WO2019183508A1 - Endothelial cell factors and methods thereof - Google Patents

Endothelial cell factors and methods thereof Download PDF

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Publication number
WO2019183508A1
WO2019183508A1 PCT/US2019/023637 US2019023637W WO2019183508A1 WO 2019183508 A1 WO2019183508 A1 WO 2019183508A1 US 2019023637 W US2019023637 W US 2019023637W WO 2019183508 A1 WO2019183508 A1 WO 2019183508A1
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Prior art keywords
cells
niche
endothelial
hspcs
family
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English (en)
French (fr)
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Leonard I. Zon
Elliott J. HAGEDORN
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Boston Childrens Hospital
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Boston Childrens Hospital
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Priority to CA3094837A priority Critical patent/CA3094837A1/en
Priority to CN201980020598.1A priority patent/CN112105721A/zh
Priority to US17/040,421 priority patent/US12146165B2/en
Priority to JP2020550792A priority patent/JP7455067B2/ja
Priority to EP19772190.5A priority patent/EP3768282A4/en
Publication of WO2019183508A1 publication Critical patent/WO2019183508A1/en
Anticipated expiration legal-status Critical
Priority to JP2024037742A priority patent/JP7683068B2/ja
Priority to US18/824,457 priority patent/US20240417695A1/en
Ceased 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
    • 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
    • A61K35/44—Vessels; Vascular smooth muscle cells; Endothelial cells; Endothelial progenitor cells
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • 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
    • C12N15/87—Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation
    • C12N15/90—Stable introduction of foreign DNA into chromosome
    • C12N15/902—Stable introduction of foreign DNA into chromosome using homologous recombination
    • C12N15/907—Stable introduction of foreign DNA into chromosome using homologous recombination in mammalian cells
    • C—CHEMISTRY; METALLURGY
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    • 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
    • C12N5/069—Vascular Endothelial cells
    • C—CHEMISTRY; METALLURGY
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    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/10—Cells modified by introduction of foreign genetic material
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • C12N2501/00—Active agents used in cell culture processes, e.g. differentation
    • C12N2501/30—Hormones
    • C12N2501/38—Hormones with nuclear receptors
    • C—CHEMISTRY; METALLURGY
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    • C12N2501/00—Active agents used in cell culture processes, e.g. differentation
    • C12N2501/60—Transcription factors
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    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • C12N2501/00—Active agents used in cell culture processes, e.g. differentation
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    • C12N2501/602—Sox-2
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    • C12N2502/00—Coculture with; Conditioned medium produced by
    • C12N2502/11—Coculture with; Conditioned medium produced by blood or immune system cells
    • C12N2502/1171—Haematopoietic stem cells
    • C—CHEMISTRY; METALLURGY
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    • C12N2502/28—Vascular endothelial cells
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    • C12N2510/00—Genetically modified cells

Definitions

  • these transcription factors include sox!8 and sox7 ; where the corresponding human factors are SOX7 and SOX18.
  • these transcription factors include rxraa and nr2f2 ; where the corresponding human factors are RXRA and NR2R2.
  • Fig. 25 is a series of images showing the reprogramming of niche endothelial cells.
  • the HSPCs cultured in the presence of the engineered endothelial niche cells can be cultured for at least 3 days longer than HSPCs that are cultured in the absence of such engineered endothelial niche cells.
  • mitobronitol mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C”); cyclophosphamide; thiotepa; taxoids, e.g. , TAXOL® paclitaxel (Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE® Cremophor-free, albumin-engineered nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.), and TAXOTERE® doxetaxel (Rhone- Poulenc Rorer, Antony, France); chloranbucil; GEMZAR® gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin, oxaliplatin and carboplatin; vinblastine; platinum; etoposide (VP- 16); ifosfamide; mitoxantrone
  • subjects can be administered a therapeutic amount of a composition comprising HSPCs, engineered endothelial niche cells, and/or transcription factors (e.g., ETV2, FLI1, ETS1, SOX18, SOX7, RXRA, or NR2F2), such as, e.g. 0.1 mg/kg, 0.5 mg/kg, 1.0 mg/kg, 2.0 mg/kg, 2.5 mg/kg, 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 40 mg/kg, 50 mg/kg, or more.
  • transcription factors e.g., ETV2, FLI1, ETS1, SOX18, SOX7, RXRA, or NR2F2
  • a subject can be one who has been previously diagnosed with or identified as suffering from or having a condition in need of treatment (e.g. myelofibrosis or a
  • myeloproliferative disorder or one or more complications related to such a condition, and optionally, have already undergone treatment for myelofibrosis or a myeloproliferative disorder or the one or more complications related to myelofibrosis or a myeloproliferative disorder.
  • polypeptides whereas the term “peptide” is often used in reference to small polypeptides, but usage of these terms in the art overlaps.
  • protein and “polypeptide” are used interchangeably herein when referring to a gene product and fragments thereof.
  • exemplary polypeptides or proteins include gene products, naturally occurring proteins, homologs, orthologs, paralogs, fragments and other equivalents, variants, fragments, and analogs of the foregoing.
  • the polypeptide described herein can be a variant of a sequence described herein.
  • the variant is a conservatively modified variant.
  • Conservative substitution variants can be obtained by mutations of native nucleotide sequences, for example.
  • A“variant,” as referred to herein, is a polypeptide substantially homologous to a native or reference polypeptide, but which has an amino acid sequence different from that of the native or reference polypeptide because of one or a plurality of deletions, insertions or substitutions.
  • a method for extra medullary hematopoiesis comprising transplanting
  • the haematopoietic niche is a supportive in vivo microenvironment comprised of distinct cell types, including specialized vascular endothelial cells that directly interact with haematopoietic stem and progenitor cells (HSPCs) to facilitate stem cell function.
  • HSPCs haematopoietic stem and progenitor cells
  • the molecular factors that specify niche endothelial cells and their pro-haematopoietic activity remain largely unknown.
  • Using multi-dimensional gene expression analyses and a chromatin accessibility assay, defined herein is a conserved gene expression signature and cis-regulatory landscape unique to sinusoidal endothelial cells in the HSPC niche.
  • In situ hybridization was performed using a standard protocol. Embryos were subsequently transferred to glycerol for scoring and imaging. In situ probes were generated by PCR amplification using a cDNA or plasmid (for transcription factors from other species) template followed by reverse transcription with digoxigenin-linked nucleotides. Primer sequences for all WISH probes used herein are provided in Table 7. WISH images for the 35 CHT-enriched genes identified by tomo-seq can be found on the world wide web at zfm.org.
  • Kidney marrow was harvested from adult zebrafish by manual dissection and then fixed in 4% PFA (for histology) or dissociated by gentle pipetting (for live cell imaging). For histology the kidney marrow was embedded in paraffin prior to sectioning; alternating sections were stained with H&E or with an antibody to GFP. Mouse EC populations were sorted as Cd45 Pdpn Cd3 l + cells.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Biomedical Technology (AREA)
  • Chemical & Material Sciences (AREA)
  • Zoology (AREA)
  • Biotechnology (AREA)
  • Wood Science & Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
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  • Microbiology (AREA)
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  • Molecular Biology (AREA)
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  • Developmental Biology & Embryology (AREA)
  • Vascular Medicine (AREA)
  • Hematology (AREA)
  • Biophysics (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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  • Apparatus Associated With Microorganisms And Enzymes (AREA)
PCT/US2019/023637 2018-03-23 2019-03-22 Endothelial cell factors and methods thereof Ceased WO2019183508A1 (en)

Priority Applications (7)

Application Number Priority Date Filing Date Title
CA3094837A CA3094837A1 (en) 2018-03-23 2019-03-22 Endothelial cell factors and methods thereof
CN201980020598.1A CN112105721A (zh) 2018-03-23 2019-03-22 内皮细胞因子及其方法
US17/040,421 US12146165B2 (en) 2018-03-23 2019-03-22 Endothelial cell factors and methods thereof
JP2020550792A JP7455067B2 (ja) 2018-03-23 2019-03-22 内皮細胞因子およびその方法
EP19772190.5A EP3768282A4 (en) 2018-03-23 2019-03-22 ENDOTHELIAL CELL FACTORS AND RELATED PROCESSES
JP2024037742A JP7683068B2 (ja) 2018-03-23 2024-03-12 内皮細胞因子およびその方法
US18/824,457 US20240417695A1 (en) 2018-03-23 2024-09-04 Endothelial cell factors and methods thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201862647433P 2018-03-23 2018-03-23
US62/647,433 2018-03-23

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US17/040,421 A-371-Of-International US12146165B2 (en) 2018-03-23 2019-03-22 Endothelial cell factors and methods thereof
US18/824,457 Division US20240417695A1 (en) 2018-03-23 2024-09-04 Endothelial cell factors and methods thereof

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CA (1) CA3094837A1 (https=)
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WO2025096798A2 (en) * 2023-10-31 2025-05-08 The Children's Medical Center Corporation Endothelial cell factors and methods thereof
CN118834915A (zh) * 2024-08-15 2024-10-25 扬州大学 一种在羊毛乳头细胞中稳定过表达的sox18慢病毒重组标签载体的构建及应用

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WO2009042910A2 (en) * 2007-09-26 2009-04-02 University Of South Florida Ship inhibition to direct hematopoietic stem cells and induce extramedullary hematopoiesis
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JP2024075624A (ja) 2024-06-04
JP7683068B2 (ja) 2025-05-26
US20240417695A1 (en) 2024-12-19
JP2021518143A (ja) 2021-08-02
JP7455067B2 (ja) 2024-03-25
EP3768282A1 (en) 2021-01-27
CA3094837A1 (en) 2019-09-26
US12146165B2 (en) 2024-11-19
US20210079343A1 (en) 2021-03-18
CN112105721A (zh) 2020-12-18
EP3768282A4 (en) 2021-12-08

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