WO2006067920A1 - Agent pharmaceutique pour therapie faisant appel a une transplantation de cellules souches de moelle osseuse - Google Patents

Agent pharmaceutique pour therapie faisant appel a une transplantation de cellules souches de moelle osseuse Download PDF

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Publication number
WO2006067920A1
WO2006067920A1 PCT/JP2005/020697 JP2005020697W WO2006067920A1 WO 2006067920 A1 WO2006067920 A1 WO 2006067920A1 JP 2005020697 W JP2005020697 W JP 2005020697W WO 2006067920 A1 WO2006067920 A1 WO 2006067920A1
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WO
WIPO (PCT)
Prior art keywords
bone marrow
marrow stem
ctack
cells
stem cells
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PCT/JP2005/020697
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English (en)
Japanese (ja)
Inventor
Hiroshi Shimizu
Riichiro Abe
Daisuke Inokuma
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National University Corporation Hokkaido University
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Application filed by National University Corporation Hokkaido University filed Critical National University Corporation Hokkaido University
Priority to JP2006548722A priority Critical patent/JPWO2006067920A1/ja
Publication of WO2006067920A1 publication Critical patent/WO2006067920A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/28—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
    • 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
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/195—Chemokines, e.g. RANTES
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators

Definitions

  • the present invention opens to the use of chemokines in a new treatment method by skin cell regeneration for congenital skin diseases that have been reported as intractable diseases, such as congenital epidermolysis bullosa.
  • EB congenital epidermolysis bullosa
  • EB congenital epidermolysis bullosa
  • EB is congenitally fragile and is understood as a collective term for congenital diseases that easily cause blistering on the skin, even when weak external force causes dissociation of the epidermal dermis (see, for example, Toshiaki Saida et al.
  • EB is a genetically diverse disease, and blister formation is based on the force generated at any site under electron microscope observation.
  • Epidermis cell blister formation simple type
  • blister formation junction type
  • dermal blister formation nutrient disorder type directly below
  • Hiroshi Shimizu “Classification of epidermolysis bullosa”, previous training course required A course materials, Japan Dermatological Association resident member Issued by the association, 2002 'Non-patent document 2).
  • keratin 5 or keratin 14 gene in the junction type in laminin 5 gene, in the nutritional disorder type VII collagen gene, mutation or injury is considered to be the cause of the onset
  • Non-Patent Document 1 edited by Toshiaki Saida et al., “Today's skin disease treatment policy”, third edition, published by Medical School, pages 308-309.
  • Non-patent document 2 Hiroshi Shimizu, “Classification of epidermolysis bullosa”, previous training course required A course material, published by the Japan Dermatological Association Members Committee, 2002.
  • Non-Patent Document 3 Daisuke Sawamura et al., “Possibility of gene therapy for epidermolysis bullosa”, 2002 West Japan Dermatology, separate volume, Vol. 64, No. 3, pp. 277-280.
  • the present invention particularly relates to a method for effectively treating or ameliorating a hereditary disease without effective pharmaceutical treatment, such as congenital epidermolysis bullosa, by a method other than gene therapy, It provides a useful medicine.
  • CTACK T-cell attracting chemo kine
  • BMDK bone marrow derived-keratinocytes
  • the present invention relates to a regenerative therapeutic drug using bone marrow stem cells containing CTACK as an active ingredient, and particularly to a regenerative therapeutic drug using transplanted bone marrow stem cells.
  • the present invention relates to a pharmaceutical comprising CTACK as an active ingredient that differentiates transplanted bone marrow stem cells into epidermal cells.
  • Regenerative treatment using bone marrow stem cells is expected as a treatment for various diseases such as angiogenesis therapy, heart failure, and liver regeneration, and the bone marrow transplant promotion foundation (http: ⁇ www.jmdp.or. jp / index.html) establishes so-called bone marrow bank to promote effective use of bone marrow stem cells is doing. Attempts have also been made to treat bone diseases by regenerating the bone marrow stem cell skin for skin diseases. However, CTACK's chemotolatato effect on bone marrow stem cells and the differentiation induction effect on epidermal cells and its bone marrow There is no report on its use for stem cell transplantation therapy.
  • the present invention uses CTACK in order to improve the efficiency in skin regenerative medicine as a treatment for skin diseases.
  • CTACK in the present invention is a protein having a total of 112 amino acid residues described in International Patent Publication WO98Z23750, or a force in which some of the amino acid residues are different from those described in the same publication. It means a protein that retains chemotratat activity against stem cells and BM DK-inducing activity.
  • CTACK functions have been known to include the selective attraction of CLA + memory T cells, skin dendritic cells (Langelnos cells), and their effects on their precursors. It has been reported that a certain healing effect is expected for skin disorders involving the immune system, such as psoriasis, skin cancer, inflammation, allergy, dermatitis, wound healing, infection, etc. Publication WO98Z23750, Janine Morales, et al., Proc. Natl. Ac ad. Sci. No. 157-165, 2002).
  • CTACK binds to CCR10, which is a chemokine receptor, and chemostratates cells such as CLA + cells, T cells, rod cells or rod precursors, and these are dermis of the skin. It has been reported that by moving into the layer and into the Z or epidermal layer, it shows therapeutic effects on skin diseases associated with immune system cells. However, it has been reported that CTA CK has the function of chemostratating bone marrow stem cells different from immune system cells and further inducing differentiation into epidermal cells! Wow! /.
  • the present invention uses CTACK's differentiation-inducing function for bone marrow stem cells, so that the use of CTACK can be applied to the treatment of skin diseases related to immune cells that have been proposed in the past, and to the application frame. It expands to the treatment of new skin diseases located outside.
  • the present invention can induce differentiation of bone marrow stem cells into epidermal cells in the field of skin damage, and is a congenital skin disease that has been considered to be particularly difficult to cure, such as congenital skin diseases. It is possible to provide a new treatment method and a pharmaceutical for the treatment of sexual epidermolysis bullosa.
  • FIG. 1 shows chemotract activity of CTACK against bone marrow stem cells by in vitro test.
  • FIG. 2 shows the activity of inducing differentiation of CTACK into bone marrow stem cells into epidermal cells in an in vivo test.
  • FIG. 3 shows the differentiation-inducing activity of CTACK to epidermal cells against bone marrow stem cells in mice pretreated with G-CSF.
  • FIG. 4 shows C TACK differentiation-inducing activity into epidermal cells against bone marrow stem cells in mice with an increased number of CD34-positive bone marrow stem cells in peripheral blood.
  • CTACK used in the present invention can be prepared recombinantly in accordance with the description of International Patent Publication No. WO98Z23750 or the literature of Morales et al.
  • CTACK which is commercially available from R & D System of Minneapolis, USA or other institutions, may also be used.
  • a bone marrow stem cell comprising an amino acid sequence in which one or more amino acids are substituted, deleted, and Z or added.
  • Polypeptides having chemoretorato activity against BMDK and activity to induce BMDK can also be used in the present invention.
  • the mutation is highly conserved, such as glycine (Gly) and proline (Pro), Gly and alanine ( Ala) or valine (Val), leucine (Leu) and isoleucine (lie), glutamic acid (Glu) and glutamine (Gin), aspartic acid (Asp) and asparagine (Asn), cysteine (Cys) and threonine (Thr),
  • Gly proline
  • Ala valine
  • Val leucine
  • Glu glutamine
  • Gin glutamic acid
  • Asp aspartic acid
  • Asparagine Asparagine
  • cysteine cysteine
  • Thr threonine
  • Examples include substitution between Thr and serine (Ser) or Ala, lysine (Lys) and arginine (Arg).
  • a gene encoding a powerful CTACK or a variant thereof can also be used for recombinant production of CTACK and the like.
  • a vector holding a DNA encoding CTACK, a host to be transformed with the vector, and the like may be used by selecting a combination described in the preceding literature or other general-purpose combinations.
  • various viruses such as baculovirus, retrovirus, vaccinia virus and the like can also be used.
  • Expression may be performed under the control of a promoter sequence specific to the CTACK gene, or another appropriate expression promoter may be used by connecting or replacing it with a promoter sequence specific to the CTACK gene.
  • the promoter used in this case may be appropriately selected according to the host and the purpose of expression.
  • the 1S host such as T7 promoter, lac promoter, trp promoter, ⁇ PL promoter is yeast.
  • PH05 promoter, GAP promoter, ADH promoter and the like can be exemplified by SV40-derived promoter, retrovirus promoter and the like when the host is an animal cell, but of course, it is not limited thereto.
  • CTACK is administered to patients who have undergone bone marrow stem cell transplantation in the form of a solution in which CTACK is dissolved in an appropriate buffer, for example, physiological saline, an emulsion in which an appropriate emulsifier is added, and the like.
  • an appropriate buffer for example, physiological saline, an emulsion in which an appropriate emulsifier is added, and the like.
  • Either a solution or a sheet form such as a nonwoven fabric holding emulsion can be used. These can be used by directly applying to or pasting the affected area.
  • Bone marrow cells were isolated from the bone marrow of mice (C57BL6) according to the method of Wiley et al. (Current Protocols of Immunology, ISS N 0-471-52276-7). Then expressed on the cell surface Antibody staining using an antibody specific for CD34 antigen (PharMingen) was performed, and CD34 positive bone marrow stem cells were separated using FACSVantage (BD Bioscience).
  • CD34 positive bone marrow stem cells suspended in DMEM medium in the upper insert of a 3 ⁇ m pore insert (Kurashiki Boseki Co., Ltd.) dissolved in the same medium in the lower plate 0 to 500 ngZml CTACK (Manufactured by R & D System) or stromal cell derived factor-1 (stroma cell derived factor-1, SDF-1) was added and incubated at 37 ° C. After 4 hours, the number of CD34-positive bone marrow stem cells that had migrated to the lower plate was counted with a hemocytometer.
  • transgenic mouse (GFP mouse, distributed by Jackson Laboratories, USA) prepared using a recombinant gene obtained by placing the GFP protein gene under the control of the ⁇ -actin promoter, the same procedure as in Example 1 was performed. Bone marrow stem cells were isolated.
  • the chimeric mice were divided into 4 groups, and immediately after the creation of a skin defect wound with a diameter of 6 mm on the back of each chimeric mouse, 1 group was CTACK (R & D System, IngZ phosphate buffered saline 30 1) SDF—l (lngZ phosphate buffered saline 30 1) in group 2, secondary lymphoid tissue chemokine (IngZ phosphate buffered saline 30 / zl) in group 3, In group 4, only the same buffer was administered locally around the wound, and the animals were raised under standard conditions until the wound was completely healed (about 28 days).
  • CTACK R & D System, IngZ phosphate buffered saline 30 1
  • SDF—l lngZ phosphate buffered saline 30 1
  • secondary lymphoid tissue chemokine IngZ phosphate buffered saline 30 / zl
  • the wound is excised, embedded in OCTcompound, and a 5 ⁇ l thick tissue piece is prepared.
  • Antibodies and fluorescent dyes against keratin 14, CTACK, and other chemokines (FITC, RI TC) Each antibody reaction was diluted 100-fold with a secondary antibody bound to Fluorescent tissue staining was performed at room temperature for 1 hour.
  • the stained tissue pieces were observed using a confocal laser microscope (Laser Scanning Confocal Imaging System MRC 1024, manufactured by Bio-Rad), and GFP positive and keratin 14 positive cells were detected. The percentage of total epidermal cells was measured as the epidermal cells.
  • Example 1 Prior to CTACK administration, Example 1 except that 150 g / kg / day of G-CSF was administered for 3 consecutive days to increase the number of CD34-positive bone marrow stem cells in peripheral blood (approximately 100 times). In the same manner as above, the ratio of epidermal cells differentiated from bone marrow stem cells in the total epidermal cells was measured (Fig. 3).
  • CD34 positive cells were separated from bone marrow cells of GFP mice using MACS (magnetic activated cell sorting, Miltenyl Biotec), and these cells (5 x 10 5 cells) were separated from normal mice.
  • Tail force was also injected intravenously to increase the number of CD34-positive bone marrow stem cells in peripheral blood, increasing the number of epidermal cells differentiated from bone marrow stem cells in the total epidermal cells. Measured ( Figure 4).

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  • Health & Medical Sciences (AREA)
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  • Veterinary Medicine (AREA)
  • Immunology (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Cell Biology (AREA)
  • Developmental Biology & Embryology (AREA)
  • Zoology (AREA)
  • Dermatology (AREA)
  • Biotechnology (AREA)
  • Virology (AREA)
  • Hematology (AREA)
  • Biomedical Technology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne un agent pharmaceutique comprenant, comme ingrédient actif, une CTACK (chimiokine attirant les lymphocytes T) efficace dans la thérapie régénérative faisant appel aux cellules souches de moelle osseuse, et notamment dans la thérapie régénérative destinée aux maladies cutanées et faisant appel aux cellules souches de moelle osseuse. Plus particulièrement, cet agent pharmaceutique permet d'obtenir une nouvelle méthode thérapeutique destinée aux maladies cutanées congénitales dont le traitement de fond est considéré comme difficile, telles que, par exemple, l'épidermolyse bulleuse congénitale.
PCT/JP2005/020697 2004-12-21 2005-11-11 Agent pharmaceutique pour therapie faisant appel a une transplantation de cellules souches de moelle osseuse WO2006067920A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2006548722A JPWO2006067920A1 (ja) 2004-12-21 2005-11-11 骨髄幹細胞移植治療用医薬

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2004-369272 2004-12-21
JP2004369272 2004-12-21

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WO2006067920A1 true WO2006067920A1 (fr) 2006-06-29

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020160024A1 (en) * 1998-12-24 2002-10-31 Schering Corpration, A New Jersey Corporation Chemokine and receptor uses; compositions; methods
WO2003024404A2 (fr) * 2001-09-20 2003-03-27 Schering Corporation Chimiokines en tant qu'agents auxiliaires de reponse immunitaire

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020160024A1 (en) * 1998-12-24 2002-10-31 Schering Corpration, A New Jersey Corporation Chemokine and receptor uses; compositions; methods
WO2003024404A2 (fr) * 2001-09-20 2003-03-27 Schering Corporation Chimiokines en tant qu'agents auxiliaires de reponse immunitaire

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
HOMEY B ET AL: "CCL27-CCR10 interactions regulate T cell-mediated skin inflammation.", NATURE MEDICINE., vol. 8, no. 2, 2002, pages 157 - 165, XP001097778 *
JUN FENG JI ET AL: "Interactions of Chemokines and Chemokine Receptors Mediated the Migration of Mesenchymal Stem Cells to the Impaired Site in the Brain After Hypoglossal Nerve Injury.", STEM CELLS., vol. 22, May 2004 (2004-05-01), pages 415 - 427, XP009055260 *
MORALES J ET AL: "CTACK, a skin-associated chemokine that preferentially attracts skin-homing memory T cells.", PNAS., vol. 96, no. 25, 1999, pages 14470 - 14475, XP002137995 *
REISS Y ET AL: "CC Chemokine Receptor (CCR)4 and the CCR10 Ligand Cutaneous T Cell-attracting Chemokine (CTACK) in Lymphocyte Trafficking to Inflamed Skin.", J EXP MED., vol. 194, no. 10, 2001, pages 1541 - 1547, XP002995901 *
VON LUTTICHAU I ET AL: "Human Adult CD34() Progenitor Cells Functionally Express the Chemokine Receptors CCR1, CCR4, CCR7, CXCR5, and CCR10 but Not CXCR4.", STEM CELLS AND DEVELOPMENT., vol. 14, 2005, pages 329 - 336, XP002995300 *

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