WO2022191341A1 - Composition pharmaceutique comprenant un exosome dérivé de cellules souches pour soulager ou traiter l'arthrite - Google Patents
Composition pharmaceutique comprenant un exosome dérivé de cellules souches pour soulager ou traiter l'arthrite Download PDFInfo
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- WO2022191341A1 WO2022191341A1 PCT/KR2021/002853 KR2021002853W WO2022191341A1 WO 2022191341 A1 WO2022191341 A1 WO 2022191341A1 KR 2021002853 W KR2021002853 W KR 2021002853W WO 2022191341 A1 WO2022191341 A1 WO 2022191341A1
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- stem cells
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- arthritis
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Classifications
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Definitions
- the present invention relates to a pharmaceutical composition for alleviating or treating arthritis.
- rheumatoid arthritis is caused by inflammation due to autoimmunity, and in degenerative arthritis, that is, osteoarthritis, degeneration such as aging occurs in chondrocytes constituting the joint, interleukin-1 and tumor
- MMP matrix metalloproteinase
- arthritis is further exacerbated by the synthesis of more MMPs due to the production of nitric oxide by inflammatory cytokines and the production of self-amplifying cytokines by the produced nitric oxide, which promotes the decomposition of the joint matrix.
- inflammatory cytokines increase the production of prostaglandin E2, a lipid metabolite, to induce an inflammatory response in arthritis.
- Osteoarthritis also called degenerative arthritis, is a type of arthritis that occurs mainly in old age without a specific organic cause. Osteoarthritis is mainly caused by damage to the bones and ligaments constituting the joint due to gradual damage or degenerative changes in the articular cartilage.
- exosomes derived from stem cells not only prevent cartilage erosion due to inflammation by alleviating and treating inflammation generated in cartilage, but also effectively alleviating inflammatory responses in surrounding tissues such as synovial membranes, thereby increasing the therapeutic effect of arthritis. It was found that the present invention was completed.
- compositions for relieving or treating arthritis comprising exosomes derived from stem cells as an active ingredient.
- Embodiment 1 A pharmaceutical composition for relieving or treating arthritis, comprising an exosome derived from proliferating adipose derived stem cells as an active ingredient; Use of exosomes derived from proliferating adipose-derived stem cells for the manufacture of medicines for alleviating or treating arthritis; Or a method for alleviating or treating arthritis, comprising administering to a subject a composition comprising an exosome derived from proliferating adipose-derived stem cells as an active ingredient.
- Embodiment 2 The pharmaceutical composition of Embodiment 1, wherein the adipose-derived stem cells are human adipose-derived stem cells; purpose; or how.
- Embodiment 3 The pharmaceutical composition according to any one of the preceding embodiments, wherein the arthritis is selected from osteoarthritis and rheumatoid arthritis; purpose; or how.
- Embodiment 4 The pharmaceutical composition according to any one of the preceding embodiments, wherein the exosomes are derived from stem cells proliferating in passages 4 to 6; purpose; or how.
- Embodiment 5 The pharmaceutical composition according to any one of the preceding embodiments, wherein the exosome is derived from stem cells proliferating in passage 5; purpose; or how.
- Embodiment 6 The pharmaceutical composition according to any one of the preceding embodiments, wherein the exosome comprises an anti-inflammatory cytokine; purpose; or how.
- Embodiment 7 The pharmaceutical composition according to any one of the preceding embodiments, wherein the anti-inflammatory cytokine is at least one selected from TIMP-1 and TIMP-2; purpose; or how.
- Embodiment 8 An injection for alleviating or treating arthritis comprising the pharmaceutical composition according to any one of the preceding embodiments.
- One aspect of the present invention is to provide a pharmaceutical composition for relieving or treating arthritis, comprising an exosome derived from proliferating adipose derived stem cells as an active ingredient.
- stem cell used in the present invention refers to not only self-renewal ability, but also when an appropriate signal is given as needed under the influence of the environment in which the cell is located, it is Cells with the ability to differentiate into branch cells.
- the stem cells of the present invention may be autologous or allogeneic stem cells, and may be derived from any type of animal, including humans and non-human mammals.
- the stem cells may be derived from the patient's autologous adipose tissue.
- adipose-derived stem cell is a stem cell derived from adipose tissue, and adipose tissue has good conditions for harvesting stem cells because it is easy to collect a large amount of tissue. , adipose-derived stem cells show stable growth and proliferation in culture and can differentiate into various cells when differentiation is induced.
- exosome refers to a membrane-structured vesicle secreted from various types of cells, and has a strong antitumor immune response including major histocompatibility and heat shock proteins, which are important immunologically important proteins. It is known to play a variety of roles, including binding to other cells and tissues and delivering membrane components, proteins, and RNA. Therefore, exosomes containing various genetic information, proteins, and growth factors related to inflammation relief can be used as a composition for treating arthritis.
- the exosomes derived from adipose-derived stem cells of the present invention contain anti-inflammatory cytokines, and thus can play an important role in alleviating and treating arthritis, such as osteoarthritis and rheumatoid arthritis, specifically TIMP- 1 (tissue inhibitors of metalloproteinases-1), TIMP-2, IL-1ra (interleukin-1 receptor antagonist), IL-4 (interluekin-4), IL-10 (Interleukin-10), TGF- ⁇ (transforming growth factor) - ⁇ ) and the like, and these cytokines have a role of inducing inhibition of inflammatory responses and inducing inhibition of inflammatory cytokines.
- TIMP- 1 tissue inhibitors of metalloproteinases-1
- TIMP-2 tissue inhibitors of metalloproteinases-1
- IL-1ra interleukin-1 receptor antagonist
- IL-4 interluekin-4
- IL-10 Interleukin-10
- TGF- ⁇ transforming growth factor
- the exosomes containing the anti-inflammatory cytokine may be derived from stem cells proliferating in subculture, preferably from stem cells proliferating in passage 4 to 6 times, more preferably in passage 5 times. may be derived from When extracting exosomes from stem cells proliferating in the passages 4 to 6, compared with the exosomes extracted from passages 3 or 7, the critical significance of significantly increasing the content of anti-inflammatory cytokines have.
- the mass (pg/protein ( ⁇ g)) of anti-inflammatory cytokines contained per protein of exosomes derived from stem cells proliferating in passages 4 to 6 was increased in passages 3 or 7 At least 2 times or more, at least 3 times or more, at least 4 times or more, at least 5 times or more, at least 6 times or more, at least 7 times or more, at least 8 times or more, at least 9 times the amount contained in exosomes derived from stem cells that fold or more, at least 10 times or more, at least 20 times or more, at least 30 times or more, at least 40 times or more, at least 50 times or more, at least 60 times or more, at least 70 times or more, at least 80 times or more, at least 90 times or more, or at least It can be 100 times or more.
- the pharmaceutical composition according to the present invention may include one or more pharmaceutically acceptable carriers, excipients or diluents together with a pharmaceutically effective amount of exosomes derived from adipose-derived stem cells.
- the pharmaceutically effective amount means an amount sufficient to improve and treat inflammation occurring in the joints.
- the exosomes derived from adipose-derived stem cells according to the present invention have a concentration of 1 ⁇ 10 7 particles/mL to 1 ⁇ 10 10 particles/kg in the pharmaceutical composition, preferably 5 ⁇ 10 7 particles/mL to 1 ⁇ It may be included at a concentration of 10 9 particles/kg.
- the concentration of the exosomes can be appropriately changed depending on the degree of progression of arthritis, the age, weight, health status, sex, administration route, and treatment period of the patient.
- the "pharmaceutically acceptable” refers to a composition that is physiologically acceptable and does not normally cause gastrointestinal disorders, allergic reactions such as dizziness or similar reactions when administered to humans.
- examples of such carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
- fillers, anti-agglomeration agents, lubricants, wetting agents, fragrances, emulsifiers and preservatives may be further included.
- composition of the present invention can be administered by formulating a unit dosage form suitable for administration in the body of a patient according to a conventional method in the pharmaceutical field, and the preparation is administered once or several times to relieve arthritis. to therapeutically effective dosages.
- Formulations suitable for this purpose include, for parenteral administration, injections such as ampoules for injection, injections such as infusion bags, and the like.
- the injection ampoule may be prepared by mixing with an injection solution immediately before use, and physiological saline, glucose, mannitol, Ringer's solution, etc. may be used as the injection solution.
- one or more pharmaceutically acceptable conventional inert carriers for example, preservatives, analgesics, solubilizers or stabilizers in the case of injections, and the like, in the case of formulations for topical administration It may further include a base (base), excipients, lubricants or preservatives and the like.
- composition or pharmaceutical preparation of the present invention prepared in this way may be administered to mammals such as rats, mice, livestock, and humans by various routes such as parenteral and oral administration, and the administration method is any method commonly used in the art.
- the administration method is not limited thereto, but the exosomes extracted from adipose-derived stem cells may be administered intravenously (intravenous injection) or administered to an arthritis site (local administration; Topical administration).
- the present invention provides an injection for alleviating or treating arthritis, comprising a pharmaceutical composition for alleviating and treating arthritis comprising the adipose-derived stem cell-derived exosome as an active ingredient.
- the injection may further include phosphate-buffered saline (PBS). That is, the injection can be used by supporting the exosomes extracted from adipose-derived stem cells in phosphate buffered saline.
- PBS phosphate-buffered saline
- the injection may include hydrogel instead of phosphate buffered saline.
- the hydrogel may be at least one selected from the group consisting of hyaluronic acid, gelatin, alginate, chitosan, fibrin, elastin, collagen, and methylcellulose, and specifically may be a hyaluronic acid hydrogel, but is not limited thereto.
- the stem cell-derived exosome according to the present invention not only prevents cartilage erosion by alleviating and treating inflammation occurring in the cartilage, but also effectively relieves the inflammatory response in surrounding tissues such as the synovial membrane, thereby fundamentally curing arthritis. .
- Figure 2 shows the content of anti-inflammatory cytokines (TIMP-1 and TIMP-2) contained in the exosomes produced for each passage.
- TRIP-1 inflammatory regulator
- hASCs Primary hASCs were purchased from CEFO Bio Co., Ltd (Seoul, Korea), and growth medium and supplements were purchased from Life Technologies (Carlsbad, CA, USA). Using normal culture medium (Dulbecco Modified Eagle Medium high glucose (DMEM) containing 10% fetal bovine serum and 1% penicillin/streptomycin), hASCs were subcultured 3 to 7 times at 37°C and 5% CO 2 conditions. proliferated. Exosomes were extracted for each passage, specifically, before extracting the exosomes, the proliferated stem cells for each passage were replaced with serum-free DMEM medium and maintained for 24 hours, and then the cell culture supernatant was recovered. Then, exosomes were isolated from the recovered cell culture supernatant by a multiple filtration system based on a tangential flow filtration system (TFF).
- DMEM Dulbecco Modified Eagle Medium high glucose
- the size and shape of the exosomes extracted from the proliferating stem cells were confirmed using a transmission electron microscope and dynamic light scattering, and the exosome membrane using flow cytometry. Surface proteins were identified.
- CD9, CD63, and CD81 known as exosome surface marker proteins, were all expressed in the extracted exosomes using flow cytometry (Fig. 1).
- Representative cytokines secreted in relation to inflammation relief include TIMP-1 (tissue inhibitors of metalloproteinases-1) and TIMP-2. It is known that there is
- BM-MSC-Exo a significant TIMP-1 content was not confirmed, and in the case of UC-MSC-Exo, it was confirmed that it contained TIMP-1, but the TIMP-1 content was significantly higher than that of hASC-Exo. was confirmed to be very low ( FIG. 3 ) (*P ⁇ 0.1).
- MIA-induced rat OA model monosodium iodoacetate (MIA)-induced rat OA model
- exosomes produced in passage 5 were administered intra-articularly every week for 3 weeks from 1 week after MIA injection. 4 weeks after MIA injection, the isolated knee joint was stained with India ink, and the observation results are shown in FIG. 4 .
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Abstract
La présente invention concerne une composition pharmaceutique à base d'exosomes pour soulager et traiter l'arthrite. Les exosomes selon la présente invention peuvent essentiellement guérir l'arthrite en soulageant et en traitant les inflammations se produisant dans le cartilage pour empêcher l'érosion du cartilage ainsi qu'en atténuant efficacement des réactions inflammatoires même dans des tissus voisins tels que la membrane synoviale.
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| JP2023555322A JP2024510191A (ja) | 2021-03-08 | 2021-03-08 | 幹細胞から由来したエクソソームを含む関節炎の緩和又は治療用医薬組成物 |
| PCT/KR2021/002853 WO2022191341A1 (fr) | 2021-03-08 | 2021-03-08 | Composition pharmaceutique comprenant un exosome dérivé de cellules souches pour soulager ou traiter l'arthrite |
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| KR20190066885A (ko) * | 2017-12-06 | 2019-06-14 | 주식회사 디자인셀 | 줄기세포 유래 엑소좀 함유 배양액을 유효성분으로 포함하는 관절염의 예방 또는 치료용 조성물 |
| CN110846274A (zh) * | 2019-11-20 | 2020-02-28 | 广东先康达生物科技有限公司 | 应用于骨关节炎中的复合细胞制剂的制备方法及复合细胞制剂的用法 |
| KR102144593B1 (ko) * | 2017-06-07 | 2020-08-13 | 주식회사 엑소스템텍 | 인간줄기세포 유래 엑소좀을 포함하는 세포 배양용 무혈청 배지 조성물 |
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| KR102144593B1 (ko) * | 2017-06-07 | 2020-08-13 | 주식회사 엑소스템텍 | 인간줄기세포 유래 엑소좀을 포함하는 세포 배양용 무혈청 배지 조성물 |
| KR20190066885A (ko) * | 2017-12-06 | 2019-06-14 | 주식회사 디자인셀 | 줄기세포 유래 엑소좀 함유 배양액을 유효성분으로 포함하는 관절염의 예방 또는 치료용 조성물 |
| CN110846274A (zh) * | 2019-11-20 | 2020-02-28 | 广东先康达生物科技有限公司 | 应用于骨关节炎中的复合细胞制剂的制备方法及复合细胞制剂的用法 |
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| CHANG HEE WOO, HARK KYUN KIM, GUN YOUNG JUNG, YOUN JAE JUNG, KYOUNG SOO LEE, YE EUN YUN, JIHOON HAN, JEONGMI LEE, WOO SUNG KIM, JI: "Small extracellular vesicles from human adipose-derived stem cells attenuate cartilage degeneration", JOURNAL OF EXTRACELLULAR VESICLES, vol. 9, no. 1735249, 9 March 2020 (2020-03-09), pages 1 - 16, XP055964759 * |
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