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WO2021035987A1 - Marqueur biologique de la fibrose du foie, cible thérapeutique et son utilisation - Google Patents

Marqueur biologique de la fibrose du foie, cible thérapeutique et son utilisation Download PDF

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Publication number
WO2021035987A1
WO2021035987A1 PCT/CN2019/118737 CN2019118737W WO2021035987A1 WO 2021035987 A1 WO2021035987 A1 WO 2021035987A1 CN 2019118737 W CN2019118737 W CN 2019118737W WO 2021035987 A1 WO2021035987 A1 WO 2021035987A1
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lect2
tie1
liver fibrosis
tie2
liver
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Chinese (zh)
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周伟杰
林媛
徐濛
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Southern Medical University
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Southern Medical University
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/55—Specular reflectivity
    • G01N21/552—Attenuated total reflection
    • G01N21/553—Attenuated total reflection and using surface plasmons
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6803—General methods of protein analysis not limited to specific proteins or families of proteins
    • G01N33/6845—Methods of identifying protein-protein interactions in protein mixtures
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value
    • G01N2500/04—Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A)
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/08—Hepato-biliairy disorders other than hepatitis
    • G01N2800/085—Liver diseases, e.g. portal hypertension, fibrosis, cirrhosis, bilirubin

Definitions

  • the present invention relates to the field of biomedicine, in particular to a biological marker, therapeutic target and use of liver fibrosis.
  • Liver fibrosis is a common liver injury symptom in patients with chronic liver disease, manifested by excessive deposition of extracellular matrix such as collagen and fibronectin in liver tissue.
  • the most common pathogenic conditions of liver fibrosis include chronic viral hepatitis, alcoholic liver disease, non-alcoholic steatohepatitis (NASH) and autoimmune hepatitis.
  • Liver fibrosis is the common pathological basis of various chronic liver diseases. Without effective intervention, liver fibrosis will evolve into cirrhosis and liver cancer. In recent years, studies have found that intervention in the process of liver fibrosis can effectively reverse liver fibrosis. Therefore, early detection of liver fibrosis is extremely important to prevent liver cirrhosis and liver cancer.
  • liver biopsy is still the standard method for diagnosing liver fibrosis, but invasive examination has disadvantages such as many complications, limited sampling, difficulty in dynamic monitoring, patient resistance, and being affected by the level of the observer.
  • various non-invasive diagnostic methods for liver fibrosis have been used clinically, which has significantly improved the diagnosis rate of liver fibrosis.
  • the detection of serological indicators is a commonly used diagnostic method for liver fibrosis.
  • liver fibrosis Currently commonly used serum markers of liver fibrosis include platelet count, coagulation factors, transaminase, type procollagen, alpha-2 macroglobulin, hyaluronic acid, carrier protein A1, haptoglobin, matrix metalloproteinase-1 tissue inhibitor and many more.
  • a single index has limited effect in diagnosing fibrosis, so multiple indexes are often combined to judge liver fibrosis. Therefore, the discovery of new diagnostic markers is of great significance for the diagnosis of liver fibrosis.
  • Leukocyte-derived chemokine 2 is a 16kDa secreted protein containing 133 amino acids and 3 intramolecular disulfide bonds (Ito et al., 2003). It was originally identified as a neutrophil chemokine. It can stimulate the growth of chondrocytes and osteoblasts (Yamagoe et al., 1996).
  • LECT2 is involved in many pathological conditions, such as sepsis (Lu et al., 2013), diabetes (Lan et al., 2014), systemic amyloidosis (Mereuta et al., 2014), liver cancer (Ong et al., 2011), Non-alcoholic fatty liver disease (NAFLD) (Yoo et al., 2017), and expansion/activation of hematopoietic stem cells (Lu et al., 2016).
  • NASH Non-alcoholic fatty liver disease
  • the purpose of the present invention is to provide a biological marker for liver fibrosis, a therapeutic target and use thereof.
  • LECT2 as a serum marker for liver fibrosis and cirrhosis.
  • the diagnostic reagent can be used to classify the clinical progress of patients with liver cirrhosis; further, the classification is Child-Pugh classification.
  • the level of serum LECT2 protein is positively correlated with grade.
  • the reagent in the preparation of a medicine, the reagent being used to inhibit the expression of LECT2, and the medicine being used for at least one of the following purposes:
  • the medicine is used for at least one of the following purposes:
  • liver fibrosis-promoting factor includes at least one of ⁇ -SMA, TGF ⁇ 1, ET1, IL33, FN1, IL11, and COL4.
  • inhibiting the expression of LECT2 is achieved by silencing LECT2; further, the silencing is achieved by at least one of shRNA, antisense nucleic acid, ribozyme, dominant negative mutation, CRISPR-Cas9, CRISPR-Cpf1, and zinc finger nuclease .
  • the reagent in the preparation of a medicine, the reagent being used to promote the expression of LECT2, and the medicine being used for at least one of the following purposes:
  • a method for screening drugs for the treatment of liver fibrosis comprising: administering candidate drugs to an animal model of liver fibrosis, and detecting the expression level of LECT2 before and after the administration, wherein the expression level of LECT2 after administration is lower than The expression level of LECT2 before administration is an indication that the candidate drug is the target drug.
  • a method for screening drugs for the treatment of liver fibrosis comprising: administering candidate drugs to an animal model of liver fibrosis, and detecting the binding of LECT2 and Tie1 after the administration, wherein the combination of LECT2 and Tie1 after administration Blocked binding is an indication that the candidate drug is the target drug.
  • the present invention discloses the function and mechanism of LECT2 in liver fibrosis. Specifically, after binding to Tie1, LECT2 interrupts Tie1/Tie2 heterodimerization, promotes Tie2/Tie2 homodimerization, and promotes Tie2 phosphorylation , Activate PPAR signal transduction, and inhibit the migration of vascular endothelial cells and blood vessel formation.
  • LECT2 overexpression inhibits portal vein angiogenesis, promotes sinusoidal capillaries and worsens fibrosis, and these changes are reversed in Lect2-KO mice.
  • Adeno-associated virus vector serotype 9 (AAV9)-LECT2 shRNA treatment significantly attenuated fibrosis.
  • the up-regulation of LECT2 is related to the stages of advanced human liver fibrosis.
  • the present invention discloses that targeted LECT2/Tie1 signal transduction can be used as a potential therapeutic target for liver fibrosis, and the serum LECT2 level can be used as a potential biomarker for diagnosing liver fibrosis.
  • LECT2 inhibits vascular endothelial cell function and angiogenesis, and promotes hepatic sinusoidal capillaries
  • LECT2 inhibits vascular endothelial cell function and angiogenesis, and promotes hepatic sinusoidal capillaries
  • FIG. 10 LECT2 dissociates Tie1/Tie2 heterodimer to promote Tie2/Tie2 homodimer
  • FIGe1 is necessary for LECT2 to regulate vascular endothelial cell function and liver fibrosis;
  • FIG. 15 AAV9-LECT2-shRNA reduces liver fibrosis
  • FIG. 16 LECT2 expression in mouse liver treated with AAV9-LECT2-shRNA.
  • Example 1 The expression level of LECT2 is positively correlated with the severity of liver fibrosis
  • Example 2 LECT2 promotes liver fibrosis
  • mice were injected with a lentiviral vector overexpressing LECT2 cDNA (Lenti-LECT2) (via tail vein), and mice injected with a blank lentiviral vector (Lenti-V) were used as controls.
  • LECT2 lentiviral vector overexpressing LECT2 cDNA
  • Lenti-V blank lentiviral vector
  • liver fibrosis mouse models including BDL-, DDC-, and MCD-induced liver fibrosis models.
  • LECT2 was elevated (Figure 4A ⁇ F).
  • Lect2 knockout mice liver fiber Chemicals are weakened ( Figure 4G ⁇ I).
  • Hepatic fibrosis factors ⁇ -SMA, TGF ⁇ 1, ET1, IL33, FN1, IL11, and COL4 are all increased in the liver fibrosis model of LECT2 overexpression mice, and decreased in the liver fibrosis model of LECT2 knockout mice ( Figure 5A, B), the expression of liver fibrosis factors increased after re-expression of LECT2 in Lect2-KO mice using Lenti-LECT2 ( Figure 5C).
  • the immortalized vascular endothelial cell line EA.hy926 was used in our in vitro study.
  • EA.hy926 cells treated with rLECT2 the mRNA levels of TGF ⁇ 1, FN1, ET1, IL33, IL11 and COL4 increased, but the mRNA level of eNOS decreased ( Figure 5G).
  • knockdown of LECT2 with siRNA (Figure 5H) reversed these effects ( Figure 5I).
  • Example 3 LECT2 inhibits vascular endothelial cell function and angiogenesis
  • LECT2 inhibited vascular endothelial cell migration and angiogenesis (Figure 6A-F).
  • LECT2 overexpression inhibited the number of portal vessels ( Figure 6G, H).
  • LECT2 knockout mice increased the number of portal vessels ( Figure 6J, K). The same is true in other models ( Figure 7A ⁇ I).
  • Example 4 LECT2 promotes hepatic sinusoidal capillarity
  • Example 6 dissociates Tie1/Tie2 heterodimer to promote Tie2/Tie2 homodimer
  • Tie1/Tie2 heterodimerization is critical to its downstream signal transmission (Saharinen et al., 2005; Seegar et al., 2010).
  • LECT2/Tie1 interaction affects the Tie1/Tie2 association.
  • rLECT2 inhibited Tie1/Tie2 binding ( Figure 10A).
  • the NanoBiT TM protein: protein interaction system was used to fuse large BiT (LgBiT) and small BiT (SmBiT) subunits with Tie1 or Tie2 ( Figure 10B).
  • LECT2-siRNA was used to knock out endogenous LECT2 in 293T cells ( Figure 11A), and then cells were transfected with Tie1/LgBiT and Tie2/SmBiT for Tie1-Tie2 interaction measurement.
  • rLECT2 reduced the luminescence signal in a dose-dependent manner ( Figure 10C).
  • NanoBiT TM system to evaluate the Tie1/Tie1 and Tie2/Tie2 interactions ( Figure 11B), and found that rLECT2 reduces Tie1/Tie2 heterodimers and increases Tie2/Tie2 homodimers, while Tie1/Tie1 is the same.
  • the source dimer was not affected by rLECT2 (Figure 10D).
  • the overexpression of rLECT2 protein and LECT2 both promoted the phosphorylation of Tie2 and MAPK p38, but inhibited the phosphorylation of Tie1 ( Figure 10E, Figure 11C).
  • Knockout of LECT2 reduced the phosphorylation of Tie2 and MAPK p38, but increased the phosphorylation of Tie1 ( Figure 10F, Figure 11D).
  • the phosphorylation of Tie2 by LECT2 is dose- and time-dependent (Figure 10E, Figure 11E).
  • Example 7 Tie1 is necessary for LECT2 to regulate vascular endothelial cell function and liver fibrosis
  • Example 8 LECT2 activates the PPAR signal pathway
  • LECT2-Tie1 is an important signal pathway that promotes liver fibrosis through MAPK/PPAR/MMP/VE-cadherin.
  • Example 9 Inhibition of LECT2 can treat liver fibrosis
  • AAV9-LECT2 shRNA or control AAV9-Ctrl shRNA was injected into C57BL/6 mice, and then CCl4 was injected twice a week for 3 weeks (the experimental design is shown in Figure 15A).
  • mice treated with AAV9-LECT2 shRNA Figure 16A-D
  • Figure 15B liver fibrosis was reduced
  • Figure 15C the mRNA expression of fibrosis factors was significantly reduced
  • Figure 15D-F increased portal vein angiogenesis and decreased blood sinus capillary vascularization were also observed in mice infected with AAV9-LECT2 shRNA
  • an increase in the frequency of open windows in LSEC was observed in AAV9-LECT2 shRNA, but not in control mice ( Figure 15G, H).
  • FIG. 15I Treatment of mice with AAV9-LECT2 shRNA significantly reduced the liver expression of LECT2 (Figure 16E-H), attenuated liver fibrosis (Figure 15J), and reduced the mRNA level of fibrotic factors ( Figure 15K). Compared with control mice, increased portal vein angiogenesis and decreased sinusoidal capillation were observed in mice treated with AAV9-LECT2 shRNA (Figure 15L-N).

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Abstract

L'invention concerne une utilisation de LECT2 en tant que marqueur sérique de la fibrose et de la cirrhose du foie, une application d'un réactif qui inhibe l'expression de LECT2 dans la préparation d'un médicament, et un procédé de criblage d'un médicament.
PCT/CN2019/118737 2019-08-27 2019-11-15 Marqueur biologique de la fibrose du foie, cible thérapeutique et son utilisation Ceased WO2021035987A1 (fr)

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CN110646615B (zh) * 2019-08-27 2021-07-13 南方医科大学 肝纤维化的生物学标志物、治疗靶点及其用途
CN113917157B (zh) * 2021-09-30 2023-07-04 同济大学 一种gmfb作为干预肝硬化治疗靶向的应用
CN114895042A (zh) * 2022-06-01 2022-08-12 云南大学 S100a11基因或蛋白作为生物标记物在制备诊断、预防或治疗肝纤维化的产品的应用
CN117165669A (zh) * 2023-04-04 2023-12-05 上海交通大学医学院附属仁济医院 用于检测肝纤维化的标志物组合的应用

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