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WO2025141211A1 - Cellules pour programmation cellulaire - Google Patents

Cellules pour programmation cellulaire Download PDF

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Publication number
WO2025141211A1
WO2025141211A1 PCT/EP2024/088672 EP2024088672W WO2025141211A1 WO 2025141211 A1 WO2025141211 A1 WO 2025141211A1 EP 2024088672 W EP2024088672 W EP 2024088672W WO 2025141211 A1 WO2025141211 A1 WO 2025141211A1
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Prior art keywords
protein
pluripotent stem
cells
stem cell
cell according
Prior art date
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PCT/EP2024/088672
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English (en)
Inventor
Angelica AGUILERA GOMEZ
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Meatable BV
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Meatable BV
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Classifications

    • 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
    • C12N5/0658—Skeletal muscle cells, e.g. myocytes, myotubes, myoblasts
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L13/00—Meat products; Meat meal; Preparation or treatment thereof
    • A23L13/40—Meat products; Meat meal; Preparation or treatment thereof containing additives
    • A23L13/42—Additives other than enzymes or microorganisms in meat products or meat meals
    • A23L13/424—Addition of non-meat animal protein material, e.g. blood, egg, dairy products, fish; Proteins from microorganisms, yeasts or fungi
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/37—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from fungi
    • C07K14/39—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from fungi from yeasts
    • 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
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/80—Fusion polypeptide containing a DNA binding domain, e.g. Lacl or Tet-repressor
    • 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
    • C12N2506/00—Differentiation of animal cells from one lineage to another; Differentiation of pluripotent cells
    • C12N2506/02—Differentiation of animal cells from one lineage to another; Differentiation of pluripotent cells from embryonic cells
    • 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
    • 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
    • C12N2830/00—Vector systems having a special element relevant for transcription
    • C12N2830/001—Vector systems having a special element relevant for transcription controllable enhancer/promoter combination
    • C12N2830/002—Vector systems having a special element relevant for transcription controllable enhancer/promoter combination inducible enhancer/promoter combination, e.g. hypoxia, iron, transcription factor
    • 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
    • C12N2830/00—Vector systems having a special element relevant for transcription
    • C12N2830/20—Vector systems having a special element relevant for transcription transcription of more than one cistron

Definitions

  • the present invention relates to a modified pluripotent cell and to a method for forward programming said cell.
  • the invention further relates to use of said modified pluripotent stem cell for tissue engineering and to a food product comprising said modified pluripotent stem cell
  • stem cell-derived cells enable studying physiological and pathological responses of human and non-human animal cell populations that are not easily accessible. This often entails the study of genes (and other forms of regulatory mechanisms encoded in non-protein-coding RNAs - ncRNAs). Unfortunately, controllable transcription or expression of genetic information in human and non-human animal cells has been proven to be particularly difficult.
  • Controlling expression of transgenes in cells is the basis of biological research. However, this has proven to be difficult in human cells and even more so in non-human animal cells, for example livestock, which are relatively less well studied and understood.
  • Cultivated meat has arisen as another alternative to traditional animal agriculture that aims to produce the muscle and adipose tissues that normally comprise animal meats, except using in vitro tissue and biological engineering techniques.
  • in vitro tissue and biological engineering techniques Despite efforts to develop robust protocols for scalable generation of animal cell types from easily accessible and renewable sources, the differentiation of animal (pluripotent) stem cells into specific cell types often remains cumbersome, lengthy, and difficult to reproduce and/or has not been established yet.
  • a first fusion protein a comprises a VP16 protein and one of a PYL1 protein; and a PP2C protein;
  • a transcriptional regulator protein may comprise a DNA binding domain, such as that from the yeast GAL4 protein.
  • a DNA binding domain such as that from the yeast GAL4 protein.
  • binding domains are well known to those skilled in the art.
  • a coding sequence for a suitable DNA binding domain comprises the sequence set out in SEQ ID NO: 3. Variants of this sequence may also be suitable for use in the invention.
  • a first fusion protein may comprise an activation domain, such as a VP16 protein, and one of a PYL1 protein; and a PP2C protein; and
  • a second fusion protein which may comprise a DNA binding domain, such as a DNA binding domain from the yeast GAL4 protein, and one of a PYL1 protein and a PP2C protein; or
  • a second fusion protein which may comprise a DNA binding domain, such as a DNA binding domain from the yeast GAL4 protein, and a PYL1 protein; or
  • the PYL1 protein and PP2C protein are brought into proximity with each other which then brings the activation domain, such as a VP16 protein, and the DNA binding domain, such as a DNA binding domain from the yeast GAL4 protein, into proximity with each other thus constituting a functional transcriptional regulator protein.
  • the activation domain such as a VP16 protein
  • the DNA binding domain such as a DNA binding domain from the yeast GAL4 protein
  • a coding sequence for a suitable ABIcs domain comprises the sequence set out in SEQ ID NO: 4. Variants of this sequence may also be suitable for use in the invention.
  • the fusion proteins described above are examples of how an abscisic acid inducible system for forward programming may be implemented.
  • the PYL and PP2C proteins may be fused to alternative proteins (i.e. other than the VP16 transactivation domain and the GAL4 DNA binding domain) which, when the PYL and PP2C proteins are in close proximity (i.e. in the presence of abscisic acid) allow a functional transcriptional regulator to be activated other than that based on GAL4 DNA binding domain and VP16 proteins. That is to say other combinations of a DNA binding domain and a transcriptional activation domain may be used.
  • a variant may have at least about 99%, at least about 98%, at least about 95%, at least about 90%, at least about 85%, at least about 80%, at least about 75% or at least about 70% sequence identity to the protein in question.
  • the activity of the transcriptional regulator protein is controlled by exogenously supplied abscisic acid or an analogue thereof. That is to say, the pluripotent stem cell is not typically one which is capable of producing endogenous abscisic acid.
  • an analogue is a compound in which one or more individual atoms have been replaced, either with a different atom, or with a different functional group.
  • Another use of the term in chemistry refers to a substance which is similar in structure to another substance.
  • Analogues to abscisic acid suitable for use in the invention will thus differ from abscisic acid chemically or structurally, but critically in the context of the invention will retain ability to control activity of the transcriptional regulator protein. Any such substance is suitable for use in in the invention as an analog of abscisic acid.
  • the nucleic acid molecules encoding the proteins according to the invention are codon-optimized for expression in mammalian cells. Methods of codon-optimization are known and have been described previously (e.g. WO 96/09378 for mammalian cells). A sequence is considered codon-optimized if at least one non-preferred codon as compared to a wildtype sequence is replaced by a codon that is more preferred.
  • a non-preferred codon is a codon that is used less frequently in an organism than another codon coding for the same amino acid, and a codon that is more preferred is a codon that is used more frequently in an organism than a non-preferred codon.
  • a transcriptional regulator protein is a protein that bind to DNA, preferably sequence- specifically to a DNA site located in or near a promoter, and either facilitating the binding of the transcription machinery to the promoter, and thus transcription of the DNA sequence (a transcriptional activator) or blocks this process (a transcriptional repressor). Such entities are also known as transcription factors.
  • the method of the invention envisages a split transcriptional regulator protein which is only active in the presence of abscisic acid (when the PYL and PP2C proteins are brought into close proximity).
  • a genetic safe harbour (GSH) site is a locus within the genome wherein a gene or other genetic material may be inserted without any deleterious effects on the cell or on the inserted genetic material. Most beneficial is a GSH site in which expression of the inserted gene sequence is not perturbed by any read-through expression from neighboring genes and expression of the inducible cassette minimizes interference with the endogenous transcription program. More formal criteria have been proposed that assist in the determination of whether a particular locus is a GSH site in future (Papapetrou et al, 201 1 , Nature Biotechnology, 29(1), 73-8. doi: 1 0. 1 038/nbt.
  • These criteria include a site that is (i) 50 kb or more from the 5’ end of any gene, (ii) 300 kb or more from any gene related to cancer, (iii) 300 kb or more from any microRNA(miRNA), (iv) located outside a transcription unit and (v) located outside ultra-conserved regions (UCR). It may not be necessary to satisfy all of these proposed criteria, since GSH already identified do not fulfil all of the criteria. It is thought that a suitable GSH will satisfy at least 2, 3, 4 or all of these criteria.
  • the first and further genomic safe harbour sites are selected from any two of the hROSA26 locus, the AAVS1 locus, the CLYBL gene or the CCR5 gene.
  • the first and further genomic safe harbour sites are located on chr1 : 152,360,840-152,360,859, chr1 : 175,942,362 -175,942,381 , chr1 :231 ,999,396-231 ,999,415, chr2: 45,708,354 - 45, 708, 373; chr8: 68,720,172 - 68,720,191 of the human genome.
  • the first and further genomic safe harbour sites are selected from any two of the safe harbour sites ROSA26, AAVS1 , the CLYBL gene and the CCR5 gene.
  • the genetic safe harbour sites are ROSA26 locus and the AAVS1 locus.
  • pluripotent stem cells includes embryonic stem cells, embryo- derived stem cells, epliblast-derived stem cells (EpiSCs), induced pluripotent stem cells and somatic cells, regardless of the method by which the pluripotent stem cells are derived. Accordingly, in certain embodiments the pluripotent stem cell is selected from the group consisting of embryonic stem cells, induced pluripotent stem cells, embryonic cell lines, and somatic cell lines. In certain embodiments, the pluripotent stem cells are epiblast-derived stem cells (EpiSCs).
  • pluripotent stem cells express one or more markers selected from the group consisting of: OCT-4, Sox2, Klf4, c-MYC, Nanog, Lin28, alkaline phosphatase, SSEA-3, SSEA-4, TRA-1-60, and TRA-1-81 .
  • Exemplary pluripotent stem cells can be generated using, methods known in the art.
  • “Induced pluripotent stem cells” iPS cells or iPSC) can be produced by protein transduction of reprogramming factors in a somatic cell.
  • the pluripotent stem cell according to the invention can be from any species. Embryonic stem cells have been successfully derived in, for example, mice, multiple species of non-human primates, and humans, and embryonic stem-like cells have been generated from numerous additional species. Thus, one of skill in the art can generate embryonic stem cells and embryo- derived stem cells from any species, including but not limited to, human, non-human primates, rodents (mice, rats), ungulates (cows, sheep, etc.), dogs (domestic and wild dogs), cats (domestic and wild cats such as lions, tigers, cheetahs), rabbits, hamsters, gerbils, squirrel, guinea pig, goats, elephants, panda (including giant panda), pigs, raccoon, horse, zebra, marine mammals (dolphin, whales, etc.) and the like.
  • iPS cells can be from any species. These iPS cells have been successfully generated using mouse and human cells. Furthermore, iPS cells have been successfully generated using embryonic, fetal, newborn, and adult tissue. Accordingly, one can readily generate iPS cells using a donor cell from any species.
  • the pluripotent stem cell according to the invention, or for use in the invention is a human or animal cell. In certain embodiments the pluripotent stem cell according to the invention, or for use in the invention if from an edible animal species.
  • the pluripotent stem cell according to the invention is from a livestock or poultry animal.
  • Livestock species include but are not limited to domestic cattle, pigs, sheep, goats, lamb, camels, water buffalo and rabbits.
  • the adipocytes that are produced according to the method as disclosed herein are for human and non-human dietary consumption.
  • the produced adipocytes can be used in the production of cultured meat for human consumption.
  • the invention provides for a use of a pluripotent stem cell as described herein or the cells obtained by the method as described herein for forward programming of cells, for example in tissue engineering.
  • the cells obtained may be suitable for use in a method of treatment and in research.
  • the use is for the production of cultured meat. That is to say, the invention provides for a use of a pluripotent stem cell as described herein or the cells obtained by the method as described herein for the production of cultured meat.
  • EplSCs Epiblast-derived Stem Cells differentiation to skeletal muscle cells.
  • Undifferentiated bEplSCs (capable of expressing MyoD1 and MYOG) may be grown as set out in International patent publication nos. WO2024/170696 and WO2024/170702.
  • RNA from undifferentiated and differentiated cells is extracted using Reliaprep Cell Miniprep System (Z6012, Promega) according to the manufacturer's instructions. RNA concentration and quality is determined with a Microvolume Spectrophotometer DS-11 (DeNovix). Five hundred nanograms of purified total RNA from every sample are first treated with DNase I to remove possible genomic DNA contamination and are subsequently reverse transcribed into cDNA using iScript gDNA Clear cDNA Synthesis Kit (1725035BUN, BioRad). Specific primers for bovine pluripotency and mature adipocyte markers are designed to perform real-time quantitative PCR analysis (table I).
  • shakers and/or bioreactors are often used to scale up to large volumes and generate the amounts of cell mass needed for a cultivated meat product at a cost competitive price.
  • primary cells are used derived from muscle biopsies.
  • primary cultures have limited self-renewal, lose their capacity to differentiate during expansion and are variable in quality between biopsies.
  • 0.5 million cells/mL are inoculated in a 150 mL shaker flask containing 12,5 mL of media and bEpiSCs-MYOD-MYOG are differentiated using a differentiation protocol. Media is changed every second day. After a set number of days of differentiation of EpiSCs-MYOD-MYOG, the extent of multinucleated skeletal muscle cells formed with elongated morphology is determined and the amount of titin protein determined.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Organic Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
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  • Rheumatology (AREA)
  • Biophysics (AREA)
  • Physics & Mathematics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Food Science & Technology (AREA)
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  • Nutrition Science (AREA)
  • Medicinal Chemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Polymers & Plastics (AREA)
  • Cell Biology (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)

Abstract

La présente invention concerne une cellule pluripotente modifiée et un procédé de programmation cellulaire de ladite cellule. L'invention concerne en outre l'utilisation de ladite cellule souche pluripotente modifiée pour l'ingénierie tissulaire et un produit alimentaire comprenant ladite cellule souche pluripotente modifiée.
PCT/EP2024/088672 2023-12-29 2024-12-30 Cellules pour programmation cellulaire Pending WO2025141211A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP23220837.1 2023-12-29
EP23220837 2023-12-29

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WO2025141211A1 true WO2025141211A1 (fr) 2025-07-03

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996009378A1 (fr) 1994-09-19 1996-03-28 The General Hospital Corporation Surexpression de proteines mammaliennes et virales
WO2015066377A1 (fr) * 2013-10-30 2015-05-07 The Curators Of The University Of Missouri Procédé destiné à spécifier et cultiver une lignée de muscle squelettique évolutive
WO2018096343A1 (fr) * 2016-11-24 2018-05-31 Cambridge Enterprise Limited Transcription contrôlable
WO2023069882A1 (fr) * 2021-10-20 2023-04-27 University Of Rochester Méthode de rajeunissement des cellules progénitrices gliales et cellules progénitrices gliales rajeunies en tant que telles
WO2024084082A1 (fr) 2022-10-21 2024-04-25 Meatable B.V. Maturation d'adipocytes
WO2024170696A1 (fr) 2023-02-15 2024-08-22 Meatable B.V. Maturation de cellules musculaires squelettiques
WO2024170702A1 (fr) 2023-02-15 2024-08-22 Meatable B.V. Maturation de cellules musculaires squelettiques

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996009378A1 (fr) 1994-09-19 1996-03-28 The General Hospital Corporation Surexpression de proteines mammaliennes et virales
WO2015066377A1 (fr) * 2013-10-30 2015-05-07 The Curators Of The University Of Missouri Procédé destiné à spécifier et cultiver une lignée de muscle squelettique évolutive
WO2018096343A1 (fr) * 2016-11-24 2018-05-31 Cambridge Enterprise Limited Transcription contrôlable
WO2023069882A1 (fr) * 2021-10-20 2023-04-27 University Of Rochester Méthode de rajeunissement des cellules progénitrices gliales et cellules progénitrices gliales rajeunies en tant que telles
WO2024084082A1 (fr) 2022-10-21 2024-04-25 Meatable B.V. Maturation d'adipocytes
WO2024170696A1 (fr) 2023-02-15 2024-08-22 Meatable B.V. Maturation de cellules musculaires squelettiques
WO2024170702A1 (fr) 2023-02-15 2024-08-22 Meatable B.V. Maturation de cellules musculaires squelettiques

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
KALLUNKI TUULA ET AL: "How to Choose the Right Inducible Gene Expression System for Mammalian Studies?", vol. 8, no. 8, 30 July 2019 (2019-07-30), XP055870170, Retrieved from the Internet <URL:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721553/pdf/cells-08-00796.pdf> DOI: 10.3390/cells8080796 *
KIM SEO WOO ET AL: "Engineering a highly sensitive biosensor for abscisic acid in mammalian cells", vol. 596, no. 19, 30 June 2022 (2022-06-30), NL, pages 2576 - 2590, XP093177305, ISSN: 0014-5793, Retrieved from the Internet <URL:https://onlinelibrary.wiley.com/doi/full-xml/10.1002/1873-3468.14431> DOI: 10.1002/1873-3468.14431 *
LIANG FSHO WQCRABTREE GR: "Engineering the ABA plant stress pathway for regulation of induced proximity", SCI SIGNAL., vol. 4, no. 164, 15 March 2011 (2011-03-15), pages rs2, XP009535150, DOI: 10.1126/scisignal.2001449
LIANG FU-SEN ET AL: "Engineering the ABA Plant Stress Pathway for Regulation of Induced Proximity", SCIENCE SIGNALING, AMERICAN ASSOCIATION FOR THE ADVANCEMENT OF SCIENCE, US, vol. 4, no. 164, 15 March 2011 (2011-03-15), pages rs2, 1 - 9, XP009535150, ISSN: 1945-0877, DOI: 10.1126/SCISIGNAL.2001449 *
MAGNONE, M.STURLA, L.GUIDA, LSPINELLI, S.BEGANI, G.BRUZZONE, S.FRESIA, C.ZOCCHI, E.: "Abscisic Acid: A Conserved Hormone in Plants and Humans and a Promising Aid to Combat Prediabetes and the Metabolic Syndrome", NUTRIENTS, vol. 12, 2020, pages 1724
PAPAPETROU ET AL., NATURE BIOTECHNOLOGY, vol. 29, no. 1, 2011, pages 73 - 8
SINGH ANSHUMAN ET AL: "Stem cells-derived in vitro meat: from petri dish to dinner plate", 20 May 2020 (2020-05-20), USA, pages 1 - 14, XP055843520, ISSN: 1040-8398, Retrieved from the Internet <URL:https://www.tandfonline.com/doi/pdf/10.1080/10408398.2020.1856036?needAccess=true> DOI: 10.1080/10408398.2020.1856036 *
STURLA, L.MANNINO, E. ET AL.: "Abscisic acid enhances glucose disposal and induces brown fat activity in adipocytes in vitro and in vivo", BIOCHIMICA ET BIOPHYSICA ACTA (BBA) - MOLECULAR AND CELL BIOLOGY OF LIPIDS, vol. 1862, no. 2, 2017, pages 131 - 144

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