WO2022114242A1 - Médicament pour le traitement de l'angiopathie ischémique - Google Patents

Médicament pour le traitement de l'angiopathie ischémique Download PDF

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WO2022114242A1
WO2022114242A1 PCT/JP2021/044001 JP2021044001W WO2022114242A1 WO 2022114242 A1 WO2022114242 A1 WO 2022114242A1 JP 2021044001 W JP2021044001 W JP 2021044001W WO 2022114242 A1 WO2022114242 A1 WO 2022114242A1
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ischemic
pharmaceutical composition
msc
angiopathy
recanalization
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PCT/JP2021/044001
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Japanese (ja)
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修 本望
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北海道公立大学法人 札幌医科大学
ニプロ株式会社
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/28—Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

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  • the present invention relates to a therapeutic agent for ischemic angiopathy including mesenchymal stem cells. More specifically, the present invention relates to a therapeutic agent for ischemic angiopathy, which is administered to a patient who cannot obtain the effect of recanalization therapy for occluded blood vessels and is characterized by improving the therapeutic effect thereof.
  • Recanalization therapy for acute ischemic stroke is the standard treatment strategy for patients with cerebral artery occlusion or stenosis.
  • 54% of patients still have an unfavorable result of 3 to 6 points for mRS (modified Rankin Score) at 90 days. ..
  • mRS modified Rankin Score
  • Non-Patent Documents 1 to 3 and Patent Document 1 mesenchymal stem cells
  • Patent Document 3 The inventors have reported that the risk of cerebral hemorrhage can be reduced by combining the recanalization therapy of occluded blood vessels with the intravenous administration of mesenchymal stem cells.
  • An object of the present invention is to improve the therapeutic effect of recanalization therapy in ischemic diseases in patients who cannot sufficiently obtain the therapeutic effect.
  • the inventors used two experimental models showing the same behavioral symptoms and ischemic cerebral infarction volume to compare the therapeutic effects of MSC administered after induction of cerebral infarction. It was confirmed that the therapeutic effect of recanalization therapy after cerebral artery occlusion (MCAO) was enhanced.
  • MCAO cerebral artery occlusion
  • the present invention relates to the following (1) to (11).
  • Recanalization therapy for occluded blood vessels comprises any one or more selected from administration of thrombolytic agents, platelet aggregation inhibitors, and blood coagulation inhibitors, and physical removal of thrombi, according to (1).
  • the pharmaceutical composition according to description.
  • (3) The pharmaceutical composition according to (1) or (2), wherein the ischemic angiopathy is ischemic cerebrovascular accident or myocardial infarction. Examples of ischemic cerebrovascular accidents include cerebral infarction and transient ischemic attack.
  • the ischemic cerebrovascular accident is a cerebral infarction.
  • the pharmaceutical composition of the present invention is administered to a patient who cannot obtain the effect of the recanalization therapy.
  • the pharmaceutical composition according to any one of (1) to (5) which improves the therapeutic effect of recanalization therapy in ischemic angiopathy.
  • the pharmaceutical composition according to (6), wherein the improvement of the therapeutic effect is 1 or 2 or more selected from the increase of local cerebral blood flow, the recovery of the microvascular system, and the improvement of behavioral function. Alternatively, the improvement of the therapeutic effect is the improvement of the function of the cranial nerve system.
  • the mesenchymal stem cells are bone marrow-derived mesenchymal stem cells.
  • the mesenchymal stem cells are mesenchymal stem cells isolated from the patient's own bone marrow to be administered.
  • a method for treating ischemic angiopathy which comprises administering a pharmaceutical composition containing mesenchymal stem cells to a patient who cannot obtain the effect of recanalization therapy for occluded blood vessels.
  • a pharmaceutical composition containing mesenchymal stem cells for patients who cannot obtain the effect of recanalization therapy for occluded blood vessels which is a method for improving the effect of recanalization therapy in the treatment of ischemic angiopathy. The method described above, characterized in that it is administered.
  • (11) Use of mesenchymal stem cells in the production of a pharmaceutical composition for treating ischemic angiopathy, wherein the pharmaceutical composition is administered to a patient who cannot obtain the effect of recanalization therapy for occluded blood vessels. The above-mentioned use, characterized in that.
  • intravenous administration of MSC can improve the therapeutic effect of recanalization therapy.
  • the present invention is expected to increase local cerebral blood flow and promote microvascular recovery, which will lead to better clinical outcomes for patients undergoing recanalization therapy.
  • FIG. 1A shows an outline of the experimental protocol.
  • 1B-1D shows MRA images (B: MRA of intact rat, C: complete occlusion of MCA 7 days after pMCAO induction, D: reopening 7 days after tMCAO induction).
  • FIG. 2 shows the results of the treadmill load test. The graph shows the maximum speed at which the rat was able to run on the treadmill at days 7, 8, 11, 14, 21, 28, 35, 42, and 49 (** P ⁇ 0.01, * P ⁇ 0). .05).
  • FIG. 3 shows the results of MRI analysis of the ischemic lesion site.
  • FIG. 3A shows representative T2WIs of the four groups.
  • FIG. 3B shows the estimated ischemic lesion volume.
  • FIG. 4 shows the result of ASL-MRI analysis.
  • FIG. 4A shows representative ASL images of the four groups 7 and 49 days after MCAO induction.
  • FIG. 4B shows the rCBF (local cerebral blood flow) rate of each group on days 7, 8, 11, 14, 21, 28, 35, 42 and 49 (** P ⁇ 0.01, * P ⁇ 0). .05).
  • FIG. 5 shows the results of three-dimensional analysis of capillaries.
  • FIGS. 5A-5D show representative confocal microscopic images of the four experimental groups 49 days after MCAO induction.
  • FIG. 5E shows the ratio of capillary volume (ipsilateral / contralateral) of the ischemic hemisphere (ipsilateral) to the contralateral control hemisphere (** P ⁇ 0.01, * P ⁇ 0.05).
  • Therapeutic agent for ischemic angiopathy The present invention cannot obtain the effect of recanalization therapy for occluded blood vessels (for example, administration of a drug containing a thrombolytic agent, a platelet aggregation inhibitor, a blood coagulation inhibitor, or physical removal of a blood clot). It relates to a pharmaceutical composition for treating ischemic angiopathy containing mesenchymal stem cells, which is characterized by being administered to a patient.
  • the mesenchymal stem cells used in the present invention are stem cells having pluripotency and self-renewal ability, which are present in trace amounts in the stromal cells of the mesenchymal tissue, such as bone cells, cartilage cells, and fat cells. It is known that it not only differentiates into bound tissue cells, but also has the ability to differentiate into nerve cells and myocardial cells.
  • Sources of mesenchymal stem cells include bone marrow, peripheral blood, umbilical cord blood, fetal embryo, brain, tooth marrow, bone, etc., but bone marrow-derived mesenchymal stem cells (bone marrow mesenchymal stem cells), especially human bone marrow.
  • Mesenchymal stem cells are preferred. Bone marrow-derived mesenchymal stem cells are 1) expected to have remarkable effects, 2) have a low risk of side effects, 3) can be expected to supply sufficient donor cells, and 4) are non-invasive treatments and are autologous transplants. 5) Low risk of infectious disease, 6) No concern about immune rejection, 7) No ethical problems, 8) Socially acceptable, 9) Widely used as general medical treatment There are advantages such as easy fixing.
  • bone marrow transplantation therapy is a treatment already used in clinical practice, and its safety has been confirmed.
  • bone marrow-derived stem cells are highly migratory, and can be expected to have a therapeutic effect by reaching the target damaged tissue not only by local transplantation but also by intravenous administration.
  • the cell may be a cell differentiated from an ES cell or an induced pluripotent stem cell (iPS cell or the like), a cell that has been established, or a cell that has been isolated and proliferated from a living body.
  • the cells may be derived from allogeneic cells or autologous cells, but mesenchymal stem cells derived from autologous cells (derived from the patient's own cells) are preferable.
  • the mesenchymal stem cells used in the present invention are preferably in an undifferentiated state. This is because undifferentiated cells have a high proliferation rate and a high survival rate after introduction into the living body.
  • the inventors have also developed a method for obtaining such cells, the details of which are described in WO2009 / 00253.
  • cells separated from bone marrow or the like under conditions that do not substantially come into contact with an anticoagulant contain human serum (preferably autologous serum) and anticoagulant. Proliferate using medium that does not contain agents (such as heparin) or contains very low concentrations.
  • the density of cells in the medium affects the nature of the cells and the direction of differentiation. In the case of mesenchymal stem cells, if the cell density in the medium exceeds 8,500 cells / cm 2 , the cell properties will change, so subculture at a maximum of 8,500 cells / cm 2 or less. Is preferable, and more preferably, subculture is performed when the number reaches 5,500 / cm 2 or more.
  • the method developed by the inventors uses a human serum-containing medium, it is desirable that the medium is exchanged as few times as possible in consideration of the burden on the serum donor, for example, at least once a week, more preferably weekly. Change the medium once or twice.
  • 107 mesenchymal stem cells can be obtained in about 12 days.
  • the grown MSC may be stored by a method such as cryopreservation (for example, in a deep freezer at ⁇ 152 ° C.) until it is used.
  • a medium containing serum preferably human serum, more preferably autologous serum
  • dextran preferably dextran
  • DMSO medium for mammalian cells such as RPMI
  • cells can be cryopreserved at ⁇ 150 ° C. in a cryopreservation solution containing 20.5 mL of normal filtration-sterilized RPMI, 20.5 mL of autologous serum collected from a patient, 5 mL of dextran, and 5 mL of DMSO.
  • DMSO can be a frost protection solution (DMSO) manufactured by Nipro Co., Ltd.
  • dextran can be a small molecule dextran L injection manufactured by Otsuka Pharmaceutical, but the DMSO is not limited thereto.
  • the number of mesenchymal stem cells is 107 or more, preferably 5 ⁇ 10 7 or more, more preferably 108 or more, still more preferably 5 ⁇ 10 8 . That is all.
  • the pharmaceutical product of the present invention is preferably a parenteral administration preparation, more preferably a parenteral systemic administration preparation, particularly an intravenous preparation.
  • Dosage forms suitable for parenteral administration include injections such as solution injections, suspension injections, emulsion injections, time-prepared injections, and implants.
  • the parenteral pharmaceutical product is in the form of an aqueous or non-aqueous isotonic sterile solution or suspension, eg, a pharmacologically acceptable carrier or medium, specifically sterile water, saline, medium.
  • physiological buffers such as PBS, vegetable oils, emulsifiers, suspensions, surfactants, stabilizers, excipients, vehicles, preservatives, binders Etc. are appropriately combined to form an appropriate unit dosage form.
  • aqueous solution for injection examples include physiological saline, medium, physiological buffer such as PBS, isotonic solution containing glucose and other auxiliary agents, such as D-sorbitol, D-mannose, D-mannitol, sodium chloride and the like.
  • physiological saline medium
  • physiological buffer such as PBS
  • isotonic solution containing glucose and other auxiliary agents such as D-sorbitol, D-mannose, D-mannitol, sodium chloride and the like.
  • an appropriate solubilizing agent such as alcohol, specifically ethanol, polyalcohol, propylene glycol, polyethylene glycol or a nonionic surfactant such as polysorbate 80, HCO-50 and the like.
  • the pharmaceuticals of the present invention are used to treat ischemic angiopathy.
  • the ischemic angiopathy refers to a state in which a local vascular disorder (for example, degeneration or obstruction) is exhibited due to a decrease in arterial blood flow, and examples thereof include ischemic cerebrovascular disorder and ischemic heart disease.
  • Ischemic cerebrovascular accident The pharmaceuticals of the present invention are used to treat ischemic cerebrovascular accidents.
  • MSC is known to have a protective effect on the brain (parenchyma and blood vessels), and has already been used for the treatment of ischemic cerebrovascular disorders such as cerebral infarction by intravenous administration.
  • ischemic cerebrovascular disorders include cerebral infarction (for example, atherosclerotic cerebral infarction, cerebral thrombosis, cerebral embolism, lacunar infarction, BAD (Branch Atheromatous Disease), Trousseu syndrome, blood coagulation abnormality, arterial dissection, venous infarction, blood vessel. Flame, anti-phospholipid antibody syndrome), transient ischemic attack (TIA) and the like.
  • cerebral infarction for example, atherosclerotic cerebral infarction, cerebral thrombosis, cerebral embolism, lacunar infarction, BAD (Branch Atheromatous Disease), Trousseu syndrome, blood coagulation abnormality, arterial dissection, venous infarction, blood vessel. Flame, anti-phospholipid antibody syndrome), transient ischemic attack (TIA) and the like.
  • Ischemic heart disease The pharmaceutical agent of the present invention is also used for treating ischemic heart disease such as myocardial infarction.
  • Myocardial infarction is a condition in which the coronary blood vessels that supply oxygen and nutrients to the heart are occluded or narrowed, the blood flow decreases, and the myocardium becomes ischemic and necrotic.
  • the pharmaceutical agent of the present invention is administered to a patient having an ischemic angiopathy who cannot obtain the effect of recanalization therapy for an occluded blood vessel.
  • recanalization therapy is the standard treatment strategy for ischemic angiopathy, and while some patients have dramatic improvement in symptoms immediately after recanalization, others do not.
  • "the effect of recanalization therapy for occluded blood vessels cannot be obtained” does not mean that there is no effect at all, but means a patient whose clinical symptoms are not sufficiently recovered.
  • mRS Modified Rankin Scale
  • NIH stroke scale an index of activities of daily living, or NIH stroke scale.
  • the pharmaceutical composition of the present invention is used for patients who do not obtain the effect of such recanalization therapy, and enhances the effect of resumption therapy.
  • the recanalization therapy for occluded blood vessels is not particularly limited, and examples thereof include administration of a drug containing a thrombolytic agent, a platelet aggregation inhibitor, and a blood coagulation inhibitor, and physical removal of a thrombus.
  • Thrombolytic agent In ischemic angiopathy (especially ischemic cerebrovascular disorder and myocardial infarction in the acute or hyperacute phase), recanalization of occluded blood vessels by lysis of thrombosis or physical removal of thrombosis is treated to prevent necrosis due to ischemia. Is the first choice.
  • the thrombolytic agent include urokinase, prourokinase, tissue plasminogen activator (t-PA), nasalplase, streptokinase and the like.
  • Platelet aggregation inhibitor (antiplatelet drug): Platelet aggregation inhibitors (antiplatelet drugs) can prevent thrombus formation by inhibiting platelet aggregation.
  • the platelet aggregation inhibitor include, but are not limited to, aspirin, clopidogrel, cilostazol, ticlopidine and the like.
  • Blood coagulation inhibitors can prevent thrombus formation by inhibiting the function of coagulation factors.
  • the blood coagulation inhibitor include, but are not limited to, antithrombin agents such as heparin, low molecular weight heparin, argatroban, danaparoid sodium, dalteparin, nadropalin, bemiparin, fondaparinux, and argatroban.
  • Examples of the physical removal method of thrombus include, but are not limited to, mechanical thrombus recovery therapy by endovascular surgery and carotid intima dissection. Further, resumption of blood flow by bypass surgery, stent treatment, balloon treatment, suction treatment, crushing by ultrasonic waves or the like may be performed.
  • the administration time of the drug of the present invention is not particularly limited as long as it is after recanalization therapy of the occluded blood vessel, but it is administered to a patient with ischemic angiopathy in the acute phase or the subacute phase, preferably the acute phase to the subacute phase. ..
  • the present invention comprising MSC when recanalization therapy of an obstructed blood vessel is received in the acute phase of ischemic angiopathy and then the recanalization therapy is not effective in the acute to subacute phase. It is preferable that the pharmaceutical composition of the above is administered.
  • the pharmaceutical agent of the present invention can improve the therapeutic effect of recanalization therapy by being used for patients who cannot obtain the effect of recanalization therapy for occluded blood vessels.
  • administration of MSCs promotes increased local cerebral blood flow, recovery of the microvascular system, and / or improvement of behavioral function.
  • ischemic angiopathy it is a clinical problem that cranial nerve system function is often not restored even after recanalization therapy.
  • Administration of MSCs improves this cranial nerve system function and enables better clinical outcomes for patients undergoing recanalization therapy of occluded vessels (eg, intravascular thrombectomy for large vessel occlusion).
  • the present invention cannot obtain the effect of recanalization therapy for occluded blood vessels (administration of drugs containing thrombolytic agents, platelet aggregation inhibitors, blood coagulation inhibitors, physical removal of thrombosis, etc.).
  • a method for treating ischemic angiopathy which comprises administering to a patient a pharmaceutical composition containing MSC.
  • MSC reduces the risk of cerebral hemorrhage by protecting the vascular endothelium and suppressing endothelial damage, and is a safe recanalization therapy for occluded blood vessels (eg, thrombolytic therapy and physical thrombosis). It has already been confirmed that (removal) will be realized.
  • intravenous administration of MSC helps to improve microcirculation, increases local cerebral blood flow, and restores microvascular system in patients who cannot obtain the effect of recanalization therapy. ..
  • tissue regeneration / repair effect of MSC the above-mentioned effect improves motor dysfunction, promotes healing of infarcted lesion site, and enables more effective treatment of ischemic angiopathy.
  • MSC middle cerebral artery occlusion
  • MSCs from Rat Bone Marrow The MSC was prepared based on the previous report (Nakazaki et al, Neuroscience 408: 361-377, 2019). That is, bone marrow obtained from the femoral bone of adult Wistar rats (6-8 weeks old) was diluted with Dulbecco's modified Eagle's medium (DMEM) to make 15 ml, and 10% heat-inactivated fetal bovine serum, 2 mM l-glutamine, 100 U. / Ml penicillin and 0.1 mg / ml streptomycin were added and incubated at 37 ° C. for 3 days in a humid atmosphere containing 5% CO 2 .
  • DMEM Dulbecco's modified Eagle's medium
  • adherent cells were exfoliated with trypsin-ethylenediaminetetraacetic acid solution (Millipore Sigma) and subcultured at 1 ⁇ 10 4 cells / ml medium.
  • trypsin-ethylenediaminetetraacetic acid solution Millipore Sigma
  • cultured MSCs after 3 passages were used.
  • a phenotypic analysis of surface antigens was performed to confirm that the MSCs were CD45 ⁇ , CD73 + , CD90 + , and CD106 ⁇ .
  • a 3-0 surgical MONOSOF suture (Medtronic) with a length of 20.0 to 24.0 mm is rounded with a flame to block the origin of the MCA, from the external carotid artery to the inside of the internal carotid artery. It was inserted into the cavity (Nagahama et al, Brain Res 1695: 37-44, 2018, Namioka et al, J Neurosurg: 1-8, 2018).
  • the same surgical MONOSOF suture (Medtronic) with a flared tip was inserted from the external carotid artery into the lumen of the internal carotid artery until the origin of the MCA was blocked for 110 minutes.
  • pMCAO rats were intravenously dosed with 1 ml DMEM containing MSCs (1.0 ⁇ 106 cells each).
  • tMCAO rats were intravenously dosed with 1 ml DMEM containing MSCs (1.0 ⁇ 106 cells each).
  • Intravenous administration was delivered from the left femoral vein. All rats received daily cyclosporine A (10 mg / kg, ip). All rats underwent treadmill loading tests and infarct volume measurements using MRI. Rats selected from each group were subjected to rCBF measurement using ASL-MRI and histological evaluation by three-dimensional analysis of capillaries.
  • Treadmill load test Treadmill load tests were performed according to previously reported (Nagahama et al. 2018 and Nakazaki et al. J Neurosurg 127: 917-926, 2017). That is, the rats were run on a treadmill (Muromachi Inc.) set at a speed of 20 m / min and an inclination of 20 ° for 20 minutes a day, 2 days a week, before inducing pMCAO or tMCAO. Rats that could not run at 70 m / min were excluded. After induction of pMCAO or tMCAO, 3 trials were performed with a cutoff time of 180 seconds.
  • the maximum speed at which the rat can run on the treadmill is 7 days after pMCAO or tMCAO induction (immediately before MSC or vehicle administration), and 8, 11, 14, 21, 28, 35, 42, and 49 days (respectively, respectively). Recorded 1, 4, 7, 14, 21, 28, 35, and 42 days after administration of the MSC or vehicle).
  • MRI measurements were performed using a 7-T MRI scanner (70/16 PharmaScan, Bruker Biospin MRI GmbH, Ettlingen, Germany). Rats were anesthetized with intraperitoneal administration of ketamine (75 mg / kg) and xylazine (10 mg / kg).
  • FIG. 1B shows the MRA of an intact animal.
  • T2WI for measurement of infarct volume.
  • the amount of ischemia was calculated from T2WI using ImageJ software (version 1.52, NIH) (Nagahama et al 2018, supra).
  • the hyperintensity regions were then summed and the slice thickness multiplied by the gap between the slices to calculate the lesion volume.
  • MR images are taken 7 days after pMCAO or tMCAO induction (immediately before MSC or vehicle administration) and 8, 11, 14, 21, 28, 35, 42, and 49 days (1, 4, 4, respectively after MSC or vehicle administration, respectively). Obtained at 7, 14, 21, 28, 35, and 42 days later).
  • [ASL] CBF images were acquired using continuous ASL by single-shot spin-echo echo-planner imaging (EPI).
  • the CBF map was calculated using the in-house code of MATLAB (The Math Works Inc.).
  • CBF was calculated at mL / 100 g / min using Baxton's general dynamic opening model. According to the previous report, a bregma-0.4 mm coronal slice was selected for quantification of cerebral blood flow (Nakazaki et al. 2017, supra).
  • Regions of interest (ROI) were placed in the ischemic cortex and the hemisphere without infarction.
  • the ASL-derived rCBF for each ROI was quantified using ImageJ software (NIH).
  • the rCBF rate was calculated based on the value of the ischemic cortex rCBF divided by the non-infarcted hemisphere rCBF.
  • tMCAO Group 4
  • MSC administration Group 3
  • ASL arterial pressure
  • MRI magnetic resonance imaging
  • the rCBF rate in Group 2 with transient obstruction dropped significantly, reaching the same level as Group 3 with permanent obstruction and MSC treatment. Therefore, the rCBF rate after transient occlusion is significantly reduced without MSC administration (Group 2).
  • the ratio of local cerebral blood flow in the two models was substantially the same on day 7 (Group 1 and Group 2 were approximately the same, Group 3 and Group 4 were approximately the same).
  • the rCBF rate in the MSC-administered group was higher than the rCBF rate in the vehicle group on days 42 and 49 after induction of pMCAO or tMCAO (Group 1 ⁇ Group 3 ⁇ Group 2 ⁇ Group 4).
  • the rCBF rate of group 4 was also higher than the rCBF rate of group 3 on the 42nd and 49th days after the induction of pMCAO or tMCAO.
  • transient occlusion (Group 4), in which MSCs were intravenously administered 7 days after lesion induction, showed the greatest therapeutic effect in the experimental group. The data is shown in FIG. 4B.
  • FIGS. 5A-5D Representative confocal microscopic images of the four experimental groups 49 days after MCAO induction are shown in FIGS. 5A-5D.
  • the ratio (ipsilateral / contralateral) is shown.
  • the ratio in group 4 was higher than the ratio in group 3.
  • the ratio of group 2 was not statistically different from the ratio of group 3.
  • transient occlusion (Group 4) treated with MSC showed the largest recovery of the microvasculature of the four groups. The results are shown in FIG. 5E.
  • MSC administration has a therapeutic effect on both pMCAO and tMCAO, but the combination of recanalization and MSC administration may give better results. From the results of this experiment, it was confirmed that the therapeutic effect of inadequate recanalization therapy (the condition does not change from pMCAO on the 7th day of recanalization) can be improved by MSC administration.
  • Intravascular thrombectomy is currently an established treatment for cerebral infarction. Patients who have undergone acute recanalization therapy may receive MSCs in clinical settings in the future. The promotion of both increased rCBF and microvascular recovery may contribute to better clinical outcomes in patients undergoing intravascular thrombectomy due to vascular occlusion.
  • the therapeutic effect of recanalization therapy for occluded blood vessels for example, administration of a drug containing a thrombus lytic agent, a platelet aggregation inhibitor, a blood coagulation inhibitor, and physical removal of a thrombus
  • recanalization therapy for occluded blood vessels for example, administration of a drug containing a thrombus lytic agent, a platelet aggregation inhibitor, a blood coagulation inhibitor, and physical removal of a thrombus

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Abstract

La présente invention concerne un agent thérapeutique pour l'angiopathie ischémique qui est une composition médicinale pour le traitement de l'angiopathie ischémique, la composition médicinale comprenant des cellules souches mésenchymateuses en tant que principe actif, l'agent thérapeutique pour l'angiopathie ischémique étant caractérisé en ce qu'il est administré à un patient pour lequel une thérapie de recanalisation d'un vaisseau sanguin occlus a été inefficace et en ce que l'effet thérapeutique de l'agent thérapeutique est amélioré.
PCT/JP2021/044001 2020-11-26 2021-11-24 Médicament pour le traitement de l'angiopathie ischémique WO2022114242A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024019063A1 (fr) * 2022-07-20 2024-01-25 富士フイルム株式会社 Procédé de production de cellules souches mésenchymateuses

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005007176A1 (fr) * 2003-06-27 2005-01-27 Renomedix Institute Inc. Traitement de maladies des nerfs craniens s'administrant par voie interne et contenant comme principe actif des cellules mesenchymateuses
JP2014517695A (ja) * 2011-05-23 2014-07-24 アジュ ユニヴァーシティー インダストリー−アカデミック コーオペレイション ファウンデーション 肝細胞増殖因子の遺伝子と、塩基性ヘリックスループヘリックスモチーフを有する神経原性転写因子の遺伝子とを導入した成体幹細胞株、及びその使用
WO2017111153A1 (fr) * 2015-12-25 2017-06-29 北海道公立大学法人 札幌医科大学 Médicament pour le traitement des infarctus cérébraux

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005007176A1 (fr) * 2003-06-27 2005-01-27 Renomedix Institute Inc. Traitement de maladies des nerfs craniens s'administrant par voie interne et contenant comme principe actif des cellules mesenchymateuses
JP2014517695A (ja) * 2011-05-23 2014-07-24 アジュ ユニヴァーシティー インダストリー−アカデミック コーオペレイション ファウンデーション 肝細胞増殖因子の遺伝子と、塩基性ヘリックスループヘリックスモチーフを有する神経原性転写因子の遺伝子とを導入した成体幹細胞株、及びその使用
WO2017111153A1 (fr) * 2015-12-25 2017-06-29 北海道公立大学法人 札幌医科大学 Médicament pour le traitement des infarctus cérébraux

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SASAKI, YUICHI: "I-9K-3-5 Synergistic effect of bone marrow mesenchymal stem cell transplantation and exercise load on experimental cerebral infarction,", THE 57TH ANNUAL MEETING OF THE JAPANESE ASSOCIATION OF REHABILITATION MEDICINE, AUGUST 19-22, 2020, vol. 57, 1 August 2020 (2020-08-01), JP, pages 128 - 129, XP009537287 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024019063A1 (fr) * 2022-07-20 2024-01-25 富士フイルム株式会社 Procédé de production de cellules souches mésenchymateuses

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