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WO2019230859A1 - Procédé pour le traitement et/ou la prévention de l'ostéoarthrite - Google Patents

Procédé pour le traitement et/ou la prévention de l'ostéoarthrite Download PDF

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Publication number
WO2019230859A1
WO2019230859A1 PCT/JP2019/021448 JP2019021448W WO2019230859A1 WO 2019230859 A1 WO2019230859 A1 WO 2019230859A1 JP 2019021448 W JP2019021448 W JP 2019021448W WO 2019230859 A1 WO2019230859 A1 WO 2019230859A1
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Prior art keywords
stem cells
dental pulp
pulp stem
osteoarthritis
culture supernatant
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Ceased
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PCT/JP2019/021448
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English (en)
Japanese (ja)
Inventor
朗仁 山本
田中　栄二
直子 小笠原
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University of Tokushima NUC
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University of Tokushima NUC
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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
    • A61K35/32—Bones; Osteocytes; Osteoblasts; Tendons; Tenocytes; Teeth; Odontoblasts; Cartilage; Chondrocytes; Synovial membrane
    • 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
    • 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

Definitions

  • the joint surface is covered with articular cartilage.
  • mechanical cartilage causes degeneration and wear of articular cartilage, resulting in deformation of articular cartilage and bone.
  • Motor dysfunction and severe pain significantly reduce the patient's QOL.
  • the treatment costs are high, and the invasion of autologous cell collection and transplantation surgery is large, and there is an urgent need to develop a new drug that promotes cartilage regeneration.
  • Dental pulp stem cells have the properties of neural stem cells and bone marrow stem cells and produce a large amount of extracellular matrix and humoral factors. Previous studies have revealed that the culture supernatant of dental pulp stem cells improves the pathology of various intractable diseases by inducing anti-inflammatory tissue regeneration type monocyte cells. For example, Patent Documents 1 and 2 and Non-Patent Documents 1 and 2 disclose that the culture supernatant of dental pulp stem cells or components thereof are effective for treating damaged sites and inflammatory diseases.
  • Non-Patent Documents 3 and 4 show that MCP-1 and sSiglec-9 produced by dental pulp stem cells interact with chondroitin sulfate present in the inflamed site to induce M2 macrophages, and M2 macrophages induce various trophic factors and It discloses the production of immunomodulators and regeneration of tissues. No direct effect of dental pulp stem cells or culture supernatants on chondrocytes has been reported.
  • the present application aims to provide a method for regenerating cartilage or a method for treating and / or preventing osteoarthritis.
  • the present inventors using a mouse degenerative temporomandibular disorder model with forced opening, administered dental pulp stem cell culture supernatant improved the roughening of the joint surface, promoted the proliferation of articular chondrocytes, and the joint morphology was Found to play.
  • the present application provides a composition for cartilage regeneration comprising dental pulp stem cells and / or culture supernatants thereof.
  • the present application provides a composition for the treatment and / or prevention of osteoarthritis comprising dental pulp stem cells and / or culture supernatants thereof.
  • the present application provides a method for producing a composition for cartilage regeneration, comprising culturing dental pulp stem cells and recovering dental pulp stem cells and / or culture supernatant thereof.
  • the present application provides a method for producing a composition for treating and / or preventing osteoarthritis, comprising culturing dental pulp stem cells and collecting dental pulp stem cells and / or culture supernatant thereof. To do.
  • the disclosure of the present application provides a method for regenerating cartilage or a method for treating and / or preventing osteoarthritis.
  • a representative temporomandibular joint CT image on the fifth day of forced opening treatment in a temporomandibular disorder model mouse is shown.
  • Panel C Opening treatment and SHED-CM administration.
  • a representative temporomandibular joint CT image on the 10th day of forced opening treatment in a temporomandibular disorder model mouse is shown.
  • Panel C Opening treatment and SHED-CM administration on days 6-10.
  • a representative temporomandibular joint CT image in a temporomandibular disorder model mouse is shown.
  • WT No opening treatment
  • Pre-treatment Opening treatment on the 5th day
  • SHED-CM Opening treatment on the 10th day, 6th to 10th day
  • SHED-CM administration SHED-CM administration
  • DMEM Opening treatment on the 10th day, 6th to 10th day DMEM administration.
  • the body weights of the temporomandibular disorder model mice in the SHED-CM administration group (CM group) and the non-administration group (DM group) are shown. Bone density (BV / TV), trabecular width (Tb / Th), and trabecular space (Tb / Sp) of temporomandibular disorder model mice in SHED-CM administration group (CM group) and non-administration group (DM group) Show.
  • the hematoxylin and eosin stained image of the temporomandibular joint tissue of a temporomandibular disorder model mouse is shown.
  • the hematoxylin and eosin stained image of the temporomandibular joint tissue of a temporomandibular disorder model mouse is shown.
  • WT No opening treatment, open5days: Opening treatment day 5, SHED-CM: Opening treatment day 10, 6-10 days SHED-CM administration, DMEM: Opening treatment day 10, 6-10 days Administration.
  • Scale bar 100 ⁇ m.
  • the Mankin score of the temporomandibular joint tissue of a temporomandibular disorder model mouse is shown.
  • DMEM DMEM was administered on the 10th and 6th to 10th days of the opening procedure
  • CM SHED-CM was administered on the 10th and 10th days of the opening procedure.
  • staining image of the temporomandibular joint tissue of a temporomandibular disorder model mouse is shown.
  • WT No opening treatment, open5days: Opening treatment day 5, SHED-CM: Opening treatment day 10, 6-10 days SHED-CM administration, DMEM: Opening treatment day 10, 6-10 days Administration.
  • Scale bar 100 ⁇ m.
  • the proteoglycan area of the temporomandibular joint tissue of a temporomandibular disorder model mouse is shown.
  • WT no opening treatment
  • DMEM administration of DMEM on the 10th and 6th day of the opening treatment
  • CM administration of SHED-CM on the 10th and 6th day of the opening treatment.
  • dental pulp stem cell means a somatic stem cell derived from the dental pulp.
  • Dental pulp stem cells can be derived from permanent or deciduous teeth.
  • dental pulp stem cells are derived from deciduous deciduous teeth.
  • the dental pulp stem cells may be derived from the same or different species as the subject to which the composition is applied, preferably from the same species (for example, if the subject is human, human origin) Dental pulp stem cells), and more preferably autologous dental pulp stem cells.
  • Dental pulp stem cells can be sorted as adherent cells in dental pulp cells.
  • the dental pulp stem cell may be an adherent cell contained in a dental pulp cell collected from a deciduous tooth or a permanent tooth or a passage cell thereof. Further, dental pulp stem cells established as a cell line may be used. Alternatively, dental pulp stem cells differentiated from pluripotent stem cells such as iPS cells and ES cells may be used.
  • the dental pulp stem cell may have at least one gene artificially modified or introduced as long as it has an effect equivalent to that of the dental pulp stem cell for cartilage regeneration and / or osteoarthritis.
  • 1, 2, 3, 4 or more genes may be introduced for the purpose of immortalization of dental pulp stem cells.
  • the effect of such dental pulp stem cells and / or culture supernatant thereof on cartilage regeneration is achieved, for example, by supplying dental pulp stem cells and / or culture supernatant thereof to an evaluation system for cartilage regeneration and evaluating the effect on cartilage regeneration. Can be evaluated.
  • an evaluation system for cartilage regeneration for example, the method described in the examples of the present application, evaluation of chondrocyte proliferation or chondrocyte death in vitro, and the like can be used.
  • the effect of dental pulp stem cells and / or culture supernatant thereof on osteoarthritis can be evaluated by, for example, supplying dental pulp stem cells and / or culture supernatant thereof to an osteoarthritis evaluation system and evaluating the effect on osteoarthritis. Can be evaluated.
  • an evaluation system for osteoarthritis for example, the methods described in the examples of the present application can be used.
  • “Culture supernatant of dental pulp stem cells” is a supernatant of a culture solution obtained by culturing dental pulp stem cells.
  • the culture supernatant is substantially free of cellular components (dental stem cells or pulp cells).
  • the cell component is removed by separating and removing the cell component after culturing. Separation of cell components from the culture medium can be performed by methods well known to those skilled in the art. Furthermore, various treatments (for example, centrifugation, concentration, solvent replacement, dialysis, freezing, drying, lyophilization, dilution, desalting, storage, etc.) may be appropriately performed on the culture solution.
  • a basic medium or a medium supplemented with serum or the like can be used.
  • Iskov modified Dulbecco medium (IMDM) (GIBCO, etc.)
  • Ham F12 medium HamF12
  • SIGMA GIBCO
  • RPMI 1640 medium etc.
  • Two or more basic media may be used in combination.
  • IMDM and HamF12 are mixed in equal amounts (for example, commercially available as trade name: IMDM / HamF12 (GIBCO)) can be mentioned. Any component that does not inhibit the survival and / or proliferation of dental pulp stem cells may be added to the medium.
  • ingredients that can be added to the medium include serum (fetal bovine serum, human serum, sheep serum, etc.), serum substitutes (Knockout serum replacement (KSR), etc.), bovine serum albumin (BSA), antibiotics, various vitamins, Various minerals can be mentioned.
  • the composition preferably does not contain serum.
  • a culture supernatant without serum can be prepared by culturing dental pulp stem cells in a medium without serum (serum-free medium).
  • a culture supernatant containing no serum can also be obtained by performing one or more subcultures and culturing the last or last several subcultures in a serum-free medium.
  • serum-free culture supernatant can also be obtained from the collected culture supernatant by removing the serum using dialysis or solvent replacement using a column.
  • dental pulp stem cells For the cultivation of dental pulp stem cells, the conditions usually used for stem cells can be applied as they are, or appropriately changed. Manufacture of dental pulp stem cells and / or culture supernatant of dental pulp stem cells can be appropriately performed by those skilled in the art. For example, the description of International Publication No. 2011/118795 (Patent Document 4), International Publication No. 2014/126176 (Patent Document 5) and the like, which are part of the present specification by reference, can be referred to. Further, for example, dental pulp stem cells and / or culture supernatants may be obtained by the following operation.
  • adherent cells selected from the dental pulp are cultured in the medium described above.
  • the cells are seeded in an adherent cell culture dish and cultured in an incubator adjusted to appropriate conditions (for example, 5% CO 2 , 37 ° C.). Subculture as necessary.
  • the cells reach the sub-confluence (the state where the cells occupy about 70% of the surface of the culture vessel) reach the confluence (the state where the cells occupy about 100% of the surface of the culture vessel)
  • the cells are cultured. It is peeled off and collected, and seeded again in a culture vessel filled with a culture solution. Subculturing may be repeated.
  • subculture is performed 1 to 8 times, and the cells are grown to the required number of cells (for example, about 1 ⁇ 10 7 cells / ml). Separation of cells from the culture vessel can be performed by a conventional method such as trypsin treatment. After the above culture, the cells may be collected and stored (eg, at 4 ° C. or ⁇ 198 ° C.).
  • the culture supernatant collected when a sufficient number of dental pulp stem cells have been cultured for a sufficient time can be used in the present composition.
  • medium is added to pulp stem cells that are about 70-100% confluent, preferably about 80-90% confluent, and about 12-72 hours, about 36-60 hours, about 42-54 hours, or about 46-50 hours, For example, after culturing for about 48 hours, the culture supernatant is collected.
  • dental pulp stem cells are cultured to about 80-90% confluence, washed, added with serum-free medium, cultured for about 48 hours, and the culture supernatant is collected.
  • the culture supernatant can be collected using, for example, a dropper or a pipette.
  • the collected culture supernatant can be used as an active ingredient of the present composition as it is or after one or more treatments.
  • the treatment include centrifugation, concentration, solvent replacement, dialysis, freezing, drying, lyophilization, dilution, desalting, and storage (eg, 4 ° C., ⁇ 80 ° C.).
  • the main culture supernatant can be appropriately concentrated. That is, the main culture supernatant may be a concentrate. As a concentration method, those skilled in the art can appropriately select and use from known methods.
  • the main culture supernatant may be lyophilized. That is, the main culture supernatant may be a lyophilized product.
  • This composition can be used for cartilage regeneration.
  • cartilage regeneration promotes chondrocyte proliferation, inhibits chondrocyte death, and / or promotes the production of cartilage matrix in vivo and / or in vitro. It means to improve the function of cartilage and to delay or stop the progression of cartilage function decline.
  • the present composition can also be used for the treatment and / or prevention of osteoarthritis.
  • osteoarthritis include osteoarthritis of the knee, osteoarthritis of the knee, hip osteoarthritis, ankle osteoarthritis, shoulder osteoarthritis, osteoarthritis of the elbow, osteoarthritis of the hand, Examples include, but are not limited to, osteoarthritis of the knee, degenerative spondyloarthrosis.
  • treating means reducing or eliminating the cause of osteoarthritis, delaying or stopping its progression in a subject with osteoarthritis, And / or alleviating, alleviating, ameliorating or eliminating the symptoms.
  • prevent refers to osteoarthritis in a subject, particularly in a subject that is likely to develop osteoarthritis but has not yet developed osteoarthritis. It means preventing the onset or reducing the possibility of developing osteoarthritis.
  • Subjects who have the potential to develop osteoarthritis but have not yet developed include those with risk factors for osteoarthritis. Examples of risk factors include heredity, occupation, obesity, cartilage fragility, trauma, joint dysplasia, joint mobility, and older age (in the case of humans, for example, 50 years old, 60 years old, 70 years old or older). However, it is not limited to these.
  • the present composition may contain a high molecular compound such as a protein secreted during cultivation by dental pulp stem cells, and a low molecular organic compound.
  • the composition can also include media-derived ingredients.
  • the present composition can take the form of liquid (liquid, gel, etc.) and solid (powder, fine granules, granules, etc.).
  • this composition can take various well-known formulation forms according to the kind of disease, the characteristic of the individual who has a disease, an administration method, and dosage.
  • the composition can contain a known pharmaceutically acceptable salt.
  • the composition is in the form of a formulation for intravenous administration. In certain embodiments, the composition is in the form of a formulation for intra-articular administration.
  • compositions Depending on the purpose and formulation form of the composition, other components that are pharmaceutically acceptable (for example, carriers, excipients, disintegrants, buffers, emulsifiers, suspension agents, soothing agents, stabilizers, Preservatives, preservatives, saline, etc.).
  • excipient lactose, starch, sorbitol, D-mannitol, sucrose and the like can be used.
  • disintegrant starch, carboxymethylcellulose, calcium carbonate and the like can be used.
  • buffering agent phosphate, citrate, acetate and the like can be used.
  • emulsifier gum arabic, sodium alginate, tragacanth and the like can be used.
  • suspending agent glyceryl monostearate, aluminum monostearate, methyl cellulose, carboxymethyl cellulose, hydroxymethyl cellulose, sodium lauryl sulfate and the like can be used.
  • soothing agent benzyl alcohol, chlorobutanol, sorbitol and the like can be used.
  • stabilizer propylene glycol, ascorbic acid or the like can be used.
  • preservatives phenol, benzalkonium chloride, benzyl alcohol, chlorobutanol, methylparaben, and the like can be used.
  • benzalkonium chloride, paraoxybenzoic acid, chlorobutanol and the like can be used.
  • Antibiotics, pH adjusting agents, growth factors for example, epidermal growth factor (EGF), nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF)
  • growth factors for example, epidermal growth factor (EGF), nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF)
  • the administration route of the composition is not particularly limited. Various known administration forms can be employed depending on the application site and the target disease. For example, parenteral administration may be systemic administration or local administration. More specifically, injection, application, or spraying to a lesion or diseased site can be mentioned. In addition, intravenous administration, intraarterial administration, intraportal administration, intradermal administration, subcutaneous administration, intramuscular administration, intraperitoneal administration, intranasal administration, intraoral administration, intraarticular administration and the like can be mentioned. In certain embodiments, the composition is administered intravenously. In certain embodiments, the composition is administered intra-articularly.
  • the dosage of this composition is not particularly limited. It can be set in consideration of the sex, age, weight, disease state, etc. of the subject. For example, a culture supernatant of about 0.01 to about 100 ml / kg body weight, about 0.1 to about 50 ml / kg body weight, about 0.5 to about 30 ml / kg body weight, or about 1 to about 10 ml / kg body weight. To be administered. Alternatively, for example, from about 0.01 to about 500 mg / kg body weight, from about 0.1 to about 300 mg / kg body weight, from about 1 to about 100 mg / kg body weight, or from about 5 to about 50 mg / kg body weight in dry weight Allow the supernatant to be administered.
  • the sex, age, weight, disease state, etc. of the subject can be considered.
  • the composition may be administered once or multiple times. In the case of multiple administrations, for example, it can be administered once to several times a day, once every 2 days to 7 days, once a week to once every several weeks, once a month to once every several months. In certain embodiments, the composition is administered in a single dose.
  • the subject to which the present composition is applied includes mammals including humans (pets, domestic animals, laboratory animals, etc.). Examples include humans, dogs, cats, rabbits, mice, cows, pigs, goats, sheep, horses, monkeys, guinea pigs, rats and mice.
  • the present application provides a method for producing the present composition, comprising culturing dental pulp stem cells and recovering dental pulp stem cells and / or culture supernatant.
  • dental pulp stem cell culture and dental pulp stem cell and / or culture supernatant collection can be performed as described above, but are not limited thereto, and any method known to those skilled in the art may be used.
  • This production method further includes a step of obtaining pulp cells from deciduous teeth or permanent teeth, a step of selecting and obtaining adhesive cells contained in the pulp cell population as pulp stem cells, and a normal preparation known to those skilled in the art. Step, for example, treatment of dental pulp stem cells and / or culture supernatant, addition of other pharmaceutically acceptable components, and / or preparation of dental pulp stem cells and / or culture supernatant in various pharmaceutical forms And the like.
  • the present application provides a method for cartilage regeneration comprising administering to a subject an effective amount of dental pulp stem cells and / or culture supernatant thereof.
  • the present application provides dental pulp stem cells and / or culture supernatants thereof for use in cartilage regeneration.
  • the present application provides use of dental pulp stem cells and / or culture supernatant thereof for producing a medicament for cartilage regeneration.
  • the present application provides a method of treating and / or preventing osteoarthritis comprising administering to a subject an effective amount of dental pulp stem cells and / or culture supernatant thereof.
  • the present application provides dental pulp stem cells and / or culture supernatants thereof for use in the treatment and / or prevention of osteoarthritis.
  • the present application provides the use of dental pulp stem cells and / or culture supernatant thereof for the manufacture of a medicament for the treatment and / or prevention of osteoarthritis.
  • a composition for cartilage regeneration comprising dental pulp stem cells and / or culture supernatant thereof.
  • the composition according to item 1 for the treatment and / or prevention of osteoarthritis [2] The composition according to item 1 for the treatment and / or prevention of osteoarthritis.
  • Osteoarthritis is degenerative temporomandibular disorder, osteoarthritis of the knee, osteoarthritis of the hip, osteoarthritis of the shoulder, osteoarthritis of the shoulder, elbow osteoarthritis, osteoarthritis of the hand, Item 4.
  • composition according to Item 2 or 3, wherein the composition is osteoarthritis or degenerative spondyloarthritis.
  • the composition according to any one of items 2 to 4, wherein the osteoarthritis is osteoarthritis of the jaw.
  • the osteoarthritis is knee osteoarthritis.
  • the composition according to any one of items 1 to 6, wherein the dental pulp stem cell is derived from a deciduous tooth.
  • the dental pulp stem cells are autologous dental pulp stem cells.
  • composition according to any one of items 1 to 9, which does not contain serum [10] The composition according to any one of items 1 to 9, which does not contain serum. [11] A method for producing the composition according to any one of items 1 to 10, comprising culturing dental pulp stem cells and recovering dental pulp stem cells and / or culture supernatant thereof.
  • Test 1 Eleven-week-old ICR mice were subjected to a forced opening procedure of 3 hours per day for 5 days, adding excessive mechanical stress to the temporal mandibular joint.
  • SHED-CM administration group 0.5 ml of SHED-CM was administered to the tail vein once a day.
  • CT of the temporomandibular joint was taken.
  • a typical result is shown in FIG.
  • the cartilage of the temporomandibular joint was deformed due to the rough surface.
  • the cartilage surface was smooth.
  • the body weight of the mice treated only with the opening treatment was remarkably decreased due to mastication disorder, but the body weight of the SHED-CM administration group was not decreased. This result indicates that SHED-CM can prevent joint deformation and impairment of function.
  • SHED-CM exerts the effect of regenerating mandibular condylar cartilage in osteoarthritis caused by physical stress and can treat joint deformation and functional disorders.
  • SHED-CM is useful for cartilage regeneration and prevention and treatment of osteoarthritis.
  • cartilage can be regenerated by pulp stem cells and / or culture supernatants thereof. Also, it becomes possible to treat and / or prevent osteoarthritis for which no definitive therapy exists.
  • the dental pulp stem cells can be collected from the deciduous deciduous teeth that have been conventionally discarded, and can be easily obtained.

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Abstract

L'invention concerne une composition de régénération de cartilage contenant des cellules souches de pulpe dentaire et/ou un surnageant de culture de celles-ci, et un procédé de production de la composition, comprenant la culture de cellules souches de pulpe dentaire et la récupération des cellules souches de pulpe dentaire et/ou du surnageant de culture de celles-ci. L'invention concerne une composition pour le traitement et/ou la prévention de l'ostéoarthrite, contenant des cellules souches de pulpe dentaire et/ou un surnageant de culture de celles-ci, et un procédé de production de la composition, comprenant la culture de cellules souches de pulpe dentaire et la récupération des cellules souches de pulpe dentaire et/ou du surnageant de culture de celles-ci.
PCT/JP2019/021448 2018-05-31 2019-05-30 Procédé pour le traitement et/ou la prévention de l'ostéoarthrite Ceased WO2019230859A1 (fr)

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JPWO2023033130A1 (fr) * 2021-09-03 2023-03-09

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