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WO2018159900A1 - Oligodésoxynucléotide leurre de type srebp-1 et composition pharmaceutique pour prévenir ou traiter une stéatose hépatique le contenant en tant que principe actif - Google Patents

Oligodésoxynucléotide leurre de type srebp-1 et composition pharmaceutique pour prévenir ou traiter une stéatose hépatique le contenant en tant que principe actif Download PDF

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Publication number
WO2018159900A1
WO2018159900A1 PCT/KR2017/006468 KR2017006468W WO2018159900A1 WO 2018159900 A1 WO2018159900 A1 WO 2018159900A1 KR 2017006468 W KR2017006468 W KR 2017006468W WO 2018159900 A1 WO2018159900 A1 WO 2018159900A1
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Prior art keywords
srebp
fatty liver
decoy
oligodioxynucleotide
liver disease
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Ceased
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English (en)
Korean (ko)
Inventor
박관규
윤성원
김정연
안현진
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Industry Academic Cooperation Foundation of Daegu Catholic University
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Industry Academic Cooperation Foundation of Daegu Catholic University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • 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
    • 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
    • C12N2310/30—Chemical structure
    • C12N2310/35—Nature of the modification
    • C12N2310/351—Conjugate
    • C12N2310/3519—Fusion with another nucleic acid
    • 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
    • C12N2310/50—Physical structure
    • C12N2310/53—Physical structure partially self-complementary or closed

Definitions

  • the present invention relates to a pharmaceutical composition for the prevention or treatment of SREBP-1 decoy oligodioxynucleotide and fatty liver disease containing the same as an active ingredient, and more particularly, to inhibit the transcription factor action of the transcription factor SREBP-1 Prevention of fatty liver disease containing SREBP-1 decoy oligodioxynucleotide and its active ingredient, which suppresses the accumulation of fat in liver tissue and reduces the inflammatory response by controlling the expression of genes related to biosynthesis Or to a pharmaceutical composition for treatment.
  • Gene therapy is a very effective method for treating and preventing various diseases by specifically inhibiting expression of specific genes by regulating the gene expression system and delivering it to a disease site.
  • the method of administering decoy oligodeoxynucleotide (decoy ODN) to transcription factors in gene therapy has recently been attempted as a tool for reducing the expression of specific genes by inhibiting the action of transcription factors.
  • a strategy to inhibit the activity of these transcription factors would be to inject decoy ODN into the cell, which binds to the transcription factor of interest in the cell. That is, since the DNA binding site of the transcription factor is bound by the decoy, the transcription factor cannot bind to the promoter of the target gene, and the activity of the transcription factor is interrupted, thereby reducing the expression of a specific gene.
  • Fatty liver refers to a state in which fat is accumulated in liver cells, and in the normal liver, fat accounts for about 5%, and more fat is accumulated in this state. Fatty liver deteriorates and the mass of fat in the hepatocytes is pushed to important components of the cells, including the nucleus, to one side, reducing the function of the hepatocytes. This leads to impaired circulation of blood and lymph in the liver. When this happens, hepatocytes cannot receive oxygen and nutrients properly, and liver function decreases.
  • Fatty liver can be divided into alcoholic fatty liver and non-alcoholic fatty liver.
  • Alcoholic fatty liver is caused by alcohol. The more alcohol you drink, the more likely it is, and if you continue to consume it, your liver's ability to metabolize alcohol will be worse. It also occurs well in poor nutrition. Some of the alcoholic fatty livers can die of alcoholic hepatitis and cirrhosis.
  • Non-alcoholic fatty liver occurs when a person consumes a lot of fat regardless of alcohol, because the liver does not synthesize much fat or release it.
  • Non-alcoholic fatty liver occurs when there are obesity, hyperlipidemia, and diabetes. It can also be caused by medications such as steroids.
  • Nonalcoholic fatty liver can also progress to nonalcoholic fatty hepatitis.
  • Alcoholic fatty liver should be treated for alcohol. If you have non-alcoholic fatty liver, maintaining a healthy lifestyle, such as losing weight with dietary control and proper exercise, can help with treatment.
  • SREBP sterol regulatory element-binding protein
  • Fatty liver has been identified as the cause and severity of the disease, but it is often not practiced by patients with fatty liver who need to improve symptoms through diet control and exercise. Therefore, there is a need for developing an effective fatty liver treatment drug.
  • Korean Patent Publication No. 2016-0089000 discloses a novel synthetic oligodioxynucleotide that simultaneously inhibits DNA and RNA, and a pharmaceutical composition for the prevention and treatment of fibrotic diseases containing the same as an active ingredient
  • Korean Patent No. 0874798 The present invention discloses a circular dumbbell-shaped decoy oligonucleotide comprising a DNA binding site
  • Korean Patent No. 1161118 discloses a novel Chi decoy oligodioxynucleotide and a pharmaceutical composition for preventing and treating renal failure containing the same as an active ingredient.
  • SREBP-1 decoy oligodioxynucleotide of the present invention and a pharmaceutical composition for preventing or treating fatty liver disease containing the same as an active ingredient is not disclosed.
  • the present invention is derived from the above requirements, the present invention provides a pharmaceutical composition for the prevention or treatment of fatty liver disease containing SREBP-1 decoy oligodioxynucleotide and the same as an active ingredient, SREBP-1 as an active ingredient
  • SREBP-1 as an active ingredient
  • the present invention was completed by confirming that decoy oligodioxynucleotides reduce liver fat content and decrease hepatic function indicators, blood total cholesterol, triglycerides and inflammatory indices in fatty liver-derived animal models.
  • the present invention is covalently linked to the SRE-1 oligodioxynucleotide of SEQ ID NO: 1 and the E-box motif oligodeoxynucleotide of SEQ ID NO: 2, DNA of two loop structure and transcription factor
  • a circular dumbbell-shaped SREBP-1 decoy oligodioxynucleotide consisting of a stem structure capable of binding to a binding site.
  • the present invention also provides a pharmaceutical composition for the prevention or treatment of fatty liver disease comprising a dumbbell-type SREBP-1 decoy oligodioxynucleotide as an active ingredient.
  • the present invention relates to a pharmaceutical composition for the prevention or treatment of SREBP-1 decoy oligodioxynucleotide and fatty liver disease containing the same as an active ingredient, the SREBP-1 decoy oligodioxynucleotide of the present invention in a fatty liver-derived animal model It has the effect of inhibiting the fat content of the liver, and has the effect of reducing the liver function indicator, blood total cholesterol, triglyceride and inflammatory index. Therefore, the composition of the present invention using SREBP-1 decoy oligodioxynucleotide as an active ingredient may be used as a functional material for the prevention and treatment of fatty liver disease.
  • SREBP-1 decoy oligodioxynucleotide is a diagram showing the structure of SREBP-1 decoy oligodioxynucleotide. It shows the structure of the SREBP-1 decoy oligodioxynucleotide including the SRE-1 and E-box motif moieties that bind to DNA.
  • Figure 2 is a result of confirming the degree of damage recovery and fat accumulation of liver tissue according to administration of SREBP-1 decoy oligodioxynucleotide using an animal model.
  • NC is a negative control group of the general diet
  • SREBP-1 decoy ODN is a group treated with SREBP-1 decoy oligodioxynucleotide in the general diet group
  • HFD + ODN is a group treated with the oligodioxynucleotide negative control group in the high-fat diet group
  • HFD + SREBP-1 decoy ODN is a group treated with SREBP-1 decoy oligodioxynucleotide in the high fat diet group.
  • FIG. 3 shows the results of immunochemical staining of the expression level of cholesterol synthase (HMG-CoA reductase, HMGCR) in liver tissue following administration of SREBP-1 decoy oligodioxynucleotide in an animal model.
  • HMG-CoA reductase HMGCR
  • NC is a negative control group of the general diet
  • SREBP-1 decoy ODN is a group treated with SREBP-1 decoy oligodioxynucleotide in the general diet group
  • HFD + ODN is a group treated with the oligodioxynucleotide negative control group in the high-fat diet group
  • HFD + SREBP-1 decoy ODN is a group treated with SREBP-1 decoy oligodioxynucleotide in the high fat diet group.
  • Figure 4 is a result of confirming the degree of protein expression of the biosynthesis-related genes of lipids in liver tissue following administration of SREBP-1 decoy oligodioxynucleotide using an animal model.
  • NC is a negative control without any treatment
  • ODN is an oligodioxynucleotide negative control.
  • NC is a negative control group of the general diet
  • SREBP-1 decoy ODN is a group treated with SREBP-1 decoy oligodioxynucleotide in the general diet group
  • HFD + ODN is a group treated with the oligodioxynucleotide negative control group in the high-fat diet group
  • HFD + SREBP-1 decoy ODN is a group treated with SREBP-1 decoy oligodioxynucleotide in the high fat diet group.
  • IL-6 expression was statistically significantly increased in the HFD group that was fed a high-fat diet compared to NC, which is a p ⁇ 0.005.
  • ⁇ indicates that IL-6 expression was statistically significantly reduced when SREBP-1 decoy ODN was administered compared to ODN, and ⁇ means p ⁇ 0.005.
  • Figure 6 is a result of confirming the mRNA expression level of inflammatory factors TNF- ⁇ , IL-1 ⁇ , IL-6 in the liver tissue according to administration of SREBP-1 decoy oligodioxynucleotide in the animal model.
  • NC is a negative control group of the general diet
  • SREBP-1 decoy ODN is a group treated with SREBP-1 decoy oligodioxynucleotide in the general diet group
  • HFD + Con ODN is a high-fat diet group treated with an oligodioxynucleotide negative control group together
  • HFD + SREBP-1 decoy ODN is a group treated with SREBP-1 decoy oligodioxynucleotide in the high-fat diet group.
  • the present invention is covalently linked to the SRE-1 oligodioxynucleotide of SEQ ID NO: 1 and the E-box motif oligodioxynucleotide of SEQ ID NO: 2, two loop structures and transcription factors It provides a circular dumbbell-shaped SREBP-1 decoy oligodioxynucleotide consisting of a stem structure capable of binding to the DNA binding site.
  • the dumbbell-type SREBP-1 decoy oligodioxynucleotide is a SRE-1 oligodioxynucleotide (SRE-1 ODN) consisting of the nucleotide sequence of SEQ ID NO: 1 and an E-box motif oligodioxynucleotide consisting of the nucleotide sequence of SEQ ID NO: 2 (E-box motif ODN) is covalently linked and consists of two loop and stem structures.
  • the stem structure is a site capable of binding to the DNA binding site of the transcription factor.
  • SRE-1 ODN 5'-GAATTCGTGTGGGGTGATTGAAAACAATCACCCCACAC-3 '(SEQ ID NO: 1)
  • E-box motif ODN 5'-GAATTCGTATCACGTGATGAAAACATCACGTGATAC-3 '(SEQ ID NO: 2)
  • the present invention also provides a pharmaceutical composition for the prevention or treatment of fatty liver disease comprising the dumbbell-type SREBP-1 decoy oligodioxynucleotide as an active ingredient.
  • the fatty liver disease includes alcoholic fatty liver disease and non-alcoholic fatty liver disease, preferably non-alcoholic fatty liver disease.
  • the non-alcoholic fatty liver disease is characterized by any one selected from the group consisting of simple fatty liver, nutrient fatty liver, hunger fatty liver, obese fatty liver, diabetic fatty liver, fatty hepatitis, liver fibrosis and cirrhosis.
  • the pharmaceutical composition of the present invention may further include a pharmaceutically acceptable carrier, excipient or diluent in addition to the dumbbell-shaped SREBP-1 decoy oligodioxynucleotide.
  • a pharmaceutically acceptable carrier such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories, and sterile injectable solutions according to conventional methods, but is not limited thereto. .
  • Carriers, excipients and diluents that may be included in the composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl Cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
  • diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, and surfactants are usually used.
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and the solid preparations include at least one excipient in the extract, for example, starch, calcium carbonate, sucrose. Or lactose, gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used.
  • Liquid preparations for oral use include suspensions, solvents, emulsions, and syrups, and may include various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. have.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories.
  • non-aqueous solvent and suspending agent propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used.
  • Witepsol, macrogol, Tween 61, cacao butter, laurin butter, glycerogelatin, and the like may be used as the base of the suppository.
  • Suitable pharmaceutically acceptable carriers and formulations are described in detail in Remington's Pharmaceutical Sciences, 19th ed., 1995.
  • Suitable dosages of the pharmaceutical compositions according to the present invention vary depending on factors such as the formulation method, mode of administration, age, weight, sex, morbidity, food, time of administration, route of administration, rate of excretion and response to response of the patient. Can be.
  • the concentration of the active ingredient included in the composition of the present invention can be determined in consideration of the purpose of treatment, the condition of the patient, the period of time, etc., and is not limited to a specific range of concentration.
  • decoy ODN decoy oligodioxynucleotide
  • SRE-1 ODN 5'-GAATTCGTGTGGGGTGATTGAAAACAATCACCCCACAC-3 '(SEQ ID NO: 1)
  • E-box motif ODN 5'-GAATTCGTATCACGTGATGAAAACATCACGTGATAC-3 '(SEQ ID NO: 2)
  • the produced oligodioxynucleotide (ODN) was denatured at 95 ° C. for 3 minutes and then annealed while lowering the temperature to 80-25 ° C.
  • the annealed ODN was ligated with T4 ligase for 16-18 hours to produce spherical Con ODN and SREBP-1 decoy ODN.
  • the structure of the ligated spherical dumbbell-shaped SREBP-1 decoy ODN is shown in FIG. 1.
  • Ligation decoy ODN was identified on a 15% non-denaturating gel.
  • a high fat diet (HFD: 21% fat and 1% cholesterol) was consumed for 12 weeks, and 10 ⁇ g decoy at 2 weeks intervals during high fat diet.
  • ODN was injected through the tail vein of the rat.
  • the NC diet fed commercial rodent feed and infused with decoy ODN under the same conditions. After 12 weeks, liver tissues were extracted or blood was used for the experiment.
  • Liver extracted from the animal model of Example 2 was prepared with paraffin sections, and H & E staining was performed to confirm the degree of damage and fat accumulation of liver tissue.
  • the liver of the subject fed the Con ODN diet was shown to have a higher degree of damage and fat accumulation than the general diet group, but the SREBP-1 decoy ODN was injected while the diet was fed a high fat diet.
  • Hepatic tissues significantly reduced liver tissue damage and fat accumulation compared to Con ODN injection group. Therefore, it was confirmed that SREBP-1 decoy ODN has an effect of suppressing liver damage and fat accumulation induced by high fat diet.
  • Example 2 Animal models of Example 2 were measured for blood alanine aminotransferase (ALT), aspartate aminotransferase (AST, aspartate aminotransferase), total cholesterol and triglyceride index using a commercial assay kit.
  • ALT blood alanine aminotransferase
  • AST aspartate aminotransferase
  • total cholesterol and triglyceride index using a commercial assay kit.
  • Table 1 the activity of plasma alanine aminotransferase and aspartic acid aminotransferase, which are indicators of liver function, was significantly increased in the high-fat diet group compared to the normal diet group, and SREBP-1 decoy
  • ODN was injected, the activity of alanine aminotransferase and aspartic acid aminotransferase was significantly decreased compared to the Con ODN injection group.
  • the total cholesterol and triglyceride index was significantly increased in the high-fat diet group compared to the normal diet group, and the total cholesterol and triglyceride index was significantly higher in the SREBP-1 decoy ODN-injected group than the Con ODN-injected group. Decreased. Therefore, SREBP-1 decoy ODN may play a role in preventing hepatic deterioration induced by high fat diet.
  • HMG-CoA reductase HMG-CoA reductase
  • HMGCR cholesterol synthase
  • FIG. 3 The expression of HMGCR protein was significantly increased when Con ODN was injected into the high-fat diet group compared to the normal diet group, and the expression of HMGCR protein was decreased when SREBP-1 decoy ODN was injected into the high-fat diet group compared to the Con ODN injection group.
  • the expression of HMGCR protein in the SREBP-1 decoy ODN-injected group was similar to that of the normal diet group.
  • treatment of SREBP-1 decoy ODN can inhibit cholesterol biosynthesis by reducing the expression of HMGCR protein.
  • Liver tissue was extracted from the animal model of Example 2 and confirmed by Western blot protein expression of genes related to lipid biosynthesis.
  • Lipid biosynthesis-related proteins were selected from SREBP-1C, Fatty acid syntase (FAS), Acetyl-CoA carboxylase (ACC), and Steroyl-CoA desaturase (SCD-1).
  • FAS Fatty acid syntase
  • ACC Acetyl-CoA carboxylase
  • SCD-1 Steroyl-CoA desaturase
  • Example 2 In the animal model of Example 2, it was confirmed that the expression of IL-6 increased by high-fat diet decreased in the group injected with SREBP-1 decoy ODN as shown in FIG. 5.
  • the group injected with SREBP-1 decoy ODN with a high-fat diet reduced the mRNA expression of inflammatory factors TNF- ⁇ , IL-1 ⁇ , IL-6 in liver tissue. Therefore, SREBP-1 decoy ODN may reduce the inflammatory response of the liver induced by high fat diet and may help prevent hepatitis.

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Abstract

La présente invention concerne un oligodésoxynucléotide leurre de type SREBP-1 et une composition pharmaceutique pour prévenir ou traiter une stéatose hépatique le contenant en tant que principe actif. Plus particulièrement, l'oligonucléotide leurre de type SREBP-1 selon la présente invention régule l'expression de gènes associés à la biosynthèse des lipides par inhibition de l'activité du facteur de transcription de SREBP-1, qui est un facteur de transcription, ce qui permet de supprimer l'accumulation de graisse dans le foie lorsqu'un modèle animal à stéatose hépatique induite est traité avec l'oligodésoxynucléotide leurre de type SREBP-1. De plus, l'oligonucléotide leurre de type SREBP-1 présente les effets de réduction de l'alanine sanguine, de l'aspartate transaminase, du cholestérol total et des indices de graisse neutre, ainsi que des indices de transaminase hépatique et de l'inflammation sanguine. Du fait de ces effets, l'oligonucléotide leurre de type SREBP-1 peut être utilisé en tant que composition pharmaceutique pour prévenir ou traiter la stéatose hépatique.
PCT/KR2017/006468 2017-02-28 2017-06-21 Oligodésoxynucléotide leurre de type srebp-1 et composition pharmaceutique pour prévenir ou traiter une stéatose hépatique le contenant en tant que principe actif Ceased WO2018159900A1 (fr)

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KR10-2017-0025847 2017-02-28
KR1020170025847A KR101869308B1 (ko) 2017-02-28 2017-02-28 Srebp-1 디코이 올리고디옥시뉴클레오티드 및 이를 유효성분으로 함유하는 지방간 질환의 예방 또는 치료용 약학 조성물

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KR102433981B1 (ko) * 2020-12-15 2022-08-19 대구가톨릭대학교산학협력단 HIF-1α 및 STAT5 전사인자를 억제하는 합성 디코이 올리고핵산 및 이를 유효성분으로 함유하는 아토피 피부염의 예방 또는 치료용 약학적 조성물

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KR101303462B1 (ko) * 2009-02-23 2013-09-05 울산대학교 산학협력단 Ｄｒｇ2 유전자의 신규한 용도
CN101674730B (zh) * 2007-02-02 2014-09-10 贝勒医学院 用于治疗代谢疾病的组合物和方法
US20150087604A1 (en) * 2011-04-22 2015-03-26 Tianjin Toptech Bio-Science & Technology Co., Ltd. Anti-fatty acid synthase polypeptide and use thereof
WO2016022753A1 (fr) * 2014-08-07 2016-02-11 Regulus Therapeutics Inc. Ciblage de micro-arn pour traiter des troubles métaboliques

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CN101674730B (zh) * 2007-02-02 2014-09-10 贝勒医学院 用于治疗代谢疾病的组合物和方法
KR101303462B1 (ko) * 2009-02-23 2013-09-05 울산대학교 산학협력단 Ｄｒｇ2 유전자의 신규한 용도
US20150087604A1 (en) * 2011-04-22 2015-03-26 Tianjin Toptech Bio-Science & Technology Co., Ltd. Anti-fatty acid synthase polypeptide and use thereof
WO2016022753A1 (fr) * 2014-08-07 2016-02-11 Regulus Therapeutics Inc. Ciblage de micro-arn pour traiter des troubles métaboliques

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Title
KIM, JAE B ET AL.: "Dual DNA binding specificity of ADD1/SREBP1 controlled by a single amino acid in the basic helix-loop-helix domain", MOLECULAR AND CELLULAR BIOLOGY, May 1995 (1995-05-01), pages 2582 - 2588, XP055538873 *

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