EP1981967A1 - TRANSFECTION D'ARNm DE CELLULES PROGÉNITRICES ADULTES POUR UNE RÉGÉNÉRATION TISSULAIRE SPÉCIFIQUE - Google Patents

TRANSFECTION D'ARNm DE CELLULES PROGÉNITRICES ADULTES POUR UNE RÉGÉNÉRATION TISSULAIRE SPÉCIFIQUE

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Publication number
EP1981967A1
EP1981967A1 EP07703360A EP07703360A EP1981967A1 EP 1981967 A1 EP1981967 A1 EP 1981967A1 EP 07703360 A EP07703360 A EP 07703360A EP 07703360 A EP07703360 A EP 07703360A EP 1981967 A1 EP1981967 A1 EP 1981967A1
Authority
EP
European Patent Office
Prior art keywords
cells
progenitor cells
mrna
target tissue
progenitor
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP07703360A
Other languages
German (de)
English (en)
Inventor
Jan Torzewski
Vinzenz Hombach
Juliane Ingeborg Marie Wiehe
Jochen Greiner
Michael Schmitt
Markus Wiesneth
Oliver Zimmermann
Hubert Schrezenmeier
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Universitaet Ulm
Original Assignee
Universitaet Ulm
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Filing date
Publication date
Application filed by Universitaet Ulm filed Critical Universitaet Ulm
Publication of EP1981967A1 publication Critical patent/EP1981967A1/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0634—Cells from the blood or the immune system
    • C12N5/0647—Haematopoietic stem cells; Uncommitted or multipotent progenitors
    • 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
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • 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
    • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
    • A61K38/179—Receptors; Cell surface antigens; Cell surface determinants for growth factors; for growth regulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A61K48/005—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • 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
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • 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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0652—Cells of skeletal and connective tissues; Mesenchyme
    • C12N5/0662—Stem cells
    • C12N5/0663—Bone marrow mesenchymal stem cells (BM-MSC)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2510/00—Genetically modified cells

Definitions

  • the present invention relates to progenitor cells, drugs containing progenitor cells and their uses for specific tissue regeneration. Such methods are needed in all medical fields, especially in the treatment of cardiovascular, hematological, nephrological, neurological, dermatological, gastroenterological or orthopedic disorders.
  • the present invention is based on these known transfection methods and has as its object to provide methods and substances as well as medicaments and their production method, with which a tissue regeneration is possible.
  • the present invention makes use of the fact that in the prior art mRNA transfection methods are already known and successfully used for tumor therapy.
  • the invention is based on the fundamental idea and the recognition that progenitor cells can be transfected with mRNA which code for a protein, the settlement of the transfected progenitor cells in a specific target tissue and / or the differentiation of the transfected progenitor cells in Promotes cells of a particular type of target tissue. This makes it possible for the first time to introduce the progenitor cells into a specific target tissue in a targeted manner and to homing there or specifically to generate target cells which can then be used further elsewhere.
  • mRNA transfection is not subject to the strict legal regulations that apply to genetically modified cells. Because by an mRNA transfection, the transfected cell is not genetically engineered, but it produces only the coded by the mRNA protein. The mRNA is rapidly degraded within the transfected cell, so that after a short time the cell is back to its original state.
  • This mechanism is now utilized by the present invention by correspondingly transfecting the progenitor cells so that they receive an impulse during a short phase in order to differentiate into specific target cells or to settle in a specific target tissue. After degradation of the introduced mRNA and the protein encoded by this mRNA, there is an unchanged cell that is not different from the cells of the target tissue in autologous progenitor cells.
  • Progenitor cells are considered to be all cells which have not yet been terminally differentiated, in particular hematopoietic progenitor cells, neuronal progenitor cells, hepatic progenitor cells, skeletal muscle, skin and / or cord blood progenitor cells.
  • Stem cells in particular of non-embryonic origin, ie adult stem cells, tissue-specific adult stem cells and other not yet fully differentiated cells, are particularly advantageously used as progenitor cells.
  • the present invention is suitable for the treatment of cardiovascular, haematological, nephrological, neurological, skin, gastroenterological and / or orthopedic diseases in which tissue is to be regenerated, due to the possibility of tissue regeneration or to produce differentiated target cells of a particular target tissue.
  • Other clinical pictures can also be treated with the method according to the invention or the cells or medicaments according to the invention.
  • Fig. 1 + 2 e.g., transfection with adhesion molecules such as selectins or integrins or myocardial transcription factors such as GATA-4 or Nkx2.5
  • Fig. 1 + 2 e.g., transfection with adhesion molecules such as selectins or integrins or myocardial transcription factors such as GATA-4 or Nkx2.5
  • Fig. 1 + 2 e.g., transfection with adhesion molecules such as selectins or integrins or myocardial transcription factors such as GATA-4 or Nkx2.5
  • chronic degenerative myocardial diseases such as dilated cardiomyopathy or chronic ischemic cardiomyopathy: intravascular or intramyocardial application of mRNA-transfected progenitor cells such as CD34-positive progenitor cells or mesenchymal stem cells
  • Leukemias Improvement of bone marrow homing of hematopoietic progenitor cells by mRNA transfection of adhesion molecules after autologous or allogeneic stem cell transplantation
  • Leukemias induction of cell differentiation of the malignant cells by mRNA transfection
  • MDS myelodysplastic syndrome
  • kidney progenitor cells such as mesenchymal stem cells (for example, transfection with renal transcription factors) for the treatment of chronic degenerative kidney disease
  • degenerative diseases of the nervous system such as M. Parkinson or M. Alzheimer: intravascular or intracerebral application of mRNA-transfected neuronal progenitor cells (eg Transfection with neuronal transcription factors) for the treatment of chronic degenerative diseases of the brain
  • adhesion molecules ie molecules which make possible the settlement of the transfected progenitor cell in the target tissue, or cardiac, hematopoietic, neuronal, renal or dermal transfection factors, which are the differentiation of the transfected progenitor cells into target cells of a corresponding target tissue promote:
  • Adhesion molecules ie molecules which make possible the settlement of the transfected progenitor cell in the target tissue, or cardiac, hematopoietic, neuronal, renal or dermal transfection factors, which are the differentiation of the transfected progenitor cells into target cells of a corresponding target tissue promote:
  • rollering factors in particular L-selectin, PSGL-I, sialyl Lewis X on leucocytes, P- or E-selectin, glycam-1, CD34, MadCAM-1 on endothelial cells, and
  • Adhesion raolecules in particular integrins such as ⁇ L ⁇ 2 (LFA-I) and ⁇ M b 2 (MAC-I) ⁇ x ⁇ 2 (pI50.95), ⁇ 4 ⁇ i, (VLA-4), ⁇ 5 ß! (VLA-5) and "Cellular adhesi- ons molecules” (CAMs) such as ICAM-I, -2, VCAM-I,
  • Hematopoietic transcription factors in particular PU-I, CEBP ⁇ , GATA-I, CD44, CD168, pI6, pI5, p21, p27 • Neuronal transcription factors
  • Renal transcription factors especially Sal I-I, Wnt family
  • FIG. 1 shows FACS analyzes of mRNA versus plasmid nucleofection of hematopoietic CD34-positive human progenitor cells (HPC);
  • Figure 2 shows the results of mRNA nucleofection of CD34-positive HPC with the cardiac Transcription factor Nkx2.5;
  • FIG. 1 shows the results of an mRNA nucleofection or a plasmid nucleofection of hematopoietic CD34-positive human progenitor cells (HPC) with the surface markers EGFP (Enhanced Green Fluorescent Protein) and LNGFR (Low-Finite Nerve Growth Factor Receptor).
  • HPC human progenitor cells
  • EGFP Enhanced Green Fluorescent Protein
  • LNGFR Low-Finite Nerve Growth Factor Receptor
  • Human CD34-positive hematopoietic progenitor cells Human CD34-positive HPC were isolated after G-CSF stimulation by leukapheresis. Immunomagnetic selection of CD34-positive cells was carried out using the CliniMACS TM system (Miltenyi Biotech GmbH, Bergisch Gladbach, Germany). The cells were seeded in RPMI medium (Invitrogen, Düsseldorf, Germany) supplemented with 10% FCS and the growth factors IL-3 (10 ng / ml), IL-6 (20 ng / ml), and SCF (100 ng / ml ) at 37 0 C, 5% CO 2 cultured. Medium was changed every other day. The viability of the cells was determined by trypan blue staining resp. Flow cytometry (scatter exclusion) determined in the standard assay.
  • MSC Human mesenchymal stem cells
  • (a) Differentiation Assay For the differentiation assays, an initial cell number of 25,000 to 100,000 cells was seeded in cell culture bottles (NUNC), and differentiation was carried out with media from Cambrex (osteogenic and adipogenic differentiation) or Miltenyi, Bergisch Gladbach, Germany (FIG. chondrogenic and osteogenic differentiation). For detection of differentiated cells, the batches were fixed in 7% paraformaldehyde, (i) osteoblasts were switched to alkaline phosphatase activity, (ii) adipogenic differentiation was stained with saturated Oil RedO solution and (iii) chondrogenic differentiation "Alcian Blue Staining" tested.
  • NUNC cell culture bottles
  • the ⁇ LNGFR vector was generated by cloning the human truncated LNGFR gene into the eukaryotic pVAX1 expression vector (Invitrogen GmbH, Düsseldorf, Germany).
  • the ⁇ LNGFR 834 bp fragment was amplified by polymerase chain reaction.
  • the pGEM4Z / EGFP / A64 plasmid was linearized with Spe I, the pVAX / delta LNGFR plasmid (Greiner et al., 2004, Homother, Transf. Med.) With Xho I (New England Biolabs, Frankfurt, Germany).
  • the linearized plasmids were purified by nucleotide removal kit (Qiagen, Hilden, Germany) and used as DNA templates for the in vitro transcription reaction, which was transcribed in a final 20 ⁇ l reaction mix at 37 ° C by T7 Opti-mRNA transcription kit (Cure Vac GmbH, Tübingen, Germany) to generate "5'-capped" in vitro transcribed mRNA.
  • CD34-positive HPC and MSC were pelleted and resuspended in human CD34 Cell Nucleofector TM Solutions (Amaxa GmbH, Cologne, Germany) at a cell density of 2-3x10 6 or 5x10 5 cells per 100 ⁇ l.
  • the cells were nucleotide-labeled with 5 ⁇ g mRNA or 2 ⁇ g plasmid DNA, the programs U-08 (for HPC) or C-17 (for MSC) of the nucleofector were used. After nucleofection, the cells were immediately mixed with 500 ⁇ l prewarmed culture medium and transferred to well plates with prewarmed medium. The cells were cultured at 37 0 C for 10 days.
  • the deltaLNGFR and EGFP expression of nucleofected and untransfected CD34-positive HPC and MSC was determined by flow cytometry 1, 3, 6, 8 and 10 days after transfection.
  • To detect deltaLNGFR the cells were incubated with "non-conjugated purified mouse monoclonal anti-human NGF antibody (Santa Cruz)" and a PE-labeled "anti mouse IgGi secondary antibody (Becton Dickinson)". Data were analyzed using Cellquest Version 3.1 software (Becton Dickinson).
  • FIG. 1A shows in the left column the nucleofection with mRNA of EGFP (upper image) or LNGFR (lower image). It can be seen that the detection of EGFP and LNGFR in the respective mRNA-transfected cells decays within a few days. Initially, however, mRNA transfection shows a very high efficiency of over 90% (EGFP / LNGFR positive cells / total number of cells). In plasmid nucleofection, only one nucleofection achieved efficiency of 60 to 70% ( Figure IA, right column), but the detection of proteins decays more slowly than in mRNA nucleofection.
  • Figure IB shows the viability of nucleated cells again for mRNA nucleofection in the left column and for plasmid nucleofection in the right column. It can be seen that mRNA transfection leads to very high viability with at least 50% viable cells (for both EGFP and LNGFR), while the viability of the transfected cells in plasmid nucleofection in particular is initially very low.
  • FIG. 2 shows the results of an mRNA nucleofection of CD34-positive HPC with the cardiac transcription factor Nkx 2.5.
  • Nkx2.5 the following protocol for mRNA transfection of Nkx2.5 was additionally used by means of nucleofection:
  • CD34-positive hematopoietic progenitor cells were pelleted, resuspended in 100 ⁇ l of "human CD34 Cell Nucleus TM Solution” (Amaxa GmbH, Cologne, Germany) and transcribed with 5 ⁇ g in vitro (CureVac, Tübingen, Germany) mRNA coding for the Nkx-2.5 protein mixed.
  • the cell suspension was nucleofixed with program U-08, then admixed with 500 ⁇ l preheated culture medium and transferred into 6-well plates with preheated culture medium. The cells were incubated for four hours at 37 0 C, 5% CO 2 before protein whole lysates were extracted.
  • FIG. 3 shows a FACS analysis of the mRNA nucleofection with EGFP mRNA or LNGFR mRNA of mesenchymal HPC. It can be seen that the efficiency of mRNA nucleofection is between 95.8% (for LNGFR) and 98.8% (for EGFP).

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Abstract

La présente invention concerne des cellules progénitrices, des médicaments contenant des cellules progénitrices, ainsi que leur utilisation pour une régénération tissulaire spécifique. Des procédés de ce genre sont nécessaires dans tous les domaines de la médecine, en particulier dans le traitement des pathologies cardiovasculaires, hématologiques, néphrologiques, neurologiques, dermatologiques, gastro-entérologiques ou orthopédiques. Les cellules progénitrices se caractérisent par le fait qu'elles sont transfectées avec de l'ARNm codant pour une protéine qui favorise l'implantation des cellules progénitrices dans un tissu cible et/ou la différenciation des cellules progénitrices en cellules cibles ou en cellules de tissus cibles.
EP07703360A 2006-02-08 2007-02-08 TRANSFECTION D'ARNm DE CELLULES PROGÉNITRICES ADULTES POUR UNE RÉGÉNÉRATION TISSULAIRE SPÉCIFIQUE Withdrawn EP1981967A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102006005827A DE102006005827B3 (de) 2006-02-08 2006-02-08 mRNA-Transfektion von adulten Progenitorzellen zur spezifischen Gewebsregeneration
PCT/EP2007/001085 WO2007090647A1 (fr) 2006-02-08 2007-02-08 TRANSFECTION D'ARNm DE CELLULES PROGÉNITRICES ADULTES POUR UNE RÉGÉNÉRATION TISSULAIRE SPÉCIFIQUE

Publications (1)

Publication Number Publication Date
EP1981967A1 true EP1981967A1 (fr) 2008-10-22

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EP07703360A Withdrawn EP1981967A1 (fr) 2006-02-08 2007-02-08 TRANSFECTION D'ARNm DE CELLULES PROGÉNITRICES ADULTES POUR UNE RÉGÉNÉRATION TISSULAIRE SPÉCIFIQUE

Country Status (4)

Country Link
US (1) US20110104127A1 (fr)
EP (1) EP1981967A1 (fr)
DE (1) DE102006005827B3 (fr)
WO (1) WO2007090647A1 (fr)

Families Citing this family (3)

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Publication number Priority date Publication date Assignee Title
EP2452688A1 (fr) 2010-11-12 2012-05-16 Ruprecht-Karls-Universität Heidelberg Utilisation de macrophages transfectés par l'ARN 10 interleukine dans des thérapies anti-inflammatoires
WO2014186334A1 (fr) 2013-05-15 2014-11-20 Robert Kruse Traduction intracellulaire d'arn circulaire
CA3024869A1 (fr) * 2016-05-20 2017-11-23 Robert Sackstein Glycoingenierie de ligands de selectine e

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Publication number Priority date Publication date Assignee Title
US6258354B1 (en) * 1989-09-29 2001-07-10 Joel S. Greenberger Method for homing hematopoietic stem cells to bone marrow stromal cells
EP1270732A1 (fr) * 2001-06-21 2003-01-02 Schuler, Gerold Transfection de cellules eucaryotes avec des polynucléotides linéaires par électroporation
US20040258669A1 (en) * 2002-11-05 2004-12-23 Dzau Victor J. Mesenchymal stem cells and methods of use thereof
WO2006116678A2 (fr) * 2005-04-28 2006-11-02 University Of Florida Research Foundation, Inc. Ciblage tissulaire de cellules souches

Non-Patent Citations (1)

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Title
A VAN DRIESSCHE ET AL: "Messenger RNA electroporation: an efficient tool in immunotherapy and stem cell research", FOLIA HISTOCHEMICA ET CYTOBIOLOGICA / POLISH ACADEMY OF SCIENCES, POLISH HISTOCHEMICAL AND CYTOCHEMICAL SOCIETY, 1 January 2005 (2005-01-01), POLAND, pages 213 - 216, XP055339194, Retrieved from the Internet <URL:https://journals.viamedica.pl/folia_histochemica_cytobiologica/article/download/4599/3854> DOI: 10.5603/4599 *

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US20110104127A1 (en) 2011-05-05
WO2007090647A1 (fr) 2007-08-16
DE102006005827B3 (de) 2007-07-26

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