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WO2016125330A1 - Médicament favorisant la régénération rétinienne - Google Patents

Médicament favorisant la régénération rétinienne Download PDF

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Publication number
WO2016125330A1
WO2016125330A1 PCT/JP2015/074162 JP2015074162W WO2016125330A1 WO 2016125330 A1 WO2016125330 A1 WO 2016125330A1 JP 2015074162 W JP2015074162 W JP 2015074162W WO 2016125330 A1 WO2016125330 A1 WO 2016125330A1
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granulin
retinal
grn1
regeneration
zebrafish
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Japanese (ja)
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原　英彰
一寛 鶴間
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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
    • A61K35/14—Blood; Artificial blood
    • A61K35/15—Cells of the myeloid line, e.g. granulocytes, basophils, eosinophils, neutrophils, leucocytes, monocytes, macrophages or mast cells; Myeloid precursor cells; Antigen-presenting cells, e.g. dendritic cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to a pharmaceutical effective for retina regeneration. Specifically, the present invention relates to a retina regeneration accelerator and its use.
  • This application claims priority based on Japanese Patent Application No. 2015-018857 filed on February 2, 2015, the entire contents of which are incorporated by reference.
  • the retina plays an important role in visual function, and the disorder causes various ophthalmic diseases such as glaucoma and age-related macular degeneration. Usually, since the retina does not regenerate, the treatment of ophthalmic diseases caused by retinal disorders must rely on symptomatic therapy.
  • Human granulin is an 88 kDa precursor protein (progranulin) with 7.5 highly conserved granulin motifs (CX5-6CX5CCX8CCX6CCXDX2HCCPX4CX5-6C) containing 12 cysteine residues. (See FIG. 1).
  • the signal peptide is cleaved into mature granulin, which is further cleaved to have peptides with various activities of about 6 kDa (granulin A, B, C, D, E, F, G, and P corresponding to 0.5). )become.
  • enzymes that cleave granulin include matrix metalloproteinases and neutrophil elastase.
  • Non-patent Document 1 Progranulin mutations are also involved in frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) and are important factors in neurodegenerative diseases (non- Patent Documents 2 and 3).
  • FTLD frontotemporal lobar degeneration
  • ALS amyotrophic lateral sclerosis
  • TNF receptor has been identified as a binding protein for progranulin, and has attracted attention (Non-patent Document 4).
  • An object of the present invention is to establish a new therapeutic means for ophthalmic diseases caused by retinal disorders or accompanied by retinal disorders such as glaucoma and age-related macular degeneration (agent for promoting retinal regeneration) (Medicine) is to provide.
  • Non-patent Document 5 Korean Patent Document 5
  • Progranulin had a photoreceptor-protecting effect similar to adipose stem cells.
  • the ratio of photoreceptor cells increased when the culture supernatant of adipose stem cells was added to primary retinal culture cells (announced at the 34th Annual Meeting of the Japanese Eye Pharmacology Society (Gifu, 2014.9.13-14)).
  • the culture supernatant of adipose stem cells contains a factor that promotes differentiation into photoreceptor cells.
  • the retina regeneration process roughly divided, it is necessary to proceed with two steps, namely, proliferation of retinal stem cells (retinal progenitor cells) and differentiation of retinal stem cells into photoreceptor cells. Therefore, promotion of differentiation into photoreceptor cells is important for regenerating the retina, but is not definitive.
  • the present inventors focused on progranulin which was shown to promote differentiation into photoreceptor cells, and decided to investigate the details of its involvement in the regeneration process.
  • mammals such as mice and humans do not regenerate the retina and central nervous system, and research on retinal regeneration is mainly performed using zebrafish, so we decided to use zebrafish to proceed with the study.
  • zebrafish There are four subtypes of zebrafish: granulin A (grnA) with 10 granulin motifs, granulin B (grnB) with 9 granulins, and granulin 1 (grn1) and 2 (grn2) with 1.5 granulin motifs. .
  • grnA is considered to be an ortholog of human progranulin and is expressed in microglia of the zebrafish retinal photopathy model.
  • GrnA is also involved in the differentiation and regeneration of zebrafish muscle. It is known that when the zebrafish retina is damaged, the Muller glia cells in the retina are dedifferentiated and differentiated into various cells such as photoreceptors and retinal ganglion cells to compensate for the damaged site and regenerate. It has been.
  • Retinal regeneration-promoting drug comprising a component selected from the group consisting of the following (1) and (2): (1) a granulin molecule, or a fragment thereof containing a granulin motif; (2) Neutrophils or culture supernatants thereof.
  • the granulin molecule is zebrafish grn1, zebrafish grn2, human progranulin or mouse progranulin, and the fragment is granulin A, granulin B, granulin C, granulin D, granulin E, granulin F, granulin G
  • the retinal regeneration-promoting agent according to [1] which is granulin P.
  • Glaucoma age-related macular degeneration, retinitis pigmentosa, diabetic retinopathy, decreased visual acuity or blindness due to trauma, Leber congenital blindness, white spotted fundus, cone dystrophy (cone rod dystrophy), Stargardt disease, macular
  • the retina according to any one of [1] to [3], which is used for treatment of a disease selected from the group consisting of dystrophy, familial drusen, central ring-shaped choroidal dystrophy, and spinocerebellar degeneration type 7 Regeneration promoter.
  • a therapeutic method comprising the step of administering a therapeutically effective amount of a component selected from the group consisting of the following (1) and (2) to a patient with an ophthalmic disease associated with a retinal disorder: (1) a granulin molecule, or a fragment thereof containing a granulin motif; (2) Neutrophils or culture supernatants thereof.
  • the present invention relates to a drug (retinal regeneration promoting drug) that promotes retina regeneration and exerts a therapeutic effect.
  • a drug receptor regeneration promoting drug
  • a component constituting the drug of the present invention (1) a granulin molecule or a fragment thereof containing a granulin motif, or (2) a neutrophil or a culture supernatant thereof is used.
  • the component (1) and the component (2) may be used in combination.
  • the component (1) when the component (1) is administered to a living body, it acts on neutrophils, or acts on a factor secreted by neutrophils to increase the expression of ascl1, retina-specifically Muller glial cells, which are glial cells, proliferate, dedifferentiate into retinal neural progenitor cells, differentiate into photoreceptor cells, etc., and retina regeneration is promoted.
  • the component (2) when the component (2) is administered to a living body, it can be expected to directly act to cause proliferation of Muller glial cells, dedifferentiation into retinal neural progenitor cells, differentiation into photoreceptor cells, etc. . If the component (1) and the component (2) are used in combination, in addition to the action effect mediated by neutrophils present in the living body, the action effect that does not involve neutrophils present in the living body can be exhibited, and the therapeutic effect I can expect an increase.
  • zebrafish grn1, zebrafish grn2, human progranulin or mouse progranulin can be used as the granulin molecule.
  • granulin A, granulin B, granulin C, granulin D, granulin E, granulin F, granulin G or granulin P which are degradation products of human progranulin, can be used.
  • granulin A and granulin F are particularly preferred components.
  • the attached sequence listing shows the amino acid sequence of zebrafish grn1 (SEQ ID NO: 1) and the gene sequence encoding it (SEQ ID NO: 2), the amino acid sequence of zebrafish grn2 (SEQ ID NO: 3.
  • the amino acid sequence of the variant is SEQ ID NO: 5 )
  • the gene sequence encoding it SEQ ID NO: 4
  • the amino acid sequence of human progranulin SEQ ID NO: 6
  • the gene sequence encoding it SEQ ID NO: 7
  • amino acid sequence of mouse progranulin mouse progranulin
  • mouse grn1 SEQ ID NO: 8
  • SEQ ID NO: 9 The attached sequence listing shows the amino acid sequence of zebrafish grn1 (SEQ ID NO: 1) and the gene sequence encoding it (SEQ ID NO: 2), the amino acid sequence of zebrafish grn2 (SEQ ID NO: 3.
  • the amino acid sequence of the variant is SEQ ID NO: 5
  • the gene sequence encoding it SEQ ID NO: 4
  • Granulin molecules or fragments thereof can also be prepared by separating and purifying from a living body, but preferably as a recombinant (recombinant protein) from the viewpoint of homogenization of quality, preparation operation, scale-up, etc.
  • a granulin molecule or fragment thereof is prepared.
  • Preparation operations can be performed in a conventional manner, for example, Molecular Cloning (Third Edition, Cold Spring Harbor Laboratory Press, New York), Current protocols in molecular biology (edited by Frederick M. Ausubel et al., 1987) become.
  • Neutrophils can be prepared by conventional methods. As specific examples of the method for preparing neutrophils, a method for preparing mouse active neutrophils and a method for preparing human neutrophils are described below.
  • HBSS Horte' balanced salt solution
  • culture may be performed at 37 ° C. and 5% CO 2 in RPMI1640 medium containing 10% FBS.
  • the culture supernatant of neutrophils can be obtained by culturing the prepared neutrophils in vitro.
  • prepared mouse or human neutrophils are seeded in a 10 cm petri dish (BD) or flask (25 cm 2 ) at 40,000 cells / ml, and cultured in HEPES-MEM or RPMI1640 without FBS for 12 to 24 hours. . Thereafter, the supernatant is collected, centrifuged at 300 ⁇ g for 5 minutes, and then sterilized by filtration using a 0.22 ⁇ m sterilizing filter (Millipore).
  • the culture supernatant is concentrated by ultrafiltration (eg using Amicon Ultra-15 (Millipore) (fractionated molecular weight 3,000)).
  • the retinal regeneration-promoting agent of the present invention can be prepared as an injection for intravitreal administration, an eye drop or an eye ointment according to a conventional method.
  • An injection for intravitreal administration can be produced, for example, by suspending or dissolving the active ingredient in an appropriate solvent (for example, distilled water for injection or physiological saline).
  • an appropriate solvent for example, distilled water for injection or physiological saline.
  • isotonic agents such as mannitol, sodium chloride, glucose, sorbit, glycerol, xylitol, fructose, maltose, mannose, stabilizers such as albumin, preservatives such as benzyl alcohol and methyl parahydroxybenzoate
  • an acid such as citric acid and a base such as diisopropanolamine can be added to the preparation as a pH adjuster.
  • An eye drop can be produced, for example, by dissolving the above active ingredient in an appropriate solvent (for example, distilled water for injection or physiological saline).
  • an appropriate solvent for example, distilled water for injection or physiological saline.
  • isotonic agents such as mannitol, sodium chloride, glucose, sorbit, glycerol, xylitol, fructose, maltose, mannose, glycerin, stabilizers such as sodium edetate, albumin, benzyl alcohol, methyl parahydroxybenzoate, etc.
  • a preservative, a surfactant such as polyoxyethylene monooleate, polyoxyl 40 stearate and the like can be added to the preparation.
  • an acid such as citric acid and a base such as diisopropanolamine can be added to the preparation as a pH adjuster.
  • the pH of the eye drop is not particularly limited as long as it is within the range acceptable for ophthalmic preparations, but is preferably 5.0 to 8.5.
  • the retinal regeneration-promoting agent of the present invention is used for the treatment of various ophthalmic diseases caused by retinal disorders or accompanied by retinal disorders (in other words, retinal regeneration has a therapeutic effect).
  • ophthalmic disease to be treated with the retinal regeneration-promoting agent of the present invention glaucoma, age-related macular degeneration, retinitis pigmentosa, diabetic retinopathy, decreased visual acuity or blindness due to trauma, Leber congenital blindness, white spotted fundus, Cone dystrophy (cone rod dystrophy), Stargardt disease, macular dystrophy, familial drusen, central crested choroidal dystrophy and spinocerebellar degeneration 7 types.
  • it is particularly effective for diseases in which degeneration occurs in photoreceptor cells.
  • the dose (use amount) of the retinal regeneration-promoting agent of the present invention may be appropriately set in consideration of the patient's condition, age, weight, dosage form, and the like.
  • an appropriate amount of the preparation containing 0.01 to 70% by weight of the active ingredient may be administered once a month.
  • the preparation containing 0.01 to 70% by weight of the active ingredient may be instilled 1 to several times a day once to several drops.
  • the treatment target of the retinal regeneration-promoting agent of the present invention is not particularly limited, and humans and non-human mammals (pet animals, domestic animals, laboratory animals, etc., specifically, for example, guinea pigs, hamsters, monkeys, cows, pigs, goats, Sheep, dogs, cats, chickens, quails, etc.).
  • the retinal regeneration-promoting agent of the present invention is applied to humans.
  • the present application includes glaucoma, age-related macular degeneration, retinitis pigmentosa, diabetic retinopathy, decreased visual acuity or blindness due to trauma, Leber congenital blindness, white spotted fundus, cone dystrophy (cone) (Body dystrophy), Stargardt disease, macular dystrophy, familial drusen, central annulus choroidal dystrophy, spinocerebellar degeneration 7 and the like, a therapeutically effective amount of the retinal regeneration promoter of the present invention is administered.
  • a featured treatment is also provided.
  • Method A 30G needle was inserted into the eyeball of a zebrafish (AB line), and the retina was damaged in 4 to 8 places. Thereafter, the eyeballs were removed between 6 hours and 7 days, and frozen sections were prepared. In addition, RNA was prepared after the retina was isolated. The frozen section was used to identify the expression site of grn1 mRNA by in situ hybridization. Simultaneously, immunostaining was performed using an anti-4C4 antibody (microglia marker) and an antiplastin antibody (microglia and neutrophil marker).
  • RNA was used for measuring the expression levels of grn1, grn2, grnA, grnB and ascl1a mRNA by PCR.
  • a morpholino oligo capable of specifically knocking down the expression of the zebrafish gene was prepared and introduced into the retina by electroporation. After introduction, BrdU was administered intraperitoneally to zebrafish. After this treatment, frozen sections were prepared and RNA was prepared. Using frozen sections, BrdU positive cells were quantified as cells in the regeneration process (using anti-BrdU antibody). RNA was used for quantification of the expression level of the gene ascl11, which is an indicator of zebrafish retinal regeneration.
  • grn1 Since the expression of grn1 was increased in the zebrafish retinal disorder model, it was decided to confirm the expression site by in situ hybridization. When examined using the grn1 antisense probe, positive cells with strong expression were observed around the damaged site 15 hours after the injury, and were confirmed even 24 hours later (FIG. 4). On the third day of injury, grn1 positivity was observed in Muller glia (FIG. 5). When immunostaining was performed using an anti-4C4 antibody that is a marker of microglia, colocalization with grn1-positive cells was hardly observed (FIG. 4). When the damaged site was immunostained with anti-4C4 antibody and antiplastin antibody (microglia and neutrophil markers), 4C4 negative / plastin positive cells were observed (FIG. 4). The shape of these cells resembled grn1-positive cells. From the above results, it was found that grn1 is highly expressed in retinal damage sites (especially neutrophils) in zebrafish.
  • grn1 MO antisense morpholino-oligo
  • RT-PCR was used to examine whether there was a change in the expression of ascl1a, which is essential for retinal regeneration. As a result, a decrease in ascl1a was observed in the retina into which grn1 MO was introduced 15 hours after injury (Fig. 6).
  • grn1 is also expressed in retinal cells other than neutrophils including Muller glia, even if they are knocked down with grn1 MO, there was no change in the expression level of ascl1a. These results suggest that grn1 cleaved by neutrophil-specific enzymes may regulate the expression level of ascla1.
  • zebrafish grn1 mRNA was cloned, a 6xHis tag sequence was added to the 3 'side, and then expressed in vitro to synthesize the grn1 protein. Purification was performed using a column for His tag and a column for buffer replacement to obtain recombinant grn1. 200 ng recombinant grn1 or vehicle was administered to the vitreous of the zebrafish retinal disorder model. Two days later, the eyeballs were removed, retinal mRNA was prepared, and the increase or decrease in retinal regeneration-related factors was confirmed by RT-PCR.
  • BrdU was intraperitoneally administered, and the eyeball was removed to prepare a frozen section. Immunofluorescence staining was performed with an anti-BrdU antibody, and the presence or absence of BrdU positive cells was observed with a fluorescence microscope.
  • the retinal regeneration-promoting agent of the present invention can be applied to the treatment of various ophthalmic diseases caused by retinal disorders or accompanied by retinal disorders.
  • Regenerative medicine using artificial pluripotent stem cells (iPS cells) or the like has attracted attention as a therapeutic means to replace conventional symptomatic treatment.
  • the present invention increases technical options for regenerative medicine, and can be used and applied as an alternative or supplement to conventional therapies.

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Abstract

La présente invention a pour objet de fournir un médicament capable de favoriser la régénération rétinienne. L'invention concerne un médicament favorisant la régénération rétinienne comprenant un constituant choisi dans le groupe comprenant (1) une molécule de granuline ou un fragment de celle-ci contenant un motif de granuline et (2) un neutrophile ou un surnageant de culture correspondant.
PCT/JP2015/074162 2015-02-02 2015-08-27 Médicament favorisant la régénération rétinienne Ceased WO2016125330A1 (fr)

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JP2015018857 2015-02-02
JP2015-018857 2015-02-02

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111032075A (zh) * 2017-06-15 2020-04-17 芝加哥大学 用于治疗癌症的方法和组合物
EP4048799A4 (fr) * 2019-10-22 2023-11-15 Applied Genetic Technologies Corporation Systèmes de virus adéno-associés (vaa) pour le traitement de maladies ou de troubles neurodégénératifs associés à la progranuline
EP4295857A4 (fr) * 2020-11-26 2025-01-01 The Asan Foundation Composition pharmaceutique pour prévenir ou traiter les fibroses, contenant une protéine, la progranuline, ou des fragments actifs de celle-ci en tant que principe actif
US12472270B2 (en) 2019-04-29 2025-11-18 University Of Washington Methods and compositions for reprogramming Müller Glia

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
KURIMOTO ET AL.: "Neutrophils Express Oncomodulin and Promote Optic Nerve Regeneration", THE JOURNAL OF NEUROSCIENCE, vol. 33, no. 37, 11 September 2013 (2013-09-11), pages 14816 - 14824 *
TSURUMA ET AL.: "Progranulin, a Major Secreted Protein of Mouse Adipose-Derived Stem Cells, Inhibits Light-Induced Retinal Degeneration", STEM CELLS TRANS MED, vol. 3, no. 1, 2014, pages 42 - 53 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111032075A (zh) * 2017-06-15 2020-04-17 芝加哥大学 用于治疗癌症的方法和组合物
JP2020524141A (ja) * 2017-06-15 2020-08-13 ザ・ユニバーシティ・オブ・シカゴＴｈｅ Ｕｎｉｖｅｒｓｉｔｙ Ｏｆ Ｃｈｉｃａｇｏ がんを処置するための方法および組成物
JP7189160B2 (ja) 2017-06-15 2022-12-13 ザ・ユニバーシティ・オブ・シカゴ がんを処置するための方法および組成物
JP2023022242A (ja) * 2017-06-15 2023-02-14 ザ・ユニバーシティ・オブ・シカゴ がんを処置するための方法および組成物
JP7529754B2 (ja) 2017-06-15 2024-08-06 ザ・ユニバーシティ・オブ・シカゴ がんを処置するための方法および組成物
US12472270B2 (en) 2019-04-29 2025-11-18 University Of Washington Methods and compositions for reprogramming Müller Glia
EP4048799A4 (fr) * 2019-10-22 2023-11-15 Applied Genetic Technologies Corporation Systèmes de virus adéno-associés (vaa) pour le traitement de maladies ou de troubles neurodégénératifs associés à la progranuline
EP4295857A4 (fr) * 2020-11-26 2025-01-01 The Asan Foundation Composition pharmaceutique pour prévenir ou traiter les fibroses, contenant une protéine, la progranuline, ou des fragments actifs de celle-ci en tant que principe actif

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