WO2023120971A1 - ÉCHAFAUDAGE, CHARGÉ DE CELLULES SOUCHES DÉRIVÉES DU TISSU ADIPEUX SUREXPRIMANT PGC-1α, POUR LA PRÉVENTION OU LE TRAITEMENT D'UNE FIBROSE HÉPATIQUE - Google Patents

ÉCHAFAUDAGE, CHARGÉ DE CELLULES SOUCHES DÉRIVÉES DU TISSU ADIPEUX SUREXPRIMANT PGC-1α, POUR LA PRÉVENTION OU LE TRAITEMENT D'UNE FIBROSE HÉPATIQUE Download PDF

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WO2023120971A1
WO2023120971A1 PCT/KR2022/017468 KR2022017468W WO2023120971A1 WO 2023120971 A1 WO2023120971 A1 WO 2023120971A1 KR 2022017468 W KR2022017468 W KR 2022017468W WO 2023120971 A1 WO2023120971 A1 WO 2023120971A1
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scaffold
liver fibrosis
stem cells
preventing
liver
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Korean (ko)
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김세준
김옥희
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가톨릭대학교 산학협력단
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/28—Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/38—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/38—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells
    • A61L27/3804—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells characterised by specific cells or progenitors thereof, e.g. fibroblasts, connective tissue cells, kidney cells
    • A61L27/3834—Cells able to produce different cell types, e.g. hematopoietic stem cells, mesenchymal stem cells, marrow stromal cells, embryonic stem cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/56—Porous materials, e.g. foams or sponges
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/28—Materials or treatment for tissue regeneration for liver reconstruction

Definitions

  • the present invention relates to a scaffold for preventing or treating hepatic fibrosis, and more particularly, to a PGC-1 ⁇ -overexpressing fat prepared by transforming adipose-derived stem cells with a vector containing a gene encoding PGC-1 ⁇ . It relates to a scaffold for preventing or treating hepatic fibrosis loaded with derived stem cells.
  • Liver fibrosis is caused by repeated chronic liver disease, which results in the activation of hepatic stellate cells (HSC) due to liver tissue damage and infiltration of inflammatory cells. It refers to the formation of a thick fibrous septa in the liver.
  • HSC hepatic stellate cells
  • liver fibrosis is generally reversible, consists of thin fibrils, and does not form nodules. In addition, if the cause of liver damage disappears, normal recovery may be possible. However, if this liver fibrosis mechanism continues repeatedly, crosslinking between connective tissues increases, thick fibrils accumulate, and the normal structure of liver lobules is lost to form nodules. It progresses to irreversible cirrhosis, and if cirrhosis persists, it eventually leads to liver cancer.
  • stem cell research has shown the possibility of tissue regeneration and has made great progress so far, but clinical application is very slow due to the absence of an “efficient delivery system that supplies a large amount of stem cells”.
  • stem cells have several disadvantages in clinical applications. One is short-lived, where most stem cells are lost within just a few days after transplantation. In addition, stem cells can potentially transform into malignant tumors.
  • numerous studies have suggested that the secretome secreted by stem cells may have similar therapeutic potential to that of stem cells, since the main operating mechanism of stem cells is secretome-mediated.
  • the present inventors searched for a way to efficiently deliver a large amount of stem cells to the human body through a scaffold, and in particular, "efficacy” and “safety” in the treatment of liver fibrosis of stem cells ” was studied at the same time. Accordingly, the present inventors have developed a coactivator, PGC-1 ⁇ (peroxisome proliferator-activated receptor gamma coactivator -1 alpha) was transduced into stem cells to enhance the therapeutic ability of stem cells. In addition, the present inventors introduced a scaffold loaded with stem cells as a method of enhancing the "safety" of stem cell therapy, thereby enhancing safety due to the effect of trapping stem cells in the scaffold, and secreting the secretome from stem cells. Since it can move freely outside the scaffold, a safer treatment effect can be expected.
  • PGC-1 ⁇ peroxisome proliferator-activated receptor gamma coactivator -1 alpha
  • PGC-1 ⁇ peroxisome proliferator-activated receptor gamma coactivator-1 alpha
  • adipose-derived stem cells to transform them into PGC-1 ⁇ -overexpressing adipose-derived stem cells
  • Extracellular matrix (ECM) Extracellular matrix (ECM) was mounted on a scaffold very similar to the liver fibrosis mouse model, and as a result of studying the treatment effect of liver fibrosis, it was confirmed that it had excellent anti-fibrotic activity, and the present invention was completed.
  • the present inventors studied whether a scaffold loaded with adipose-derived stem cells overexpressing PGC-1 ⁇ prepared by transforming adipose-derived stem cells with a vector containing a gene encoding PGC-1 ⁇ could be used for the treatment of liver fibrosis
  • the present invention was completed by experimentally demonstrating and confirming that the scaffold had excellent anti-fibrotic activity in a liver fibrosis animal model.
  • an object of the present invention is to provide a scaffold for preventing or treating hepatic fibrosis loaded with stem cells transformed with a vector containing a gene encoding PGC-1 ⁇ (peroxisome proliferator-activated receptor gamma coactivator-1 alpha). is in providing
  • Another object of the present invention is to provide a pharmaceutical composition for preventing or treating hepatic fibrosis comprising, as an active ingredient, a scaffold loaded with stem cells transformed with a vector containing a gene encoding PGC-1 ⁇ . .
  • Another object of the present invention is to prevent liver fibrosis, which includes transforming a vector containing a gene encoding PGC-1 ⁇ into isolated stem cells and mounting the transformed stem cells on a scaffold, or It is to provide a method for manufacturing a scaffold for treatment.
  • the present invention provides a scaffold for preventing or treating hepatic fibrosis, in which stem cells transformed with a vector containing a gene encoding PGC-1 ⁇ (peroxisome proliferator-activated receptor gamma coactivator-1 alpha) are loaded.
  • PGC-1 ⁇ peroxisome proliferator-activated receptor gamma coactivator-1 alpha
  • the present invention provides a pharmaceutical composition for preventing or treating hepatic fibrosis, comprising as an active ingredient a scaffold loaded with stem cells transformed with a vector containing a gene encoding PGC-1 ⁇ .
  • the present invention provides a kit for preventing or treating hepatic fibrosis, including a scaffold loaded with stem cells transformed with a vector containing a gene encoding PGC-1 ⁇ .
  • the present invention comprises the steps of transforming a vector containing a gene encoding PGC-1 ⁇ into isolated stem cells; And it provides a method for preparing a scaffold for preventing or treating hepatic fibrosis, comprising the step of mounting the transformed stem cells on the scaffold.
  • the present invention provides the use of a scaffold loaded with stem cells transformed with a vector containing a gene encoding PGC-1 ⁇ for the prevention or treatment of hepatic fibrosis.
  • the present invention provides a method for preventing or treating liver fibrosis, comprising administering to a subject in need thereof a scaffold loaded with stem cells transformed with a vector containing a gene encoding PGC-1 ⁇ . to provide.
  • the present invention provides the use of a scaffold loaded with stem cells transformed with a vector containing a gene encoding PGC-1 ⁇ for the manufacture of a drug for treating liver fibrosis.
  • the stem cell may be an adipose-derived stem cell (ASC), but is not limited thereto.
  • ASC adipose-derived stem cell
  • the scaffold may include serum-derived components, but is not limited thereto.
  • the liver fibrosis may be caused by liver toxin, but is not limited thereto.
  • the liver toxin is a substance that causes damage or disease to liver tissue, and is thioacetamide (TAA), carbon tetrachloride (CCl4), tert-butyl hydroperoxide (tBHP), acetaminophen ( acetaminophen), tacrine, rubratoxin B, and hydrogen peroxide (H 2 O 2 ), but may be one or more selected from the group consisting of, but is not limited thereto.
  • TAA thioacetamide
  • CCl4 carbon tetrachloride
  • tBHP tert-butyl hydroperoxide
  • acetaminophen acetaminophen
  • tacrine acetaminophen
  • rubratoxin B rubratoxin B
  • hydrogen peroxide H 2 O 2
  • the present invention relates to a scaffold for preventing or treating hepatic fibrosis in which stem cells transformed with a vector containing a gene encoding PGC-1 ⁇ (peroxisome proliferator-activated receptor gamma coactivator-1 alpha) are loaded.
  • the scaffold according to the present invention induces a decrease in alanine transaminases (ALT) blood concentration, a decrease in the expression of liver fibrosis markers, an increase in the expression of cell proliferation markers, and an increase in the expression of anti-apoptotic markers, resulting in excellent liver fibrosis Since it shows a therapeutic effect, it can be used for the prevention, treatment, or improvement of various diseases related to liver fibrosis.
  • ALT alanine transaminases
  • Figure 1 shows mouse liver tissue obtained at 3 weeks after transplanting a scaffold loaded with adipose-derived stem cells transformed with PGC-1 ⁇ into a liver fibrosis mouse model prepared by treatment with thioacetamide (TAA). It shows the image of the state (“TAA+ASC” refers to the group in which PGC-1 ⁇ -transformed adipose-derived stem cells were injected into the tail vein of liver fibrosis model mice, and “TAA+Scaffold “Equipped ASC” refers to a group transplanted with a scaffold loaded with adipose-derived stem cells transformed with PGC-1 ⁇ into the epidermis of a liver fibrosis model mouse).
  • TAA+ASC refers to the group in which PGC-1 ⁇ -transformed adipose-derived stem cells were injected into the tail vein of liver fibrosis model mice
  • TAA+Scaffold “Equipped ASC” refers to a group transplanted with a scaffold loaded with
  • FIG. 2 shows alanine transaminases confirmed through serological tests at 1, 2, and 3 weeks after transplanting a scaffold loaded with adipose-derived stem cells transformed with PGC-1 ⁇ into a liver fibrosis mouse model prepared by TAA treatment. It represents the blood concentration of (ALT) (U/L) (“TAA+ASC” means a group in which PGC-1 ⁇ -transformed adipose-derived stem cells were injected into the tail vein of liver fibrosis model mice. and “TAA + scaffold-mounted ASC” refers to a group transplanted with a scaffold loaded with adipose-derived stem cells transformed with PGC-1 ⁇ into the epidermis of a liver fibrosis model mouse).
  • FIG 3 shows the results of H&E staining and analysis of mouse liver tissue obtained at 3 weeks after transplanting a scaffold equipped with adipose-derived stem cells transformed with PGC-1 ⁇ into a liver fibrosis mouse model prepared by TAA treatment.
  • TAA+ASC refers to a group in which PGC-1 ⁇ -transformed adipose-derived stem cells were injected into the tail vein of liver fibrosis model mice
  • TAA+scaffold-mounted ASC refers to liver fibrosis Refers to a group transplanted with a scaffold loaded with adipose-derived stem cells transformed with PGC-1 ⁇ into the epidermis of a model mouse).
  • Figure 4 shows ⁇ -SMA, a fibrosis marker, in mouse liver tissue obtained at 3 weeks after transplanting a scaffold equipped with adipose-derived stem cells transformed with PGC-1 ⁇ into a liver fibrosis mouse model prepared by TAA treatment.
  • TAA+ASC refers to a group in which PGC-1 ⁇ -transformed adipose-derived stem cells were injected into the tail vein of liver fibrosis model mice
  • TAA+scaffold “Equipped ASC” refers to a group transplanted with a scaffold loaded with adipose-derived stem cells transformed with PGC-1 ⁇ into the epidermis of a liver fibrosis model mouse).
  • TAA+ASC refers to a group in which adipose-derived stem cells transformed with PGC-1 ⁇ were injected into the tail vein of liver fibrosis model mice
  • TAA+ASC with scaffold means a group transplanted with a scaffold loaded with adipose-derived stem cells transformed with PGC-1 ⁇ into the epidermis of a liver fibrosis model mouse).
  • ASC is PGC-1 ⁇
  • ASC hepatic fibrosis marker
  • the present invention is to prevent or treat liver fibrosis loaded with stem cells transformed with a vector containing a gene encoding peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 ⁇ ) provides a scaffold for
  • the term “PGC-1 ⁇ ” regulates mitochondrial biosynthesis and function by coupling with nuclear respiratory factor-1 (NRF-1), mitochondrial DNA transcription factor A (mtTFA), and other metabolic transcriptional nuclear factors, resulting in As such, it regulates the expression and activity of mitochondrial antioxidant enzymes.
  • NEF-1 nuclear respiratory factor-1
  • mtTFA mitochondrial DNA transcription factor A
  • the PGC-1 ⁇ is encoded by the PPARGC1A gene.
  • the PGC-1 ⁇ is a known protein, and specific information about it can be found in a public database such as Uniprot (registration number: Q5VV67). Therefore, those skilled in the art can prepare a gene encoding PGC-1 ⁇ and a vector containing the gene by referring to a known amino acid sequence or a nucleotide sequence encoding the same.
  • coding refers to a polypeptide as "coding” when it can be transcribed and/or translated to produce mRNA for the polypeptide and/or fragment thereof, either in its native state or when manipulated by methods well known to those skilled in the art. Refers to polynucleotides referred to as ".
  • polynucleotide refers to a polymeric form of nucleotides of any length, either ribonucleotides or deoxyribonucleotides.
  • polynucleotide refers to single, double, or multi-stranded DNA or RNA, genomic DNA, cDNA, DNA-RNA hybrids, or purine and pyrimidine bases or other naturally, chemically or biochemically modified, unnatural, or polymers comprising derivatized nucleotide bases.
  • polynucleotides encoding the proteins of interest are amino acids of proteins expressed from the coding region due to codon degeneracy or considering codons preferred in organisms intended to express the proteins.
  • Various modifications can be made to the coding region within the range that does not change the sequence, and various modifications can be made to the region other than the coding region within the range that does not affect gene expression, and such modified genes are also within the scope of the present invention. Included in will be well understood by those skilled in the art.
  • nucleic acid bases may be mutated by substitution, deletion, insertion, or a combination thereof, and these are also included in the scope of the present invention.
  • Stem cells transformed with a vector containing the gene encoding PGC-1 ⁇ according to the present invention are cells genetically engineered with the vector, and may be transduced, transformed, or transformed with the vector. Indicates an infected host cell.
  • the cell can express the introduced nucleic acid molecule or vector to produce the fusion protein according to the present invention.
  • suitable cells mention may be made of bacterial cells such as Escherichia coli, fungal cells such as yeast, insect cells such as Sf9, animal cells such as CHO or COS, plant cells and the like. The selection of a suitable host is believed to be obvious to one skilled in the art from the teachings herein.
  • Stem cells transformed with the vector containing the gene encoding PGC-1 ⁇ of the present invention can express (produce) the PGC-1 ⁇ protein from the vector. That is, the transformed stem cells are stem cells that overexpress PGC-1 ⁇ . Preferably, the transformed stem cells may have enhanced mitochondrial function. For example, the amount of biosynthesis of the transformed mitochondria, the amount of cellular respiration by mitochondria, the amount of ATP production by mitochondria, etc. may be increased.
  • the recombinant vector containing the polynucleotide may use various vectors known in the art, and a promoter, terminator, and enhancer may be used depending on the type of host cell to produce the protein.
  • An expression control sequence such as an enhancer, a sequence for membrane targeting or secretion, etc. may be appropriately selected and combined in various ways according to the purpose.
  • Vectors of the present invention include, but are not limited to, plasmid vectors, cosmid vectors, bacteriophage vectors and viral vectors. Suitable vectors include expression control elements such as promoters, operators, initiation codons, stop codons, polyadenylation signals and enhancers, as well as signal sequences or leader sequences for membrane targeting or secretion, and may be prepared in various ways depending on the purpose.
  • the vector contains an antibiotic resistance gene commonly used in the art as a selection marker, for example, ampicillin, gentamicin, carbenicillin, chloramphenicol, streptomycin, kanamycin, geneticin, neomycin, There are genes for resistance to puromycin and tetracyclines.
  • an antibiotic resistance gene commonly used in the art as a selection marker, for example, ampicillin, gentamicin, carbenicillin, chloramphenicol, streptomycin, kanamycin, geneticin, neomycin.
  • the recombinant vector may be transformed or transfected into stem cells.
  • the term “transformation” or “transfection” refers to a process in which a foreign nucleotide sequence is introduced into a cell.
  • a known transfection method can be used as a transformation method, and for example, a microinjection method (Capecchi, M.R., Cell 22, 479 (1980)), a calcium phosphate precipitation method (Graham, F.L. et al., Virology 52, 456 (1973)), electroporation (Neumann, E. et al., EMBO J. 1, 841 (1982)), liposome-mediated transfection (Wong, T.K. et al., Gene, 10, 87 (1980)), DEAE-dextran treatment (Gopal, Mol. Cell Biol. 5, 1188-1190 (1985)), and gene bombardment (Yang et al., Proc. Natl. Acad. Sci. USA 87 , 9568-9572 (1990)), etc., but are not limited thereto.
  • the step of selecting transformed cells can be easily performed using the phenotype expressed by the selection marker of the vector described above.
  • the selectable marker is a specific antibiotic resistance gene
  • transformed cells can be easily selected by culturing the transformant in a medium containing the antibiotic.
  • stem cell refers to a cell that has the ability to continue to proliferate, that is, the ability to self-renew, and has the ability to differentiate into various types of specific cell types, including embryonic stem cells and induced pluripotent stem cells. cells and adult stem cells.
  • embryonic stem cell refers to embryonic stem cells derived from a fertilized egg produced by combining sperm, which is a male reproductive cell, and egg, which is a female reproductive cell.
  • Embryonic stem cells are obtained from the inner cell aggregation of blastocysts before implantation and have the ability to differentiate into cells of all tissues, but are undifferentiated cells that can proliferate indefinitely in an undifferentiated state if culture conditions are given.
  • cell differentiation is induced in the desired direction and can be used as a cell therapy for diseases such as nerve, diabetes, and hematology, so that a single embryonic stem cell line is expected to be used for the treatment of numerous patients.
  • induced pluripotent stem cells refers to cells induced to have pluripotent differentiation potential through an artificial dedifferentiation process, and is also referred to as induced pluripotent stem cells (iPSCs).
  • iPSCs induced pluripotent stem cells
  • adult stem cells refers to primitive cells isolated from mammalian tissues, including humans, just before differentiation, which have the ability to proliferate indefinitely and various types of cells (e.g., fat cells, cartilage). Cells, muscle cells, bone cells, etc.) are stem cells that can differentiate.
  • the stem cells may be adipose-derived stem cells (ASC).
  • ASC adipose-derived stem cells
  • the term "adipose-derived stem cell (ASC)” is a stem cell isolated from adipose tissue that can differentiate into most mesenchymal cells such as adipocytes, osteoblasts, chondroblasts, and myofibroblasts. , pre-adipocytes, stromal cells, multipotent adipose-derived cells, or adipose-derived adult stem cells.
  • the adipose-derived stem cells may be derived from mammals including, but not limited to, pigs, cattle, primates, and humans that can be transplanted into humans.
  • mesenchymal stem cells represent the typical adult stem cell
  • adipose-derived stem cells are usually used as adipose-derived mesenchymal stem cells do.
  • Mesenchymal stem cells are routinely isolated from bone marrow (BM) aspirates, validated as pluripotent cell populations, and can be induced to express fat, bone and cartilage markers.
  • adipose-derived stem cell is one of the most utilized mesenchymal stem cells (MSC), and is easier to collect than bone marrow, exists in large quantities, and is available for various surgeries. It can be obtained widely through the use of the bone marrow, and has many advantages, such as the acquisition rate is about 1000 times higher than that of bone marrow (2% vs 0.002%), and it has a fast proliferation rate.
  • the scaffold may include serum-derived components or be composed of serum-derived components.
  • the scaffold may be a support for 3-dimensional cell culture, and a scaffold known in the art as well as a scaffold improved or newly developed to be more suitable for cell culture may be applied without limitation.
  • the scaffold of the present invention is an extracellular matrix (ECM)-like scaffold, and may have characteristics very similar to decellularized actual liver tissue ECM.
  • the scaffold may include serum-derived proteins.
  • the serum-derived proteins include serum albumin, lipoprotein, haptoglobin, transferrin, ceruloplasmin, immunoglobulin, various complements, fibrinogen, prothrombin, plasminogen, kininogen, prekalikrein, fibronectin, ⁇ 2-HS- It may be selected from glycoproteins, angiotensinogen, hormones, and the like, but is not limited thereto.
  • the scaffold may be prepared by treating serum-derived proteins with a cross-linking agent to induce cross-linking of the proteins and then reducing them with a reducing agent.
  • the scaffold may be a porous cell scaffold. The pore size of the scaffold may be 150 to 400 ⁇ m.
  • the present inventors have demonstrated a more excellent anti-fibrotic effect when the transfected stem cells are loaded on a scaffold and administered than when the stem cells transformed with the PGC1- ⁇ expression vector are directly administered to a mouse model of hepatic fibrosis. was confirmed to appear.
  • liver fibrosis may be used interchangeably with the term “liver fibrosis”.
  • hepatic fibrosis or hepatic fibrotic disease refers to a disease in which the shape or function of the liver is damaged due to accumulation of fibrosis due to continuous damage to liver cells or liver tissue.
  • the fibrosis is a phenomenon in which excessive fibrous connective tissue is formed in an organ or tissue in a wound healing process for repeated damage to cells or tissues.
  • liver cirrhosis may result.
  • liver fibrosis is reversible, composed of thin fibrils, and is known to have no nodule formation.
  • liver cirrhosis is pathologically a chronic disease accompanied by necrosis, inflammation, and fibrosis of hepatocytes, and ultimately progresses to diseases such as liver cirrhosis complications such as liver decompensation and liver cancer, leading to death.
  • the present inventors have demonstrated that a scaffold loaded with stem cells (i.e., stem cells overexpressing PGC-1 ⁇ ) transfected with a vector containing a gene encoding PGC-1 ⁇ according to the present invention can induce hepatic fibrosis It was confirmed that liver fibrosis was inhibited and liver damage was improved in the model mouse. Therefore, the scaffold loaded with transformed stem cells according to the present invention can treat liver fibrosis by inhibiting and improving liver tissue fibrosis. In addition, the present invention can exert a therapeutic effect on diseases caused or induced due to liver fibrosis, such as liver cirrhosis, steatohepatitis, and non-alcoholic steatohepatitis.
  • diseases caused or induced due to liver fibrosis such as liver cirrhosis, steatohepatitis, and non-alcoholic steatohepatitis.
  • the liver fibrosis may be caused by liver toxin.
  • the liver toxin is a substance that causes damage or disease to liver tissue, and includes thioacetamide (TAA), carbon tetrachloride (CCl4), tert-butyl hydroperoxide (tBHP), acetaminophen, and tacrine. It may be one or more selected from the group consisting of (tacrine), rubratoxin B, and hydrogen peroxide (H 2 O 2 ), but is not limited thereto.
  • a pharmaceutical composition for preventing or treating hepatic fibrosis comprising, as an active ingredient, a scaffold loaded with stem cells transformed with a vector containing the gene encoding PGC-1 ⁇ do.
  • the information on the scaffold loaded with stem cells transformed with a vector containing the gene encoding PGC-1 ⁇ is another aspect of the present invention described above, “prevention of liver fibrosis or Since it is the same as the content described in "Therapeutic scaffold", these are used and will not be described redundantly.
  • the content of the scaffold loaded with the transformed stem cells in the composition of the present invention can be appropriately adjusted according to the symptoms of the disease, the progress of the symptoms, the condition of the patient, etc., for example, 0.0001 to 99.9 based on the weight of the total composition. % by weight, or 0.001 to 50% by weight, but is not limited thereto.
  • the content ratio is a value based on the dry amount after removing the solvent.
  • the pharmaceutical composition according to the present invention may further include suitable carriers, excipients and diluents commonly used in the manufacture of pharmaceutical compositions.
  • the excipient may be, for example, one or more selected from the group consisting of a diluent, a binder, a disintegrant, a lubricant, an adsorbent, a moisturizer, a film-coating material, and a controlled release additive.
  • compositions according to the present invention are powders, granules, sustained-release granules, enteric granules, solutions, eye drops, elsilic agents, emulsions, suspensions, spirits, troches, perfumes, and limonadese, respectively, according to conventional methods.
  • tablets, sustained-release tablets, enteric tablets, sublingual tablets, hard capsules, soft capsules, sustained-release capsules, enteric capsules, pills, tinctures, soft extracts, dry extracts, fluid extracts, injections, capsules, perfusate It can be formulated and used in the form of external preparations such as warning agents, lotions, pasta agents, sprays, inhalants, patches, sterile injection solutions, or aerosols, and the external agents are creams, gels, patches, sprays, ointments, and warning agents.
  • lotion, liniment, pasta, or cataplasma may have formulations such as the like.
  • Carriers, excipients and diluents that may be included in the pharmaceutical composition according to the present invention include lactose, dextrose, sucrose, oligosaccharide, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, 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 commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants.
  • Additives for the liquid formulation according to the present invention include water, dilute hydrochloric acid, dilute sulfuric acid, sodium citrate, sucrose monostearate, polyoxyethylene sorbitol fatty acid esters (tween esters), polyoxyethylene monoalkyl ethers, lanolin ethers, Lanolin esters, acetic acid, hydrochloric acid, aqueous ammonia, ammonium carbonate, potassium hydroxide, sodium hydroxide, prolamine, polyvinylpyrrolidone, ethyl cellulose, sodium carboxymethyl cellulose, and the like may be used.
  • a solution of white sugar, other sugars, or a sweetener may be used, and aromatics, coloring agents, preservatives, stabilizers, suspending agents, emulsifiers, thickeners, etc. may be used as necessary.
  • Purified water may be used in the emulsion according to the present invention, and emulsifiers, preservatives, stabilizers, fragrances, etc. may be used as needed.
  • Suspension agents according to the present invention include acacia, tragacantha, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, sodium alginate, hydroxypropylmethylcellulose (HPMC), HPMC 1828, HPMC 2906, HPMC 2910, etc. Agents may be used, and surfactants, preservatives, stabilizers, colorants, and fragrances may be used as needed.
  • Injections according to the present invention include distilled water for injection, 0.9% sodium chloride injection, IV injection, dextrose injection, dextrose + sodium chloride injection, PEG, lactated IV injection, ethanol, propylene glycol, non-volatile oil-sesame oil , solvents such as cottonseed oil, peanut oil, soybean oil, corn oil, ethyl oleate, isopropyl myristate, and benzene benzoate; solubilizing agents such as sodium benzoate, sodium salicylate, sodium acetate, urea, urethane, monoethylacetamide, butazolidine, propylene glycol, twins, nijuntinamide, hexamine, and dimethylacetamide; buffers such as weak acids and their salts (acetic acid and sodium acetate), weak bases and their salts (ammonia and ammonium acetate), organic compounds, proteins, albumin, peptone, and gums; tonicity agents such as sodium chlor
  • the suppository according to the present invention includes cacao butter, lanolin, witapsol, polyethylene glycol, glycerogelatin, methylcellulose, carboxymethylcellulose, a mixture of stearic acid and oleic acid, subanal, cottonseed oil, peanut oil, palm oil, cacao butter + Cholesterol, Lecithin, Lannet Wax, Glycerol Monostearate, Tween or Span, Imhausen, Monolen (Propylene Glycol Monostearate), Glycerin, Adeps Solidus, Buytyrum Tego-G -G), Cebes Pharma 16, Hexalide Base 95, Cotomar, Hydroxycote SP, S-70-XXA, S-70-XX75 (S-70-XX95), Hyde Hydrokote 25, Hydrokote 711, Idropostal, Massa estrarium (A, AS, B, C, D, E, I, T), Massa-MF, Masupol, Masupol-15, Neos
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations contain at least one excipient, for example, starch, calcium carbonate, sucrose, etc. ) or by mixing lactose and gelatin.
  • excipients for example, starch, calcium carbonate, sucrose, etc.
  • lubricants such as magnesium stearate and talc are also used.
  • Liquid preparations for oral administration include suspensions, solutions for oral administration, emulsions, syrups, etc.
  • various excipients such as wetting agents, sweeteners, aromatics, and preservatives may be included.
  • Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried formulations, and suppositories.
  • Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used as non-aqueous solvents and suspending agents.
  • composition according to the present invention is administered in a pharmaceutically effective amount.
  • pharmaceutically effective amount means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level is the type of patient's disease, severity, activity of the drug, It may be determined according to factors including sensitivity to the drug, administration time, route of administration and excretion rate, duration of treatment, drugs used concurrently, and other factors well known in the medical field.
  • the pharmaceutical composition according to the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered single or multiple times. Considering all of the above factors, it is important to administer an amount that can obtain the maximum effect with the minimum amount without side effects, which can be easily determined by a person skilled in the art to which the present invention belongs.
  • the pharmaceutical composition of the present invention can be administered to a subject by various routes. All modes of administration can be envisaged, eg oral administration, subcutaneous injection, intraperitoneal administration, intravenous injection, intramuscular injection, paraspinal space (intrathecal) injection, sublingual administration, buccal administration, intrarectal insertion, vaginal It can be administered by intraoral insertion, ocular administration, otic administration, nasal administration, inhalation, spraying through the mouth or nose, dermal administration, transdermal administration, and the like.
  • the pharmaceutical composition of the present invention is determined according to the type of drug as an active ingredient together with various related factors such as the disease to be treated, the route of administration, the age, sex, weight and severity of the disease of the patient.
  • the effective amount of the composition according to the present invention may vary depending on the patient's age, sex, and weight, and is generally 0.001 to 150 mg per 1 kg of body weight, preferably 0.01 to 100 mg per day or every other day, or 1 It can be administered in 1 to 3 divided doses per day.
  • the dosage is not limited to the scope of the present invention in any way.
  • the administration of the pharmaceutical composition of the present invention is not to be administered locally to the liver tissue site where the disease to be treated has occurred. desirable.
  • “individual” means a subject in need of treatment of a disease, and more specifically, a human or non-human primate, mouse, rat, dog, cat, horse, cow, etc. of mammals.
  • administration means providing a given composition of the present invention to a subject by any suitable method.
  • prevention refers to any action that suppresses or delays the onset of a desired disease
  • treatment means that the desired disease and its resulting metabolic abnormality are improved or improved by administration of the pharmaceutical composition according to the present invention. All actions that are advantageously altered are meant, and “improvement” means any action that reduces a parameter related to a target disease, for example, the severity of a symptom, by administration of the composition according to the present invention.
  • the pharmaceutical composition of the present invention is prepared in unit dosage form by formulation using a pharmaceutically acceptable carrier and/or excipient according to a method that can be easily performed by those skilled in the art. or it may be prepared by incorporating into a multi-dose container.
  • the formulation may be in the form of a solution, suspension or emulsion in an oil or aqueous medium, or may be in the form of an extract, powder, granule, tablet or capsule, and may additionally contain a dispersing agent or stabilizer.
  • transforming the isolated stem cells with a vector containing a gene encoding PGC-1 ⁇ ; And mounting the transformed stem cells on the scaffold; provides a method for preparing a scaffold for preventing or treating hepatic fibrosis, including.
  • the stem cells may be adipose-derived stem cells (ASC).
  • ASC adipose-derived stem cells
  • the scaffold in the manufacturing method, may be composed of serum-derived components, is an extracellular matrix (ECM)-like scaffold, and has characteristics very similar to decellularized real liver tissue ECM.
  • ECM extracellular matrix
  • the liver fibrosis may be caused by liver toxin, and the liver toxin is a substance that causes damage or disease to liver tissue, thioacetamide (TAA) 1 selected from the group consisting of carbon tetrachloride (CCl4), tert-butyl hydroperoxide (tBHP), acetaminophen, tacrine, rubratoxin B, and hydrogen peroxide (H 2 O 2 ) It may be more than one species, but is not limited thereto.
  • TAA thioacetamide
  • CCl4 carbon tetrachloride
  • tBHP tert-butyl hydroperoxide
  • H 2 O 2 hydrogen peroxide
  • the present invention comprises the steps of transforming a vector containing a gene encoding PGC-1 ⁇ into isolated stem cells; And it provides a method for preparing a scaffold for preventing or treating hepatic fibrosis, comprising the step of mounting the transformed stem cells on the scaffold.
  • the present invention comprises the steps of (S1) transforming a vector containing a gene encoding PGC-1 ⁇ into isolated stem cells; and (S2) mounting the transformed stem cells on the scaffold.
  • the manufacturing method may further include culturing the scaffold loaded with the transformed stem cells after the step (S2).
  • the culturing may be performed for 1 hour to 52 hours, 1 hour to 48 hours, 12 hours to 52 hours, 12 hours to 48 hours, 24 hours to 52 hours, or 24 hours to 48 hours.
  • ASC Human adipose-derived stem cells
  • FBS Thermo Fisher Scientific
  • penicillin 100 U/mL penicillin
  • streptomycin Thermo Fisher Scientific
  • adipose-derived stem cells prepared by transforming ASC into ASC overexpressing PGC-1 ⁇ .
  • the ASC (PGC-1 ⁇ -ASC) transformed to overexpress PGC-1 ⁇ was cultured for 24 hours, then exchanged with DMEM low-glucose medium, and after 24 hours, PGC-1 ⁇ -ASC was separated from the culture plate After being loaded on a protinet scaffold (Danagreen) and cultured on the plate for 24 to 48 hours, the effect of the PGC-1 ⁇ -ASC loaded scaffold was confirmed in an animal model of hepatic fibrosis.
  • ALT alanine transaminase
  • H&E staining was first performed by the following deparaffinization process: After incubation of the slides in an oven at 60 ° C for 1 hr, xylene 5 min 3 times, 100% EtOH 5 min, 90% EtOH 3 min, 80% EtOH 3 min, 70% EtOH 3min, washing 5min. Thereafter, after treatment with Harris Hematoxylin 7min, 1% HCL-EtOH 10 sec, 0.3% Ammonia, and Eosin, and dehydration, the tissue samples were examined under a laser-scanning microscope (Eclipse TE300; Nikon).
  • Tissue samples were examined under a laser-scanning microscope (Eclipse TE300; Nikon).
  • mice 7-8 week old BALB/c mice (Orient Bio) were used.
  • a liver fibrosis model was constructed by treating the abdominal cavity of mice with TAA at 200 mg/kg three times a week for 5 weeks. Evaluation of anti-fibrotic activity after injecting PGC-1 ⁇ -ASC into the tail vein of a liver fibrosis model mouse or transplanting a scaffold loaded with PGC-1 ⁇ -ASC into the epidermis of a liver fibrosis model mouse under general anesthesia did
  • PGC-1 ⁇ -ASC was injected into the tail vein of a liver fibrosis model mouse into a liver fibrosis mouse model prepared by treating BALB/c mouse abdominal cavity with TAA at 200 mg/kg three times a week for 5 weeks ('TAA +ASC'), after implanting the scaffold loaded with PGC-1 ⁇ -ASC into the epidermis of a liver fibrosis model mouse (marked as 'TAA + scaffold-mounted ASC'), the state of the mouse liver obtained at 3 weeks was observed. .
  • the scaffold loaded with PGC-1 ⁇ -ASC of the present invention was higher than the group in which PGC-1 ⁇ -ASC was injected into the tail vein of liver fibrosis model mice.
  • the group transplanted into the liver fibrosis model mouse epidermis it was confirmed that liver fibrosis was inhibited (FIG. 1).
  • PGC-1 ⁇ -ASC was injected into the tail vein of a liver fibrosis model mouse into a liver fibrosis mouse model prepared by treating BALB/c mouse abdominal cavity with TAA at 200 mg/kg three times a week for 5 weeks ('TAA +ASC'), after implanting the scaffold loaded with PGC-1 ⁇ -ASC into the epidermis of a liver fibrosis model mouse (marked as 'TAA + scaffold-mounted ASC'), serological examination at 1, 2, and 3 weeks ALT blood concentration was confirmed through.
  • the group in which the scaffold loaded with PGC-1 ⁇ -ASC of the present invention was transplanted into the epidermal epidermis of the liver fibrosis model mouse showed liver It was confirmed that the blood concentration of ALT, which is a marker for confirming damage, was reduced (FIG. 2).
  • PGC-1 ⁇ -ASC was injected into the tail vein of a liver fibrosis model mouse into a liver fibrosis mouse model prepared by treating BALB/c mouse abdominal cavity with TAA at 200 mg/kg three times a week for 5 weeks ('TAA +ASC'), after implanting a scaffold loaded with PGC-1 ⁇ -ASC into the epidermis of a liver fibrosis model mouse (marked as 'TAA + scaffold-mounted ASC'), H&E staining of mouse liver tissue obtained at 3 weeks and analyzed.
  • PGC-1 ⁇ -ASC was injected into the tail vein of a liver fibrosis model mouse into a liver fibrosis mouse model prepared by treating BALB/c mouse abdominal cavity with TAA at 200 mg/kg three times a week for 5 weeks ('TAA +ASC'), transplanted a scaffold loaded with PGC-1 ⁇ -ASC into the epidermis of a liver fibrosis model mouse (marked as 'TAA + scaffold-mounted ASC'), and then sacrificed the mouse at 3 weeks to obtain liver tissue did Immunohistochemical staining of ⁇ -SMA, a fibrosis marker, and Masson's trichrome staining, which can confirm the degree of fibrosis in the obtained liver tissue, were performed.
  • the fibrosis area (collagen-stained area) increased by TAA treatment was higher than the group in which PGC-1 ⁇ -ASC was injected into the tail vein of liver fibrosis model mice. It was observed that a significant decrease was observed in the group implanted with the PGC-1 ⁇ -ASC scaffold of the invention in the epidermis of a liver fibrosis model mouse, confirming that the ability to inhibit liver fibrosis was improved (FIG. 5).
  • PGC-1 ⁇ -ASC was injected into the tail vein of a liver fibrosis model mouse into a liver fibrosis mouse model prepared by treating BALB/c mouse abdominal cavity with TAA at 200 mg/kg three times a week for 5 weeks ('TAA +ASC'), transplanted a scaffold loaded with PGC-1 ⁇ -ASC into the epidermis of a liver fibrosis model mouse (marked as 'TAA + scaffold-mounted ASC'), and then sacrificed the mouse at 3 weeks to obtain liver tissue did Expression of hepatic fibrosis markers ( ⁇ -SMA, TGF- ⁇ 1, MMP-2), cell proliferation markers (PCNA), and anti-apoptotic markers (BCL-2) in the obtained liver tissue was measured by Western blotting. Confirmed.
  • the group in which the scaffold loaded with PGC-1 ⁇ -ASC of the present invention was transplanted into the epidermal epidermis of the liver fibrosis model mouse showed liver
  • the present invention relates to a scaffold for preventing or treating hepatic fibrosis in which stem cells transformed with a vector containing a gene encoding PGC-1 ⁇ (peroxisome proliferator-activated receptor gamma coactivator-1 alpha) are loaded.
  • the scaffold according to the present invention induces excellent liver fibrosis by inducing a decrease in alanine transaminases (ALT) blood concentration, a decrease in the expression of liver fibrosis markers, an increase in the expression of cell proliferation markers, and an increase in the expression of anti-apoptotic markers. Since it shows a therapeutic effect, it can be used for the prevention, treatment, or improvement of various diseases related to liver fibrosis.
  • ALT alanine transaminases

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Abstract

La présente invention concerne un échafaudage pour la prévention ou le traitement de la fibrose hépatique et, plus spécifiquement, un échafaudage, chargé de cellules souches dérivées du tissu adipeux surexprimant PGC-1α, pour la prévention ou le traitement de la fibrose hépatique, les cellules souches dérivées du tissu adipeux étant préparées par transformation de cellules souches dérivées du tissu adipeux avec un vecteur comprenant un gène qui code pour PGC-1α. L'échafaudage selon la présente invention induit une diminution de la concentration d'alanine transaminases (ALT) dans le sang, une diminution de l'expression de marqueurs de fibrose hépatique, une augmentation de l'expression de marqueurs de prolifération cellulaire, et une augmentation de l'expression de marqueurs anti-apoptotiques de façon à présenter d'excellents effets de traitement de fibrose hépatique, et peut ainsi être développé en tant que principe actif d'une composition pour la prévention, le traitement ou le soulagement de la fibrose hépatique.
PCT/KR2022/017468 2021-12-23 2022-11-08 ÉCHAFAUDAGE, CHARGÉ DE CELLULES SOUCHES DÉRIVÉES DU TISSU ADIPEUX SUREXPRIMANT PGC-1α, POUR LA PRÉVENTION OU LE TRAITEMENT D'UNE FIBROSE HÉPATIQUE WO2023120971A1 (fr)

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