WO2018117253A1 - Acide nucléique inhibant l'expression du facteur b du complément - Google Patents

Acide nucléique inhibant l'expression du facteur b du complément Download PDF

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WO2018117253A1
WO2018117253A1 PCT/JP2017/046096 JP2017046096W WO2018117253A1 WO 2018117253 A1 WO2018117253 A1 WO 2018117253A1 JP 2017046096 W JP2017046096 W JP 2017046096W WO 2018117253 A1 WO2018117253 A1 WO 2018117253A1
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nucleic acid
double
stranded nucleic
antisense strand
strand
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PCT/JP2017/046096
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Japanese (ja)
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陽史 山田
清 清水
宏徒 岩井
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協和発酵キリン株式会社
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/712—Nucleic acids or oligonucleotides having modified sugars, i.e. other than ribose or 2'-deoxyribose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/713—Double-stranded nucleic acids or oligonucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing

Definitions

  • the present invention relates to a nucleic acid for use in suppressing the expression of complement factor B or a pharmaceutical composition containing the nucleic acid.
  • Complements are a group of proteins in the blood that mediate immune responses. Complement effects include phagocytosis of pathogenic bacteria by phagocytic cells, damage to viruses with outer membranes, and loss of infectivity. Is mentioned. Among complements, C3 is the most abundant in serum, and its action is controlled by being activated by complement factor B (CFB) in the alternative pathway (non-patented) Reference 1).
  • CFB complement factor B
  • C3 continues to be activated due to abnormalities in regulatory factors related to the alternative pathway of the complement or stabilization with autoantibodies to C3 convertase, atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria Disease (PNH), age-related macular degeneration (AMD), membranoproliferative glomerulonephritis (MPGN), C3 nephritis, membranous nephropathy, rapidly progressive glomerulonephritis (RPGN), acute kidney injury (AKI), Known to be associated with the onset of diseases such as ANCA-related vasculitis, lupus nephritis, asthma, autoimmune diseases (eg systemic lupus erythematosus (SLE), psoriasis, optic myelitis, myasthenia gravis) Patent Documents 2 and 3).
  • aHUS atypical hemolytic uremic syndrome
  • PNH paroxysmal
  • complement factor B is present in the blood at a relatively high concentration of 300 ⁇ g / mL ( Non-patent document 4), it is not easy to continue to inhibit all these complement factor B by, for example, a general antibody drug.
  • an antisense method is known as a method for suppressing gene expression itself (Patent Document 1).
  • oligonucleotides complementary to the target gene mRNA or mRNA precursor are introduced into the target gene mRNA or mRNA precursor in two. It forms a chain and can specifically suppress the expression of the target gene.
  • RNAi RNA interference
  • the expression of the target gene can be specifically suppressed by introducing a double-stranded RNA (siRNA) having the same sequence as the target gene (Patent Document 2).
  • Patent Document 3 A part of the antisense sequence targeting the human complement factor B gene has been disclosed (Patent Document 3). Moreover, although a part of siRNA sequence targeting the gene is disclosed (Patent Document 4), the present invention is a sequence different from these sequences.
  • An object of the present invention is to provide a nucleic acid capable of suppressing the expression of complement factor B.
  • Another object of the present invention is to provide a pharmaceutical composition for preventing or treating a disease associated with the expression of complement factor B.
  • the present invention relates to the following (1) to (15).
  • a double-stranded nucleic acid comprising a sense strand and an antisense strand, and comprising a double-stranded region of at least 11 base pairs, wherein at least 17 nucleotides and at most 30 in the antisense strand
  • a double-stranded nucleic acid that reduces the expression of the CFB gene that is complementary to a target CFB mRNA sequence selected from the group described in Tables 1-1 to 1-3 .
  • the antisense strand wherein the double-stranded region is 11 to 27 base pairs and is complementary to a target CFB mRNA sequence selected from the group described in Table 1-1 to Table 1-3
  • the double-stranded nucleic acid according to (1) wherein the sense strand is 21 nucleotides in length and the antisense strand is 21-23 nucleotides in length.
  • the antisense strand comprises a sequence selected from the group described in the “antisense strand” of Table 1-1 to Table 1-3 and Table 2-1 to Table 2-2.
  • the sense strand comprises a sequence selected from the group described in the “sense strand” of Table 1-1 to Table 1-3 and Table 2-1 to Table 2-2. Double-stranded nucleic acid.
  • Two pairs according to (1) comprising a pair of sense strands / antisense strands selected from the group consisting of the sense strand / antisense strand described in Table 1-1 to Table 1-3 Strand nucleic acid.
  • a pair of sense strands / antisense selected from the group consisting of the sense strand / antisense strand described in Table 2-1 to Table 2-2, Table 3-1 to Table 3-2, and Table 4 The double-stranded nucleic acid according to (1), comprising a sense strand sequence.
  • (12) A single-stranded nucleic acid comprising only an antisense strand of the double-stranded nucleic acid according to any one of (1) to (11).
  • a pharmaceutical composition comprising the nucleic acid according to any one of (1) to (12).
  • a method for treating a disorder mediated by an abnormality in the alternative pathway of the complement comprising an effective amount of the nucleic acid according to any one of (1) to (12) or the pharmaceutical according to (13) Administering the composition to a human in need of such treatment.
  • the disorder is atypical hemolytic uremic syndrome, paroxysmal nocturnal hemoglobinuria, age-related macular degeneration, membranoproliferative glomerulonephritis, C3 nephritis, membranous nephropathy, rapidly progressive glomerulonephritis (RPGN), acute kidney injury (AKI), ANCA-related vasculitis, lupus nephritis, asthma or autoimmune disease.
  • nucleic acid of the present invention or the pharmaceutical composition containing the nucleic acid is useful for the treatment / prevention of a disorder mediated by an abnormality in the alternative pathway of complement.
  • the CFB gene (gene encoding CFB) targeted by the nucleic acid of the present invention has a cDNA base sequence (SEQ ID NO: 1) corresponding to the full-length mRNA of human CFB registered as Genbank Accession No. NM_001710 It is said that naturally occurring variants thereof (see, for example, Hum. Mutat. 31: E1445-E1460 (2010), refsnp No. rs12614, rs641153, etc.) can also serve as target genes for the nucleic acids of the present invention. Not too long.
  • mRNA of CFB gene of biological species other than human can also be a target gene of the nucleic acid of the present invention.
  • NM_008198 or NM_001142706 is the cDNA base sequence corresponding to the full-length mRNA of the mouse CFB gene
  • Genbank Accession No. NM_212466 is the cDNA base sequence corresponding to the full-length mRNA of the rat CFB gene
  • the cynomolgus CFB gene is Examples of the cDNA base sequence corresponding to the full-length mRNA include Genbank Accession No. XM_005553440.2
  • examples of the cDNA base sequence corresponding to the full-length mRNA of the rhesus monkey CFB gene include Genbank Accession No. XM_015136029.1.
  • nucleic acid of the present invention a nucleic acid containing a base sequence complementary to CFB mRNA is called an antisense strand nucleic acid, and a nucleic acid containing a base sequence complementary to the base sequence of an antisense strand nucleic acid is Also referred to as sense strand nucleic acid.
  • the term “nucleic acid of the present invention” is used to include an antisense strand nucleic acid, a sense strand nucleic acid, and a double-stranded nucleic acid paired with a sense strand and an antisense strand nucleic acid. .
  • the nucleic acid of the present invention may be any molecule as long as it is a molecule obtained by polymerizing nucleotides or molecules having functions equivalent to the nucleotides, such as RNA or deoxyribonucleotide polymers that are ribonucleotide polymers.
  • derivatives containing at least one molecule having a function equivalent to nucleotide in these nucleic acids are also included in the nucleic acid of the present invention.
  • Uracil (U) can be uniquely read as thymine (T).
  • nucleotide derivatives examples include nucleotide derivatives.
  • the nucleotide derivative may be any molecule as long as it is a molecule in which nucleotides have been modified.
  • a molecule in which ribonucleotides or deoxyribonucleotides are modified is preferably used.
  • nucleotide examples include a sugar moiety-modified nucleotide, a phosphodiester bond-modified nucleotide, a base-modified nucleotide, and a nucleotide in which two or more of the sugar moiety, phosphodiester bond and base are modified.
  • any or all of the chemical structure of the sugar of the nucleotide may be modified or substituted with any substituent, or substituted with any atom.
  • '-Modified nucleotides are preferably used.
  • 2′-modified nucleotides include, for example, the 2′-OH group of ribose is H, OR, R, R′OR, SH, SR, NH 2 , NHR, NR 2 , N 3 , CN, F, Cl, Br and Substituted with a substituent selected from the group consisting of I (R is alkyl or aryl, preferably alkyl having 1 to 6 carbon atoms, and R ′ is alkylene, preferably alkylene having 1 to 6 carbon atoms) Examples include 2'-modified nucleotides, preferably 2'-OH groups substituted with H, F or methoxy groups, more preferably 2'-OH groups substituted with F or methoxy groups. .
  • 2'-OH group is 2- (methoxy) ethoxy group, 3-aminopropoxy group, 2-[(N, N-dimethylamino) oxy] ethoxy group, 3- (N, N-dimethylamino) propoxy group, 2- A substituent selected from the group consisting of [2- (N, N-dimethylamino) ethoxy] ethoxy group, 2- (methylamino) -2-oxoethoxy group, 2- (N-methylcarbamoyl) ethoxy group and 2-cyanoethoxy group Examples thereof include substituted nucleotides.
  • the 2′-modified nucleotide is preferably contained in an amount of 50 to 100%, more preferably 70 to 100%, and still more preferably 90 to 100% with respect to the nucleotide in the double-stranded nucleic acid region.
  • a double-stranded nucleic acid to which 2′-modified nucleotides are applied for example, a pair of senses selected from the group consisting of the sense strand / antisense strand described in Table 3-1, Table 3-2 and Table 4
  • N (M) represents 2'-O-methyl-RNA
  • N (F) represents 2'-F-RNA
  • p represents phosphorylation.
  • N represents A, C, G, or U.
  • examples of the sugar-modified nucleotide include a crosslinked structure-type artificial nucleic acid (BNA) having two circular structures by introducing a crosslinked structure into the sugar moiety, specifically, the 2′-position.
  • Locked Nucleic Acid LNA
  • Ethylene bridged nucleic acid Ethylene bridged nucleic acid
  • EAA Ethylene bridged nucleic acid
  • cEt Constrained Ethyl
  • AmNA AmNA
  • scpBNA 2'-O, 4'-C-Spirocyclopropylene bridged nucleic acid
  • PNA peptide nucleic acid
  • OPNA oxypeptide nucleic acid
  • PRNA peptide ribonucleic acid
  • the phosphodiester bond-modified nucleotide is any nucleotide that has been modified or substituted with an arbitrary substituent for a part or all of the chemical structure of the phosphodiester bond of the nucleotide, or with any atom.
  • a nucleotide in which a phosphodiester bond is replaced with a phosphorothioate bond a nucleotide in which a phosphodiester bond is replaced with a phosphorodithioate bond
  • a nucleotide in which a phosphodiester bond is replaced with an alkylphosphonate bond a phosphate
  • Examples thereof include nucleotides in which a diester bond is substituted with a phosphoramidate bond.
  • any or all of the nucleotide base chemical structure modified or substituted with an arbitrary substituent or substituted with an arbitrary atom may be used.
  • oxygen atoms are substituted with sulfur atoms
  • hydrogen atoms are substituted with alkyl groups having 1 to 6 carbon atoms, halogens, etc.
  • methyl groups are hydrogen, hydroxymethyl, alkyl groups with 2 to 6 carbon atoms, etc.
  • amino group is substituted with an alkyl group having 1 to 6 carbon atoms, an alkanoyl group having 1 to 6 carbon atoms, an oxo group, a hydroxy group, or the like.
  • nucleotide derivatives include nucleotide derivatives modified with at least one of nucleotide or sugar moiety, phosphodiester bond or base, ligands such as lipids such as cholesterol, fatty acids, tocopherols, retinoids, N-acetylgalactosamine (GalNAc) , Sugars such as galactose (Gal) and mannose (Man), full antibodies, fragment antibodies such as Fab, scFv, VHH, proteins such as low density lipoprotein (LDL), human serum albumin, RGD, NGR, R9, CPP, etc.
  • ligands such as lipids such as cholesterol, fatty acids, tocopherols, retinoids, N-acetylgalactosamine (GalNAc) , Sugars such as galactose (Gal) and mannose (Man), full antibodies, fragment antibodies such as Fab, scFv, VHH, proteins such as low density lipoprotein (LDL),
  • Peptides such as phenazine, phenanthridine, anthraquinone, folic acid, synthetic polymers such as synthetic polyamino acids, nucleic acid aptamers, acridine, fluorescein, rhodamine, coumarin dyes, Cy3 series, Alexa series (registered trademark), Black hole quencher And other chemical substances such as a fluorophore added directly or via a linker.
  • synthetic polymers such as synthetic polyamino acids, nucleic acid aptamers, acridine, fluorescein, rhodamine, coumarin dyes, Cy3 series, Alexa series (registered trademark), Black hole quencher And other chemical substances such as a fluorophore added directly or via a linker.
  • polyamine addition nucleotide derivatives examples include 6-FAM-added nucleotide derivatives and biotin-added nucleotide derivatives, and preferably include GalNAc-added nucleotide derivatives.
  • modifying agent capable of reacting on the solid phase during the extension reaction on the solid phase. It can also be obtained by previously synthesizing and purifying nucleic acids into which a functional group such as an amino group, mercapto group, azide group or triple bond has been introduced, and allowing a modifier to act on them.
  • the nucleotide derivative may form a crosslinked structure such as an alkylene structure, a peptide structure, a nucleotide structure, an ether structure, an ester structure, or a combination of at least one of these with other nucleotides or nucleotide derivatives in the nucleic acid.
  • the nucleic acid of the present invention includes those in which some or all atoms in the nucleic acid molecule are substituted with atoms (isotopes) having different mass numbers.
  • “complementary” means a relationship that allows base pairing between two bases, for example, a moderate hydrogen such as a relationship between adenine and thymine or uracil, and a relationship between guanine and cytosine. It means a double-stranded structure as a whole double-stranded region through a bond.
  • an antisense strand complementary to CFB mRNA means that one or more base substitutions may be included in the base sequence that is completely complementary to the partial base sequence of the mRNA.
  • the antisense strand contains 1 to 8, preferably 1 to 6, 1 to 4, 1 to 3, particularly 2 or 1 mismatch bases to the target sequence of the target gene. You may have. For example, if the antisense strand is 21 bases long, it may have 6, 5, 4, 3, 2 or 1 mismatch bases with respect to the target sequence of the target gene.
  • the position of the mismatch may be the 5 ′ end or 3 ′ end of each sequence.
  • the term “complementary” includes a case where one nucleotide sequence is a sequence in which one or more bases are added and / or deleted in a base sequence that is completely complementary to the other nucleotide sequence.
  • CFB mRNA and the antisense strand nucleic acid of the present invention have one or two bulge bases in the antisense strand and / or target CFB mRNA region due to addition and / or deletion of a base in the antisense strand. May be.
  • nucleic acid of the present invention is a nucleic acid containing a base sequence complementary to a partial base sequence of CFBCFmRNA and / or a nucleic acid containing a base sequence complementary to the base sequence of the nucleic acid
  • any nucleic acid can be used. It may be composed of nucleotides or derivatives thereof.
  • a nucleic acid containing a base sequence complementary to the target CFB mRNA sequence and a nucleic acid containing a base sequence complementary to the base sequence of the nucleic acid form a double strand.
  • the length of the sequence capable of forming a duplex is usually 11 to 35 bases, preferably 15 to 30 bases, more preferably 17 to 25 bases, and 17 to 23 bases. Bases are more preferred, with 19 to 23 bases being particularly preferred. It is also preferred that it consists of 21 to 23 bases.
  • nucleic acid containing a base sequence complementary to the target CFB mRNA sequence is used.
  • nucleic acids 1 to 3 bases, preferably 1 to 2 bases, more preferably 1 A base deleted, substituted or added may be used.
  • the nucleic acid that suppresses CFB expression is a nucleic acid containing a base sequence complementary to the target CFB mRNA sequence, and is complementary to the single-stranded nucleic acid that suppresses CFB expression or the target CFB mRNA sequence.
  • a double-stranded nucleic acid that consists of a nucleic acid containing a basic sequence and a nucleic acid containing a base sequence complementary to the base sequence of the nucleic acid and suppresses the expression of CFB is preferably used.
  • a double-stranded nucleic acid refers to a nucleic acid having a double-stranded region in which two nucleotide chains are paired.
  • a double-stranded region refers to a portion where nucleotides constituting a double-stranded nucleic acid or a derivative thereof constitute a base pair to form a double strand.
  • the double-stranded region is usually 11 to 27 base pairs, preferably 15 to 25 base pairs, more preferably 15 to 23 base pairs, still more preferably 17 to 21 base pairs, and particularly preferably 17 to 19 base pairs.
  • the single-stranded nucleic acid constituting the double-stranded nucleic acid usually consists of 11 to 30 bases, preferably 15 to 29 bases, more preferably 15 to 27 bases, and 15 to 25 bases. More preferably, it consists of 17-23 bases, most preferably 19-23 bases. It is also preferred that it consists of 21 to 23 bases.
  • the double-stranded nucleic acid of the present invention has an additional nucleotide or nucleotide derivative that does not form a duplex on the 3 ′ side or 5 ′ side following the double-stranded region, this is referred to as an overhang.
  • the nucleotide constituting the overhang may be ribonucleotide, deoxyribonucleotide or a derivative thereof.
  • the double-stranded nucleic acid having a protruding portion one having a protruding portion consisting of 1 to 6 bases, usually 1 to 3 bases at the 3 ′ end or 5 ′ end of at least one strand is used.
  • Those having a protruding portion are preferably used, and examples thereof include those having a protruding portion made of dTdT or UU.
  • Overhangs can be on the antisense strand only, the sense strand only, and both the antisense and sense strands.
  • the antisense strand is an oligonucleotide strand consisting of at least 17 nucleotides and at most 30 nucleotides including a double-stranded region and a subsequent overhang, and is described in Table 1-1 to Table 1-3. Is sufficiently complementary to a target CFB mRNA sequence selected from the selected group.
  • the double-stranded nucleic acid of the present invention includes, for example, a nucleic acid molecule (WO2005 / 089287) that generates the above-mentioned double-stranded nucleic acid by the action of a ribonuclease such as Dicer, and a 3′-end or 5′-end overhang.
  • a double-stranded nucleic acid that forms a blunt end a double-stranded nucleic acid in which only the sense strand protrudes (US2012 / 0040459), and the like can also be used.
  • double-stranded nucleic acid of the present invention a nucleic acid having the same sequence as the base sequence of the target gene or its complementary strand may be used, but the 5 ′ end or 3 ′ of at least one strand of the nucleic acid may be used.
  • a double-stranded nucleic acid comprising a nucleic acid from which one to four bases have been deleted and a nucleic acid containing a base sequence complementary to the base sequence of the nucleic acid may be used.
  • the double-stranded nucleic acid of the present invention includes a double-stranded RNA (dsRNA) in which RNAs form a double strand, a double-stranded DNA (dsDNA) in which DNAs form a double strand, or a double strand of RNA and DNA. It may be a hybrid nucleic acid that forms a strand. Alternatively, one or both of the double strands may be a chimeric nucleic acid of DNA and RNA. Double-stranded RNA (dsRNA) is preferred.
  • the second nucleotide from the 5 ′ end of the antisense strand of the present invention is preferably complementary to the second ribonucleotide from the 3 ′ end of the target CFB mRNA sequence, and 2-7 from the 5 ′ end of the antisense strand. More preferably, the second nucleotide is completely complementary to the 2-7 th ribonucleotide from the 3 ′ end of the target CFB mRNA sequence, and the 2-11 th nucleotide from the 5 ′ end of the antisense strand is the target CFB More preferably, it is completely complementary to ribonucleotides 2 to 11 from the 3 ′ end of the mRNA sequence.
  • the 11th nucleotide from the 5 ′ end of the antisense strand in the nucleic acid of the present invention is preferably complementary to the 11th ribonucleotide from the 3 ′ end of the target CFBCF mRNA sequence, and the 5 ′ end of the antisense strand. It is more preferable that the 9th to 13th nucleotides are completely complementary to the 9th to 13th ribonucleotides from the 3 ′ end of the target CFB mRNA sequence, and the 7th to 15th nucleotides from the 5 ′ end of the antisense strand Is more preferably completely complementary to the 7th to 15th ribonucleotides from the 3 ′ end of the target CFB mRNA sequence.
  • the method for producing the nucleic acid of the present invention is not particularly limited, and examples thereof include a method using known chemical synthesis or an enzymatic transcription method.
  • methods using known chemical synthesis include phosphoramidite method, phosphorothioate method, phosphotriester method, CEM method [Nucleic Acid Research, 35, 3287 (2007)].
  • ABI3900 high-throughput nucleic acid synthesis Can be synthesized by a machine (Applied Biosystems). After the synthesis is completed, elimination from the solid phase, deprotection of the protecting group, purification of the target product, and the like are performed. It is desirable to obtain a nucleic acid having a purity of 90% or more, preferably 95% or more by purification.
  • the synthesized and purified sense strand and antisense strand are in an appropriate ratio, for example, 0.1 to 10 equivalents, preferably 0.5 to 2 equivalents of sense strand to 1 equivalent of antisense strand.
  • 0.9 to 1.1 equivalents, more preferably equimolar amounts are mixed and then annealed, or the mixed product may be used directly without the step of annealing.
  • Annealing may be performed under any conditions that can form a double-stranded nucleic acid, but usually, the sense strand and the antisense strand are mixed in approximately equimolar amounts and then heated at about 94 ° C. for about 5 minutes.
  • Examples of the enzymatic transcription method for producing the nucleic acid of the present invention include a transcription method using a phage RNA polymerase such as T7, T3, or SP6 RNA polymerase using a plasmid or DNA having the target base sequence as a template.
  • a phage RNA polymerase such as T7, T3, or SP6 RNA polymerase using a plasmid or DNA having the target base sequence as a template.
  • the nucleic acid of the present invention can be introduced into cells using a transfection carrier, preferably a cationic carrier such as a cationic liposome. It can also be directly introduced into cells by the calcium phosphate method, electroporation method or microinjection method.
  • a transfection carrier preferably a cationic carrier such as a cationic liposome. It can also be directly introduced into cells by the calcium phosphate method, electroporation method or microinjection method.
  • a vector that can be introduced into cells and expressed can be used.
  • the nucleic acid or the like can be expressed by inserting the sequence encoding the nucleic acid of the present invention downstream of the promoter in the expression vector, constructing the expression vector, and introducing it into a cell.
  • Expression vectors include pCDNA6.2-GW / miR (Invitrogen), pSilencer® 4.1-CMV (Ambion), pSINsi-hH1 DNA (Takara Bio), pSINsi-hU6 DNA (Takara Bio), pENTR / U6 (Invitrogen) etc. can be mentioned.
  • virus vectors include retrovirus vectors, lentivirus vectors, adenovirus vectors, adeno-associated virus vectors, and the like.
  • the antisense strand and the sense strand of the present invention are, for example, the nucleotide sequence (sequence) of cDNA (sense strand) of full-length mRNA of human CFB registered as Genbank Accession No. NM_001710. It can be designed based on the number 1). In addition, by comparing the cDNA sequence of full-length mRNA of human CFB with the cDNA sequence of full-length mRNA of CFB from other species, an antisense strand that suppresses CFB mRNA expression in multiple species. The sense strand can also be designed.
  • the nucleic acid having CFB expression suppressing activity includes the antisense strand nucleic acid of the present invention containing a base sequence complementary to CFB ⁇ ⁇ ⁇ ⁇ mRNA and the nucleic acid of the present invention containing a base sequence complementary to the base sequence of the nucleic acid.
  • Examples thereof include double-stranded nucleic acids consisting of a sense strand nucleic acid and having CFB expression suppression activity.
  • the single-stranded nucleic acid constituting the double-stranded nucleic acid usually consists of 11 to 30 bases, preferably 15 to 29 bases, more preferably 15 to 27 bases, and more preferably 15 to 25 bases. More preferably, it consists of 17 to 23 bases, most preferably 19 to 23 bases.
  • the double-stranded nucleic acid usually has a double-stranded region consisting of 15 to 27 base pairs, preferably 15 to 25 base pairs, more preferably 15 to 23 base pairs, and even more preferably 15 to 21 base pairs.
  • CFB expression can be suppressed by introducing these double-stranded nucleic acids into cells.
  • the double-stranded nucleic acid of the present invention can suppress the expression of CFB mRNA after being introduced into cells at a concentration of several pM to several nM and then cultured for 24 hours or more, for example 48 hours.
  • the evaluation of the CFB ⁇ ⁇ mRNA expression inhibitory activity of the double-stranded nucleic acid of the present invention is carried out by transfecting the nucleic acid or the like into a human cell line using a cationic liposome or the like, culturing for a certain time, Can be carried out by quantifying the expression level of CFB mRNA.
  • the nucleic acid having a CFB expression suppressing activity is a nucleic acid having a base sequence complementary to a part of the base sequence of CFB ⁇ mRNA, and suppresses the expression of CFB.
  • Single-stranded nucleic acid is exemplified.
  • the single-stranded nucleic acid constituting the nucleic acid usually consists of 8 to 30 bases, preferably 12 to 30 bases, more preferably 12 to 20 bases. It is also preferred that it consists of 21 to 23 bases.
  • CFB expression can be suppressed by introducing these single-stranded nucleic acids into cells.
  • the single-stranded nucleic acid of the present invention can suppress the expression of CFB mRNA after being introduced into cells at a concentration of several pM to several nM and then cultured for 24 hours or more, for example 48 hours.
  • the evaluation of the CFB mRNA expression inhibitory activity of the single-stranded nucleic acid of the present invention was carried out by transfecting the nucleic acid or the like into a human cell line using a cationic liposome, etc. This can be done by quantifying the expression level of CFB mRNA in the strain.
  • the nucleic acid of the present invention may contain a ligand.
  • the ligand may directly modify the 5 ′ end, 3 ′ end and / or the inside of the sequence of the nucleic acid of the present invention.
  • the ligand contained in the nucleic acid of the present invention may be a molecule having affinity for a biomolecule.
  • lipids such as cholesterol, fatty acid, tocopherol, retinoid, N-acetylgalactosamine (GalNAc), galactose (Gal ), Sugars such as mannose (Man), full antibodies, fragment antibodies such as Fab, scFV, VHH, proteins such as low density lipoprotein (LDL), human serum albumin, peptides such as RGD, NGR, R9, CPP,
  • Examples include low molecular weight compounds such as folic acid, synthetic polymers such as synthetic polyamino acids, or nucleic acid aptamers, but the invention is not limited to these, and these may be used in appropriate combinations.
  • a modifying agent capable of reacting on the solid phase is allowed to react, thereby 5 ′ end, 3 ′ end and / or sequence. Modifications can be made to the inside, but are not limited thereto. It can also be obtained by previously synthesizing and purifying nucleic acids into which a functional group such as an amino group, mercapto group, azide group or triple bond has been introduced, and allowing a modifier to act on them.
  • composition of the present invention also relates to a pharmaceutical composition containing a nucleic acid such as the above double-stranded nucleic acid or single-stranded nucleic acid as an active ingredient.
  • the pharmaceutical composition of the present invention can further contain a carrier effective for transferring nucleic acid into cells.
  • the pharmaceutical composition of the present invention comprises atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), age-related macular degeneration (AMD), membranoproliferative glomerulonephritis (MPGN), C3 Nephritis, membranous nephropathy, rapidly progressive glomerulonephritis (RPGN), acute kidney injury (AKI), ANCA-related vasculitis, lupus nephritis, asthma, autoimmune diseases (eg systemic lupus erythematosus (SLE), psoriasis, optic nerve Such as myelitis and myasthenia gravis).
  • aHUS atypical hemolytic uremic syndrome
  • PNH paroxysmal nocturnal hemoglobinuria
  • AMD age-related macular degeneration
  • MPGN membr
  • Examples of carriers that are effective for transferring nucleic acids into cells include cationic carriers.
  • Examples of the cationic carrier include cationic liposomes and cationic polymers.
  • a carrier utilizing a viral envelope may be used as an effective carrier for transferring nucleic acids into cells.
  • As the cationic polymer JetSI (Qbiogene), Jet-PEI (polyethyleneimine; Qbiogene) and the like are preferably used.
  • As a carrier using a viral envelope GenomeOne (registered trademark) (HVJ-E liposome; Ishihara Sangyo Co., Ltd.) is preferably used.
  • the composition containing the nucleic acid of the present invention and the above carrier can be prepared by methods known to those skilled in the art. For example, it can be prepared by mixing a carrier dispersion having an appropriate concentration and a nucleic acid solution.
  • a cationic carrier since the nucleic acid is usually negatively charged in an aqueous solution, it can be easily prepared by mixing in an aqueous solution by a conventional method.
  • the aqueous solvent used for preparing the composition include electrolyte solutions such as water for injection, distilled water for injection, and physiological saline, and sugar solutions such as glucose solution and maltose solution.
  • conditions such as pH and temperature when preparing the composition can be appropriately selected by those skilled in the art.
  • the composition can be made into a uniform composition by carrying out a dispersion treatment using an ultrasonic dispersion device or a high-pressure emulsification device if necessary.
  • the optimum method and conditions for the preparation of the composition containing the carrier and the nucleic acid depend on the carrier to be used. Therefore, those skilled in the art can select the optimum method for the carrier to be used without being bound by the above method.
  • the pharmaceutical composition of the present invention includes, for example, a composite organic particle composed of nucleic acid and lead particles and a lipid membrane that coats the composite particle, and a polar organic solvent in which the component of the lipid film is soluble.
  • Liposomes in which a liquid containing the polar organic solvent is present in a concentration that can disperse the components of the lipid membrane and the composite particles can also be dispersed in the liquid that is contained are preferably used, but are not limited thereto.
  • the lead particles include lipid aggregates, liposomes, emulsion particles, polymers, metal colloids, and fine particle preparations, and liposomes are preferably used.
  • the lead particles in the present invention may be composed of a complex obtained by combining two or more lipid aggregates, liposomes, emulsion particles, polymers, metal colloids, fine particle formulations, etc., and lipid aggregates, liposomes, emulsion particles, A complex formed by combining a polymer, a metal colloid, a fine particle preparation, and the like with another compound (eg, sugar, lipid, inorganic compound, etc.) may be used as a constituent component.
  • another compound eg, sugar, lipid, inorganic compound, etc.
  • lipid membrane that coats the composite particles examples include non-cationic lipids, lipids that prevent particle aggregation, and cationic lipids as constituent components.
  • composition can be prepared according to the method described in, for example, International Publication No. 2006/080118 Pamphlet.
  • the mixing ratio of the nucleic acid and the carrier contained in the pharmaceutical composition of the present invention is suitably 1 to 200 parts by weight of the carrier with respect to 1 part by weight of the nucleic acid.
  • the amount is preferably 2.5 to 100 parts by weight, more preferably 7 to 25 parts by weight, based on 1 part by weight of the nucleic acid.
  • the average size of the pharmaceutical composition of the present invention is preferably about 10 nm to 300 nm, more preferably about 30 nm to 200 nm, and even more preferably about 50 nm to 150 nm.
  • the pharmaceutical composition of the present invention may contain a pharmaceutically acceptable carrier or diluent in addition to the above carrier.
  • Pharmaceutically acceptable carriers or diluents and the like are essentially chemically inert and harmless compositions that do not affect the biological activity of the pharmaceutical composition of the present invention at all. Examples of such carriers or diluents include but are not limited to salt solutions, sugar solutions, glycerol solutions, ethanol and the like.
  • disorders mediated by abnormalities in the alternative complement pathway include atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), age-related macular degeneration (AMD), Membranoproliferative glomerulonephritis (MPGN), C3 nephritis, membranous nephropathy, rapidly progressive glomerulonephritis (RPGN), acute kidney injury (AKI), ANCA-related vasculitis, lupus nephritis, asthma, autoimmune disease ( For example, systemic lupus erythematosus (SLE), psoriasis, optic neuritis, myasthenia gravis, etc.).
  • aHUS atypical hemolytic uremic syndrome
  • PNH paroxysmal nocturnal hemoglobinuria
  • AMD age-related macular degeneration
  • MPGN Membranoproliferative glomerulonephritis
  • the pharmaceutical composition of the present invention comprises atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), age-related macular degeneration (AMD), membranoproliferative glomerulonephritis (MPGN) , C3 nephritis, membranous nephropathy, rapidly progressive glomerulonephritis (RPGN), acute kidney injury (AKI), ANCA-related vasculitis, lupus nephritis, asthma, autoimmune diseases (eg systemic lupus erythematosus (SLE), psoriasis , Neuromyelitis optica, myasthenia gravis, etc.) or the like.
  • aHUS atypical hemolytic uremic syndrome
  • PNH paroxysmal nocturnal hemoglobinuria
  • AMD age-related macular degeneration
  • MPGN membranoproliferative glomerulonephritis
  • the pharmaceutical composition of the present invention contains an amount of the complex effective for treating or preventing a disease and is provided in a form that can be appropriately administered to a patient.
  • the preparation form of the pharmaceutical composition of the present invention may be, for example, injections, eye drops, liquids for inhalation, etc., for example, external preparations such as ointments, lotions and the like.
  • the concentration range of the active ingredient in the pharmaceutical composition of the present invention is usually 0.001 to 25% (w / v), preferably 0.1 to 10% (w / v), more preferably 0.5 ⁇ 5% (w / v).
  • the pharmaceutical composition of the present invention may contain an appropriate amount of any pharmaceutically acceptable additive, for example, an emulsification aid, a stabilizer, an isotonic agent, a pH adjuster and the like. Any pharmaceutically acceptable additive can be added in an appropriate step before or after dispersion of the complex.
  • the pharmaceutical composition of the present invention can also be prepared as a lyophilized preparation.
  • a freeze-dried preparation can be prepared by subjecting a nucleic acid and a carrier to dispersion treatment and then freeze-drying treatment.
  • the lyophilization treatment can be performed by a conventional method. For example, a predetermined amount of the complex solution after the above dispersion treatment is aseptically dispensed into a vial, preliminarily dried for about 2 hours under a condition of about -40 to -20 ° C, and about 0 to 10 ° C. Primary drying under reduced pressure, followed by secondary drying under reduced pressure at about 15-25 ° C. and lyophilization. Then, for example, by replacing the inside of the vial with nitrogen gas and stoppering, a freeze-dried preparation of the pharmaceutical composition of the present invention can be obtained.
  • the freeze-dried preparation can be used after re-dissolving by adding any appropriate solution.
  • a solution include electrolytes such as water for injection and physiological saline, glucose solution, and other general infusion solutions.
  • the amount of this solution varies depending on the application and is not particularly limited, but it is preferably 0.5 to 2 times the amount before lyophilization, or 500 ml or less.
  • the pharmaceutical composition of the present invention can be administered to animals including humans, for example, intravenous administration, intraarterial administration, oral administration, tissue administration, transdermal administration, transmucosal administration, or rectal administration. It is preferable to administer by an appropriate method according to the symptoms. In particular, intravenous administration, transdermal administration, and transmucosal administration are preferably used. Moreover, local administration, such as local administration in cancer, can also be performed. Examples of dosage forms suitable for these administration methods include various injections, oral preparations, drops, absorbents, eye drops, ointments, lotions, suppositories and the like.
  • the dose of the pharmaceutical composition of the present invention is preferably determined in consideration of nucleic acid, dosage form, patient condition such as age and weight, administration route, nature and degree of disease, etc. As an adult, it is 0.1 mg to 10 g / day, preferably 1 mg to 500 mg / day per day. In some cases, this may be sufficient, or vice versa. It can also be administered once to several times a day, and can be administered at intervals of 1 to several days.
  • the present invention is further a method of treating disorders mediated by abnormalities of the alternative complement pathway, wherein a therapeutically effective amount of a nucleic acid of the invention or a pharmaceutical composition of the invention is treated as such.
  • a method comprising the step of administering to a human in need of proper treatment.
  • the treatment method of the present invention is preferably an atypical hemolytic uremic syndrome, paroxysmal nocturnal hemoglobinuria, age-related macular degeneration, membranoproliferative glomerulonephritis, C3 nephritis, membranous nephropathy, rapidly progressive Glomerulonephritis (RPGN), acute kidney injury (AKI), ANCA-related vasculitis, lupus nephritis, asthma, autoimmune diseases (eg systemic lupus erythematosus (SLE), psoriasis, optic neuromyelitis, myasthenia gravis)
  • autoimmune diseases eg systemic lupus erythematosus (SLE), psoriasis, optic neuromyelitis, myasthenia gravis
  • SLE systemic lupus erythematosus
  • Other processes and conditions are not limited at all.
  • the administration method, dose, preparation method and the like of the pharmaceutical composition of the present invention can be used.
  • n (n 2 to 124) and the antisense strand shown in SEQ ID NO: [n + 123] make a pair).
  • the double-stranded nucleic acid and RNAiMax transfection reagent described in Table 1-1 to Table 1-3 are mixed with Opti-MEM medium (manufactured by Life Technology Co., Ltd., catalog number 11058-021) And add 20 ⁇ L of siRNA / RNAiMax mixture to each 96-well culture plate so that the final concentration of double-stranded nucleic acid is 1 nM or 0.1 nM, and 37 ° C and 5% CO 2 conditions. Cultured for 24 hours.
  • Table 1-1 to Table 1-3 may be collectively referred to as Table 1.
  • Table 2 shows the sense strand sequence and antisense strand sequence of a double-stranded nucleic acid different from Table 1 that targets the same sequence as the target CFB mRNA sequence listed in Table 1 (in Tables 1 and 2). , The same last four digits of the double-stranded nucleic acid number target the same CFB mRNA sequence).
  • sequences obtained by 2'-modifying the nucleotide sugar part of the sequences shown in Table 2 are shown in Table 3 (in Tables 2 and 3, the last four digits of the double-stranded nucleic acid numbers are the same, but the base sequences are the same) (This corresponds to a sequence that is different but not modified).
  • the double-stranded nucleic acid described in Table 4 is obtained by 2′-modifying the sugar part of the nucleotide with respect to some of the double-stranded nucleic acids described in Table 1 or Table 2.
  • the double-stranded nucleic acid and RNAiMax transfection reagent listed in Table 4 are diluted with Opti-MEM medium (life technology, catalog number 11058-021). 20 ⁇ L of siRNA / RNAiMax mixture was added to each 96-well culture plate so that the final concentration of the chain nucleic acid was 0.1 nM or 0.03 nM, and cultured for 24 hours at 37 ° C. under 5% CO 2 .
  • the present invention provides a nucleic acid having CFB expression inhibitory activity, a pharmaceutical composition containing the nucleic acid as an active ingredient, and the like.
  • the nucleic acid and pharmaceutical composition of the present invention suppress the expression of CFB, atypical hemolytic uremic syndrome, paroxysmal nocturnal hemoglobinuria, age-related macular degeneration, membranoproliferative glomerulonephritis, C3 nephritis, membrane Nephropathy, rapidly progressive glomerulonephritis (RPGN), acute kidney injury (AKI), ANCA-related vasculitis, lupus nephritis, asthma, autoimmune diseases (eg systemic lupus erythematosus (SLE), psoriasis, optic neuromyelitis, It is useful in the treatment and prevention of disorders mediated by abnormalities in the alternative pathway of the complement such as myasthenia gravis).

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Abstract

L'invention concerne : un acide nucléique présentant une activité d'inhibition de l'expression du facteur B du complément ; une composition médicale comprenant l'acide nucléique ; et un agent prophylactique ou thérapeutique, ledit agent comprenant l'acide nucléique, pour le syndrome hémolytique et urémique atypique, l'hémoglobinurie paroxystique nocturne, la dégénérescence maculaire liée à l'âge, la glomérulonéphrite membranoproliférative, la néphrite à C3, la néphropathie membraneuse, la glomérulonéphrite rapidement progressive (GRP), une lésion rénale aiguë (LRA), la vasculite associée aux ANCA, la néphropathie lupique, l'asthme ou une maladie auto-immune.
PCT/JP2017/046096 2016-12-23 2017-12-22 Acide nucléique inhibant l'expression du facteur b du complément WO2018117253A1 (fr)

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Publication number Priority date Publication date Assignee Title
CN110951915A (zh) * 2019-11-21 2020-04-03 南方医科大学南方医院 一种慢性乙型肝炎抗病毒治疗应答疗效预测的引物以及试剂盒
WO2023018523A3 (fr) * 2021-07-17 2023-08-24 Sirnaomics, Inc. Produits et compositions
WO2024008114A1 (fr) * 2022-07-08 2024-01-11 北京福元医药股份有限公司 Arnsi pour inhiber l'expression du facteur b du complément, composition pharmaceutique et conjugué associés, et utilisation de celui-ci

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US20070088154A1 (en) * 2002-11-14 2007-04-19 Dharmacon Inc. siRNA targeting complement factor B
WO2015089368A2 (fr) * 2013-12-12 2015-06-18 Alnylam Pharmaceuticals, Inc. Composition d'arni d'élément de complément et procédés pour les utiliser
JP2016507514A (ja) * 2013-01-08 2016-03-10 ベニテック バイオファーマ リミテッド 加齢黄斑変性の処置
JP2016533765A (ja) * 2013-09-13 2016-11-04 アイオーニス ファーマシューティカルズ， インコーポレーテッドＩｏｎｉｓ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ，Ｉｎｃ． 補体ｂ因子の調節薬
WO2017135397A1 (fr) * 2016-02-05 2017-08-10 協和発酵キリン株式会社 Oligonucléotide antisens destiné à supprimer l'expression du facteur du complément b

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US20070088154A1 (en) * 2002-11-14 2007-04-19 Dharmacon Inc. siRNA targeting complement factor B
JP2016507514A (ja) * 2013-01-08 2016-03-10 ベニテック バイオファーマ リミテッド 加齢黄斑変性の処置
JP2016533765A (ja) * 2013-09-13 2016-11-04 アイオーニス ファーマシューティカルズ， インコーポレーテッドＩｏｎｉｓ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ，Ｉｎｃ． 補体ｂ因子の調節薬
WO2015089368A2 (fr) * 2013-12-12 2015-06-18 Alnylam Pharmaceuticals, Inc. Composition d'arni d'élément de complément et procédés pour les utiliser
WO2017135397A1 (fr) * 2016-02-05 2017-08-10 協和発酵キリン株式会社 Oligonucléotide antisens destiné à supprimer l'expression du facteur du complément b

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110951915A (zh) * 2019-11-21 2020-04-03 南方医科大学南方医院 一种慢性乙型肝炎抗病毒治疗应答疗效预测的引物以及试剂盒
WO2023018523A3 (fr) * 2021-07-17 2023-08-24 Sirnaomics, Inc. Produits et compositions
WO2024008114A1 (fr) * 2022-07-08 2024-01-11 北京福元医药股份有限公司 Arnsi pour inhiber l'expression du facteur b du complément, composition pharmaceutique et conjugué associés, et utilisation de celui-ci

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