3至10為脫氧核糖核苷酸，其餘核苷酸為核糖核苷酸 <223> Synthetic oligonucleotide: binding DNA/RNA molecule: nucleotides 3 to 10 are deoxyribonucleotides, and the remaining nucleotides are ribonucleotides

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (1)..(1) <222> (1)..(1)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 未歸類特徵 <221> Uncategorized features

<222> (1)..(13) <222> (1)..(13)

<223> 硫代磷酸酯-核苷酸間鍵結 <223> Phosphorothioate-internucleotide linkage

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (2)..(2) <222> (2)..(2)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (11)..(11) <222> (11)..(11)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (12)..(12) <222> (12)..(12)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (13)..(13) <222> (13)..(13)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<400> 124 <400> 124

<210> 125 <210> 125

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成寡核苷酸：結合DNA/RNA分子：核苷酸3至10為脫氧核糖核苷酸，其餘核苷酸為核糖核苷酸 <223> Synthetic oligonucleotide: binding DNA/RNA molecule: nucleotides 3 to 10 are deoxyribonucleotides, and the remaining nucleotides are ribonucleotides

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (1)..(1) <222> (1)..(1)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 未歸類特徵 <221> Uncategorized features

<222> (1)..(13) <222> (1)..(13)

<223> 硫代磷酸酯-核苷酸間鍵結 <223> Phosphorothioate-internucleotide linkage

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (2)..(2) <222> (2)..(2)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (11)..(11) <222> (11)..(11)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (12)..(12) <222> (12)..(12)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (13)..(13) <222> (13)..(13)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<400> 125 <400> 125

<210> 126 <210> 126

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成寡核苷酸：結合DNA/RNA分子：核苷酸3至10為脫氧核糖核苷酸，其餘核苷酸為核糖核苷酸 <223> Synthetic oligonucleotide: binding DNA/RNA molecule: nucleotides 3 to 10 are deoxyribonucleotides, and the remaining nucleotides are ribonucleotides

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (1)..(1) <222> (1)..(1)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 未歸類特徵 <221> Uncategorized features

<222> (1)..(13) <222> (1)..(13)

<223> 硫代磷酸酯-核苷酸間鍵結 <223> Phosphorothioate-internucleotide linkage

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (2)..(2) <222> (2)..(2)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (11)..(11) <222> (11)..(11)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (12)-(12) <222> (12)-(12)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (13)..(13) <222> (13)..(13)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<400> 126 <400> 126

<210> 127 <210> 127

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成寡核苷酸：結合DNA/RNA分子：核苷酸3至10為脫氧核糖核苷酸，其餘核苷酸為核糖核苷酸 <223> Synthetic oligonucleotide: binding DNA/RNA molecule: nucleotides 3 to 10 are deoxyribonucleotides, and the remaining nucleotides are ribonucleotides

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (1)..(1) <222> (1)..(1)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 未歸類特徵 <221> Uncategorized features

<222> (1)..(13) <222> (1)..(13)

<223> 硫代磷酸酯-核苷酸間鍵結 <223> Phosphorothioate-internucleotide linkage

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (2)..(2) <222> (2)..(2)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (11)..(11) <222> (11)..(11)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (12)..(12) <222> (12)..(12)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (13)..(13) <222> (13)..(13)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<400> 127 <400> 127

<210> 128 <210> 128

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成寡核苷酸：結合DNA/RNA分子：核苷酸3至10為脫氧核糖核苷酸，其餘核苷酸為核糖核苷酸 <223> Synthetic oligonucleotide: binding DNA/RNA molecule: nucleotides 3 to 10 are deoxyribonucleotides, and the remaining nucleotides are ribonucleotides

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (1)..(1) <222> (1)..(1)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 未歸類特徵 <221> Uncategorized features

<222> (1)..(13) <222> (1)..(13)

<223> 硫代磷酸酯-核苷酸間鍵結 <223> Phosphorothioate-internucleotide linkage

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (2)..(2) <222> (2)..(2)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (11)..(11) <222> (11)..(11)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (12)..(12) <222> (12)..(12)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (13)..(13) <222> (13)..(13)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<400> 128 <400> 128

<210> 129 <210> 129

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成寡核苷酸：結合DNA/RNA分子：核苷酸3至10為脫氧核糖核苷酸，其餘核苷酸為核糖核苷酸 <223> Synthetic oligonucleotide: binding DNA/RNA molecule: nucleotides 3 to 10 are deoxyribonucleotides, and the remaining nucleotides are ribonucleotides

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (1)..(1) <222> (1)..(1)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 未歸類特徵 <221> Uncategorized features

<222> (1)..(13) <222> (1)..(13)

<223> 硫代磷酸酯-核苷酸間鍵結 <223> Phosphorothioate-internucleotide linkage

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (2)..(2) <222> (2)..(2)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (11)..(11) <222> (11)..(11)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (12)..(12) <222> (12)..(12)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (13)..(13) <222> (13)..(13)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<400> 129 <400> 129

<210> 130 <210> 130

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成寡核苷酸：結合DNA/RNA分子：核苷酸3至10為脫氧核糖核苷酸，其餘核苷酸為核糖核苷酸 <223> Synthetic oligonucleotide: binding DNA/RNA molecule: nucleotides 3 to 10 are deoxyribonucleotides, and the remaining nucleotides are ribonucleotides

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (1)..(1) <222> (1)..(1)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 未歸類特徵 <221> Uncategorized features

<222> (1)..(13) <222> (1)..(13)

<223> 硫代磷酸酯-核苷酸間鍵結 <223> Phosphorothioate-internucleotide linkage

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (2)..(2) <222> (2)..(2)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (11)..(11) <222> (11)..(11)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (12)..(12) <222> (12)..(12)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (13)..(13) <222> (13)..(13)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<400> 130 <400> 130

<210> 131 <210> 131

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成寡核苷酸：結合DNA/RNA分子：核苷酸3至10為脫氧核糖核苷酸，其餘核苷酸為核糖核苷酸 <223> Synthetic oligonucleotide: binding DNA/RNA molecule: nucleotides 3 to 10 are deoxyribonucleotides, and the remaining nucleotides are ribonucleotides

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (1)..(1) <222> (1)..(1)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 未歸類特徵 <221> Uncategorized features

<222> (1)..(13) <222> (1)..(13)

<223> 硫代磷酸酯-核苷酸間鍵結 <223> Phosphorothioate-internucleotide linkage

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (2)..(2) <222> (2)..(2)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (11)..(11) <222> (11)..(11)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (12)..(12) <222> (12)..(12)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (13)..(13) <222> (13)..(13)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<400> 131 <400> 131

<210> 132 <210> 132

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成寡核苷酸：結合DNA/RNA分子：核苷酸3至10為脫氧核糖核苷酸，其餘核苷酸為核糖核苷酸 <223> Synthetic oligonucleotide: binding DNA/RNA molecule: nucleotides 3 to 10 are deoxyribonucleotides, and the remaining nucleotides are ribonucleotides

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (1)..(1) <222> (1)..(1)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 未歸類特徵 <221> Uncategorized features

<222> (1)..(13) <222> (1)..(13)

<223> 硫代磷酸酯-核苷酸間鍵結 <223> Phosphorothioate-internucleotide linkage

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (2)..(2) <222> (2)..(2)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (11)..(11) <222> (11)..(11)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (12)..(12) <222> (12)..(12)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (13)..(13) <222> (13)..(13)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<400> 132 <400> 132

<210> 133 <210> 133

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成寡核苷酸：結合DNA/RNA分子：核苷酸3至10為脫氧核糖核苷酸，其餘核苷酸為核糖核苷酸 <223> Synthetic oligonucleotide: binding DNA/RNA molecule: nucleotides 3 to 10 are deoxyribonucleotides, and the remaining nucleotides are ribonucleotides

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (1)..(1) <222> (1)..(1)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 未歸類特徵 <221> Uncategorized features

<222> (1)..(13) <222> (1)..(13)

<223> 硫代磷酸酯-核苷酸間鍵結 <223> Phosphorothioate-internucleotide linkage

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (2)..(2) <222> (2)..(2)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (11)..(11) <222> (11)..(11)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (12)..(12) <222> (12)..(12)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (13)..(13) <222> (13)..(13)

<223> 5-甲基胞嘧啶；2'-O,4'-C亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C methylene-linked bicyclic nucleotide

<400> 133 <400> 133

<210> 134 <210> 134

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成寡核苷酸：結合DNA/RNA分子：核苷酸3至10為脫氧核糖核苷酸，其餘核苷酸為核糖核苷酸 <223> Synthetic oligonucleotide: binding DNA/RNA molecule: nucleotides 3 to 10 are deoxyribonucleotides, and the remaining nucleotides are ribonucleotides

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (1)..(1) <222> (1)..(1)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 未歸類特徵 <221> Uncategorized features

<222> (1)..(13) <222> (1)..(13)

<223> 硫代磷酸酯-核苷酸間鍵結 <223> Phosphorothioate-internucleotide linkage

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (2)..(2) <222> (2)..(2)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (11)..(11) <222> (11)..(11)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (12)..(12) <222> (12)..(12)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (13)..(13) <222> (13)..(13)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<400> 134 <400> 134

<210> 135 <210> 135

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成寡核苷酸：結合DNA/RNA分子：核苷酸3至10為脫氧核糖核苷酸，其餘核苷酸為核糖核苷酸 <223> Synthetic oligonucleotide: binding DNA/RNA molecule: nucleotides 3 to 10 are deoxyribonucleotides, and the remaining nucleotides are ribonucleotides

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (1)..(1) <222> (1)..(1)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 未歸類特徵 <221> Uncategorized features

<222> (1)..(13) <222> (1)..(13)

<223> 硫代磷酸酯-核苷酸間鍵結 <223> Phosphorothioate-internucleotide linkage

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (2)..(2) <222> (2)..(2)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (11)..(11) <222> (11)..(11)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (12)..(12) <222> (12)..(12)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (13)..(13) <222> (13)..(13)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<400> 135 <400> 135

<210> 136 <210> 136

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成寡核苷酸：結合DNA/RNA分子：核苷酸3至10為脫氧核糖核苷酸，其餘核苷酸為核糖核苷酸 <223> Synthetic oligonucleotide: binding DNA/RNA molecule: nucleotides 3 to 10 are deoxyribonucleotides, and the remaining nucleotides are ribonucleotides

<220> <220>

<321> 修飾鹼基 <321> modified base

<222> (1)..(1) <222> (1)..(1)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 未歸類特徵 <221> Uncategorized features

<222> (1)..(13) <222> (1)..(13)

<223> 硫代磷酸酯-核苷酸間鍵結 <223> Phosphorothioate-internucleotide linkage

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (2)..(2) <222> (2)..(2)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (11)..(11) <222> (11)..(11)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (12)..(12) <222> (12)..(12)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (13)..(13) <222> (13)..(13)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<400> 136 <400> 136

<210> 137 <210> 137

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成寡核苷酸：結合DNA/RNA分子：核苷酸3至10為脫氧核糖核苷酸，其餘核苷酸為核糖核苷酸 <223> Synthetic oligonucleotide: binding DNA/RNA molecule: nucleotides 3 to 10 are deoxyribonucleotides, and the remaining nucleotides are ribonucleotides

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (1)..(1) <222> (1)..(1)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 未歸類特徵 <221> Uncategorized features

<222> (1)..(13) <222> (1)..(13)

<223> 硫代磷酸酯-核苷酸間鍵結 <223> Phosphorothioate-internucleotide linkage

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (2)..(2) <222> (2)..(2)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (11)..(11) <222> (11)..(11)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (12)..(12) <222> (12)..(12)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (13)..(13) <222> (13)..(13)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<400> 137 <400> 137

<210> 138 <210> 138

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成寡核苷酸：結合DNA/RNA分子：核苷酸3至10為脫氧核糖核苷酸，其餘核苷酸為核糖核苷酸 <223> Synthetic oligonucleotide: binding DNA/RNA molecule: nucleotides 3 to 10 are deoxyribonucleotides, and the remaining nucleotides are ribonucleotides

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (1)..(1) <222> (1)..(1)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 未歸類特徵 <221> Uncategorized features

<222> (1)..(13) <222> (1)..(13)

<223> 硫代磷酸酯-核苷酸間鍵結 <223> Phosphorothioate-internucleotide linkage

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (2)..(2) <222> (2)..(2)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (11)..(11) <222> (11)..(11)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (12)..(12) <222> (12)..(12)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (13)..(13) <222> (13)..(13)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<400> 138 <400> 138

<210> 139 <210> 139

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成寡核苷酸：結合DNA/RNA分子：核苷酸3至10為脫氧核糖核苷酸，其餘核苷酸為核糖核苷酸 <223> Synthetic oligonucleotide: binding DNA/RNA molecule: nucleotides 3 to 10 are deoxyribonucleotides, and the remaining nucleotides are ribonucleotides

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (1)..(1) <222> (1)..(1)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 未歸類特徵 <221> Uncategorized features

<222> (1)..(13) <222> (1)..(13)

<223> 硫代磷酸酯-核苷酸間鍵結 <223> Phosphorothioate-internucleotide linkage

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (2)..(2) <222> (2)..(2)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (11)..(11) <222> (11)..(11)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (12)..(12) <222> (12)..(12)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (13)..(13) <222> (13)..(13)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<400> 139 <400> 139

<210> 140 <210> 140

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成寡核苷酸：結合DNA/RNA分子：核苷酸3至10為脫氧核糖核苷酸，其餘核苷酸為核糖核苷酸 <223> Synthetic oligonucleotide: binding DNA/RNA molecule: nucleotides 3 to 10 are deoxyribonucleotides, and the remaining nucleotides are ribonucleotides

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (1)..(1) <222> (1)..(1)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 未歸類特徵 <221> Uncategorized features

<222> (1)..(13) <222> (1)..(13)

<223> 硫代磷酸酯-核苷酸間鍵結 <223> Phosphorothioate-internucleotide linkage

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (2)..(2) <222> (2)..(2)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (11)..(11) <222> (11)..(11)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (12)..(12) <222> (12)..(12)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (13)..(13) <222> (13)..(13)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<400> 140 <400> 140

<210> 141 <210> 141

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成寡核苷酸：結合DNA/RNA分子：核苷酸3至10為脫氧核糖核苷酸，其餘核苷酸為核糖核苷酸 <223> Synthetic oligonucleotide: binding DNA/RNA molecule: nucleotides 3 to 10 are deoxyribonucleotides, and the remaining nucleotides are ribonucleotides

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (1)..(1) <222> (1)..(1)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 未歸類特徵 <221> Uncategorized features

<222> (1)..(13) <222> (1)..(13)

<223> 硫代磷酸酯-核苷酸間鍵結 <223> Phosphorothioate-internucleotide linkage

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (2)..(2) <222> (2)..(2)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (11)..(11) <222> (11)..(11)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (12)..(12) <222> (12)..(12)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (13)..(13) <222> (13)..(13)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<400> 141 <400> 141

<210> 142 <210> 142

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成寡核苷酸：結合DNA/RNA分子：核苷酸3至10為脫氧核糖核苷酸，其餘核苷酸為核糖核苷酸 <223> Synthetic oligonucleotide: binding DNA/RNA molecule: nucleotides 3 to 10 are deoxyribonucleotides, and the remaining nucleotides are ribonucleotides

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (1)..(1) <222> (1)..(1)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 未歸類特徵 <221> Uncategorized features

<222> (1)..(13) <222> (1)..(13)

<223> 硫代磷酸酯-核苷酸間鍵結 <223> Phosphorothioate-internucleotide linkage

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (2)..(2) <222> (2)..(2)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (11)..(11) <222> (11)..(11)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (12)..(12) <222> (12)..(12)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (13)..(13) <222> (13)..(13)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<400> 142 <400> 142

<210> 143 <210> 143

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成寡核苷酸：結合DNA/RNA分子：核苷酸3至10為脫氧核糖核苷酸，其餘核苷酸為核糖核苷酸 <223> Synthetic oligonucleotide: binding DNA/RNA molecule: nucleotides 3 to 10 are deoxyribonucleotides, and the remaining nucleotides are ribonucleotides

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (1)..(1) <222> (1)..(1)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 未歸類特徵 <221> Uncategorized features

<222> (1)..(13) <222> (1)..(13)

<223> 硫代磷酸酯-核苷酸間鍵結 <223> Phosphorothioate-internucleotide linkage

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (2)..(2) <222> (2)..(2)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (11)..(11) <222> (11)..(11)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (12)..(12) <222> (12)..(12)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (13)..(13) <222> (13)..(13)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<400> 143 <400> 143

<210> 144 <210> 144

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成寡核苷酸：結合DNA/RNA分子：核苷酸3至10為脫氧核糖核苷酸，其餘核苷酸為核糖核苷酸 <223> Synthetic oligonucleotide: binding DNA/RNA molecule: nucleotides 3 to 10 are deoxyribonucleotides, and the remaining nucleotides are ribonucleotides

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (1)..(1) <222> (1)..(1)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 未歸類特徵 <221> Uncategorized features

<222> (1)..(13) <222> (1)..(13)

<223> 硫代磷酸酯-核苷酸間鍵結 <223> Phosphorothioate-internucleotide linkage

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (2)..(2) <222> (2)..(2)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (11)..(11) <222> (11)..(11)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (12)..(12) <222> (12)..(12)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (13)..(13) <222> (13)..(13)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<400> 144 <400> 144

<210> 145 <210> 145

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成寡核苷酸：結合DNA/RNA分子：核苷酸3至10為脫氧核糖核苷酸，其餘核苷酸為核糖核苷酸 <223> Synthetic oligonucleotide: binding DNA/RNA molecule: nucleotides 3 to 10 are deoxyribonucleotides, and the remaining nucleotides are ribonucleotides

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (1)..(1) <222> (1)..(1)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 未歸類特徵 <221> Uncategorized features

<222> (1)..(13) <222> (1)..(13)

<223> 硫代磷酸酯-核苷酸間鍵結 <223> Phosphorothioate-internucleotide linkage

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (2)..(2) <222> (2)..(2)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (11)..(11) <222> (11)..(11)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (12)..(12) <222> (12)..(12)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (13)..(13) <222> (13)..(13)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<400> 145 <400> 145

<210> 146 <210> 146

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成寡核苷酸：結合DNA/RNA分子：核苷酸3至10為脫氧核糖核苷酸，其餘核苷酸為核糖核苷酸 <223> Synthetic oligonucleotide: binding DNA/RNA molecule: nucleotides 3 to 10 are deoxyribonucleotides, and the remaining nucleotides are ribonucleotides

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (1)..(1) <222> (1)..(1)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 未歸類特徵 <221> Uncategorized features

<222> (1)..(13) <222> (1)..(13)

<223> 硫代磷酸酯-核苷酸間鍵結 <223> Phosphorothioate-internucleotide linkage

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (2)..(2) <222> (2)..(2)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (11)..(11) <222> (11)..(11)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (12)..(12) <222> (12)..(12)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (13)..(13) <222> (13)..(13)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<400> 146 <400> 146

<210> 147 <210> 147

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成寡核苷酸：結合DNA/RNA分子：核苷酸3至10為脫氧核糖核苷酸，其餘核苷酸為核糖核苷酸 <223> Synthetic oligonucleotide: binding DNA/RNA molecule: nucleotides 3 to 10 are deoxyribonucleotides, and the remaining nucleotides are ribonucleotides

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (1)..(1) <222> (1)..(1)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 未歸類特徵 <221> Uncategorized features

<222> (1)..(13) <222> (1)..(13)

<222> 硫代磷酸酯-核苷酸間鍵結 <222> Phosphorothioate-internucleotide linkage

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (2)..(2) <222> (2)..(2)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (11)..(11) <222> (11)..(11)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (12)..(12) <222> (12)..(12)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (13)..(13) <222> (13)..(13)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<400> 147 <400> 147

<210> 148 <210> 148

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成寡核苷酸：結合DNA/RNA分子：核苷酸3至10為脫氧核糖核苷酸，其餘核苷酸為核糖核苷酸 <223> Synthetic oligonucleotide: binding DNA/RNA molecule: nucleotides 3 to 10 are deoxyribonucleotides, and the remaining nucleotides are ribonucleotides

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (1)..(1) <222> (1)..(1)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 未歸類特徵 <221> Uncategorized features

<222> (1)..(13) <222> (1)..(13)

<223> 硫代磷酸酯-核苷酸間鍵結 <223> Phosphorothioate-internucleotide linkage

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (2)..(2) <222> (2)..(2)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (11)..(11) <222> (11)..(11)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (12)..(12) <222> (12)..(12)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (13)..(13) <222> (13)..(13)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<400> 148 <400> 148

<210> 149 <210> 149

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成寡核苷酸：結合DNA/RNA分子：核苷酸3至10為脫氧核糖核苷酸，其餘核苷酸為核糖核苷酸 <223> Synthetic oligonucleotide: binding DNA/RNA molecule: nucleotides 3 to 10 are deoxyribonucleotides, and the remaining nucleotides are ribonucleotides

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (1)..(1) <222> (1)..(1)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 未歸類特徵 <221> Uncategorized features

<222> (1)..(13) <222> (1)..(13)

<223> 硫代磷酸酯-核苷酸間鍵結 <223> Phosphorothioate-internucleotide linkage

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (2)..(2) <222> (2)..(2)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (11)..(11) <222> (11)..(11)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (12)..(12) <222> (12)..(12)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (13)..(13) <222> (13)..(13)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<400> 149 <400> 149

<210> 150 <210> 150

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成寡核苷酸：結合DNA/RNA分子：核苷酸3至10為脫氧核糖核苷酸，其餘核苷酸為核糖核苷酸 <223> Synthetic oligonucleotide: binding DNA/RNA molecule: nucleotides 3 to 10 are deoxyribonucleotides, and the remaining nucleotides are ribonucleotides

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (1)..(1) <222> (1)..(1)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 未歸類特徵 <221> Uncategorized features

<222> (1)..(13) <222> (1)..(13)

<223> 硫代磷酸酯-核苷酸間鍵結 <223> Phosphorothioate-internucleotide linkage

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (2)..(2) <222> (2)..(2)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (11)..(11) <222> (11)..(11)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (12)..(12) <222> (12)..(12)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (13)..(13) <222> (13)..(13)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<400> 150 <400> 150

<210> 151 <210> 151

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成寡核苷酸：結合DNA/RNA分子：核苷酸3至10為脫氧核糖核苷酸，其餘核苷酸為核糖核苷酸 <223> Synthetic oligonucleotide: binding DNA/RNA molecule: nucleotides 3 to 10 are deoxyribonucleotides, and the remaining nucleotides are ribonucleotides

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (1)..(1) <222> (1)..(1)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 未歸類特徵 <221> Uncategorized features

<222> (1)..(13) <222> (1)..(13)

<223> 硫代磷酸酯-核苷酸間鍵結 <223> Phosphorothioate-internucleotide linkage

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (2)..(2) <222> (2)..(2)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (11)..(11) <222> (11)..(11)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (12)..(12) <222> (12)..(12)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (13)..(13) <222> (13)..(13)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<400> 151 <400> 151

<210> 152 <210> 152

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成基核苷酸：結合DNA/RNA分子：核苷酸3至10為脫氧核糖核苷酸，其餘核苷酸為核糖核苷酸 <223> Synthetic nucleotide: binding DNA/RNA molecule: nucleotides 3 to 10 are deoxyribonucleotides, and the remaining nucleotides are ribonucleotides

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (1)..(1) <222> (1)..(1)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 未歸類特徵 <221> Uncategorized features

<222> (1)..(13) <222> (1)..(13)

<223> 硫代磷酸酯-核苷酸間鍵結 <223> Phosphorothioate-internucleotide linkage

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (2)..(2) <222> (2)..(2)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (11)..(11) <222> (11)..(11)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (12)..(12) <222> (12)..(12)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (13)..(13) <222> (13)..(13)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<400> 152 <400> 152

<210> 153 <210> 153

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成寡核苷酸：結合DNA/RNA分子：核苷酸3至10為脫氧核糖核苷酸，其餘核苷酸為核糖核苷酸 <223> Synthetic oligonucleotide: binding DNA/RNA molecule: nucleotides 3 to 10 are deoxyribonucleotides, and the remaining nucleotides are ribonucleotides

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (1)..(1) <222> (1)..(1)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷鹼 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleobase

<220> <220>

<221> 未歸類特徵 <221> Uncategorized features

<222> (1)..(13) <222> (1)..(13)

<223> 硫代磷酸酯-核苷酸間鏈結 <223> Phosphorothioate-internucleotide linkage

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (2)..(2) <222> (2)..(2)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (11)..(11) <222> (11)..(11)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (12)..(12) <222> (12)..(12)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (13)..(13) <222> (13)..(13)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<400> 153 <400> 153

<210> 154 <210> 154

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成寡核苷酸：結合DNA/RNA分子：核苷酸3至10為脫氧核糖核苷酸，其餘核苷酸為核糖核苷酸 <223> Synthetic oligonucleotide: binding DNA/RNA molecule: nucleotides 3 to 10 are deoxyribonucleotides, and the remaining nucleotides are ribonucleotides

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (1)..(1) <222> (1)..(1)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 未歸類特徵 <221> Uncategorized features

<222> (1)..(13) <222> (1)..(13)

<223> 硫代磷酸酯-核苷酸間鍵結 <223> Phosphorothioate-internucleotide linkage

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (2)..(2) <222> (2)..(2)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (11)..(11) <222> (11)..(11)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (12)..(12) <222> (12)..(12)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (13)..(13) <222> (13)..(13)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<400> 154 <400> 154

<210> 155 <210> 155

<211> 13 <211> 13

<212> DNA <212> DNA

<213> 人工序列 <213> Artificial sequence

<220> <220>

<223> 合成寡核苷酸：結合DNA/RNA分子：核苷酸4至10為脫氧核糖核苷酸-其餘核苷酸為核糖核苷酸 <223> Synthetic oligonucleotide: binding DNA/RNA molecule: nucleotides 4 to 10 are deoxyribonucleotides - the remaining nucleotides are ribonucleotides

<220> <220>

<221> 未歸類特徵 <221> Uncategorized features

<222> (1)..(13) <222> (1)..(13)

<223> 硫代磷酸酯-核苷酸間鍵結 <223> Phosphorothioate-internucleotide linkage

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (1)..(1) <222> (1)..(1)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (2)..(2) <222> (2)..(2)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (3)..(3) <222> (3)..(3)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (11)..(11) <222> (11)..(11)

<223> 5-甲基胞嘧啶；2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 5-methylcytosine; 2'-O, 4'-C-methylene-linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (12)..(12) <222> (12)..(12)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<220> <220>

<221> 修飾鹼基 <221> modified base

<222> (13)..(13) <222> (13)..(13)

<223> 2'-O,4'-C-亞甲基連接雙環核苷酸 <223> 2'-O, 4'-C-methylene linked bicyclic nucleotide

<400> 155 <400> 155

Claims (13)

一種鹼基長度8~80之反義寡核苷酸，其係抑制補體B因子之表現者，並且能夠於嚴格之條件下與包含序列編號53~103中之任一個所表示之靶鹼基序列的核酸進行雜交。 An antisense oligonucleotide having a base length of 8 to 80 which inhibits the expression of complement B factor and which is capable of expressing a target base sequence represented by any one of SEQ ID NOs: 53 to 103 under stringent conditions. The nucleic acid is hybridized. 一種鹼基長度8~80之反義寡核苷酸，其係抑制補體B因子之表現者，並且含有序列編號2~52中之任一個所表示之反義鹼基序列之連續之至少8個鹼基。 An antisense oligonucleotide having a base length of 8 to 80 which inhibits the expression of the complement B factor and contains at least 8 consecutive antisense base sequences represented by any one of SEQ ID NOs: 2 to 52 Base. 一種鹼基長度8~80之反義寡核苷酸，其含有與序列編號53~103中之任一個所表示之鹼基序列互補之鹼基序列。 An antisense oligonucleotide having a base length of 8 to 80, which comprises a base sequence complementary to the nucleotide sequence represented by any one of SEQ ID NOs: 53 to 103. 如請求項3之反義寡核苷酸，其包含序列編號2~52中之任一個所表示之鹼基序列。 The antisense oligonucleotide of claim 3, which comprises the base sequence represented by any one of SEQ ID NOs: 2 to 52. 如請求項4之反義寡核苷酸，其含有於序列編號2~52中之任一個所表示之鹼基序列中有1個乃至複數個鹼基經缺失、取代、***或附加之序列。 The antisense oligonucleotide of claim 4, which comprises a sequence in which one or more of the base sequences represented by any one of SEQ ID NOs: 2 to 52 are deleted, substituted, inserted or added. 一種反義寡核苷酸，其包含序列編號2~52中之任一個所表示之鹼基序列。 An antisense oligonucleotide comprising the base sequence represented by any one of SEQ ID NOs: 2 to 52. 如請求項1至6中任一項之反義寡核苷酸，其中5'末端附近及/或3'末端附近由糖部修飾核苷酸所構成。 The antisense oligonucleotide according to any one of claims 1 to 6, wherein the vicinity of the 5' end and/or the vicinity of the 3' end is composed of a sugar-modified nucleotide. 一種反義寡核苷酸，其包含序列編號104~154及155中之任一個所表示之核苷酸序列。 An antisense oligonucleotide comprising the nucleotide sequence represented by any one of SEQ ID NOs: 104 to 154 and 155. 一種反義寡核苷酸，其包含序列編號118、125、150及155中之任一個所表示之核苷酸序列。 An antisense oligonucleotide comprising the nucleotide sequence represented by any one of SEQ ID NO: 118, 125, 150 and 155. 如請求項1至9中任一項之反義寡核苷酸，其含有配位子。 The antisense oligonucleotide of any one of claims 1 to 9, which contains a ligand. 一種醫藥組合物，其含有如請求項1至10中任一項之反義寡核苷酸。 A pharmaceutical composition comprising the antisense oligonucleotide of any one of claims 1 to 10. 一種治療由補體旁路途徑之異常所介導之障礙之方法，其包括將治療上有效量之如請求項1至10中任一項之反義寡核苷酸或如請求項11之醫藥組合物投予需要此種治療之人之步驟。 A method of treating a disorder mediated by an abnormality of the complement alternative pathway, comprising a therapeutically effective amount of an antisense oligonucleotide according to any one of claims 1 to 10 or a pharmaceutical combination according to claim 11 The steps of administering a person who needs such treatment. 如請求項12之方法，其中上述障礙係非典型溶血性***症候群、陣發性夜間血紅素尿症、老年性黃斑變性症、膜性增殖性腎小球腎炎、C3腎炎、膜性腎病、急進性腎小球腎炎(RPGN)、急性腎損傷(AKI)、哮喘、或自體免疫疾病。 The method of claim 12, wherein the disorder is atypical hemolytic uremic syndrome, paroxysmal nocturnal hemoglobinuria, age-related macular degeneration, membranous proliferative glomerulonephritis, C3 nephritis, membranous nephropathy, Acute glomerulonephritis (RPGN), acute kidney injury (AKI), asthma, or autoimmune disease.
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