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WO2018034314A1 - Agent d'activation de cellules souches mésenchymateuses - Google Patents

Agent d'activation de cellules souches mésenchymateuses Download PDF

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Publication number
WO2018034314A1
WO2018034314A1 PCT/JP2017/029483 JP2017029483W WO2018034314A1 WO 2018034314 A1 WO2018034314 A1 WO 2018034314A1 JP 2017029483 W JP2017029483 W JP 2017029483W WO 2018034314 A1 WO2018034314 A1 WO 2018034314A1
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Prior art keywords
mesenchymal stem
stem cell
cells
age
stem cells
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Japanese (ja)
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本望　修
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Nipro Corp
Sapporo Medical University
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Nipro Corp
Sapporo Medical University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/01—Hydrocarbons
    • A61K31/015—Hydrocarbons carbocyclic
    • 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
    • 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

Definitions

  • the present invention uses ⁇ -carotene as a mesenchymal stem cell activator and stem cell age-improving agent, and tissue repair by using the mesenchymal stem cell activator or stem cell age-improving agent and mesenchymal stem cells in combination -Regarding regenerative medicine.
  • MSC mesenchymal Stem Cell
  • neurotrophic / protective action by neurotrophic factor angiogenic action (recovery of cerebral blood flow), and nerve regeneration .
  • humoral factors such as BDNF (Brain Derived Neurotrophic Factor) and GDNF (Glial Derived Neurotrophic Factor) which are neurotrophic factors.
  • BDNF Brain Derived Neurotrophic Factor
  • GDNF Glial Derived Neurotrophic Factor
  • angiogenesis one is that MSC accumulated in the lesion site secretes angiogenic factors and induces angiogenesis, and the other is that the administered MSC itself is vascularized. It is to differentiate into endothelium to form new blood vessels.
  • MSC accumulated in the lesion promotes endogenous neurogenesis
  • the other is that the administered MSC itself becomes a nerve cell / glial cell. It is to differentiate.
  • all of the above-mentioned mechanisms of action are only speculations from the observed phenomenon, and a mechanism for treating cerebral infarction and spinal cord injury by intravenous administration of MSC has not been demonstrated.
  • ⁇ -carotene is a kind of carotenoid, has a strong antioxidant action, and is converted into vitamin A as needed in the body. Therefore, it is known that ⁇ -carotene has a function of maintaining normal mucosa, skin, immune function, and visual acuity, but its action on mesenchymal stem cells and its mechanism have not been elucidated.
  • the object of the present invention is to elucidate the action of physiologically active substances on the profile and therapeutic effects of mesenchymal stem cells (MSC), and based on the results, the development of cranial nerves, age-related changes, and damage healing are referred to as stem cell homeostasis. From a viewpoint, it is providing the new treatment method with respect to an intractable neurological disease.
  • MSC mesenchymal stem cells
  • mesenchymal stem cells in the bone marrow have a decreased number of cells and proliferative capacity as a result of aging.
  • administration of ⁇ -carotene activates mesenchymal stem cells, and It was confirmed that the number increased and showed high proliferation ability.
  • administration of ⁇ -carotene improved motor function and increased plasticity.
  • the present invention has been completed based on the above findings and relates to the following (1) to (11).
  • a mesenchymal stem cell activator comprising ⁇ -carotene as an active ingredient;
  • mesenchymal stem cell activator according to any one of (1) to (3) above, wherein the mesenchymal stem cells are CD24 negative; (5) An agent for improving stem cell age of mesenchymal stem cells, comprising ⁇ -carotene as an active ingredient; (6) The stem cell age improving agent according to (5), wherein the mesenchymal stem cells are mesenchymal stem cells derived from bone marrow or blood; (7) The agent for improving stem cell age according to (6) above, wherein the bone marrow or blood is bone marrow or blood of a subject receiving mesenchymal stem cells.
  • mesenchymal stem cells can be activated and the stem cell age can be rejuvenated by administration (intake) of ⁇ -carotene.
  • MSCs mesenchymal stem cells
  • ⁇ -carotene administration of ⁇ -carotene.
  • Figure 1 shows the bone marrow between the ginseng juice administration group (graph right) ingested ginseng juice from 24 to 62 weeks of age and the control group at 8 weeks of age (graph left) and 62 weeks of age (graph center). It is the graph which compared the proliferative ability of a leaf stem cell.
  • the vertical axis of the graph is the number of cells, and the horizontal axis is the number of passages (passage number (P), passage number (Day)). From the left of the graph, P0Day9 (9th day of primary culture), P1Day9 (1st passage, 3rd day), P2Day4 (2nd passage, 4th day), P3Day5 (3rd passage, day), P4Day6 (1st day) 4th passage, 6th day).
  • FIG. 2 compares the proliferative ability of bone marrow mesenchymal stem cells between the ⁇ -carotene administration group (graph right) in which ⁇ -carotene was intraperitoneally administered from 33 to 43 weeks of age and the same 43-week-old control group (graph left). It is a graph. The vertical axis of the graph is the number of cells, and the horizontal axis is the number of passages (passage number (P), passage number (Day)). From the left, P0Day9 (9th day of primary culture), P1Day9 (1st and 3rd day), P2Day4 (2nd and 4th day), P3Day5 (3rd and 5th day), P4Day6 (1st day) 4th passage, 6th day).
  • FIG. 3 compares the proliferative ability of bone marrow mesenchymal stem cells between the ginseng juice administration group (graph right) in which ginseng juice was orally ingested from 33 to 43 weeks of age and the same 43-week-old control group (graph left). It is a graph. The vertical axis of the graph is the number of cells, and the horizontal axis is the number of passages (passage number (P), passage number (Day)). From the left of the graph, P0Day9 (9th day of primary culture), P1Day9 (1st passage, 3rd day), P2Day4 (2nd passage, 4th day), P3Day5 (3rd passage, 5th day), P4Day6 ( 4th passage, 6th day).
  • FIG. 4 shows an outline of the experimental protocol of Example 2.
  • FIG. 5 is a graph comparing the improvement in motor function between the ⁇ -carotene administration group and the control group in cerebral infarction (subacute stage) model rats. The vertical axis of the graph is the maximum speed (m / min) that the rat can run, and the horizontal axis is the age of the rat.
  • FIG. 6 is a graph comparing the improvement in motor function between the MSC group and the DMEM group (control group) in cerebral infarction (chronic phase) model rats. The vertical axis of the graph is the maximum speed (m / min) that the rat can run, and the horizontal axis is the age of the rat.
  • the “mesenchymal stem cell activator” is a composition having an effect of reviving the number, proliferation ability and cell function of mesenchymal stem cells (MSC) which have decreased with aging or disease. Means.
  • the “mesenchymal stem cell activator” of the present invention has ⁇ carotene as an active ingredient, has the effect of activating MSC and rejuvenating its stem cell age.
  • the “mesenchymal stem cell activator” of the present invention can improve its tissue repair / regeneration ability and enhance the therapeutic effect of cerebral infarction, spinal cord injury, dementia and the like.
  • the “stem cell age-improving agent” is a composition for rejuvenating the stem cell age, and has a mesenchymal stem cell (MSC) cell number, proliferative ability and cell function that have decreased with aging and disease. Means a composition having a rejuvenating effect.
  • Stem cells are known to decrease in number, proliferation ability, differentiation ability, and stem cell functions associated with tissue repair / regeneration associated with aging. MSCs emerge from the bone marrow into peripheral blood, support systemic metabolism, and contribute to the maintenance of organs including blood vessels and epidermis. When the number and function of MSCs decline, aging progresses or they become ill (stem cell failure).
  • the “stem cell age” is an index indicating a cell age different from the actual age, in other words, a youth of a living body or a cell.
  • the “mesenchymal stem cell” is a stem cell having pluripotency and self-replicating ability that is present in a small amount in a stromal cell of a mesenchymal tissue, such as bone cell, chondrocyte, adipocyte, etc. In addition to differentiating into connective tissue cells, it is known to have the ability to differentiate into neurons and cardiomyocytes.
  • Mesenchymal stem cells exist throughout the body such as bone marrow, peripheral blood, umbilical cord blood, fetal embryo, placenta, fat, and brain.
  • mesenchymal stem cells derived from human bone marrow or blood (bone marrow mesenchymal stem cells).
  • human bone marrow mesenchymal stem cells are preferred.
  • Bone marrow mesenchymal stem cells 1) Expected to have significant effects, 2) Low risk of side effects, 3) Expected to supply sufficient donor cells, 4) Non-invasive treatment and autotransplantation possible 5) Low risk of infection, 6) No immune rejection, 7) No ethical problems, 8) Social acceptance, 9) Widespread establishment as general medical care There are advantages such as.
  • bone marrow transplantation is a treatment already used in clinical practice, and its safety has been confirmed.
  • bone marrow-derived stem cells are highly migratory and can reach the target damaged tissue not only by local transplantation but also by intravenous administration, and a therapeutic effect can be expected.
  • the cell may be a cell induced to differentiate from an ES cell or an induced pluripotent stem cell (iPS cell or the like), a cell established, or a cell isolated and proliferated from a living body.
  • the cells may be derived from other cells or autologous cells, but mesenchymal stem cells derived from autologous cells (derived from the patient's own cells) are preferred.
  • the mesenchymal stem cells are CD24 negative, which is a differentiation marker. It is preferable that the cells maintain an undifferentiated state.
  • CD24-negative mesenchymal stem cells are characterized by a high proliferation rate and a high survival rate after introduction into the living body.
  • ⁇ -carotene By using in combination with a mesenchymal stem cell activator or a stem cell age-improving agent ( ⁇ -carotene), It can be expected to establish a new therapeutic strategy and improve the therapeutic effect of refractory neurological diseases such as cerebral infarction, spinal cord injury, and dementia due to high MSC.
  • the inventors have also developed a method for obtaining such undifferentiated mesenchymal stem cells, the details of which are described in WO2009 / 002503.
  • the mesenchymal stem cells are positive for at least one selected from CD73, CD90, CD105, and CD200, and At least one selected from CD19, CD34, CD45, CD74, CD79 ⁇ , and HLA-DR is characterized by being negative.
  • the mesenchymal stem cells used in the present invention are positive for two or more of CD73, CD90, CD105, and CD200, and negative for four or more of CD19, CD34, CD45, CD74, CD79 ⁇ , and HLA-DR. It is characterized by being.
  • the mesenchymal stem cells used in the present invention are characterized by being positive for CD73, CD90, CD105, and CD200 and negative for CD19, CD34, CD45, CD74, CD79 ⁇ , and HLA-DR. It is done.
  • cells separated from bone marrow fluid or the like under conditions that do not substantially contact with an anticoagulant contain human serum (preferably autologous serum), and anticoagulation Growth is performed using a medium that does not contain an agent (such as heparin) or contains a very low concentration.
  • the density of the cells in the medium affects the nature of the cells and the direction of differentiation.
  • the properties of the cells change, so subculture at a maximum of 8,500 cells / cm 2 or less. More preferably, the subculture is performed when the number of cells reaches 5500 cells / cm 2 or more.
  • the medium is changed as few times as possible in consideration of the burden on the serum donor, for example, at least once a week, more preferably a week. Replace the medium once or twice.
  • the subculture is repeated until the total number of cells reaches 10 8 or more.
  • the number of cells required may vary depending on the purpose of use.
  • the number of mesenchymal stem cells required for transplantation for the treatment of cerebral infarction is considered to be 10 7 or more.
  • 10 7 mesenchymal stem cells can be obtained in about 12 days.
  • the proliferated mesenchymal stem cells may be stored by a technique such as cryopreservation (for example, in a deep freezer at ⁇ 152 ° C.) until use, if necessary.
  • a medium containing serum preferably human serum, more preferably autologous serum
  • dextran DMSO (medium for mammalian cells such as RPMI)
  • DMSO medium for mammalian cells
  • cells can be suspended and stored frozen at -150 ° C. in a cryopreservation solution containing 20.5 mL of normal filter-sterilized RPMI, 20.5 mL of autologous serum collected from patients, 5 mL of dextran, and 5 mL of DMSO.
  • Cryoserve and Dextran manufactured by Nipro Corporation can use low molecular dextran L injection manufactured by Otsuka Pharmaceutical, but are not limited thereto.
  • a “medicine repair / regeneration drug containing mesenchymal stem cells” is a cell preparation containing the above-mentioned “mesenchymal stem cells (MSC)”, and is a damaged site or an aging site due to aging (particularly, Nervous system tissues such as the brain and spinal cord are repaired and regenerated (WO 2009/034708). Furthermore, the inventors have also found that administration of MSC improves synapse formation and plasticity (Japanese Patent Application Nos. 2016-091286 and 2016-091300).
  • Synapse formation means that axons extending from nerve cells properly extend to the vicinity of the target cells and axons that establish neural connections, reach the target, and between the axon end and the target cells and axons. It is a process of forming synapses, and an important process of forming correct neural circuits. When the MSC according to the present invention reaches the affected area, it has the effect of reconstructing the neural circuit by differentiating into nerve cells and axons and forming synapses.
  • Plastic plasticity refers to a phenomenon in which nerve cells and brain circuits create an optimal treatment system according to the environment and needs.
  • the MSC according to the present invention also has a function of promoting “brain plasticity” that functions beyond the normal range so that an uninjured site compensates for the function of the damaged site.
  • MSC meenchymal stem cells
  • the number of mesenchymal stem cells contained in the “medicament for tissue repair / regeneration containing mesenchymal stem cells” is 10 7 or more, preferably 5 ⁇ 10 7 or more, more preferably 10 8 or more, and further preferably 5 ⁇ 10 8 or more.
  • tissue repair / regeneration drug containing mesenchymal stem cells is preferably a parenteral preparation, more preferably a parenteral systemic preparation, particularly an intravenous preparation.
  • parenteral preparation preferably a parenteral systemic preparation, particularly an intravenous preparation.
  • dosage form suitable for parenteral administration include injections such as solution injections, suspension injections, emulsion injections, injections prepared at the time of use, and grafts.
  • a preparation for parenteral administration is in the form of an aqueous or non-aqueous isotonic sterile solution or suspension, for example, a pharmacologically acceptable carrier or vehicle, specifically, sterile water or saline, Medium (especially medium used for culturing mammalian cells such as RPMI), physiological buffer solution such as PBS, vegetable oil, emulsifier, suspension agent, surfactant, stabilizer, excipient, vehicle, preservative, binding
  • a pharmacologically acceptable carrier or vehicle specifically, sterile water or saline, Medium (especially medium used for culturing mammalian cells such as RPMI), physiological buffer solution such as PBS, vegetable oil, emulsifier, suspension agent, surfactant, stabilizer, excipient, vehicle, preservative, binding
  • physiological buffer solution such as PBS, vegetable oil, emulsifier, suspension agent, surfactant, stabilizer, excipient, vehicle, preservative, binding
  • Aqueous solutions for injection include, for example, physiological saline, culture media, physiological buffers such as PBS, isotonic solutions containing glucose and other adjuvants, such as D-sorbitol, D-mannose, D-mannitol, sodium chloride, etc. And may be used in combination with an appropriate solubilizing agent such as alcohol, specifically ethanol, polyalcohol, propylene glycol, polyethylene glycol or a nonionic surfactant such as polysorbate 80, HCO-50, or the like.
  • physiological saline such as PBS
  • isotonic solutions containing glucose and other adjuvants such as D-sorbitol, D-mannose, D-mannitol, sodium chloride, etc.
  • an appropriate solubilizing agent such as alcohol, specifically ethanol, polyalcohol, propylene glycol, polyethylene glycol or a nonionic surfactant such as polysorbate 80, HCO-50, or the like.
  • the “mesenchymal stem cell activator” or “stem cell age-improving agent” ( ⁇ -carotene) of the present invention can enhance the therapeutic effect of MSC by activating MSC and rejuvenating stem cell age.
  • the mesenchymal stem cell activator or stem cell age-improving agent of the present invention is used in combination with "a tissue repair / regeneration drug containing mesenchymal stem cells" to improve the therapeutic effect of MSC administration. Can be expected to do. Below, the effect is described concretely.
  • a cerebral infarction is a pathological condition in which cerebral ischemia is caused by occlusion or stenosis of a cerebral artery, and brain tissue becomes necrotic or close to this condition.
  • Mesenchymal stem cells have a protective effect on the brain (parenchyma and blood vessels), and in acute and subacute cerebral infarction, administration of MSC reduces infarct volume and improves behavioral function.
  • Administration of a mesenchymal stem cell activator or a stem cell age-improving agent can be expected to enhance the effect.
  • Necrotic cells and damaged nerve fibers do not return to their original state in the chronic phase. Therefore, in chronic cerebral infarction, in addition to preventing recurrence, recovery of non-dead cells and cells that have stopped functioning around necrotic cells and reducing the disease state are the main treatment. Has been considered. However, administration of MSC promotes reconstruction of the neural circuit and compensation by normal tissue, thereby making it possible to restore motor function and brain function even in chronic cerebral infarction. Administration of the mesenchymal stem cell activator or stem cell age-improving agent of the present invention can be expected to enhance the effect.
  • MSCs of the present invention are amyotrophic lateral sclerosis (ALS), Parkinson's disease, progressive supranuclear palsy (PSP), Huntington's disease, multiple system atrophy (MSA), black It is also useful for neurodegenerative diseases such as striatal degeneration (SND), Shy-Drager syndrome, olive bridge cerebellar atrophy (OPCA), spinocerebellar degeneration (SCD) and the like.
  • Administration of the mesenchymal stem cell activator or stem cell age-improving agent of the present invention can be expected to further enhance its therapeutic effect.
  • vascular dementia can be treated with mesenchymal stem cells .
  • Alzheimer-type dementia and vascular dementia have similar pathological conditions, and in Alzheimer-type dementia, improvement of cognitive function by MSC can be expected.
  • Administration of the mesenchymal stem cell activator or stem cell age-improving agent of the present invention can be expected to further enhance the therapeutic effect of MSC on dementia.
  • MSC of the present invention is used for schizophrenia, manic depression, personality disorder, mood disorder, psychological development disorder, stress-related disorder, autism, learning disorder, It is also useful for mental disorders such as emotional disorders, mental retardation, sleep disorders, eating disorders, identity disorders, dissociative disorders, adaptation disorders, alcoholic disorders, addictions.
  • Administration of the mesenchymal stem cell activator or stem cell age-improving agent of the present invention can be expected to further enhance its therapeutic effect.
  • the MSC of the present invention improves higher-order functions such as attention disorder, memory disorder, aphasia, forgetfulness, apraxia, executive function, and emotional disorder.
  • administration of the mesenchymal stem cell activator or stem cell age-improving agent of the present invention can be expected to enhance the effect.
  • Life extension MSC of the present invention has effects of rejuvenation, physical strength enhancement and life extension in healthy individuals, and in patients with intractable neurological diseases such as dementia and cerebral infarction and spinal cord injury, Combined with improvement of motor function, it has a life extension effect after treatment.
  • Administration of the mesenchymal stem cell activator or stem cell age-improving agent of the present invention can be expected to enhance the effect.
  • the dose of the mesenchymal stem cell activator or stem cell age-improving agent of the present invention is not particularly limited, and is appropriately determined according to the administration (intake) method, the age of the subject, and the health condition.
  • the administration route of the mesenchymal stem cell activator or stem cell age-improving agent of the present invention is not particularly limited, but oral administration (intake) is simple and preferable.
  • the mesenchymal stem cell activator or the stem cell age-improving agent of the present invention contains ⁇ -carotene, its form / shape is not particularly limited, and may be a food or drink such as carrot juice or a supplement.
  • the mesenchymal stem cell activator of the present invention may be formulated into a liquid, tablet, capsule or the like together with a pharmacologically acceptable carrier.
  • Example 1 Effect on ⁇ -carotene mesenchymal stem cells
  • ginseng juice oral intake
  • SD rats female
  • the carrot juice administration group consists of 100% carrot juice from Chiba Prefecture (made by Ihashi Sangyo Co., Ltd. (Ikiiki Carrot Museum Sukoyaka)), about 100 ml / animal / day, and MF food (made by Oriental Yeast Co., Ltd.) as a free feed for 24 weeks.
  • DMEM Dulbecco's modified Eagle's medium
  • the control group was reared with free feeding (food: MF) and free water, and bone marrow (two femurs and two tibias) was collected at 8 and 62 weeks of age.
  • the collected bone marrow cells were subcultured 4 times in the same manner as in (1), and the number of cells was counted at the time of subculture. Evaluation was carried out by comparing the number of cultured cells (average number of 5 or 8 cells) per passage of the collected bone marrow up to P4.
  • ⁇ -carotene has a significant MSC activation effect and stem cell age rejuvenation effect. That is, by ingesting ⁇ -carotene, it can be expected that the tissue maintenance / repair / regeneration effect of MSC is improved, and the therapeutic effect of rejuvenation and illness (cerebral infarction, spinal cord injury, dementia, etc.) is improved.
  • Example 2 Effect of ⁇ -carotene administration in cerebral infarction (subacute stage) model rats Materials and Methods (1) Cerebral Infarction (Subacute Phase) Model Rat A rat middle cerebral artery occlusion (MCAO) model was used as a cerebral infarction model. As previously reported, 9-week-old female SD rats (200-250 g) were anesthetized with ketamine (75 mg / kg) and xylazine (10 mg / kg), and 20.0-22.0 mm embolic thread (MONOSOF) was externally necked. Inserted from the artery, permanent middle cerebral artery occlusion was performed (Honma T. et al., Exp. Neurol. 2006; 199: 56-66.
  • MCAO Cerebral Infarction
  • MCAO Middle cerebral artery occlusion
  • FIG. 4 shows the protocol of this embodiment.
  • Reference Example 1 Effects of MSC administration in cerebral infarction (chronic phase) model rats Materials / Methods (1) Preparation of rat bone marrow-derived mesenchymal stem cells Experiments were performed in accordance with animal experiment management regulations of Sapporo Medical University. According to previous reports, bone marrow obtained from femurs of adult SD rats was diluted to 25 ml with Dulbecco's modified Eagle's medium (DMEM) and heat-inactivated 10% FBS, 2 mM l-glutamine, 100 U / ml penicillin, 0.1 mg / ml streptomycin was added and incubated for 3 days at 37 ° C. in 5% CO 2 atmosphere (Kim S. et al., Brain Res.
  • DMEM Dulbecco's modified Eagle's medium
  • MSC group MS rats of SD rats 8 weeks after MCAO, DMEM containing 1.0 ⁇ 10 6 P2 in 1 ml were administered from the femoral vein.
  • DMEM group 1 ml of DMEM was administered from the femoral vein.
  • the present invention is useful for establishing a new therapeutic strategy and improving the therapeutic effect of intractable neurological diseases such as cerebral infarction, spinal cord injury, and dementia caused by MSC.

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Abstract

La présente invention concerne l'utilisation de β-carotène à titre d'agent d'activation de cellules souches mésenchymateuses et d'agent d'amélioration des cellules souches avec l'âge, et dans le domaine de la réparation tissulaire et de la médecine régénérative par utilisation combinée dudit agent d'activation de cellules souches mésenchymateuses ou agent d'amélioration des cellules souches avec l'âge et de cellules souches mésenchymateuses.
PCT/JP2017/029483 2016-08-18 2017-08-17 Agent d'activation de cellules souches mésenchymateuses Ceased WO2018034314A1 (fr)

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WO2020162580A1 (fr) 2019-02-07 2020-08-13 北海道公立大学法人 札幌医科大学 Composition pharmaceutique destinée à prévenir la resténose intra-stent
WO2020201763A1 (fr) * 2019-04-02 2020-10-08 Noordeen Mohamed Hamza Réparation tissulaire

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