WO2011071027A1 - Molécule d'arn interférence capable d'inhiber l'expression de protéine socs3 codée par le gène socs3, et utilisation de celle-ci - Google Patents

Molécule d'arn interférence capable d'inhiber l'expression de protéine socs3 codée par le gène socs3, et utilisation de celle-ci Download PDF

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WO2011071027A1
WO2011071027A1 PCT/JP2010/071858 JP2010071858W WO2011071027A1 WO 2011071027 A1 WO2011071027 A1 WO 2011071027A1 JP 2010071858 W JP2010071858 W JP 2010071858W WO 2011071027 A1 WO2011071027 A1 WO 2011071027A1
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dna
shrna
vector
myocardial infarction
sirna
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秀雄 安川
豊治 大場
勉 今泉
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学校法人久留米大学
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    • 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
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/14—Type of nucleic acid interfering N.A.
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/50—Physical structure
    • C12N2310/53—Physical structure partially self-complementary or closed
    • C12N2310/531—Stem-loop; Hairpin

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  • the present invention relates to an RNA interference molecule capable of suppressing the expression of SOCS3 protein encoded by the SOCS3 gene, a DNA encoding the same, a vector containing the DNA, and a nanocapsule or liposome encapsulating them.
  • the present invention also relates to a therapeutic agent for myocardial infarction, particularly acute myocardial infarction, and an agent for suppressing cell death during myocardial infarction, which contain these as active ingredients.
  • the present invention also relates to a method for treating acute myocardial infarction and a method for suppressing cell death during myocardial infarction.
  • Cytokines such as G-CSF (Granulocyte Colony-stimulating Factor), EPO (Erythropoietin), and LIF (Leukemia Inhibitory Factor) promote the survival of cardiomyocytes, reduce the infarct area of acute myocardial infarction, and suppress myocardial remodeling It is known (Non-Patent Document 1, etc.). However, the clinical trial of G-CSF for acute myocardial infarction cases has been effective and ineffective, and the evaluation has not been determined.
  • G-CSF Granulocyte Colony-stimulating Factor
  • EPO Erythropoietin
  • LIF Leukemia Inhibitory Factor
  • the main object of the present invention is to provide a novel therapeutic agent for myocardial infarction and an inhibitor of cell death during myocardial infarction.
  • a knockout mouse in which the SOCS3 gene was disrupted specifically in the myocardium and the expression of the SOCS3 protein was blocked was reduced myocardial infarction region, left ventricular expansion suppression, cardiac contraction function decrease suppression, cytokine (EPO, G-CSF, and Increased expression of LIF, enhancement of STAT3 phosphorylation, suppression of apoptosis, promotion of Bcl-xL expression, enhanced expression of TFAM (Mitochondrial transcriptional factor A), enhanced angiogenesis, enhanced expression of angiogenic factors (HGF, IGF, Midkine) was recognized.
  • shRNAs and siRNAs based on these shRNAs have the ability to inhibit SOCS3 protein expression, can suppress myocyte death, and can prevent, improve, or treat myocardial infarction.
  • EPO EPO, G-CSF, and LIF
  • STAT3 phosphorylation enhancement STAT3 phosphorylation enhancement
  • apoptosis suppression Bcl-xL expression promotion
  • TFAM expression Through enhancement, enhancement of angiogenesis, and increased expression of
  • siRNA that inhibits or suppresses the expression of the SOCS3 protein, a vector containing shRNA and a DNA encoding shRNA, or a plasmid that leads to the siRNA, the cytokine (EPO, G-CSF, and LIF) described above ) And introduced into the details of the myocardium in the myocardial infarction more effectively during myocardial infarction, suppression of myocardial infarction area, suppression of left ventricular expansion, suppression of cardiac contraction function decline, cytokine (EPO, G-CSF) And LIF), STAT3 phosphorylation enhancement, apoptosis suppression, Bcl-xL expression promotion, TFAM expression enhancement, angiogenesis enhancement, angiogenesis factor (HGF, IGF, Midkine) It can suppress myocardial cell death and prevent, improve or treat myocardial infarction.
  • cytokine EPO, G-CSF, and LIF
  • the shRNA itself or the siRNA derived from the shRNA obtained by the above method or other methods is also used in myocardial cells at the time of myocardial infarction. Suppression, upregulation of cytokines (EPO, G-CSF, and LIF), enhancement of STAT3 phosphorylation, suppression of apoptosis, promotion of Bcl-xL expression, enhancement of TFAM expression, enhancement of angiogenesis, angiogenesis factors (HGF, IGF, It is possible to prevent, improve, or treat myocardial infarction by suppressing myocardial cell death through increased expression of Midkine).
  • EPO cytokines
  • G-CSF G-CSF
  • LIF enhancement of STAT3 phosphorylation
  • suppression of apoptosis promotion of Bcl-xL expression
  • enhancement of TFAM expression enhancement of angiogenesis, angiogenesis factors (HGF, IGF, It is possible to prevent, improve, or treat myocardial infarction by suppressing myocardial cell
  • Item 1 A DNA in which an antisense DNA of 21 to 30 bases that is completely complementary to the conserved region of SOCS3 and a sense DNA that can be paired with this antisense DNA are linked by a linker DNA.
  • Item 2. A DNA in which an antisense DNA having a maximum of 30 bases comprising the base sequence of SEQ ID NO: 1 or SEQ ID NO: 2 and a sense DNA capable of pairing with the antisense DNA are linked by a linker DNA.
  • Item 4. A vector in which the DNA of Item 1 or 2 is linked so as to allow expression.
  • Item 6. A composition comprising the DNA according to Item 1 or 2, the shRNA or siRNA according to Item 3, the vector according to Item 4, or the nucleic acid-encapsulated capsule or liposome according to Item 5 and erythropoietin.
  • Item 8 The DNA according to Item 1 or 2, the shRNA or siRNA according to Item 3, the vector according to Item 4, the nucleic acid-encapsulated capsule or liposome according to Item 5, or the composition according to Item 6 as an active ingredient, An inhibitor of cardiomyocyte death during myocardial infarction.
  • Item 10. Item 3. The DNA according to Item 1 or 2, the shRNA or siRNA according to Item 3, the vector according to Item 4, the nucleic acid-encapsulated capsule according to Item 5, or used for suppressing myocardial cell death during myocardial infarction. 7. A liposome or the composition according to item 6. Item 11. Item 3.
  • Use of a liposome or the composition according to Item 6. Item 12.
  • Item 3. The DNA according to item 1 or 2, the shRNA or siRNA according to item 3, the vector according to item 4, the nucleic acid-encapsulated capsule according to item 5, or a method for producing an inhibitor of cardiomyocyte death during myocardial infarction.
  • the DNA according to Item 1 or 2, the shRNA or siRNA according to Item 3, the vector according to Item 4, the nucleic acid-encapsulated capsule or liposome according to Item 5, or the composition according to Item 6 is administered to a mammal.
  • Item 14 The DNA according to Item 1 or 2, the shRNA or siRNA according to Item 3, the vector according to Item 4, the nucleic acid-encapsulated capsule or liposome according to Item 5, or the composition according to Item 6 is administered to a mammal. , A method for inhibiting cardiomyocyte death during myocardial infarction.
  • the present invention was demonstrated for the first time that myocardial infarction can be effectively improved by knocking out the SOCS3 gene. Furthermore, a nucleic acid sequence encoding shRNA that can effectively suppress the production of SOCS3 protein that promotes myocardial necrosis of myocardial infarction was provided. This nucleic acid sequence is incorporated into a vector or a plasmid and introduced into cardiomyocytes during myocardial infarction (particularly acute myocardial infarction), thereby producing an effect of suppressing the progression of cardiomyocyte necrosis associated with myocardial infarction.
  • the expression of SOCS3 protein is suppressed.
  • the effect of suppressing the progression of necrosis is brought about.
  • siRNA, shRNA, DNA, Vector In the DNA of the present invention, a 21-30 base antisense DNA that is completely complementary to the SOCS3 conserved region and a sense DNA that can be paired with this antisense DNA are linked by a linker DNA. DNA.
  • the length of the antisense DNA is preferably 19-30 bases, more preferably 21-29 bases.
  • Examples of DNA that can express an RNA interference molecule capable of knocking down the SOCS3 gene particularly effectively include the following.
  • the DNA of the present invention is preferably DNA in which an antisense DNA comprising the nucleotide sequence of SEQ ID NO: 1 or SEQ ID NO: 2 and a sense DNA capable of pairing with the antisense DNA are linked by a linker DNA.
  • an antisense DNA comprising the nucleotide sequence of SEQ ID NO: 1 or SEQ ID NO: 2 and a sense DNA capable of pairing with the antisense DNA are linked by a linker DNA.
  • CCGCT TCGAC TGTGT ACTCA AGCTG GTGC SEQ ID NO: 1
  • GCCAC CTGGA CTCCT ATGAG AAAGT GACC SEQ ID NO: 2
  • the antisense DNA has a total of 1 to 3 bases, preferably 1 to 2 bases, and more preferably 1 base nucleotide added to the 5 ′ end and / or 3 ′ end of SEQ ID NO: 1 or 2 May have been.
  • the antisense DNA may be DNA having a maximum of 33 bases.
  • Antisense DNA consisting of the nucleotide sequence of SEQ ID NO: 1 or SEQ ID NO: 2 is preferred because it has the highest specificity for the target SOCS3 gene.
  • the antisense DNA sequences of SEQ ID NOs: 1 and 2 are completely complementary to the SOCS3 portion.
  • the sense DNA that can be paired with the antisense DNA may contain a mismatch sequence with the antisense DNA.
  • the number of mismatched bases in the sense DNA is preferably 1 to 3, more preferably 1 to 2, and even more preferably 1. Further, there may be no mismatch base between the sense DNA and the antisense DNA.
  • a mismatch is generally formed by substituting another base that is not complementary by substitution, but a mismatch formed by deleting a base corresponding to a specific base of antisense DNA from the sense DNA sequence, Mismatches formed by inserting a base that does not correspond to the antisense DNA into the sense DNA sequence, and mismatches formed by adding any base to the 3 'or 5' end of the sense DNA sequence are also mismatched. Included in the array. Among these, a base substitution type mismatch is preferable in terms of high target recognition efficiency.
  • the linker DNA that connects the antisense DNA and the sense DNA is a structure for forming the hairpin structure of shRNA.
  • the base sequence of the linker DNA is not particularly limited except for the termination sequence that prevents the generation of shRNA.
  • the length of the linker DNA is preferably 6 to 11 bases, more preferably 7 to 9 bases.
  • shRNA loop sequences expressed from such linker sequences include sequences beginning with UU, such as UUCAAGAGA, CUUCCUGUCA (SEQ ID NO: 3), CCACACC, and the like (Lee NS. Et al. (2002) Nat. Biotech. 20, 500-505; Paddison PJ. Et al. (2002) Genes and Dev. 16, 948-958; Sui G. et al. (2002) Proc. Natl. Acad. Sci. USA 99, 5515-5520; CP. Et al. (2002) Nat. Biotech. 20, 505-508; Kawasaki H. et al. (2003) Nucleic Acids Res. 31, 700-707
  • the above DNA encoding shRNA expresses shRNA under a suitable promoter.
  • the promoter may be either a pol II system or a pol III system as long as it can express shRNA, but a pol III system suitable for expression of a short RNA such as shRNA is preferred.
  • polIII promoters include U6 promoter, SV40 early promoter, H1 promoter, tRNA promoter, retroviral LTR promoter, adenovirus VA1 promoter, 5S rRNA promoter, 7SK RNA promoter, 7SL RNA promoter, H1 RNA promoter, etc. Can be mentioned. Of these, the U6 promoter is preferred.
  • the terminator sequence is not particularly limited, and examples thereof include a sequence in which 4 or more T (thymine) and A (adenine) are continuous, and a sequence that can form a palindromic structure. Among them, a sequence in which 4 or more Ts are continuous is preferable, and TTTT is more preferable.
  • a retrovirus vector in mammalian cells, for example, a retrovirus vector, an adenovirus vector, an adeno-associated virus vector, a vaccinia virus vector, a lentivirus, as a vector containing a promoter, shRNA-encoding DNA, and preferably an shRNA expression unit consisting of a terminator
  • examples thereof include viral vectors such as vectors, herpes virus vectors, alpha virus vectors, EB virus vectors, papilloma virus vectors, foamy virus vectors.
  • plasmid vectors include pBAsi vectors, pSUPER vectors, pSilencer, and pRS shRNA.
  • a plasmid vector is preferable because of low genotoxicity, tumorigenicity, and immunogenicity, and a pRS shRNA vector is particularly preferable.
  • the DNA of the present invention is intended to suppress the expression of SOCS3 by expressing shRNA in cardiomyocytes.
  • an extrachromosomal vector or plasmid it is preferable to use an extrachromosomal vector or plasmid, adenovirus vector, adeno-associated virus vector, vaccinia virus vector, alphavirus vector, pBAsi vector, pSUPER vector, A vector such as pSilencer or pRS shRNA may be used.
  • a vector having the ability to integrate into the chromosome and a vector such as a retrovirus vector, a lentivirus vector, a herpesvirus vector, or an EB virus vector is selected. Use it.
  • a SOCS3 gene (mRNA) can be knocked out easily by introducing a vector that can be integrated into the chromosome into animals including humans.
  • shRNA or siRNA is included in a bio-nanocapsule that can be delivered specifically to myocardium and administered intravenously to the living body, And a method of preparing a vector incorporating SOCS3-shRNA into adeno-associated virus 9 (AAV9) and administering it intravenously to a living body.
  • the vector may contain a selectable marker. Selectable markers can be selected from neomycin resistance genes, hygromycin resistance genes, drug resistance markers such as puromycin resistance genes, markers that can be selected using enzyme activities such as galactosidase, and fluorescence emission such as GFP.
  • a marker, an EGF receptor, a selection marker that can be selected using a surface antigen such as B7-2 or CD4 as an indicator may be used.
  • a selectable marker is necessary for DNA preparation, and it is recommended to use a marker for monitoring expression.
  • ShRNA expressed from the DNA of the present invention is processed in vivo to generate siRNA.
  • RNA Nucleic Acid-Encapsulated Polymer Capsule or Liposomes
  • the above-described siRNA, shRNA, DNA encoding them, and vectors can be encapsulated in polymer capsules or liposomes. Since RNA is easily degraded by RNAse, it can be easily used as a medicine by encapsulating in capsules or liposomes.
  • the polymer constituting the capsule include polymer nano micelles, PGLA name spheres, and bio-nanocapsules. Among these, polymer micelles are preferable.
  • the average particle size of the capsule is usually preferably about 50 to 250 nm, more preferably about 90 to 150 nm.
  • nucleic acid-encapsulated capsule can be produced, for example, by an emulsion method.
  • methods for producing nucleic acid-encapsulated liposomes are well known, and for example, they can be produced by the methods described in JP-A-2004-143200 and JP-A-2004-302250.
  • other active ingredients and additives used in medicine can be encapsulated in the polymer capsule or liposome.
  • siRNA, shRNA, DNA encoding the same, vector, and nucleic acid-encapsulated polymer capsule or liposome of the present invention described above are used for the prevention, amelioration, or treatment of myocardial infarction, and myocardial cell death during myocardial infarction. It can be used as an active ingredient of an inhibitor of the above or a necrosis inhibitor of cardiomyocytes.
  • the preparation may be either an orally administered agent or a parenterally administered agent. Examples of the orally administered agent include powders, granules, tablets, tablets, pills, capsules, chewable agents, emulsions, liquids, syrups and the like. Solid preparations are prepared by blending the above active ingredients with pharmaceutically acceptable carriers and additives.
  • excipients such as sucrose, lactose, glucose, starch, mannitol; binders such as gum arabic, gelatin, crystalline cellulose, hydroxypropylcellulose, methylcellulose; disintegrants such as carmellose, starch; citric anhydride Stabilizers such as sodium laurate and glycerol are blended. Further, it may be coated or encapsulated with gelatin, white sugar, gum arabic, carnauba wax or the like.
  • the liquid preparation is prepared, for example, by dissolving or dispersing the above active ingredient in water, ethanol, glycerin, simple syrup, or a mixture thereof.
  • the content of the active ingredient in the orally administered agent is not particularly limited, but for example, the vector weight may be about 1 ⁇ g to 1 g, preferably about 1 to 500 mg.
  • parenteral administration agents include injections and suppositories.
  • the injection include intravenous injection, subcutaneous injection, intradermal injection, intramuscular injection, and drip injection.
  • the injection can be prepared by dissolving, suspending or emulsifying the above-mentioned active ingredient in a sterile aqueous or oily liquid usually used for injection.
  • the aqueous liquid for injection include isotonic solutions containing physiological saline, glucose and other adjuvants.
  • Suitable solubilizers such as alcohols (eg, ethanol), polyalcohols (eg, propylene glycol, polyethylene glycol), nonionic surfactants (eg, polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor) oil)) or the like.
  • examples of the oily liquid include sesame oil and soybean oil.
  • benzyl benzoate, benzyl alcohol, or the like may be used in combination.
  • the content of the active ingredient in the injection may be, for example, several ⁇ g to several hundred mg, preferably about 50 to 200 mg, more preferably about 100 mg in terms of the weight of the vector of the present invention.
  • cytokines that promote cardiomyocyte survival such as G-CSF (granulocyte colony stimulating factor), EPO (erythropoietin), and LIF (leukemia cell growth factor) can be used in combination. This enhances the effect of treating myocardial infarction or the effect of prolonging the life of cardiomyocytes.
  • G-CSF granulocyte colony stimulating factor
  • EPO erythropoietin
  • LIF leukemia cell growth factor
  • EPO is a glycoprotein composed of 165 amino acids and having a molecular weight of about 34,000.
  • EPO functions as a hormone that promotes red blood cell production. EPO is mainly produced by renal tubular stromal cells. Therefore, when chronic renal failure occurs, the necessary amount of EPO is not produced and anemia is likely to occur.
  • EPO genetically modified EPO is commercially available and can be purchased.
  • examples of commercially available products of EPO include epoetin ⁇ (trade name: Espoo, Kyowa Hakko Kirin) and epoetin ⁇ (trade name: Epogin, Chugai Pharmaceutical).
  • the present invention encompasses a composition comprising siRNA, shRNA, DNA, vector, or nucleic acid-encapsulating polymer capsule or liposome and EPO.
  • the weight ratio of siRNA, shRNA, DNA, vector, or nucleic acid-encapsulated polymer capsule or liposome to EPO is about 1: 0.1 to 20 is preferred, about 1: 1 to 10 is more preferred, and about 1: 3 to 6 is even more preferred.
  • the present invention provides the above-described active ingredient (siRNA, shRNA of the present invention described above, DNA encoding these, vector, nucleic acid-encapsulating polymer capsule or liposome, or EPO-containing composition), mammal, In particular, it includes a method for preventing, improving, or treating myocardial infarction, a method for suppressing myocardial cell death in myocardial infarction, or a method for prolonging myocardial cell life, which is administered to humans.
  • the administration subject is preferably a myocardial infarction patient.
  • the dose of the active ingredient is preferably about 10 to 1000 ⁇ g, more preferably about 30 to 300 ⁇ g, still more preferably about 50 to 200 ⁇ g per day.
  • the present invention also relates to the use of the active ingredient described above for the production of a preventive, ameliorating or therapeutic agent for myocardial infarction, an inhibitor of myocardial cell death in myocardial infarction, or a proliferating agent for cardiomyocytes in myocardial infarction. Include.
  • the present invention also includes the above-mentioned active ingredient used for prevention, amelioration or treatment of myocardial infarction, suppression of myocardial cell death in myocardial infarction, or prolongation of myocardial cell life in myocardial infarction.
  • Example 1 Using the Cre-loXp system, myocardial specific SOCS3-deficient mice were generated in UCSD (University of California, San Diego).
  • the Cre-loXp system is a knockout mouse production system under specific conditions.
  • the part to be deleted is sandwiched between loxp with directionality, and the enzyme Cre recombinase is expressed to cut out the part sandwiched between loxp.
  • This is a system for knocking out a gene containing the part. Specifically, a mouse expressing loxp sandwiching exon2 of the SOCS3 gene and a mouse expressing Cre specifically in the myocardium were respectively prepared and mated.
  • Example 3 The heart of a myocardium-specific SOCS3 knockout mouse was removed, and the protein was extracted by homogenization in a solubilization buffer. The extracted protein was subjected to SDS-PAGE, and its expression was confirmed by Western blotting using antibodies against SOCS3, Bcl-xl, Bad, caspase3, and Bax. The results are shown in FIG. GAPDH is shown as a control. In the heart of myocardial-specific SOCS3-deficient mice after acute myocardial infarction, the expression of Bcl-xl, an apoptosis-inhibiting protein, was increased and the expression of Bad, Bax, and caspase3, which are apoptosis-promoting proteins, was suppressed.
  • Example 4 An shRNA expression vector having both SOCS3 sense and antisense was constructed and stably expressed in NIH3T3 cells. Specifically, the cultured NIH3T3 cells were transfected with a SOCS3 shRNA expression vector using Lipofectamine 2000 (FIG. 6). The cells were stimulated with interleukin-6, and the cells were collected 24 to 48 hours later, added with a solubilizing buffer, centrifuged, and the supernatant was collected to extract the protein. SDS-PAGE was performed, and expression was confirmed by Western blot using a SOCS3 antibody (FIG. 7). It was confirmed that the production of SOCS3 protein was clearly suppressed by the shRNA expression vector having the above target sequence. Therefore, it is considered that acute myocardial infarction can be prevented by suppressing the expression of SOCS3 with this shRNA expression vector and suppressing myocardial cell death during myocardial infarction.

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Abstract

La présente invention concerne : un ADN comprenant un ADN antisens qui est composé de jusqu'à 30 nucléotides et comprend la séquence nucléotidique représentée par SEQ ID NO: 1 ou SEQ ID NO: 2 et un ADN sens qui peut être apparié avec l'ADN antisens, ledit ADN antisens et ledit ADN sens étant mutuellement reliés par un ADN lieur ; un ARNsh ou un ARNsi exprimé à partir de l'ADN ; un vecteur comprenant l'ADN ; et une capsule ou un liposome dans lequel l'ADN, l'ARNsh, l'ARNsi ou le vecteur est encapsulé. L'ADN, l'ARNsh, l'ARNsi, le vecteur, la capsule et le liposome peuvent empêcher l'infarctus du myocarde et avoir un effet de prolongation de la durée de vie sur les myocytes cardiaques lorsqu'un infarctus du myocarde s'est produit. En utilisant l'ADN, l'ARNsh, l'ARNsi, le vecteur, la capsule ou le liposome en combinaison avec l'érythropoïétine, les effets décrits ci-dessus peuvent être davantage améliorés.
PCT/JP2010/071858 2009-12-08 2010-12-07 Molécule d'arn interférence capable d'inhiber l'expression de protéine socs3 codée par le gène socs3, et utilisation de celle-ci WO2011071027A1 (fr)

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Cited By (2)

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Publication number Priority date Publication date Assignee Title
WO2017078100A1 (fr) * 2015-11-06 2017-05-11 国立大学法人熊本大学 Composition pharmaceutique destinée à prévenir ou à traiter l'insuffisance cardiaque
CN109735616A (zh) * 2019-03-22 2019-05-10 吉林大学 Socs3基因在急性心肌梗死风险预测标记物中的用途

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017078100A1 (fr) * 2015-11-06 2017-05-11 国立大学法人熊本大学 Composition pharmaceutique destinée à prévenir ou à traiter l'insuffisance cardiaque
US11235073B2 (en) 2015-11-06 2022-02-01 National University Corporation Kumamoto University Method for treating or preventing heart failure
CN109735616A (zh) * 2019-03-22 2019-05-10 吉林大学 Socs3基因在急性心肌梗死风险预测标记物中的用途

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