WO2006046584A1 - Remède pour des traumatismes de cellules visuelles - Google Patents

Remède pour des traumatismes de cellules visuelles Download PDF

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Publication number
WO2006046584A1
WO2006046584A1 PCT/JP2005/019654 JP2005019654W WO2006046584A1 WO 2006046584 A1 WO2006046584 A1 WO 2006046584A1 JP 2005019654 W JP2005019654 W JP 2005019654W WO 2006046584 A1 WO2006046584 A1 WO 2006046584A1
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WIPO (PCT)
Prior art keywords
cells
derived
retinal
hgf
bdnf
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PCT/JP2005/019654
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English (en)
Japanese (ja)
Inventor
Noriyuki Kuno
Fumihiko Takamatsu
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Santen Pharmaceutical Co., Ltd.
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Publication of WO2006046584A1 publication Critical patent/WO2006046584A1/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
    • 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
    • A61K35/35—Fat tissue; Adipocytes; Stromal cells; Connective tissues
    • 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
    • A61K38/185—Nerve growth factor [NGF]; Brain derived neurotrophic factor [BDNF]; Ciliary neurotrophic factor [CNTF]; Glial derived neurotrophic factor [GDNF]; Neurotrophins, e.g. NT-3
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A61K9/0051—Ocular inserts, ocular implants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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 sustained-release composition
  • a sustained-release composition comprising a crosslinked gelatin hydrogel impregnated with hepatocyte growth factor (HGF), brain-derived neurotrophic factor (BDNF) or reticulopigment epithelium-derived neurotrophic factor (PEDF).
  • HGF hepatocyte growth factor
  • BDNF brain-derived neurotrophic factor
  • PEDF reticulopigment epithelium-derived neurotrophic factor
  • the therapeutic agent of the disease which causes the photoreceptor cell disorder which consists of.
  • the present invention also provides a sustained release composition in which a crosslinked gelatin hydrogel is impregnated with HGF, BDNF or PEDF, and a visual cell comprising a photoreceptor cell or a cell having a role of regenerating or complementing the function, or the function thereof. It is related with the material for making it.
  • a photoreceptor cell is a cell that converts a light stimulus to the retina into an electrical signal, and controls an important function related to optical sensation and vision.
  • diseases that cause photoreceptor cell damage include retinal pigment degeneration, cone dystrophy, age-related macular degeneration, macular edema, retinal detachment, cancer-related retinopathy, retinal vein occlusion, and retinal pigment epithelial detachment. These diseases are refractory and are not easily cured even by the administration of existing drugs, and once denatured, the function of the detached photoreceptor cells cannot be restored. Furthermore, it is desired to regenerate the function of photoreceptor cells. As a new treatment method, regenerative medicine in which cells and tissues of own and other families are transplanted to replace and regenerate dysfunctional cells, tissues and organs has been attempted.
  • HGF hepatocyte growth factor
  • Patent Document 1 Non-Patent Document 1
  • Patent Document 2 describes an invention related to an HGF sustained-release preparation, and an HGF sustained-release preparation obtained by combining HGF and a gelatin hydrogel having specific physical properties can be used as an angiogenesis-promoting agent or an arterial disease therapeutic agent. Is stated.
  • BDNF Moon-derived neurotrophic factor
  • Patent Document 3 describes that ophthalmic solutions or eye ointments containing BDNF are effective in treating age-related macular degeneration and retinal pigment degeneration.
  • Patent Document 4 describes that retinal pigment epithelium-derived neurotrophic factor (PEDF) is effective in treating retinal diseases.
  • Patent Document 5 describes an invention relating to a material for cell transplantation, such as hydrogel, and that a hydrogel containing a cell growth factor such as hepatocyte growth factor (HGF) is effective as a therapeutic agent for heart failure. Is stated.
  • Patent Document 6 describes an invention relating to a therapeutic agent for regenerating a tissue organ composed of cells and a cell growth factor, and a therapeutic agent combining a precursor cell with bFGF (basic fibroblast growth factor). It has been reported that adipose tissue regenerates when implanted under the skin.
  • bFGF basic fibroblast growth factor
  • Patent Document 1 Japanese Patent Publication No. 4-72840
  • Patent Document 2 International Publication No. 03Z007982 Pamphlet
  • Patent Document 3 Japanese Patent Laid-Open No. 2003-48851
  • Patent Document 4 U.S. Patent No. 6451763
  • Patent Document 5 JP 2002-145797
  • Patent Document 6 Japanese Patent Laid-Open No. 2001-316285
  • HGF hepatocyte growth factor
  • BDNF brain-derived neurotrophic factor
  • PDF retinal pigment epithelium
  • PEDF retinal pigment epithelium
  • all sustained-release compositions obtained by impregnating cross-linked gelatin hydrogel with HGF, BDNF, or PEDF exhibit an excellent inhibitory effect on photoreceptor cell degeneration.
  • the release composition and the adipose-derived stromal cells were combined, it was found that photoreceptor cells or their functions regenerate and the effect of suppressing photoreceptor cell degeneration is enhanced and sustained, leading to the present invention.
  • a therapeutic agent for diseases causing visual cell damage comprising a sustained release composition comprising a crosslinked gelatin hydrogel impregnated with at least one of the following components 1) to 3):
  • HGF Hepatocyte growth factor
  • BDNF Brain-derived neurotrophic factor
  • PEDF retinal pigment epithelium
  • a therapeutic agent for diseases causing visual cell damage comprising a sustained release composition in which at least one of the following components 1) to 3) is impregnated in a crosslinked gelatin hydrogel and the following component 4):
  • HGF Hepatocyte growth factor
  • BDNF Brain-derived neurotrophic factor
  • PEDF retinal pigment epithelium
  • retinal degenerative disease is retinitis pigmentosa, cone dystrophy, age-related macular degeneration, age-related macular degeneration, macular edema, retinal detachment, cancer-related retinopathy, retinal vein occlusion or retinal pigment epithelial detachment (1) to the therapeutic agent according to (3),
  • stromal cells are adipose-derived stromal cells
  • HGF Hepatocyte growth factor
  • BDNF Brain-derived neurotrophic factor
  • PEDF retinal pigment epithelium
  • the first invention is a method wherein a crosslinked gelatin hydrogel is impregnated with hepatocyte growth factor (HGF), brain-derived neurotrophic factor (BDNF) or retinal pigment epithelium-derived neurotrophic factor (PEDF).
  • HGF hepatocyte growth factor
  • BDNF brain-derived neurotrophic factor
  • PEDF retinal pigment epithelium-derived neurotrophic factor
  • HGF sustained release composition, the BDNF sustained release composition, and the PEDF sustained release composition all stabilize HGF, BDNF, and PEDF as well as long-term.
  • Hepatocyte growth factor (HGF), brain-derived neurotrophic factor (BDNF), and retinal pigment epithelium-derived neurotrophic factor (PEDF) in the present invention are all purified to such a degree that they can be used as pharmaceuticals. It is not particularly limited as long as it is a thing, and may be a natural type or a recombinant type.
  • HGF human growth factor
  • examples of natural HGF include primary culture of cultured mesenchymal cells such as liver, lung, kidney, spleen, plasma, platelet force extract, fibroblasts, vascular endothelial cells, macrophages, and cell cultures. Examples include supernatants and those derived from these cell extracts.
  • the thread-replaceable HGF may be one in which one or more amino acids in the amino acid sequence of the thread-replaceable HGF are substituted, deleted, or added as long as it has substantially the same action as the natural HGF.
  • one or more sugar chains in the amino acid sequence of recombinant HGF may be substituted, deleted, or added.
  • HGF may be a natural HGF or a modified form of recombinant HGF (for example, a complex with a polymer material such as polyethylene glycol or lecithin).
  • Examples of natural BDNF include extracts of brain, spinal cord, heart, lung, and skeletal muscle strength. It is.
  • Recombinant BDNF may be one in which one or more amino acids in the amino acid sequence of recombinant BDNF are substituted, deleted, or added as long as it has substantially the same action as natural BDNF.
  • one in which one or more sugar chains in the amino acid sequence of recombinant BDNF are substituted, deleted, or added may be used.
  • BDNF may be natural BDNF or a modified form of recombinant BDNF (for example, a complex with a polymer material such as polyethylene glycol or lecithin).
  • Examples of natural PEDF include extracts from the retina, primary culture cells of retinal pigment epithelial cells and culture supernatants of cell lines, and cell extracts thereof.
  • Recombinant PEDF may be one in which one or more amino acids in the amino acid sequence of recombinant PEDF are substituted, deleted, or added as long as it has substantially the same action as natural PEDF.
  • one or more sugar chains in the amino acid sequence of recombinant PEDF may be substituted, deleted, or added.
  • PDEDF may be a natural PEDF or a modified form of recombinant PEDF (for example, a complex with a polymer material such as polyethylene glycol or lecithin).
  • photocytopathy refers to a condition in which the photocell is damaged by various factors.
  • diseases causing photocytopathy include retinal pigment degeneration.
  • retinal degenerative diseases such as cone dystrophy, age-related macular degeneration, age-related macular disease, macular edema, retinal detachment, cancer-related retinopathies, retinal vein occlusion, and retinal pigment epithelial detachment.
  • crosslinked gelatin hydrogel refers to a hydrogel obtained by crosslinking gelatin, and is not particularly limited as long as it is a hydrogel obtained by crosslinking gelatin. Include those having at least one of the following physical properties 1) to 4).
  • Gelatin constituting the crosslinked gelatin hydrogel is acidic gelatin or basic gelatin.
  • Gelatin constituting the crosslinked gelatin hydrogel has a molecular weight of 0.5 to 200,000 danoleton under the non-reducing conditions of SDS-PAGE.
  • Gelatin constituting the crosslinked gelatin hydrogel has an isoelectric point of 4.5 to 9.5.
  • Water content power of crosslinked gelatin hydrogel is 0 to 99%.
  • HGF sustained-release composition HGF, BDNF sustained-release composition or PEDF sustained-release composition of the present invention
  • HGF, BDNF or PEDF and a cross-linked gelatin hydrogel form a complex.
  • the hydrogel is hydrolyzed by proteolytic enzymes, and the gelatin gradually becomes water-soluble. This is thought to contribute to the sustained release of BDNF or PEDF.
  • Gelatin is not particularly limited, and can be obtained, for example, by alkaline hydrolysis treatment or acid hydrolysis treatment from skin, tendon or collagen of animals such as cattle.
  • HGF or BDNF acidic gelatin obtained by alkali treatment of type I collagen derived from urchin bone is preferred, for example, S-4 manufactured by Nitta Gelatin Co., Ltd. Can be mentioned.
  • PEDF a basic gelatin obtained by acid treatment of type I collagen derived from pig skin is preferred, for example, AP-150 manufactured by Nitta Gelatin Co., Ltd. It is done.
  • the gelatin of the present invention preferably has a molecular weight of 0.5 to 200,000 daltons under non-reducing conditions of SDS-PAGE.
  • the isoelectric point of the gelatin of the present invention is preferably 4.5 to 9.5.
  • BDNF is used, the isoelectric point of 4.5 to 5.5 is more preferable.
  • PEDF is used, 7.0 to 9.5 is more preferable.
  • the isoelectric point is obtained by preparing a 1% gelatin aqueous solution, filtering the solution through a cation column or an anion column, and measuring the pH of the filtered aqueous solution.
  • the crosslinking method for obtaining the crosslinked gelatin hydrogel of the present invention is not particularly limited.
  • gelatin may be crosslinked by thermal dehydration, ultraviolet irradiation, electron beam irradiation, chemical crosslinking, or a combination thereof. it can.
  • Preferred methods are thermal dehydration without using a crosslinking agent, ultraviolet irradiation or electron beam irradiation.
  • the shape of the crosslinked gelatin hydrogel of the present invention is not particularly limited, and examples thereof include particles, sheets, disks, columns, and prisms.
  • a particulate form is preferred, and when it is transplanted or embedded in a wide range of modified sites, a sheet form is preferred.
  • the preparation of the particulate crosslinked gelatin hydrogel is preferably carried out as follows. For example, put olive oil in a three-necked round bottom flask equipped with a stirring motor and a propeller. Stir at a rotational speed of about 600 rpm, add gelatin aqueous solution dropwise to this to prepare a WZO emulsion, cool, add acetone, ethyl acetate, etc., stir, and centrifuge to collect gelatin particles. The collected gelatin particles are further washed with acetone, ethanol, etc. and dried. The dried gelatin particles are put into a constant-temperature vacuum dryer or the like and subjected to thermal dehydration crosslinking.
  • a particulate dry cross-linked gelatin hydrogel is thus obtained.
  • these dry-crosslinked gelatin hydrogel particles are impregnated with aqueous solutions of HGF, BDNF, and PEDF, the particulate HGF sustained-release composition, BDNF sustained-release composition, or PEDF sustained-release composition (drug-containing crosslinked gelatin hydrogel) Microspheres) are obtained.
  • a sheet-like, disc-like, cylindrical, and prismatic crosslinked gelatin hydrogel is preferably carried out as follows.
  • a sheet-like dried crosslinked gelatin hydrogel can be obtained by extruding an aqueous gelatin solution into a sheet and drying it followed by thermal dehydration crosslinking or ultraviolet crosslinking.
  • the molded product is dried and subjected to thermal dehydration crosslinking or UV crosslinking to obtain a dry crosslinked gelatin hydrogel having a disk shape, a cylindrical shape, or a prism shape. it can.
  • the particle size of the particulate crosslinked gelatin hydrogel can be appropriately selected depending on the purpose of use, but is preferably 500 ⁇ m or less, more preferably 200 ⁇ m or less.
  • the film thickness can be appropriately selected according to the purpose of use, but it is preferably 200 ⁇ m or less, more preferably 100 ⁇ m or less.
  • the water content of the crosslinked gelatin hydrogel of the present invention can be appropriately selected depending on the purpose of use, but it is preferably 30 to 99 wZw%, more preferably 40 to 98 wZw%.
  • the weight ratio of HGF, BDNF or PEDF and gelatin relative to the HGF sustained-release composition, BDNF sustained-release composition or PEDF sustained-release composition of the present invention is not particularly limited, but a preferred weight ratio is HGF.
  • the second invention is a method in which a crosslinked gelatin hydrogel is impregnated with hepatocyte growth factor (HGF), brain-derived neurotrophic factor (BDNF) or retinal pigment epithelium-derived neurotrophic factor (PEDF).
  • HGF hepatocyte growth factor
  • BDNF brain-derived neurotrophic factor
  • PEDF retinal pigment epithelium-derived neurotrophic factor
  • a releasable composition, a therapeutic agent for a disease causing a photoreceptor damage comprising a cell having a role of regenerating or complementing a photoreceptor cell or a function thereof, and a material for regenerating the photoreceptor cell or a function thereof.
  • an HGF sustained-release composition, a BDNF sustained-release composition, or a PEDF sustained-release composition and cells that play a role in regenerating or complementing photoreceptor cells or their functions.
  • the visual cell or its function is regenerated and the effect of suppressing retinal degeneration is enhanced.
  • the photoreceptor cell used in the present invention or a cell having a role of regenerating or complementing the function thereof is not particularly limited.
  • a stromal cell such as an adipose-derived stromal cell or a bone marrow stromal cell, an undifferentiated cell Leaf cells, retinal stem (progenitor) cells, retinal pigment epithelial cells, iris pigmented epithelial cells, neural stem cells, hematopoietic stem cells, skin stem cells, embryonic stem cells (ES cells), embryonic germ stem cells (EG cells), and embryos
  • ES cells embryonic stem cells
  • EG cells embryonic germ stem cells
  • embryos include the above-mentioned cells induced to differentiate from sex stem cells, embryonic germ stem cells, etc., preferably stromal cells, more preferably adipose-derived stromal cells.
  • the cells that play a role to regenerate or complement the photoreceptor cells or their functions may be collected from the tissue strength of the
  • a human adipose tissue mass collected by adipose tissue is crushed with a scissors and scissors, and the resulting strips are shaken with a collagenase solution, filtered through a filter, and centrifuged to obtain cell groups. Collect. Next, only the collected cell group strength adherent cells are collected, cultured in an incubator, and proliferated to obtain adipose-derived stromal cells.
  • the adipose-derived stromal cells include those into which a photoreceptor cell-specific homeobox gene and a gene encoding a factor exhibiting a neuroprotective action or a degeneration inhibitory action are introduced.
  • a photoreceptor-specific homeobox gene is a gene or differentiation trait that has a region-specific expression pattern of a photoreceptor cell and controls region-specific morphogenesis in the process of photoreceptor cell development.
  • genes involved in the expression of, such as Crx, Otx2, Nrl, Chx 10 etc. are mentioned.
  • BDNF brain-derived neurotrophic factor
  • PEDF retinal pigment epithelium-derived neurotrophic factor
  • HGF cell growth factor
  • a method for introducing a gene encoding a factor that exhibits a degeneration-inhibiting action into a stromal cell having a photoreceptor-specific homeobox gene or a neuroprotective action is not particularly limited.
  • the lipofussion method Physics and physics introduction methods such as the Electo mouth position method, calcium phosphate method, and gene gun method, adenovirus vector, adeno-associated virus vector, retrovirus vector, Sendai virus vector, Sendai virus envelope vector, etc. The method using is mentioned.
  • HGF sustained-release composition, BDNF sustained-release composition or PEDF sustained-release composition and fat-derived stromal cells obtained by the above method are mixed to regenerate photoreceptor cells or their functions. A material is obtained.
  • the HGF sustained-release composition, the BDNF sustained-release composition or the PEDF sustained-release composition of the present invention comprises a pharmaceutically acceptable stabilizer, preservative, solubilizer, and pH adjustment as necessary. May contain additives such as agents, thickeners, suspending agents, buffering agents, tonicity agents, preservatives, soothing agents, antioxidants, etc. it can.
  • additives such as agents, thickeners, suspending agents, buffering agents, tonicity agents, preservatives, soothing agents, antioxidants, etc. it can.
  • sugars or lipids having amino acids, amino groups, phosphate groups, sulfate groups, SH groups, carboxyl groups, etc. may be added. it can.
  • the present invention also provides a visual cell disorder comprising administering to a patient a therapeutically effective amount of a sustained release composition in which a crosslinked gelatin hydrogel is impregnated with at least one of HGF, BDNF and PEDF.
  • a method for treating diseases causing photoreceptor cell damage comprising administering to a patient in an effective amount, and a sustained-release composition and photoreceptor cells in which at least one of HGF, BDNF and PEDF is impregnated in a crosslinked gelatin hydrogel Or a combination with a cell that plays a role in regenerating or complementing its function is effective for treatment
  • the present invention also relates to a method for regenerating a photoreceptor cell or a function thereof, which comprises administering a suitable amount to a patient.
  • the dosage of the therapeutic agent for diseases causing photoreceptor cell damage and the material for regenerating photoreceptor cells or their functions according to the present invention takes into consideration the disease site, the degree of disease, the age and weight of the patient, and the like. and can be appropriately adjusted, HGF (BDNF, PEDF) is preferably from 0. OOl ⁇ lOOO ⁇ g range preferred tool as in the range of 0.01 to 500 8.
  • HGF BDNF, PEDF
  • it may be injected as an injection into the site of photoreceptor damage or the surrounding tissue (subretinal, intraretinal, intravitreal, etc.), and the site of photoreceptor damage or the surrounding tissue (subretinal, Transplanted into the retina, vitreous, etc.).
  • the HGF sustained-release composition, BDNF sustained-release composition, PEDF sustained-release composition of the present invention, and these sustained-release compositions and the photoreceptors or their functions are regenerated or complemented.
  • Combinations with cells that have a role include: retinitis pigmentosa, cone dystrophy, age-related macular degeneration, age-related macular disease, macular edema, retinal detachment, cancer-related retinopathy, retinal vein occlusion, retinal chromatic epithelial detachment It is useful as a therapeutic agent for diseases that cause photoreceptor cell disorders such as, and is an excellent material for regenerating photoreceptor cells or their functions.
  • HGF-impregnated crosslinked gelatin hydrogel microsphere suspension HGF ⁇ / z gZmg microsphere concentration: 2.5 wZv%).
  • Green fluorescent protein transgenic rats (3 weeks old) were euthanized by over anesthesia with jetyl ether, and subcutaneous fat was collected. The collected subcutaneous fat was shredded with scissors in phosphate buffered saline (5 ml), and 5 ml of collagenase solution (2 mgZml) was added and shaken at 37 ° C for 15-20 minutes. After shaking, 10 ml of Medium 99 containing 10% urine fetal serum (10 ml, manufactured by Invitrogen) was added to form a suspension. The suspension was filtered through a sterile 200 m filter to remove cell clumps.
  • the filtrate is centrifuged (2000 rpm, 5 minutes), the supernatant is removed, the residue is suspended in Medium 99 (10 ml) containing 10% ushi fetal serum, and this suspension is centrifuged again (1000 rpm, 10 minutes). Minutes). After removal of the supernatant, the residue is suspended in 5 ml of Medium 99 containing 10% urine fetal serum, seeded in a culture flask, and maintained at 37 ° C and 5% CO.
  • HGF-impregnated crosslinked gelatin hydrogel microsphere suspension was suspended under the retina of both eyes of 3-week-old RCS rats. Each suspension was injected with 5 ⁇ 1 (HGF, BDNF, PEDF; 0.5 g, microspheres; 125 g) / eye. Phosphate buffered saline was used as a control.
  • an electroretinogram was taken and the amplitude of the b wave was measured.
  • the residual rate of b wave at 4 weeks after subretinal administration was calculated based on the b wave amplitude before administration (100%).
  • the test results are shown in Fig. 1 [HGF], Fig. 2 [BDNF] and Fig. 3 [PEDF]. (The effect of suppressing retinal degeneration is greater as the residual rate of b-wave amplitude is higher.) 0 Yes, the survival rate is the average value.
  • the HGF impregnated crosslinked gelatin hydrogel microsphere suspension, BDNF impregnated crosslinked gelatin hydrogel microsphere suspension, PEDF impregnated crosslinked gelatin hydrogel microsphere suspension When injected, V and shift were excellent in suppressing retinal degeneration.
  • V is also a photoreceptor cell or its function Regenerated and drug-impregnated crosslinked gelatin hydrogel micro
  • the effect of suppressing retinal degeneration was further enhanced compared to the case of injecting sufuair under the retina.
  • Adipose-derived stromal cells 4X10 7 Concentrated glycerin 2omg
  • FIG. 1 shows a b wave at 4 weeks after subretinal administration in a retinal degeneration inhibition test using a suspension of HGF-impregnated crosslinked gelatin hydrogel microspheres and a mixture thereof with adipose-derived stromal cells. It is a graph which shows an amplitude residual ratio (average value).
  • Figure 2 shows the b-wave amplitude at 4 weeks after subretinal administration in a retinal degeneration inhibition test using a BDNF-impregnated crosslinked gelatin hydrogel microsphere suspension and a mixture of it with adipose-derived stromal cells. It is a graph which shows a residual rate (average value).
  • FIG. 3 shows a b wave at 4 weeks after subretinal administration in a retinal degeneration suppression test using a PEDF-impregnated crosslinked gelatin hydrogel microsphere suspension and a mixture thereof with adipose-derived stromal cells. It is a graph which shows an amplitude residual ratio (average value).

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Abstract

L'invention a pour objet de rechercher un remède qui est efficace contre des maladies intraitables provoquant des traumatismes des cellules visuelles telles que la dégénérescence du pigment rétinien, la dystrophie des cônes, la dégénérescence maculaire liée à l'âge, la macule liée à l'âge, l'oedème maculaire, le décollement rétinien et ainsi de suite et de fournir une matière qui est utile pour régénérer des cellules visuelles ou des fonctions de celles-ci. Des compositions à libération prolongée, dans lesquelles le facteur de croissance des hépatocytes (HGF), le facteur neutrophique dérivé du cerveau (BDNF) ou le facteur dérivé de l'épithélium pigmentaire (PEDF) est imprégné d'un hydrogel de gélatine réticulée, présentent chacune un excellent effet de suppression de la dégénérescence rétinienne. Lorsqu'une telle composition est combinée à des cellules interstitielles dérivées de graisse et qu'elle est administrée de façon sous-rétinienne, les cellules visuelles ou les fonctions de celles-ci peuvent être régénérées et l'effet de suppression de la dégénérescence rétinienne peut être renforcé et prolongé.
PCT/JP2005/019654 2004-10-26 2005-10-26 Remède pour des traumatismes de cellules visuelles WO2006046584A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011058449A2 (fr) 2009-11-16 2011-05-19 Hmfra Hungary Limited Liability Company Préparations ophtalmiques basées sur un facteur neurotrophique dérivé du cerveau (bdnf) et leur utilisation
US20120237473A1 (en) * 2011-03-14 2012-09-20 University Of Medicine And Dentistry Of New Jersey Compositions And Methods For Cell Based Retinal Therapies
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
EP3636275A4 (fr) * 2017-06-08 2021-03-10 NexThera Co., Ltd. Composition pharmaceutique pour prévenir ou traiter une maladie néovasculaire, contenant du collagène de type i et un peptide de facteur dérivé de l'épithélium pigmentaire en tant que principes actifs

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WO2011058449A2 (fr) 2009-11-16 2011-05-19 Hmfra Hungary Limited Liability Company Préparations ophtalmiques basées sur un facteur neurotrophique dérivé du cerveau (bdnf) et leur utilisation
US20120237473A1 (en) * 2011-03-14 2012-09-20 University Of Medicine And Dentistry Of New Jersey Compositions And Methods For Cell Based Retinal Therapies
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
EP3636275A4 (fr) * 2017-06-08 2021-03-10 NexThera Co., Ltd. Composition pharmaceutique pour prévenir ou traiter une maladie néovasculaire, contenant du collagène de type i et un peptide de facteur dérivé de l'épithélium pigmentaire en tant que principes actifs
US11197918B2 (en) 2017-06-08 2021-12-14 Nexthera Co., Ltd. Pharmaceutical composition for preventing or treating neovascular disease, containing collagen type i and pigment epithelium derived factor peptide as active ingredients

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