WO2002005840A1 - Compositions medicinales favorisant la fixation de cellules transplantees - Google Patents

Compositions medicinales favorisant la fixation de cellules transplantees Download PDF

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Publication number
WO2002005840A1
WO2002005840A1 PCT/JP2001/006166 JP0106166W WO0205840A1 WO 2002005840 A1 WO2002005840 A1 WO 2002005840A1 JP 0106166 W JP0106166 W JP 0106166W WO 0205840 A1 WO0205840 A1 WO 0205840A1
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site
hgf
cells
pharmaceutical composition
diabetic
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PCT/JP2001/006166
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English (en)
Japanese (ja)
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Yoshiki Sawa
Satoshi Taketani
Shigeru Miyagawa
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Cardio, Inc.
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Priority to AU2001271064A priority Critical patent/AU2001271064A1/en
Publication of WO2002005840A1 publication Critical patent/WO2002005840A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1833—Hepatocyte growth factor; Scatter factor; Tumor cytotoxic factor II
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • 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
    • 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

Definitions

  • the present invention relates to a pharmaceutical composition for promoting cell colonization of transplanted cells to a disease-damaged site, comprising a hepatocyte growth factor (HGF) or an HGF gene as an active ingredient, and apoptosis of transplanted cells to a disease-damaged site.
  • HGF hepatocyte growth factor
  • the present invention relates to a pharmaceutical composition for suppressing fibrosis at a diseased site. More specifically, a pharmaceutical composition containing HGF or an HGF gene as an active ingredient for promoting the transplantation of transplanted cardiomyocytes to a damaged myocardial site and suppressing apoptosis of transplanted cardiomyocytes or fibrosis at a damaged myocardial site
  • the present invention relates to a pharmaceutical composition for medical use.
  • the present invention also relates to a method for treating ischemic or diabetic organ diseases, which comprises injecting transplantation cells and HGF or the HGF gene into a diseased site. More specifically, the present invention relates to a method for treating ischemic or diabetic heart disease, which comprises injecting cardiomyocytes and HGF or HGF gene into a damaged myocardial site. In particular, the present invention relates to a method for treating myocardial infarction or cardiomyopathy by administering cardiomyocytes for transplantation and HGF or the HGF gene to a site of cardiac ischemia due to myocardial infarction or an injured myocardial site due to cardiomyopathy.
  • Myocardial infarction is a disease in which ischemic ischemia occurs in the perfused area due to severe stenosis or occlusion due to various lesions of the coronary artery.
  • classifications for determining the severity of myocardial infarction and by using these in combination, individual pathological conditions can be more clearly understood. For example, classification based on time course, morphological classification based on the extent and location of the myocardium, the size of the necrosis, ventricular reconstruction after myocardial death and infarction, and hemodynamics related to treatment and prognosis Classification, classification by clinical severity, and the like. What is judged to be high in severity according to these classifications is severe myocardial infarction according to the present invention. There is no accurate treatment method for severe myocardial infarction to date. It is a situation where only the plant is left.
  • Cardiomyopathy is a general term for diseases caused by structural and functional abnormalities of the myocardium.Secondary cardiomyopathy secondary to underlying diseases such as hypertension, metabolic disorders, and ischemia, and obvious underlying diseases It is classified as idiopathic cardiomyopathy (ICM) that develops without any. Pathological changes include myocardial hypertrophy, fibrosis, and degeneration.
  • ICM idiopathic cardiomyopathy
  • cardiomyopathy has a fairly widespread spectrum, from relatively obvious causes to those with completely unknown causes.
  • research is being carried out to identify the cause and elucidate the pathogenic mechanism, and no reliable treatment method has yet been found.
  • Heart failure is a condition in which the heart itself is impaired, such as cardiac insufficiency, circulatory insufficiency, and reduced contractile force, and the inability to circulate the required quantity and quality of blood to the organs throughout the body is called heart failure.
  • cardiomyopathy is a terminal symptom of heart disease. Severe heart failure is defined as severe heart failure, also known as end-stage heart failure.
  • transplantation of own atrial cells and right ventricular cells into affected areas of the heart disorder is now being considered as a new trial for the treatment of severe heart failure, severe myocardial infarction and cardiomyopathy (Cell Engineering, 19, 860- 863 (2000)).
  • transplantation rate of transplanted cardiomyocytes is only about 20 to 30% at most.
  • An object of the present invention is to provide a pharmaceutical composition for promoting cell colonization of transplanted cells for treating ischemic or diabetic organ diseases. More specifically, it is an object of the present invention to provide a therapeutic method for transplanting cardiomyocytes suitable for treating severe myocardial infarction or cardiomyopathy, for which no effective therapeutic method has been found based on these drugs and compositions.
  • the present inventors have conducted intensive studies to solve the above problems, and as a result, have found that colonization of transplanted cells is promoted by performing cell transplantation using HGF or an HGF gene in combination.
  • HGF or the HGF gene was used in cardiomyocyte cell transplantation. It was found that when used, the colonization of the cardiomyocytes was promoted, and the apoptosis of the transplanted cardiomyocytes and the fibrosis of the cardiomyocytes at the damaged site of the transplantation destination were suppressed. The cardiac function was significantly improved, and a comparison of the cell findings showed that the cardiomyocytes were clearly mature.
  • the present inventor has found that by injecting HGF or HGF gene and cardiomyocytes directly into the affected myocardium, colonization of the transplanted cardiomyocytes and regeneration of the cardiomyocytes become possible, and without performing heart transplantation. It has been found that cardiomyocyte transplantation can be used to treat severe heart failure, severe myocardial infarction and cardiomyopathy.
  • the use of the HGF or the HGF gene of the present invention is also effective for cell transplantation therapy for ischemic organ disease.
  • ischemic organ disease For example, not only cardiomyocyte transplantation to the above-mentioned myocardial infarction site, but also cerebral ischemia, transplantation of neural progenitor cells to the site of cerebral infarction or cells that can be differentiated into nerve cells, myocardial infarction site, skeletal muscle ischemia Transplantation of vascular endothelial cells or cells that can be divided into vascular endothelial cells into the site has become possible.
  • the use of the HGF or the HGF gene of the present invention is also effective for a cell transplantation method for diabetic organ disease.
  • the gist of the present invention is:
  • a pharmaceutical composition comprising hepatocyte growth factor (HGF) or an HGF gene as an active ingredient, for promoting cell colonization of transplanted cells at a disease-damaged site;
  • HGF hepatocyte growth factor
  • composition according to (6) which is administered together with a hepatic insulin secreting cell having a reduced insulin secretion ability, or administered together with a cell capable of differentiating into a vascular endothelial cell to a limb having impaired circulation.
  • a pharmaceutical composition comprising HGF or an HGF gene as an active ingredient, for suppressing apoptosis of transplanted cells into a diseased lesion or fibrosis at the diseased lesion,
  • (23) a method of promoting colonization of transplanted cells, which comprises administering HGF or an HGF gene to the diseased lesion when administering the cells for transplantation to the diseased lesion,
  • transplanted cells are cardiomyocytes
  • transplanted cells are cells capable of differentiating into insulin-secreting cells or vascular endothelial cells
  • (29) a method for treating ischemic or diabetic organ disease, comprising administering an HGF or HGF gene together with transplanted cells to an ischemic or diabetic disease disorder site;
  • HGF gene is in the form of a viral vector or a non-viral vector capable of expressing HGF.
  • biocompatible material is a copolymer of silicone, collagen, gelatin or glycolic acid / lactic acid.
  • transplanted cells are cells capable of differentiating into insulin-secreting cells or vascular endothelial cells
  • transplanted cell is a cell capable of transferring to insulin-secreting cells or vascular endothelial cells
  • biocompatible material is a copolymer of silicone, collagen, gelatin or glycolic acid / lactic acid
  • FIG. 1 is a graph showing comparative data of improvement in cardiac function.
  • FIG. 2 is a graph showing the degree of improvement in myocardial blood flow at the injured myocardial site (infarct lesion).
  • FIG. 3 is a tissue fragment micrograph showing the fixation of transplanted cardiomyocytes at the administration site stained with HF.
  • FIG. 4 is a micrograph of a tissue slice showing that cell adhesion factors (connexin43, Desmin) were confirmed between cardiomyocytes and that a Gap junction was formed.
  • cell adhesion factors connexin43, Desmin
  • FIG. 5 is a tissue fragment micrograph showing the viability of the transplanted cardiomyocytes.
  • FIG. 6 is a graph showing the inhibitory effect of cardiomyocyte fibrosis by the combined use of the HGF gene.
  • the HGF used in the present invention is a known substance. As long as it is purified to the extent that it can be used as a medicine, HGF prepared by various methods can be used. For example, Toyobo Code No. HGF-101 etc.) May be used.
  • the HGF can be obtained by culturing primary cultured cells or cell lines that produce HGF, and separating and purifying it from a culture supernatant or the like.
  • an HGF-encoding gene is incorporated into an appropriate vector by genetic engineering techniques, inserted into an appropriate host, and transformed to obtain the desired recombinant HGF from the culture supernatant of this transformant. (For example,
  • the host cell is not particularly limited, and various host cells conventionally used in genetic engineering techniques, for example, Escherichia coli, yeast, or animal cells can be used.
  • the HGF thus obtained may have one or more amino acids in its amino acid sequence replaced, deleted and Z or added, as long as it has substantially the same action as natural HGF.
  • the sugar chain may be substituted, deleted and Z- or added.
  • the HGF gene used in the present invention refers to a gene capable of expressing HGF, and includes a part of the gene sequence as long as the expressed polypeptide is substantially the same as HGF. Also include a gene in which is deleted or replaced by another base, another base sequence is inserted into the base, or a base is bonded to the 5 'end and the Z or 3' end. Further, a gene that hybridizes with a gene encoding HGF under stringent conditions and encodes a protein having the same function as HGF may be used. Examples of such a gene include the HGF gene described in Nature, 342, 440 (1989), JP-A-5-111383, Biochem. Biophys. Res. Thus, these genes can be used in the present invention. These genes can be obtained by the well-known PCR method or can be chemically synthesized. In addition, these methods can be combined with, for example, site-directed mutagenesis, ordinary hybridization, and the like.
  • the dosage form When administering the HGF gene to a patient, the dosage form may be a non-viral vector dosage form, a viral vector dosage form, or a naked DNA It is roughly divided into three types of administration by the indirect injection method, and its preparation method and administration method are described in detail in experimental manuals and other documents. (Separate volume experimental medicine, basic technology of gene therapy, Yodosha, 1996, separate volume experiment Medicine, Gene Transfer & Expression Analysis Experimental Method, Yodosha, 1997). The details are described below.
  • a method of incorporating DNA encoding the HGF of the present invention into a gene expression vector and introducing a DNA molecule using a liposome ribosome method, HVJ-ribosome method, catonic ribosome method, ribofectin method, ribofector method) Mining method), microinjection method, transfer of DNA molecule into cells together with carrier (metal particles) by gene gun (Gene Gun), etc.
  • expression vectors used here include pCAGGS (Gene 108, 193-200 (1991)), pBK-CMV, pcDN A3.1, pZeo SV (Invitrogen, Stratagene) and the like. Vector.
  • HVJ-ribosome encapsulates DNA in ribosomes made of lipid bilayer, and then fuses this liposome with inactivated Sendai virus (Hemagglutinating virus of Japan: HVJ). Things.
  • the HV J-liposome method is characterized by having a very high fusion activity with the cell membrane as compared with the conventional liposome method, and is a preferable introduction form.
  • HVJ-Liposome preparation method is described in the literature (Experimental Medicine Separate Volume, Basic Techniques for Gene Therapy, Yodosha, 1996, Gene Transfer & Expression Analysis Experimental Method, Yodosha, 1997, J. Clin. Invest. 93, 1458- 1464 (1994), Am. J. Physiol.
  • the HVJ is preferably the Z strain (available from ATCC), but basically other HVJ strains (eg, ATCC VR-907 and ATCC VR-105) can also be used.
  • a typical example of a virus vector is a method using a virus vector such as a recombinant adenovirus or retrovirus. More specifically, for example, detoxified retrovirus, adenovirus, adeno-associated virus, herpes virus
  • the DNA of the present invention is introduced into a DNA virus such as Nores, vaccinia-inoles, box-inoles, poliovirus, Cymbis virus, Sendai virus, SV40, immunodeficiency virus (HIV) or RNA virus, and the DNA is introduced into cells.
  • HIV immunodeficiency virus
  • RNA virus RNA virus
  • the direct DNA injection method is, for example, a method in which the above-mentioned expression plasmid, which is a non-viral vector, is dissolved in physiological saline and administered as it is.
  • Circulation, 96 (Suppl. ⁇ ), 382-388 (1997) Can be directly injected into tissues such as skeletal muscle, myocardium, subcutaneous, liver, and thyroid.
  • HGF human endothelial growth factor
  • various preparation forms for example, liquid preparations suitable for each of the above-mentioned administration forms can be taken.
  • a route of administration of HGF it can be directly administered to tissues such as skeletal muscle, myocardium, spleen, liver, and thyroid.
  • the preparation may be, for example, an injection containing HGF or an HGF gene as an active ingredient.
  • the injection can be prepared by a conventional method. For example, after dissolving in an appropriate solvent (buffer such as PBS, physiological saline, sterilized water, etc.), sterilizing by filtration with a filter or the like, and then aseptically It can be prepared by filling in a suitable container. A conventional carrier or the like may be added to the injection as needed.
  • ribosomes such as HV J-ribosome used when administering the HGF gene can be in the form of a ribosome preparation such as a suspending agent, a freezing agent, and a centrifugal concentrated cryogenic agent.
  • the HVJ ribosome preparation is a gene preparation prepared for administering the HGF gene, and is preferably administered parenterally.
  • administration methods using a non-invasive catheter or non-invasive syringe can be.
  • injection of the HGF gene directly into the myocardium from the intraventricular cavity can be mentioned.
  • a sustained-release preparation mini-pellet preparation, etc.
  • implant it near the affected part or use an osmotic pump or the like. It can also be used for continuous and gradual administration to the affected area.
  • the biocompatible material that can be used in such a sustained-release preparation is not particularly limited as long as it is biocompatible.
  • specific examples of the non-degradable synthetic polymer include, for example, silicone and ethylene-butyl acetate. Examples include copolymers, polyurethane, polyethylene, polytetrafluoroethylene, polypropylene, polyatalylate, and polymethacrylate. Silicone is preferred from the viewpoint of easy molding.
  • biodegradable synthetic polymers include, for example, collagen, gelatin, monohydroxycarponic acids (eg, glycolic acid, lactic acid, hydroxybutyric acid, etc.), hydroxydicarboxylic acids (eg, malic acid, etc.), hydroxy Polymers, copolymers, or mixtures thereof synthesized from one or more of tricarboxylic acids (eg, cunic acid, etc.) by non-catalytic dehydration polycondensation, poly (1-cyanoacrylate), polyamino acids (eg, polyamino acids) Poly-anhydrides such as mono- ⁇ -benzyl-L-glutamic acid) and maleic anhydride copolymers (eg, styrene-maleic acid copolymer).
  • monohydroxycarponic acids eg, glycolic acid, lactic acid, hydroxybutyric acid, etc.
  • hydroxydicarboxylic acids eg, malic acid, etc.
  • the type of polymerization may be random, block, or graft.
  • monohydroxycarboxylic acids, hydroxydicarboxylic acids, or hydroxytricarboxylic acids have an optically active center in the molecule, D-, L-, or DL- Any of the bodies can be used.
  • a copolymer of glycolic acid and lactic acid can be used.
  • silicone, collagen, gelatin, or a glycolic acid / lactic acid copolymer is particularly preferred as a biocompatible material for a sustained-release preparation.
  • the dosage form of the sustained-release preparation is not particularly limited as long as it is a dosage form suitable for achieving the object of the present invention, and examples thereof include a rod shape (pellet shape, cylinder shape, needle shape, etc.), a tablet shape, and a disc shape. Shaped, spherical, and sheet-like preparations can also be made.
  • the HGF gene content of the preparation of the present invention can be appropriately adjusted depending on the disease to be treated, the age and weight of the patient, etc., and usually, a viral vector containing the DNA of the present invention. Alternatively, it is 0.0001 to 100 mg, preferably 0.001 to 10 mg as a non-viral vector, and it is preferable to administer it once every several days to several months.
  • the dose of the HGF gene is selected from the range of about 1 to about 4000 ⁇ g, preferably about 10 to about 400 g per adult patient, as the amount of the HGF gene encoding HGF.
  • the HGF content of the preparation of the present invention can be appropriately adjusted in the same manner according to the disease to be treated, the age and weight of the patient, etc., but usually 6 // g to 600 mg, preferably Is 60 g to 6 Omg, which is preferably administered once every few days to several months.
  • any cell can be appropriately used as long as the cell can be transplanted to a site of a damaged tissue associated with an ischemic or diabetic organ disease.
  • ischemic or diabetic organ disease For example, in heart diseases such as severe heart failure and severe myocardial infarction, cardiomyocytes, smooth muscle cells, fibroblasts, skeletal muscle-derived cells (particularly satellite cells), bone marrow cells (particularly myocardium) Bone marrow cells differentiated into like cells) and the like.
  • transplantation cells can be appropriately selected for other organs.
  • transplantation of neural progenitor cells into cerebral ischemia / cerebral infarct site or cells capable of differentiating into neural cells, differentiation into vascular endothelial cells or vascular endothelial cells into myocardial infarction site / skeletal muscle ischemic site Transplantation of natural cells is an example of the transplanted cells.
  • cells used for cell transplantation for diabetic organ damage are variously examined for diseases such as impaired blood circulation of the kidney, knee, peripheral nerves, eyes, and limbs, can be mentioned.
  • the dose of the transplanted cells can be appropriately adjusted depending on the disease to be treated, the age of the patient, the transplanted cells to be treated, and the like.
  • the dose of the transplanted cells of the present invention is 1 ⁇ 10 4 to 10 11. It is preferable to administer HGF or the HGF gene once a few days to several months at the same time.
  • the range is 1 ⁇ 10 4 to 10 11 , preferably 1 ⁇ 10 6 to 10 9.
  • the dose is selected from the box.
  • an endogenous cardioprotective factor or a cardiomyocyte regeneration factor can be used in combination.
  • factors such as TGF- and heat shock protein (HSP), which are highly expressed during cardiomyocyte injury, reduce myocardial injury and are involved in myocardial repair. I can do it.
  • HGF- and heat shock protein HSP
  • EGF repair various cell damages in tissues, and these genes can also be used.
  • factors involved in myocardial protection and regeneration can be considered.
  • the HGF or HGF gene can be introduced into cardiac myocardial cells alone or in combination as described above, and highly expressed, thereby synthesizing a target protein necessary for damaged cardiomyocytes and the like.
  • the myocardial cells and the like can be restored and regenerated, and the recovery and normalization of the cardiac function that has fallen into cardiomyopathy can be performed. Therefore, it can be used not only for patients with severe cardiomyopathy, but also for those with mild ongoing disease.
  • the present invention is particularly effective in heart disease. According to the present invention, it becomes possible to repair the injured myocardium that has fallen into heart failure and to improve the heart function. Thus, a new rescue path was possible for patients with severe heart failure, severe myocardial infarction, cardiomyopathy, etc., for whom there was no cure other than heart transplantation.
  • Example 1 Effect of HGF gene administration on transplantation of cultured cardiomyocytes to rat ischemic heart
  • the HGF gene used was prepared as follows. First, 2 ml of an HVJ-liposome preparation was prepared from 200 ⁇ of 11 GF cDNA plasmid. The HGF cDNA plasmid content in the liposome preparation was 20% of the plasmid used (40 ⁇ g of plasmid was contained in the preparation). 0.2 ml of this 2 ml HV J-liposome preparation was administered.
  • Administration was performed by injecting and administering cardiomyocytes and the HGF gene to three sites of the injured myocardium, respectively.
  • EF ejection fraction
  • Figure 2 shows an example of the results.
  • a comparison between the control (Ligation model) and the case of cardiomyocyte transplantation + HGF gene administration (cellTx + HGF) showed an improvement in myocardial blood flow at the injured myocardial site (infarct lesion).
  • Sections of the administration site were prepared and confirmed by microscopic histological evaluation.
  • HF dyeing As shown in Fig. 3 after the color, in the cardiomyocyte transplantation + HGF gene administration group (cellTx + HGF), the transplanted cardiomyocytes settled in the injured myocardium (infarct lesion), and the transplanted cardiomyocytes developed well. However, the increase in cell diameter was histologically observed.
  • cell adhesion factors such as connexin43 and Desmin were confirmed between cardiomyocytes, and formation of Gap junction was observed.
  • apoptosis cells were searched by TUNEL staining.
  • Fig. 5 shows the stained image. According to the results, apoptosis of the transplanted cardiomyocytes was observed in the cardiomyocyte transplantation group (cellTx), but not in the cardiomyocyte transplantation + HGF gene administration group (cellTx + HGF).
  • Administration is performed by injecting and administering cardiomyocytes and HGF to the three sites of the injured myocardium, respectively.
  • the following methods are used to evaluate the improvement of cardiac function and the improvement of myocardial blood flow at 4 and 8 weeks after cardiomyocyte transplantation.
  • ejection fraction Is measured.
  • the evaluation of cardiac function improvement can also be evaluated by expressing the degree of improvement assuming that the value of one solid before transplantation is 1. Compared with the control group and the cardiomyocyte transplantation group (cellTx), marked improvement is seen in the cardiomyocyte transplantation + HGF administration group (cellTx + HGF).
  • Apoptosis cells can be evaluated by TUNEL staining. Apoptosis of the transplanted cardiomyocytes is observed in the cardiomyocyte transplantation group (cellTx), but not in the cardiomyocyte transplantation + HGF administration group (cellTx + HGF).
  • a rat myocardial infarction model was prepared as in Example 2, two weeks later, divided into three groups,
  • For the control group 0.2 ml of the medium alone is administered into the ischemic area around the infarct area.
  • the cardiomyocyte transplantation group 1 ⁇ 10 7 cultured cardiomyocytes are injected together with the medium into the ischemic site around the infarct area.
  • the cardiomyocyte transplantation + HGF sustained release preparation administration group 0.2 ml of a liquid HGF sustained release preparation is administered. Administration is performed by injecting and administering cardiomyocytes and HGF to three sites of the affected myocardium, respectively.
  • the HGF gene or HGF can promote the colonization of cardiomyocytes transplanted into the affected area of the injured myocardium, and can also suppress apoptosis of the transplanted cardiomyocytes and fibrosis at the damaged site. Therefore, the HGF gene or HGF can be effectively used for treatment of severe myocardial infarction or cardiomyopathy by cardiomyocyte transplantation.

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Abstract

Dans le traitement de l'infarctus du myocarde grave ou de la myocardiopathie par transplantation de cellules myocardiques dans le site affecté, on peut promouvoir la fixation des cellules myocardiques transplantées et inhiber l'apoptose desdites cellules et la fibrose du site myocardique endommagé en administrant un gène d'HGF ou un HGF audit site. On peut ainsi traiter efficacement l'infarctus du myocarde grave ou la myocardiopathie.
PCT/JP2001/006166 2000-07-18 2001-07-17 Compositions medicinales favorisant la fixation de cellules transplantees WO2002005840A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006077675A1 (fr) * 2005-01-24 2006-07-27 Kringle Pharma Inc. Inhibiteur de fibrose pour un organe implante
EP1810696A1 (fr) * 2004-10-29 2007-07-25 AnGes MG, Inc. Therapie genique pour le traitement d 'insuffisances cardiaques

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WO2001026694A1 (fr) * 1999-10-08 2001-04-19 Medgene Bioscience, Inc. Therapie genique pour cardiomyopathie

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1810696A1 (fr) * 2004-10-29 2007-07-25 AnGes MG, Inc. Therapie genique pour le traitement d 'insuffisances cardiaques
EP1810696A4 (fr) * 2004-10-29 2008-03-05 Anges Mg Inc Therapie genique pour le traitement d 'insuffisances cardiaques
WO2006077675A1 (fr) * 2005-01-24 2006-07-27 Kringle Pharma Inc. Inhibiteur de fibrose pour un organe implante
US7696170B2 (en) 2005-01-24 2010-04-13 Kringle Pharma Inc. Fibrosis inhibitor for implanted organ
US8076289B2 (en) 2005-01-24 2011-12-13 Kringle Pharma Inc. Fibrosis inhibitor for implanted organ
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