WO2012121485A2 - Procédé pour induire la migration in vivo de cellules souches - Google Patents

Procédé pour induire la migration in vivo de cellules souches Download PDF

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Publication number
WO2012121485A2
WO2012121485A2 PCT/KR2012/000618 KR2012000618W WO2012121485A2 WO 2012121485 A2 WO2012121485 A2 WO 2012121485A2 KR 2012000618 W KR2012000618 W KR 2012000618W WO 2012121485 A2 WO2012121485 A2 WO 2012121485A2
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WO
WIPO (PCT)
Prior art keywords
tissue
stem cells
damaged
composition
cells
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Ceased
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PCT/KR2012/000618
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English (en)
Korean (ko)
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WO2012121485A3 (fr
Inventor
이진우
박민성
김윤희
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Tegoscience Inc
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Tegoscience Inc
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Publication date
Priority claimed from KR1020120001563A external-priority patent/KR101466811B1/ko
Application filed by Tegoscience Inc filed Critical Tegoscience Inc
Priority to JP2013557637A priority Critical patent/JP5828916B2/ja
Priority to EP12754399.9A priority patent/EP2684575B1/fr
Priority to CN201280011945.2A priority patent/CN103561788B/zh
Priority to US14/003,364 priority patent/US9220757B2/en
Publication of WO2012121485A2 publication Critical patent/WO2012121485A2/fr
Publication of WO2012121485A3 publication Critical patent/WO2012121485A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • 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
    • A61L27/58—Materials at least partially resorbable by the body
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/252—Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/412—Tissue-regenerating or healing or proliferative agents

Definitions

  • the present invention relates to an implant composition for treating damaged tissue and a method for in vivo migration of therapeutic cells to a damaged tissue site.
  • Stem cells are cells that can differentiate the organisms that make up the tissue into a variety of cells. These stem cells collectively refer to the undifferentiated cells from the embryonic, fetal and adult tissues before they are differentiated. . Stem cells are differentiated into specific cells due to differentiation stimulation (environment), and unlike differentiated cells in which cell division is stopped, they can proliferate because they can produce the same cells as themselves by cell division. i ferat ion (expansion) is characterized in that it can be differentiated into other cells by different environment or differentiation stimulus, so that it has plasticity in differentiation. Articular cartilage is an avascular tissue consisting mainly of protein polysaccharide and type 2 collagen and contains about 5 »of chondrocytes in the tissue volume [1].
  • Autologous chondrocyte transplantation and bone marrow are the representative biological methods for treating damaged articular cartilage. Perforation, etc.
  • Autologous chondrocyte transplantation is a method of culturing autologous chondrocytes and transplanting them into defective areas, but the disadvantages of repeated surgery and donor limitation are disadvantages.
  • Bone marrow perforation is performed using the bone marrow-derived mesenchymal stem cells that have been perforated to the subchondral bone of the cartilage defect and introduced into the defect along with the bone marrow. How to treat cartilage. This method is relatively simple and economical, but the result is inconsistent, and tissue regeneration is not smooth when the number of incoming mesenchymal stem cells is insufficient [3-7].
  • the present inventors endeavored to develop a method for effectively inducing cells necessary for tissue regeneration to damaged sites for the treatment of damaged tissue sites.
  • the term “chemotactic factor” refers to extracellular matrix molecules and secreted proteins that diffuse from tissue to activate chemotaxis, for example, the TGF transforming growth factor family, the BMP bone morphogenetic protein family, CDMP (c art i lage ⁇ -derived morphogenetic proteins), f ibroblast growth factor (FGF) family, connect ive tissue growth factors (CTGF) family, platelet-derived growth factor (PDGF) family, VEGFCvascular endothelial growth factor (PDGF) family, extracellular Matrix molecules (eg, osteopontin, fibronectin, hyaluronic acid, heparin, thrombospondine, collagen, vitronectin, etc.) and chemokines.
  • TGF transforming growth factor family
  • BMP bone morphogenetic protein family CDMP (c art i lage ⁇ -derived morphogenetic proteins), f ibroblast growth factor (FGF) family, connect ive tissue growth factors (CTGF) family, plate
  • the chemotactic factor of the present invention includes chemokines.
  • chemokines that can be used in the present invention are CCL20 (MIP-3 ⁇ ), CCL 19, CCL21, CCL27, CCL28, CXCL8 IL-8), CXCL9, CXCL 10, CXCL11, CXCL12 ( SDF-1), CXCL 16, CXCL 13, CXCL5, CXCL6, CCL2 (MCP-1), CCL8, CCL 13, CCL25, CCL3, CCL4, CCL5, CCL7, CCL 14, CCL15, CCL 16, CCL23, CX3CL1, XCLl , XCL2, CCL1, CCL 17, CCL22, CCL11, CCL24, CCL26, CXCL1, CXCL2, CXCL3 and CXCL7, more preferably CCL20, CCL19, CCL21, CCL27, CCL28, CXCL8, CXCL9, CXCL10, CXCL11, CXCL12, CXCL16, CXCL13, CX
  • amino acid sequences of CCL20 and CXCL8 are described in SEQ ID NO: 1 and SEQ ID NO: 2, respectively.
  • the concentration of chemokine used in the present invention is 10-1,000 ng / ml per biodegradable support (1 g), more preferably 2 to 800 ng per biodegradable support (1 g). / ml, even more preferably 35 kPa 700 ng / ml per biodegradable support (1 g), most preferably 50-500 ng / ml per biodegradable support (1 g).
  • biodegradable scaffolds refers to a three-dimensional structure consisting of a biodegradable polymer containing the chemotactic factor, and is damaged to a target location (eg, damaged articular cartilage or skin tissue) through transplantation. It functions as a support for inducing the migration of cells required for tissue regeneration.
  • the biodegradable scaffold of the present invention is a biocompatible material, which generally forms a porous micro scaffold to provide a physical scaffold for the cells to migrate, and is provided for the influx of cells for treatment or regeneration to the implanted position. .
  • the damaged tissue treated with the composition of the present invention is bone tissue, joint tissue or skin tissue.
  • MSCs Mesenchymal stem cells
  • MSCs are nonhematopoietic stromal cells that can differentiate and regenerate mesenchymal tissues such as bone, cartilage, muscle, ligaments, tendons and fat.
  • MSCs are known to be present in the bone marrow in small numbers (eg, about 1 per 10,000 monocytes).
  • MSCs may have the ability to multiply and multiply by multiples while maintaining growth and multisystem differentiation.
  • MSCs appear to migrate to damaged tissues, their trafficking and tissue homing are processes that are not accurately understood.
  • Bone disease or articular cartilage disease that can be treated by the composition of the present invention includes arthritis, osteoporosis, osteochondrosis, osteochondritis, incomplete osteoplasia, osteomyelitis, osteoprogenitors, cartilage dysplasia, including osteoarthritis and rheumatoid arthritis, Cartilage, chondroma, chondrosarcoma, intervertebral herniation, Klipel-pile syndrome, deformative osteoarthritis, cystic fibrosis, and articular cartilage disease associated with tissue damage from accidents, fractures, wounds, joint damage, autoimmune diseases, diabetes and cancer Including It is not limited to this.
  • keratinocyte is also referred to in the art as “skin cells”, “keratin cells” or “keratin forming cells,” and is present in the basal layer of the epidermis and thus, “basal cell” or “basal.” It is also called “basal keratinocyte”, it is meant to include all of them.
  • Skin diseases that can be treated by the compositions of the present invention include burns, frostbite, wounds, keloids, chemical destruction of tissues, abrasions, bone fractures, lacerations, avulsions, penetrating wounds ( penetrated wounds, cuts, contusion or bruise, skin ulcers, keratosis, bedsores, ulcers and acne.
  • the term “pharmaceutically effective amount” means an amount sufficient to achieve the therapeutic or regenerative activity of the damaged tissue described above.
  • the pharmaceutical composition of the present invention includes a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers included in the pharmaceutical compositions of the present invention are those commonly used in the preparation of lactose, dextrose, sucrose, sorbetle, manny, starch, acacia rubber, calcium phosphate, alginate, Gelatin, silicate, microcrystalline cellulose, polyvinylpyridone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil Including, but not limited to.
  • the pharmaceutical composition of the present invention may further include a lubricant, a humectant, a sweetener, a flavoring agent, an emulsifier, a suspending agent, a preservative, and the like.
  • a lubricant e.g., talc, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, a kaolin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mann
  • compositions of the present invention can be administered directly to the injured site, for example by subcutaneous injection, intramuscular injection, transdermal administration, intraarticular injection, or the like.
  • Suitable dosages of the pharmaceutical compositions of the present invention may be prescribed in various ways depending on factors such as formulation method, mode of administration, age of patient, weight, sex, morbidity, food, time of administration, route of administration, rate of excretion and reaction response. Can be.
  • the pharmaceutical composition of the present invention can be easily carried out by those skilled in the art according to the present invention, Formulated with pharmaceutically acceptable carriers and / or excipients may be prepared in unit dose form or may be prepared by incorporation into a multi-dose container.
  • the formulation may be in the form of solutions, suspensions, syrups or emulsions in oils or aqueous media, or may be in the form of axes, powders, powders, granules, tablets or capsules, and may further comprise dispersants or stabilizers.
  • the compositions of the invention can be implanted in living mammals, more preferably in damaged joint sites (eg articular cartilage) or skin tissue.
  • the mammal is not particularly limited, and preferably includes humans, mice, rats, rabbits, monkeys, pigs, horses, cows, sheep, antelopes, dogs and cats. Preferably humans and mice are included.
  • the present invention provides a method for in vivo migration of therapeutic cells to a damaged tissue site comprising the following steps:
  • Biodegradable in a solution comprising at least one chemoactic factor selected from the group consisting of IL (inter leukin) -8, Macrophage Inflammatory Protein (MIP) ⁇ 3a, derivatives thereof, and combinations thereof. Dipping the biodegradable scaffolds; And
  • biodegradable support in a solution comprising one or more chemoactic factors selected from the group consisting of IL (inter leukin) -8, MIPC Macrophage Inflammatory Protein (3 ⁇ ), derivatives thereof, and combinations thereof dipping (biodegradable scaffolds); And (b) implanting the biodegradable support into a damaged tissue site. Since the chemotactic factor and biodegradable support used in the method of the present invention have already been described above, the description thereof is omitted to avoid excessive duplication.
  • the present invention provides an implant composition for treating damaged tissue and a method for in vivo migration of therapeutic cells to a damaged tissue site.
  • Tissue regeneration by implanting a biodegradable scaffold with the chemotactic factor (e.g. IL-8 or MIP-3a) of the present invention at an injured location (e.g. bone tissue, articular cartilage or skin). Damaged tissues can be treated by inducing / promoting homing of cells.
  • a biodegradable scaffold with the chemotactic factor e.g. IL-8 or MIP-3a
  • an injured location e.g. bone tissue, articular cartilage or skin. Damaged tissues can be treated by inducing / promoting homing of cells.
  • composition of the present invention can be applied to the treatment of damaged bone tissue, articular cartilage or skin tissue more simply and efficiently compared to the prior art itself, as well as in the treatment of cells using taga cells. It can be used as a useful therapeutic aid by making efficient use of high therapeutic plastic resources.
  • the upper panel of 3 a shows the results of the Masson trichrome staining, and the lower panel shows the expression of cartilage marker genes.
  • 3B shows the results of Von kossa staining.
  • NC negative control
  • PC positive control.
  • 4 shows the results of in vitro chemotaxis of bMSCs and keratinocytes, respectively.
  • 5 shows the in vivo chemotaxis of bMSCs.
  • the upper panel shows the results of animal experiments (W, Note) and the lower panel shows the PLGA scaffold transplantation diagram containing chemokines.
  • Figure 6 is a result showing the visual observation (A) and pathological findings (B) after in vivo chemotactic observation of bMSCs.
  • In vitro cell chemotaxis was assessed by culturing cells using 8 / i-hole sized transwell inserts (Falcon, Germany) and counting cells that migrated through the micropores toward chemokines.
  • In vitro cell chemotaxis was performed by PLGA scaffolds containing chemokines (IL-8, MIP-3a) implanted subcutaneously into the tail blood vessels by injecting fluorescently labeled 1.5X10 6 MSCs (Seohyun Kim, Korea Research Institute of Science and Technology) Movement toward the doctor was observed with a real-time imaging device (Optix, ART, USA).
  • the chemotaxis of mesenchymal stem cells of candidates selected in vitro and in vivo was evaluated.
  • cytochemistry towards TNFa was observed in vitro using a transwell insert (FIG. 4A).
  • IL-8 and MIP-3a induced cytochemistry most frequently in vitro (FIG. 4B), and chemotaxis increased more significantly when these two materials were used in combination. It was confirmed (FIG. 4C).
  • IL-8 and MIP-3a confirmed that the keratin cells essential for skin tissue regeneration can be introduced experimentally.
  • IL-8 and MIP-3a induced cytochemistry of keratinocytes (FIG. 4D). ).

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Transplantation (AREA)
  • Engineering & Computer Science (AREA)
  • Dermatology (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Immunology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Zoology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biomedical Technology (AREA)
  • Molecular Biology (AREA)
  • Materials For Medical Uses (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Abstract

La présente invention concerne une composition implantable pour traiter un tissu endommagé et un procédé pour induire une migration in vivo d'une cellule pour le traitement d'une région de tissu endommagée. La présente invention traite le tissu endommagé par induction/promotion de l'écotropisme d'une cellule pour la génération de tissu par implantation d'un échafaudage biodégradable ayant été mis en réaction avec des facteurs chimiotactiques (par exemple, IL-8 ou MIP-3α) à un emplacement endommagé (par exemple, un cartilage articulaire ou la peau). Par conséquent, la composition de la présente invention peut non seulement être appliquée au traitement d'un tissu osseux endommagé, un cartilage articulaire, ou un tissu cutané plus commodément et efficacement par comparaison à la technologie conventionnelle, mais peut également être utilisée en tant qu'agent de supplément de traitement utile dans le traitement de cellules utilisant une cellule allogénique en permettant l'utilisation efficace de ressources cellulaires pour le traitement, les ressources cellulaires étant extrêmement limitées.
PCT/KR2012/000618 2011-03-08 2012-01-26 Procédé pour induire la migration in vivo de cellules souches Ceased WO2012121485A2 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP2013557637A JP5828916B2 (ja) 2011-03-08 2012-01-26 幹細胞のインビボ移動誘導方法
EP12754399.9A EP2684575B1 (fr) 2011-03-08 2012-01-26 Procédé pour induire la migration in vivo de cellules souches
CN201280011945.2A CN103561788B (zh) 2011-03-08 2012-01-26 干细胞的体内迁移诱导方法
US14/003,364 US9220757B2 (en) 2011-03-08 2012-01-26 Method for inducing in vivo migration of stem cell

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
KR10-2011-0020221 2011-03-08
KR20110020221 2011-03-08
KR1020120001563A KR101466811B1 (ko) 2011-03-08 2012-01-05 줄기세포의 인 비보(ｉｎ ｖｉｖｏ) 이동 유도방법
KR10-2012-0001563 2012-01-05

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WO2012121485A2 true WO2012121485A2 (fr) 2012-09-13
WO2012121485A3 WO2012121485A3 (fr) 2012-12-13

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Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070184087A1 (en) * 2006-02-06 2007-08-09 Bioform Medical, Inc. Polysaccharide compositions for use in tissue augmentation

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