WO2017204231A1 - Agent thérapeutique pour dysfonctionnement cérébral comprenant des cellules dérivées de cordon ombilical - Google Patents

Agent thérapeutique pour dysfonctionnement cérébral comprenant des cellules dérivées de cordon ombilical Download PDF

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WO2017204231A1
WO2017204231A1 PCT/JP2017/019281 JP2017019281W WO2017204231A1 WO 2017204231 A1 WO2017204231 A1 WO 2017204231A1 JP 2017019281 W JP2017019281 W JP 2017019281W WO 2017204231 A1 WO2017204231 A1 WO 2017204231A1
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umbilical cord
cells
derived
therapeutic agent
derived cells
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PCT/JP2017/019281
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Japanese (ja)
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登紀子 長村
丈雄 向井
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国立大学法人 東京大学
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Priority to JP2018519569A priority Critical patent/JP7126703B2/ja
Publication of WO2017204231A1 publication Critical patent/WO2017204231A1/fr

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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
    • A61K35/48—Reproductive organs
    • A61K35/51—Umbilical cord; Umbilical cord blood; Umbilical stem cells

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  • the present invention relates to a therapeutic agent for brain disorders containing umbilical cord-derived cells.
  • Perinatal neonatal cerebral dysfunction is a condition that is associated with a frequency of 1 to 2 in 1000 births, causes cerebral palsy throughout the rest of the life, and places a heavy burden not only on the person but also on the rearing family. .
  • Perinatal cerebral disorders that cause cerebral palsy include hypoxic-ischemic encephalopathy, cerebral hemorrhage, and periventricular leukomalacia, and the main pathologic conditions of these are active oxygen resulting from intracellular Ca rise and mitochondrial dysfunction It is an inflammatory pathological condition that is elevated, macrophage activation and associated hypercytokinemia.
  • cerebral hemorrhage is likely to be associated with premature infants, with the most severe symptoms and poor prognosis.
  • hypothermia is effective as a treatment method, it is only effective for one out of 8 to 9 children. In addition, there is no established treatment method other than hypothermia therapy.
  • Non-patent Document 1 So far, clinical studies have been conducted in which autologous bone marrow-derived mesenchymal cells are directly administered to cerebral palsy patients, and their effectiveness has been reported (Non-patent Document 1). Moreover, although there is a report of administration of umbilical cord-derived cells, no significant improvement has been achieved in some motor functions (Non-patent Document 2).
  • the present inventors have found that venous administration of a cell population containing cells prepared from umbilical cord tissue including amnion, blood vessels, perivascular tissue and Walton Jelly caused cerebral hemorrhage.
  • the present inventors have found that it is possible to improve the behavior of brain disorders and have completed the present invention.
  • the present invention relates to the following: [1] A therapeutic agent for brain damage, comprising umbilical cord-derived cells. [2] The therapeutic agent according to [1], which is for intravenous administration. [3] The therapeutic agent according to [1] or [2], wherein the umbilical cord-derived cell is a cell prepared from umbilical cord tissue including amniotic membrane, blood vessels, perivascular tissue and Walton jelly.
  • the umbilical cord-derived cell is (I) cells having the characteristics that CD105, CD73, CD90, CD44, HLA-classI, HLA-G5 and PD-L2 are positive, and (ii) CD45, CD34, CD11b, CD19 and HLA-ClassII are negative
  • the therapeutic agent according to any one of [1] to [3].
  • the umbilical cord-derived cell is (Iii) The therapeutic agent according to any one of [1] to [4], wherein the expression of any one gene and / or protein of IDO, PGE2, and PD-L1 is induced under conditions of inflammation.
  • the brain disorder is cerebral palsy.
  • (i) CD105, CD73, CD90, CD44, HLA-class I, HLA-G5 and PD-L2 are positive, and (ii) CD45, CD34, CD11b, CD19 and HLA-Class II are negative.
  • the umbilical cord-derived cell according to [8] wherein expression of any one gene of IDO, PGE2, and PD-L1 and / or protein is induced under conditions of inflammation.
  • the umbilical cord-derived cell according to [8] or [9] which is for intravenous administration.
  • the umbilical cord-derived cell according to any one of [8] to [12], wherein the brain disorder is cerebral palsy.
  • a method for treating brain damage using umbilical cord-derived cells [15] The treatment method according to [14], wherein umbilical cord-derived cells are intravenously administered.
  • the umbilical cord-derived cells are cells prepared from umbilical cord tissue including amniotic membrane, blood vessels, perivascular tissue and Walton jelly.
  • the umbilical cord-derived cell is (I) CD105, CD73, CD90, CD44, HLA-class I, HLA-G5 and PD-L2 are positive, and (ii) CD45, CD34, CD11b, CD19 and HLA-Class II are negative [14] To [16]. [18] The treatment method according to [17], wherein the umbilical cord-derived cells are induced to express (iii) genes and / or proteins of IDO, PGE2, and PD-L1 under conditions of inflammation. [19] The treatment method according to any one of [14] to [18], wherein the brain disorder is a brain disorder in a fetus or a neonatal period. [20] The treatment method according to any one of [14] to [19], wherein the brain disorder is cerebral palsy.
  • a treatment of brain disorders comprising a cell population comprising cells prepared from umbilical cord tissue including amnion, blood vessels, perivascular tissue and Walton jelly and / or administered intravenously
  • An agent can be provided.
  • FIG. 1 shows the results of measuring the expression level of mRNA of IDO in umbilical cord-derived cells by quantitative PCR (ratio to the positive control GAPDH).
  • FIG. 2 shows the results of measuring the protein concentration of PGE2 in the culture supernatant obtained by co-culturing MLR and umbilical cord-derived cells by ELISA.
  • FIG. 3 shows a stained image of a brain tissue section collected after PBS was administered to a neonatal cerebral hemorrhage model mouse. The lower figure shows an enlarged image of the upper frame, and shows an immunostained image stained with antibodies against MAP2 and GFAP. MAP2 is shown in green and GFAP is shown in red.
  • FIG. 1 shows the results of measuring the expression level of mRNA of IDO in umbilical cord-derived cells by quantitative PCR (ratio to the positive control GAPDH).
  • FIG. 2 shows the results of measuring the protein concentration of PGE2 in the culture supernatant obtained by co-culturing MLR and umbilical cord-
  • FIG. 4 shows a schematic diagram of a schedule for preparation, treatment and evaluation of a neonatal cerebral hemorrhage model mouse.
  • a cerebral hemorrhage model is prepared by intracerebral blood administration, and therapeutic cells are administered on the eighth day after birth (Day 8), and on the 15th day and 22 days after birth. It shows that the evaluation was performed by MRI and the behavioral evaluation was performed on the 23rd day after birth.
  • FIG. 5 shows the results of pharmacokinetics using umbilical cord-derived cells into which a Luciferase gene was introduced. In vivo imaging of luminescence by Luciferase at 6 hours, 3 days, 4 days, 5 days, 7 days, 14 days and 21 days after cell administration is shown.
  • FIG. 6 shows the behavioral trajectory of a 10 minute open field test mouse.
  • the figure below shows a graph of the number of behavioral distances and the number of standing behaviors (rearing) in cerebral hemorrhage model mice and normal mice after administration of umbilical cord-derived cells (MSC) or negative control (PBS).
  • FIG. 7 shows the measurement results of the stride (forelimb stride, hindlimb stride and forelimb hindlimb distance) or hindlimb angle in cerebral hemorrhage model mice and normal mice after administration of umbilical cord-derived cells (MSC) or negative control (PBS).
  • the figure below shows the abduction of the left foot in each mouse as a result of measuring the hind limb angle.
  • FIG. 8 shows the measurement results of MRI in cerebral hemorrhage model mice after administration of umbilical cord-derived cells (MSC) or negative control (PBS) on the 15th day after birth (FIG. 8A) and 22 days after birth (FIG. 8B).
  • FIG. 9 shows immunostained images stained with antibodies against MAP2 and GFAP and DAPI in periventricular tissues of cerebral hemorrhage model mice after administration of non-treated mice, negative control (PBS) or umbilical cord-derived cells (MSC).
  • MAP2 is shown in green and GFAP is shown in red, and DAPI (nucleus) is shown in blue.
  • FIG. 8 shows the measurement results of MRI in cerebral hemorrhage model mice after administration of umbilical cord-derived cells (MSC) or negative control (PBS) on the 15th day after birth (FIG. 8A) and 22 days after birth (FIG. 8B).
  • FIG. 9 shows immunostained images stained with antibodies against MAP2 and GFAP and
  • FIG. 10 shows HE-stained images of periventricular tissue of cerebral hemorrhage model mice after treatment with untreated mice, negative control (PBS) or umbilical cord-derived cells (MSC).
  • FIG. 11 shows MBP-stained images of periventricular tissue of cerebral hemorrhage model mice after administration of non-treated mice, negative control (PBS) or umbilical cord-derived cells (MSC).
  • FIG. 12 shows histologically quantitative evaluation of MBP-stained images of periventricular tissues of untreated mice, cerebral hemorrhage model mice after administration of negative control (PBS) or umbilical cord-derived cells (MSC), and white matter volume ( %) Is shown.
  • FIG. 10 shows HE-stained images of periventricular tissue of cerebral hemorrhage model mice after treatment with untreated mice, negative control (PBS) or umbilical cord-derived cells (MSC).
  • FIG. 11 shows MBP-stained images of periventricular tissue of cerebral hemorrhage model mice after administration of non-treated mice
  • FIG. 13 shows a TUNEL-stained image of the periventricular tissue of cerebral hemorrhage model mice after untreated mice, negative control (PBS) administration or umbilical cord-derived cells (MSC) administration.
  • FIG. 14 shows histologically quantitative evaluation of TUNEL-stained images of periventricular tissue of untreated mice, cerebral hemorrhage model mice after administration of negative control (PBS) or umbilical cord-derived cells (MSC). The result of calculating the ratio (%) is shown.
  • FIG. 15 shows the results of behavioral evaluation (measurement of behavioral distance in 10 minutes) after umbilical cord-derived cells (UC-MSC) obtained by culturing under cerebral hemorrhage model mice were administered to the facial vein. Indicates.
  • FIG. 14 shows histologically quantitative evaluation of TUNEL-stained images of periventricular tissue of untreated mice, cerebral hemorrhage model mice after administration of negative control (PBS) or umbilical cord-derived cells (MSC). The result of calculating the ratio (%)
  • FIG. 16 shows the results of behavioral evaluation (measurement of the number of rises) after umbilical cord-derived cells (UC-MSC) obtained by culturing under cerebral hemorrhage model mice were administered to the facial vein.
  • FIG. 17 shows the results of BDNF and HGF mRNA expression levels in umbilical cord-derived cells measured by quantitative PCR (ratio to positive control GAPDH).
  • FIG. 18 shows the results of measuring the protein concentrations of BDNF and HGF in a culture supernatant obtained by co-culturing mouse neurons and umbilical cord-derived cells by a bead assay.
  • FIG. 19 shows the results of examining the effect of umbilical cord-derived cell administration to cerebral hemorrhage model mice (influence on serum NGF content).
  • FIG. 20 shows the results of examining the effect of umbilical cord-derived cell administration to cerebral hemorrhage model mice (influence on serum BDNF content).
  • FIG. 21 shows the results of examining the effect of umbilical cord-derived cell administration to cerebral hemorrhage model mice (influence on serum HGF content).
  • FIG. 22 shows the results of evaluating the survival of cells in each organ after administration of umbilical cord-derived cells to adult mice.
  • FIG. 23 shows the results of immunostaining (HLA-Class I and CD105) of brain sections of mice administered with umbilical cord-derived cells via the jugular vein.
  • the umbilical cord is a white tubular tissue connecting the fetus and the placenta, and means a tissue not containing the placenta and umbilical cord blood.
  • the umbilical cord of the present invention is not particularly limited as long as it is an umbilical cord collected from a mammal.
  • the umbilical cord of a primate mammal More preferably, it is a human umbilical cord.
  • the umbilical cord may be an umbilical cord collected from a treatment target or an umbilical cord collected from other than the treatment target. From the viewpoint of not being restricted at the time of preparation, it is desirable to use an umbilical cord collected from other than the treatment target.
  • the umbilical cord-derived cells of the present invention exhibit therapeutic effects without being excluded due to immune rejection or the like, even if they are umbilical cord-derived cells collected from other than the treatment target, as shown in Examples described later. It has been confirmed.
  • the umbilical cord can be recovered by appropriately removing the placenta from the placenta and the postpartum tissue including the umbilical cord delivered by transvaginal delivery and cesarean section.
  • aseptic or antibacterial treatment may be performed.
  • Umbilical cord blood removal is performed by rinsing with an anticoagulant solution such as a heparin-containing solution.
  • Sterile or antibacterial treatment is not particularly limited, but is a medium supplemented with popidone iodine or supplemented with one or more antibiotics and / or antifungal agents such as penicillin, streptomycin, amphotericin B, gentamicin, and nystatin.
  • erythrocytes may be used as a method for selectively lysing erythrocytes.
  • a method well known in the art such as incubation in a hypertonic medium or a hypotonic medium by lysis with ammonium chloride can be used.
  • the umbilical cord-derived cell of the present invention means a cell population prepared using the umbilical cord as a raw material.
  • a step of cutting the umbilical cord (2) a step of culturing an umbilical cord section, and (3 ) A method including the step of passaging is exemplified.
  • a method including the step of passaging is exemplified.
  • another method for preparing the cell (A) a step of cutting the umbilical cord or an enzyme treatment, or a step of dissociating the tissue by both, (B) a step of culturing the umbilical cord tissue, (C) passage The method including the process to do is illustrated.
  • the umbilical cord-derived cells may be a heterogeneous cell population rather than a uniform cell population.
  • the umbilical cord-derived cells of the present invention may be defined as a cell population having the following characteristics; (A) shows the adhesiveness to the plastic under the culture conditions in the standard medium, (B) CD105, CD73, CD90, CD44, HLA-class I, HLA-G5 and PD-L2 are positive, CD45, CD34, CD11b, CD19 and HLA-Class II are negative, and (c) conditions of inflammation Below, expression of genes and / or proteins of IDO, PGE2, and PD-L1 is induced.
  • positive refers to a negative control cell that does not express the antigen or a negative control reaction that uses an antibody that does not react with the antigen by an analysis method such as flow cytometry that is detected using the antigen-antibody reaction.
  • negative means that detection is equivalent or less than negative control cells that do not express the antigen or negative control reactions that use antibodies that do not react with the antigen. Means that.
  • HLA-class I means HLA-A, B or C
  • HLA-Class II means HLA-DR, DQ or DP.
  • the condition of inflammation refers to the condition of contact with an inflammatory cytokine such as interferon ⁇ .
  • the umbilical cord obtained by the above-described method is cut by mechanical force (shredding force or shearing force) in a state containing amniotic membrane, blood vessel, perivascular tissue and Walton jelly. Can be done.
  • the umbilical cord section obtained by cutting is exemplified by a size of 1 to 10 mm 3 , 1 to 5 mm 3 , 1 to 4 mm 3 , 1 to 3 mm 3 or 1 to 2 mm 3 .
  • the umbilical cord obtained by the above-described method can be performed in a step of dissociating the tissue by enzyme treatment in a state containing amniotic membrane, blood vessels, perivascular tissue and Walton jelly.
  • the enzyme treatment include enzyme treatment with collagenase, dispase, hyaluronidase, and the like.
  • the steps (2) and (B) of culturing the umbilical cord section of the present invention can be performed by seeding the cut umbilical cord section in a culture vessel and culturing it in a culture solution suitable for umbilical cord-derived cells.
  • the digestive enzyme treatment is not performed on the umbilical cord section.
  • the incubator is not particularly limited as long as it is an incubator having a solid surface, but the “solid surface” means any material capable of binding to the umbilical cord-derived cells of the present invention.
  • a material is a plastic material that has been treated (eg, increased hydrophilicity) to promote the binding of mammalian cells to its surface.
  • the shape of the culture vessel having a solid surface is not particularly limited, but a petri dish or a flask is preferably used.
  • a culture solution suitable for umbilical cord-derived cells is obtained by adding serum to the basal medium and / or albumin, transferrin, fatty acid, insulin, sodium selenite, cholesterol, collagen precursor, trace element, 2 - May be made by adding one or more serum replacements, such as mercaptoethanol, 3'-thiolglycerol.
  • serum replacements such as mercaptoethanol, 3'-thiolglycerol.
  • serum replacements such as mercaptoethanol, 3'-thiolglycerol.
  • These media may contain substances such as lipids, amino acids, proteins, polysaccharides, vitamins, growth factors, low molecular compounds, antibiotics, antifungal agents, antioxidants, pyruvate, buffers, inorganic salts, etc. May be added.
  • the basal medium is, for example, Dulbecco's Modified Eagle's Medium (DMEM) (high glucose or low glucose), modified DMEM, DMEM / MCDB 201, Eagle's basal medium, Ham's F10 medium (F10), Ham ' s F-12 medium (F12), Iscove's modified Dulbecco (IMDM) medium, Fischer's medium, mesenchymal stem cell growth medium (MSCGM), DMEM / F12, RPMI 1640, CELL-GRO-FREE, and mixed media thereof Is mentioned.
  • DMEM Dulbecco's Modified Eagle's Medium
  • DMEM / MCDB 201 Eagle's basal medium
  • Eagle's basal medium Ham's F10 medium (F10), Ham ' s F-12 medium (F12)
  • Iscove's modified Dulbecco (IMDM) medium Fischer's medium
  • MSCGM mesenchymal stem cell growth medium
  • serum examples include, but are not limited to, human serum, fetal bovine serum (FBS), bovine serum, calf serum, goat serum, horse serum, pig serum, sheep serum, rabbit serum, rat serum and the like.
  • FBS fetal bovine serum
  • bovine serum calf serum
  • goat serum horse serum
  • pig serum sheep serum
  • rabbit serum rat serum
  • 5 v / v% to 15 v / v%, preferably 10 v / v% may be added to the basal medium.
  • fatty acids include, but are not limited to, linoleic acid, oleic acid, linolenic acid, arachidonic acid, myristic acid, palmitoyl acid, palmitic acid, and stearic acid.
  • Examples of the lipid include, but are not limited to, phosphatidylserine, phosphatidylethanolamine, phosphatidylcholine, and the like.
  • Amino acids include, but are not limited to, for example, L-alanine, L-arginine, L-aspartic acid, L-asparagine, L-cysteine, L-cystine, L-glutamic acid, L-glutamine, L-glycine and the like.
  • proteins include, but are not limited to, ecotin, reduced glutathione, fibronectin and ⁇ 2-microglobulin.
  • polysaccharide examples include glycosaminoglycans, and among the glycosaminoglycans, hyaluronic acid, heparan sulfate and the like are particularly exemplified, but the polysaccharide is not limited thereto.
  • Growth factors include, for example, platelet derived growth factor (PDGF), epidermal growth factor (EGF), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), insulin-like growth factor-1 (IGF-1), Examples include leukocyte inhibitory factor (LIF), basic fibroblast growth factor (bFGF), transforming growth factor beta (TGF- ⁇ ), hepatocyte growth factor (HGF), connective tissue growth factor (CTGF) and erythropoietin.
  • PDGF platelet derived growth factor
  • EGF epidermal growth factor
  • FGF fibroblast growth factor
  • VEGF vascular endothelial growth factor
  • IGF-1 insulin-like growth factor-1
  • LIF leukocyte inhibitory factor
  • bFGF basic fibroblast growth factor
  • TGF- ⁇ transforming growth factor beta
  • HGF connective tissue growth factor
  • erythropoietin erythropoietin.
  • Antibiotics and / or antifungal agents include
  • the umbilical cord section In this step (2) and (B), it is desirable to hold the umbilical cord section with a plate or the like during the culture period from the viewpoint of preventing the seeded umbilical cord section from floating in the culture solution.
  • the plate include a plate described in JP-A-2015-70824.
  • the cells are cultured under 0 to 5% CO 2 .
  • the cells are cultured under 2 to 25% O 2 , more preferably under 5 to 20% O 2 .
  • the culture is preferably performed at 25 to 40 ° C, more preferably at 37 ° C.
  • the cells migrate from the umbilical cord section and are cultured until the cells become 50%, 60%, 70%, 80% or more confluent with respect to the incubator. preferable. After incubation, to remove unbound cells and cell debris, the cells are washed and detached with a release agent containing trypsin, EDTA solution, collagenase, dispase, hyaluronidase or mixtures thereof, and the cells and umbilical cord sections are removed. Only the cells can be obtained as umbilical cord-derived cells by filtering the stripping solution containing the cells using a cell strainer or the like. The obtained umbilical cord-derived cells can be seeded in the above-mentioned incubator and cultured using the above-mentioned culture solution.
  • the umbilical cord-derived cells can be appropriately proliferated to the required number by subculture.
  • the cells may be peeled off with a release agent containing trypsin, EDTA solution, collagenase, dispase, hyaluronidase or a mixture thereof, and seeded at a suitable cell density in a separately prepared culture vessel, and the culture may be continued.
  • typical cell densities are 100 cells / cm 2 to 100,000 cells / cm 2 , 500 cells / cm 2 to 50,000 cells / cm 2 , 1,000 to 10,000 cells. / Cm 2 , 2,000 to 10,000 cells / cm 2, etc. are exemplified.
  • the cell density is between 2,000 and 10,000 cells / cm 2 . It is preferable to adjust the period until reaching appropriate confluency to 3 to 7 days. During culturing, the medium may be changed as necessary.
  • the passages of the present steps (3) and (C) may be performed until aging when cell division stops.
  • the cells are preferably subcultured 3 to 25 times, more preferably 4 to 12 times.
  • surface antigens and the like may be analyzed by a conventional method using flow cytometry or the like. Moreover, you may evaluate by measuring the amount of various proteins produced from the said cell.
  • the obtained umbilical cord-derived cells may be prepared for treatment as they are or may be stored frozen.
  • Cryopreservation is performed by suspending cells in a cryopreservation solution that can sufficiently preserve umbilical cord-derived cells, and storing the cells at ⁇ 80 ° C. to ⁇ 180 ° C.
  • the cryopreservation solution is not particularly limited, and examples thereof include an aqueous solution containing a freeze protection agent and glucose.
  • frost damage protective agents include dimethyl sulfoxide (hereinafter referred to as DMSO), dextran, glycerol, propylene glycol, and 1-methyl-2-pyrrolidone.
  • frost damage preventive agent DMSO and propylene glycol are preferable, and DMSO is particularly preferable.
  • the frost damage protective agent is preferably contained in the cryopreservation solution in an amount of 1.0 to 15.0 w / v%, more preferably 5.0 to 15.0 w / v%, and 5.0 to 12.0 w. / V% is more preferable, and 8.0 to 11.0 w / v% is particularly preferable.
  • the glucose contained in the cryopreservation solution is preferably contained in the cryopreservation solution in an amount of 0.5 to 10.0 w / v%, more preferably 1.0 to 10.0 w / v%. More preferably, it is contained in an amount of 0.0 to 8.0 w / v%, and particularly preferably 2.0 to 5.0 w / v%.
  • the cryopreservation solution may further contain other components.
  • other components include a pH adjuster and a thickener.
  • the pH adjuster include sodium bicarbonate, HEPES, and phosphate buffer.
  • BSS Basic Stock Solution
  • the pH adjuster is preferably used as appropriate in order to adjust the pH in the cryopreservation solution to about 6.5 to 9.0, preferably 7.0 to 8.5.
  • the phosphate buffer in the present invention is sodium chloride, monosodium phosphate (anhydrous), monopotassium phosphate (anhydrous), disodium phosphate (anhydrous), trisodium phosphate (anhydrous), potassium chloride, And potassium dihydrogen phosphate (anhydrous), and sodium chloride, monosodium phosphate (anhydrous), potassium chloride, or potassium dihydrogen phosphate (anhydrous) is particularly preferable.
  • the pH adjuster is preferably contained in the cryopreservation solution in an amount of 0.01 to 1.0 w / v%, more preferably 0.05 to 0.5 w / v%.
  • the cryopreservation solution may or may not contain natural animal-derived components.
  • natural animal-derived components include the aforementioned serum and basal medium.
  • the cryopreservation solution preferably does not contain natural animal-derived components.
  • there is no problem of quality differences between lots of natural animal-derived components, and various cytokines, growth factors, hormones, etc. contained in serum The risk of changes in the properties of cells in the umbilical cord tissue due to components unnecessary for cell storage can be avoided, and furthermore, the influence of components unknown in the basal medium can also be avoided. Therefore, a cryopreservation solution that does not contain natural animal-derived components is very useful particularly in clinical use.
  • the cryopreservation solution may further contain a thickener.
  • the thickener is not particularly limited as long as it can constitute a cryopreservation solution that can sufficiently preserve the umbilical cord tissue.
  • the thickener include carboxymethyl cellulose (hereinafter referred to as CMC), sodium carboxymethyl cellulose (hereinafter referred to as CMC-Na), organic acid polymer, propylene glycol alginate, sodium alginate and the like.
  • CMC and CMC-Na are preferable, and CMC-Na is particularly preferable.
  • the organic acid polymers sodium polyacrylate is preferred.
  • the thickener is preferably contained in the cryopreservation solution in an amount of 0.1 to 1.0 w / v%, more preferably 0.1 to 0.5 w / v%, and more preferably 0.2 to 0.4 w. More preferably, the content is / v%.
  • the cryopreservation solution is preferably an aqueous solution.
  • the osmotic pressure of the cryopreservation solution is preferably 1000 mOsm or more, more preferably 1000 to 2700 mOsm, in order to maintain the performance as a preservation solution.
  • a preferable cryopreservation solution is an aqueous solution containing a thickener, a frost damage protective agent, and glucose, and does not contain natural animal-derived components.
  • a more preferred example is an aqueous solution containing CMC-Na, DMSO, and glucose and not containing natural animal-derived components.
  • the cryopreservation solution contains 0.1 to 1.0 w / v% CMC-Na, 1.0 to 15.0 w / v% DMSO, and 0.5 to 10.0 w glucose.
  • the umbilical cord-derived cells obtained by the above method can be prepared as a therapeutic agent for brain injury by mixing with an infusion preparation.
  • umbilical cord-derived cells that have been cryopreserved may be suspended in a cryopreservation solution and may be used directly as a therapeutic agent for brain injury after thawing, or may be prepared as a therapeutic agent for brain injury by mixing with an infusion preparation. good.
  • the culture solution or cryopreservation solution in which the cells are suspended may be mixed with the infusion preparation or the like. After the cells are separated from the solvent by centrifugation or the like, only the cells are mixed with the infusion preparation. May be.
  • the “infusion preparation” in the present invention is not particularly limited as long as it is a solution used in human treatment.
  • physiological saline, 5% glucose solution, Ringer solution, lactated Ringer solution, acetate Ringer solution, No. 1 solution, No. 2, No. 3, No. 4, No. 4, etc. are mentioned.
  • the therapeutic agent for cerebral disorder of the present invention includes a kit in which an umbilical cord-derived cell and an infusion preparation are combined.
  • a pharmaceutically acceptable carrier may be further added.
  • the carrier means a suspension agent, a solubilizing agent, a stabilizer, a tonicity agent, a preservative, an adsorption inhibitor, a surfactant, a diluent, a medium, pH adjustment for administering a therapeutic agent.
  • Agents, soothing agents, buffering agents, sulfur-containing reducing agents, antioxidants and the like can be appropriately added.
  • suspending agent examples include methyl cellulose, polysorbate 80, hydroxyethyl cellulose, gum arabic, tragacanth powder, sodium carboxymethyl cellulose, polyoxyethylene sorbitan monolaurate and the like.
  • solution adjuvant examples include polyoxyethylene hydrogenated castor oil, polysorbate 80, nicotinamide, polyoxyethylene sorbitan monolaurate, macrogol, castor oil fatty acid ethyl ester, and the like.
  • stabilizer examples include dextran 40, methylcellulose, gelatin, sodium sulfite, and sodium metasulfate.
  • isotonic agent examples include D-mannitol and sorbitol.
  • Examples of the preservative include methyl paraoxybenzoate, ethyl paraoxybenzoate, sorbic acid, phenol, cresol, chlorocresol and the like.
  • Examples of the adsorption inhibitor include human serum albumin, lecithin, dextran, ethylene oxide propylene oxide copolymer, hydroxypropyl cellulose, methyl cellulose, hydrogenated castor oil, and polyethylene glycol.
  • Examples of flow reducing agents include N-acetylcysteine, N-acetylhomocysteine, thiochitoic acid, thiodiglycol, thioethanolamine, thioglycerol, thiosorbitol, thioglycolic acid and its salts, sodium thiosulfate, glutathione, Examples thereof include those having a sulfohydryl group such as a thioalkanoic acid having 1 to 7 carbon atoms.
  • antioxidants examples include erythorbic acid, dibutylhydroxytoluene, butylhydroxyanisole, ⁇ -tocopherol, tocopherol acetate, L-ascorbic acid and salts thereof, L-ascorbyl palmitate, L-ascorbic acid stearate, sodium bisulfite And chelating agents such as sodium sulfite, triamyl gallate, propyl gallate or sodium ethylenediaminetetraacetate (EDTA), sodium pyrophosphate and sodium metaphosphate.
  • EDTA sodium ethylenediaminetetraacetate
  • inorganic salts such as sodium chloride, potassium chloride, calcium chloride, sodium phosphate, potassium phosphate, and sodium bicarbonate; organic salts such as sodium citrate, potassium citrate, and sodium acetate; sugars such as glucose, etc.
  • the component added to may be added appropriately.
  • ACD-A solution composition composed of sodium citrate hydrate, citric acid hydrate, glucose, etc.
  • ACD-A solution composition composed of sodium citrate hydrate, citric acid hydrate, glucose, etc.
  • infusion preparations in which cells are mixed are organic substances such as biopolymers, inorganic substances such as hydroxyapatite, specifically, collagen matrices, polylactic acid polymers or copolymers, polyethylene glycol polymers or copolymers and chemical derivatives thereof. May be mixed with.
  • Examples of the method for administering the therapeutic agent for cerebral disorder of the present invention include intracerebral administration, intrathecal administration, intramuscular administration, subcutaneous administration, intravenous administration and the like, and the effects are shown in the following examples.
  • Intravenous administration is particularly preferred because it can be administered safely and stably regardless of the administration technique.
  • the dose of the therapeutic agent for cerebral disorder of the present invention is an amount of cells that, when administered to a subject, can obtain a therapeutic effect on a disease compared to a subject not administered.
  • the specific dose can be appropriately determined depending on the subject's age, body weight, ischemic range, symptoms, etc.
  • the number of umbilical cord-derived cells is 10 4 to 10 9 cells / kg per administration.
  • the body weight is 10 4 to 10 8 pieces / kg body weight, 10 4 to 10 7 pieces / kg body weight, and more preferably 10 4 to 10 8 pieces / kg body weight.
  • the number of administrations of the therapeutic agent for cerebral disorder of the present invention may be administered a plurality of times, for example, 2, 3, 4, 5 or more times. However, it may be determined as appropriate.
  • the administration interval in the case of multiple administrations may be determined as appropriate while confirming the therapeutic effect of the subject. For example, once a day, once a week, once every two weeks, once a month or once for 3 months One time, once every six months, etc.
  • brain disorder is a comprehensive term including not only acute and chronic disorders of the central nervous system but also symptoms or diseases.
  • Acute brain injury includes, but is not limited to, cerebral hemorrhage, cerebral ischemia or cerebral infarction (including embolic and thrombotic obstruction), cerebral contusion, cerebral palsy, hypoxic ischemic encephalopathy, periventricular Examples include leukomalacia and shaken baby syndrome.
  • Cerebral hemorrhage refers to intracranial (epidural, subdural, subarachnoid, and intracerebral) caused by high blood pressure, arteriosclerosis, trauma, brain tumor, cerebral arteriovenous malformation, or cerebral arteriovenous dissection. Means bleeding.
  • Chronic brain disorders include but are not limited to Alzheimer's disease, Pick's disease, Lewy body disease, progressive supranuclear palsy, multisystem atrophy, amyotrophic lateral sclerosis, degenerative ataxia, Examples include cerebral cortex basal ganglia degeneration, subacute sclerosing panencephalitis, Huntington's disease, Parkinson's disease, progressive multifocal leukoencephalopathy, and familial autonomic dysfunction.
  • adaptation to acute brain injury is preferable, and adaptation to brain injury in the fetus or neonatal period is more preferable.
  • the brain disorder in the fetus or neonatal period include cerebral hemorrhage, cerebral ischemia, cerebral contusion, cerebral palsy, hypoxic ischemic encephalopathy, periventricular leukomalacia or shaken baby syndrome.
  • the treatment of cerebral disorders in the fetus or neonatal period includes treatment of secondary cerebral disorders caused by the first cerebral disorder, for example, cerebral palsy that develops due to cerebral ischemia in the fetus or neonatal period. To do.
  • Treatment of secondary brain damage resulting from the first brain injury in the fetus or neonatal period is not necessarily performed at the onset of the first brain injury, for example one week after the onset of the first brain injury Even after 2 weeks, 3 weeks, 4 weeks, 2 months, 3 months, 4 months, 5 months, 6 months, 1 year or more good.
  • the present invention encompasses therapeutic agents administered to infants, toddlers, children or adults for secondary brain disorders resulting from the first brain disorder in the fetus or neonatal period. From the viewpoint of high therapeutic effect, it is more preferable to administer the therapeutic agent of the present invention as soon as possible after brain injury.
  • the therapeutic agent of the present invention is as early as possible after birth, for example, within 14 days without waiting for a definitive diagnosis. Is preferably administered.
  • a fetus is a growing child in the mother's body, a child from the eighth week of pregnancy to before childbirth, and a newborn is a child from 0 to less than 28 days after birth.
  • An infant is a child who is 28 years old or older and younger than 1 year old
  • an infant is a child who is 1 year old or older and younger than 6 years old
  • a child is a child who is 6 years old or older and younger than 20 years old.
  • An adult means a person over 20 years old. Therefore, fetal or neonatal period means a period from the eighth week of pregnancy to less than 28 days after birth.
  • the treatment of cerebral disorder is not only to return the above-mentioned pathological condition of cerebral disorder to a normal state, but also to alleviate symptoms, delay progression, delay onset, or prevent onset. Is included.
  • the therapeutic agent for brain injury of the present invention may be used in combination with other therapeutic agents, or may be used as a single agent.
  • the present invention also includes a method for treating brain damage using umbilical cord-derived cells.
  • the therapeutic method of the present invention includes a therapeutic method using the therapeutic agent for brain disorders containing the umbilical cord-derived cells of the present invention described above, and the above description can be applied as a specific explanation.
  • the treatment method of the present invention is preferably a treatment method in which umbilical cord-derived cells are administered intravenously.
  • the umbilical cord-derived cells may be cells prepared from umbilical cord tissue including amniotic membrane, blood vessels, perivascular tissue and Walton jelly.
  • the umbilical cord-derived cells are positive for (i) CD105, CD73, CD90, CD44, HLA-class I, HLA-G5 and PD-L2, and (ii) CD45, CD34, CD11b, CD19 and HLA-Class II Is preferably negative. If the brain disorder is a fetal or neonatal brain disorder, particularly cerebral palsy, the treatment method of the present invention has a remarkable effect.
  • Umbilical cord-derived cells were collected by the method described in Cytotherapy, 18, 229-241, 2016. Briefly, all tissue elements of the umbilical cord (including amniotic membrane, blood vessels, perivascular tissue and Walton Jerry) collected with the consent of the donor and approved by the Ethics Committee of the University of Tokyo Medical Science Institute ) Is cut into 1 to 2 mm 3 fragments, seeded on a culture dish, covered with Cell Amigo (Enomoto Chain Co., Ltd.), ⁇ -minimum essential medium supplemented with 10% fetal bovine serum (FBS) and antibiotics. Obtained by a modified explant method of culturing in ( ⁇ MEM). The cell properties are plastic adherence.
  • FBS fetal bovine serum
  • HLA-G5 and PD-L2 were positive.
  • HLA-G was weakly positive
  • CD49d (ITGA4) and CD184 (CXCR4) were negative to weakly positive
  • CD29 (ITGB1) was positive. The presence or absence of surface antigen expression was confirmed by FACS analysis using a specific antibody against each antigen.
  • Umbilical cord-derived cells are highly expressing HGF (Hepatic Growth Factor) genes under normal conditions, and IDO (Indoleamine 2,3-dioxygenase) gene expression under inflammatory conditions (IFN- ⁇ 100 ng / mL). Induction was confirmed by Realtime PCR. The results for IDO are shown in FIG. In particular, HGF expression was found to be higher in umbilical cord-derived cells than in bone marrow-derived mesenchymal stem cells. Moreover, it was confirmed by ELISA that umbilical cord-derived cells were co-cultured with MLR (allogeneic lymphocyte mixed reaction) to induce the secretion of PGE2 (FIG. 2). In FIG.
  • Lot1 to Lot4 represent lots of umbilical cord-derived cells.
  • PHA-L phytohemagglutinin-L is a reagent that causes inflammation nonspecifically.
  • Neonatal cerebral hemorrhage model mouse An artificial cerebral hemorrhage model was prepared by administering 20 ⁇ L of adult mouse blood into the right ventricle of a B6 Albino newborn mouse 5 to 7 days after birth. When the cerebral hemorrhage model was photographed by MRI, enlargement of the ventricle was observed in the T2 image. In the cerebral ventricle (affected side) to which bleeding was performed, GFAP-positive fibers (red), which are intermediate filaments, were more often observed than in the normal ventricle (normal side) (FIG. 3).
  • Neonatal cerebral hemorrhage (degree III to IV) is common in premature babies and progresses almost to cerebral palsy. The mechanism was inflammation and nerve damage caused by bleeding, and it was suggested that umbilical cord-derived cells have an action to improve these.
  • MRI findings did not clearly show the effect of umbilical cord-derived cell administration on ventricular enlargement (FIG. 8).
  • clinical findings do not necessarily correlate with imaging findings and clinical symptoms (movement disorders), and thus improvement in behavioral evaluation is considered to be an effect of umbilical cord-derived cells.
  • GFAP positive cells glia cells; red
  • MAP2 positive cells Neuron cells
  • a decrease in green but in the group administered with umbilical cord-derived cells, many MAP2-positive cells were observed in the same manner as in the untreated (no bleeding) mice (FIG. 9).
  • a GFAP positive cell is a cell which looks white.
  • FIG. 14 shows the result of FIG. 13 in numerical form. From the above, it was confirmed that administration of umbilical cord-derived cells has an effect of recovery of nerve cells or prevention of nerve cell loss.
  • IVH in a figure has shown Intraventricular hemorrhage (intraventricular hemorrhage). The same applies to the subsequent drawings.
  • BDNF Brain-derived neurotrophic factor
  • HGF HGF expression levels in umbilical cord-derived cells
  • Cerebral cortical neurons of embryonic day 16 mice were primary cultured and cultured in an OGD (oxygen-glucose depletion) environment with 8% oxygen and glucose free for 10 hours to create an in vitro cerebral ischemia model.
  • Mouse neurons and umbilical cord-derived cells were co-cultured, and the protein concentrations of BDNF and HGF in the supernatant were measured by a bead assay.
  • an artificial cerebral hemorrhage model was prepared, and the concentrations of Human-BDNF, Human-NGF (Nerve growth factor), and Human-HGF were measured by a bead assay using the serum of the model mouse.
  • NGF was not observed in all groups (FIG. 19), but BDNF and HGF were in the umbilical cord-derived cell administration group, and the concentration was increased in 9 out of 14 animals (FIGS. 20 and 21).

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Abstract

En cas de dysfonctionnement cérébral induit par une hémorragie ou une ischémie cérébrale, il est nécessaire de traiter une maladie causale, c'est-à-dire une hémorragie ou une ischémie, et il est également nécessaire de favoriser la protection ou la régénération de cellules nerveuses ou similaire qui sont endommagées par la maladie causale. La présente invention aborde le problème de la fourniture d'une cellule dérivée de cordon ombilical ayant l'effet de favoriser la protection ou la régénération mentionnée ci-dessus de cellules nerveuses et similaire. La présente invention aborde en outre le problème de fourniture d'un agent thérapeutique pour un dysfonctionnement cérébral, qui peut exercer son effet par une voie d'administration plus simple. La présente invention concerne un agent thérapeutique pour un dysfonctionnement cérébral, qui comprend des cellules dérivées de cordon ombilical. L'agent thérapeutique selon la présente invention est, de préférence, administré par voie intraveineuse. Les cellules dérivées de cordon ombilical sont, de préférence, des cellules préparées à partir d'un amnios, d'un vaisseau sanguin, d'un tissu périvasculaire ou d'un tissu de cordon ombilical comprenant la gelée de Wharton.
PCT/JP2017/019281 2016-05-24 2017-05-23 Agent thérapeutique pour dysfonctionnement cérébral comprenant des cellules dérivées de cordon ombilical WO2017204231A1 (fr)

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WO2019195554A1 (fr) * 2018-04-04 2019-10-10 Duke University Méthodes de traitement de la paralysie cérébrale et de l'encéphalopathie hypoxique-ischémique à l'aide de cellules stromales mésenchymateuses dérivées de tissu de cordon ombilical humain
US20200016213A1 (en) * 2018-07-12 2020-01-16 Duke University Methods of Treating Cerebral Palsy Using High Dose Allogeneic Umbilical Cord Blood
CN111727046A (zh) * 2018-07-17 2020-09-29 仿生技术支持有限公司 类二十烷酸产生促进剂
JP6967308B1 (ja) * 2020-06-30 2021-11-17 国立大学法人高知大学 胎児付属物由来組織細胞培養上清を含む脳神経障害治療剤
WO2022004823A1 (fr) 2020-06-30 2022-01-06 国立大学法人高知大学 Agent thérapeutique de neuropathie crânienne contenant un surnageant de culture pour des cellules monocytiques du sang de cordon ombilical
WO2022102784A1 (fr) * 2020-11-16 2022-05-19 ヒューマンライフコード株式会社 Préparation cellulaire à utiliser pour prévenir la réduction de masse musculaire
WO2022180911A1 (fr) * 2021-02-26 2022-09-01 国立大学法人東京大学 Préparation cellulaire pour utilisation dans le traitement du syndrome hémophagocytaire
WO2023054317A1 (fr) * 2021-09-30 2023-04-06 国立大学法人東京大学 Préparation cellulaire utilisée pour le traitement de la neuropathie due aux radiations
WO2024075676A1 (fr) * 2022-10-03 2024-04-11 キッズウェル・バイオ株式会社 Agent pour le traitement ou la prévention de la paralysie cérébrale

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EP3773486A4 (fr) * 2018-04-04 2021-12-15 Duke University Méthodes de traitement de troubles du spectre autistique à l'aide de cellules stromales mésenchymateuses dérivées de tissu de cordon ombilical humain
WO2019195554A1 (fr) * 2018-04-04 2019-10-10 Duke University Méthodes de traitement de la paralysie cérébrale et de l'encéphalopathie hypoxique-ischémique à l'aide de cellules stromales mésenchymateuses dérivées de tissu de cordon ombilical humain
WO2019195506A1 (fr) 2018-04-04 2019-10-10 Duke University Méthodes de traitement de troubles du spectre autistique à l'aide de cellules stromales mésenchymateuses dérivées de tissu de cordon ombilical humain
CN112236152A (zh) * 2018-04-04 2021-01-15 杜克大学 使用人脐带组织来源的间充质基质细胞治疗脑性瘫痪和缺氧缺血性脑病的方法
US20200016213A1 (en) * 2018-07-12 2020-01-16 Duke University Methods of Treating Cerebral Palsy Using High Dose Allogeneic Umbilical Cord Blood
CN111727046A (zh) * 2018-07-17 2020-09-29 仿生技术支持有限公司 类二十烷酸产生促进剂
JP6967308B1 (ja) * 2020-06-30 2021-11-17 国立大学法人高知大学 胎児付属物由来組織細胞培養上清を含む脳神経障害治療剤
WO2022004823A1 (fr) 2020-06-30 2022-01-06 国立大学法人高知大学 Agent thérapeutique de neuropathie crânienne contenant un surnageant de culture pour des cellules monocytiques du sang de cordon ombilical
WO2022004816A1 (fr) 2020-06-30 2022-01-06 国立大学法人高知大学 Agent thérapeutique contre un trouble du nerf crânien comprenant un surnageant de culture de cellules tissulaires dérivées d'appendice fœtal
JP2022016722A (ja) * 2020-06-30 2022-01-24 国立大学法人高知大学 胎児付属物由来組織細胞培養上清を含む脳神経障害治療剤
WO2022102784A1 (fr) * 2020-11-16 2022-05-19 ヒューマンライフコード株式会社 Préparation cellulaire à utiliser pour prévenir la réduction de masse musculaire
JPWO2022102784A1 (fr) * 2020-11-16 2022-05-19
WO2022180911A1 (fr) * 2021-02-26 2022-09-01 国立大学法人東京大学 Préparation cellulaire pour utilisation dans le traitement du syndrome hémophagocytaire
WO2023054317A1 (fr) * 2021-09-30 2023-04-06 国立大学法人東京大学 Préparation cellulaire utilisée pour le traitement de la neuropathie due aux radiations
WO2024075676A1 (fr) * 2022-10-03 2024-04-11 キッズウェル・バイオ株式会社 Agent pour le traitement ou la prévention de la paralysie cérébrale

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