WO2020112195A1 - Compositions, technologies et procédés d'utilisation de plérixafor pour améliorer l'édition de gènes - Google Patents

Compositions, technologies et procédés d'utilisation de plérixafor pour améliorer l'édition de gènes Download PDF

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Publication number
WO2020112195A1
WO2020112195A1 PCT/US2019/049018 US2019049018W WO2020112195A1 WO 2020112195 A1 WO2020112195 A1 WO 2020112195A1 US 2019049018 W US2019049018 W US 2019049018W WO 2020112195 A1 WO2020112195 A1 WO 2020112195A1
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WO
WIPO (PCT)
Prior art keywords
gene
cells
gene editing
triplex
plerixafor
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PCT/US2019/049018
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English (en)
Inventor
Elias QUIJANO
W. Mark Saltzman
Peter Glazer
James M. Coull
Marshall FORDYCE
Derek Sim
Original Assignee
Yale University
Trucode Gene Repair, Inc.
Priority date (The priority date 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 date listed.)
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Publication date
Application filed by Yale University, Trucode Gene Repair, Inc. filed Critical Yale University
Publication of WO2020112195A1 publication Critical patent/WO2020112195A1/fr

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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
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/16—Hydrolases (3) acting on ester bonds (3.1)
    • C12N9/22—Ribonucleases RNAses, DNAses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • 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
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/15—Nucleic acids forming more than 2 strands, e.g. TFOs
    • C12N2310/152—Nucleic acids forming more than 2 strands, e.g. TFOs on a single-stranded target, e.g. fold-back TFOs
    • 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
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/31—Chemical structure of the backbone
    • C12N2310/318—Chemical structure of the backbone where the PO2 is completely replaced, e.g. MMI or formacetal
    • C12N2310/3181—Peptide nucleic acid, PNA
    • 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
    • C12N2320/00—Applications; Uses
    • C12N2320/30—Special therapeutic applications
    • C12N2320/31—Combination therapy

Definitions

  • Substitution at the gamma position creates chirality and provides helical pre-organization to the PNA oligomer, and may yield substantially increased binding affinity to the target DNA (Rapireddy, et al., Biochemistry, 50(19):3913-8 (2011), He et al.,“The Structure of a g-modified peptide nucleic acid duplex”, Mol. BioSyst. 6:1619-1629 (2010); and Sahu et al., “Synthesis and Characterization of Conformationally Preorganized, (R)- Diethylene Glycol-Containing g-Peptide Nucleic Acids with Superior Hybridization Properties and Water Solubility”, J. Org. Chem, 76:5614- 5627) (2011)).
  • Other advantageous properties can be conferred depending on the chemical nature of the specific substitution at the gamma position (the “R” group in the illustration of the Chiral gRNA, above).
  • PNAs may require even fewer purines to a form a triple helix.
  • a triple helix may be formed with a target sequence containing fewer than 8 purines. Therefore, PNAs may be designed to target a site on duplex nucleic acid containing between 6-30 polypurine:polypyrimidines, preferably, 6-25 polypurine:polypyrimidines, more preferably 6-20
  • Specificity and binding affinity of the pseudocomplemetary oligonucleotides may vary from oligomer to oligomer, depending on factors such as length, the number of G:C and A:T base pairs, and the formulation.
  • recombination for example, a substitution, a deletion, or an insertion of one or more nucleotides.
  • Successful recombination of the donor sequence results in a change of the sequence of the target region.
  • This strategy exploits the ability of a triplex to provoke DNA repair, potentially increasing the probability of recombination with the homologous donor DNA. It is understood in the art that in most cases, a greater number of homologous positions within the donor fragment will increase the probability that the donor fragment will be recombined into the target sequence, target region, or target site.
  • Non-tethered or unlinked fragments may range in length from 20 nucleotides to several thousand.
  • the donor oligonucleotide molecules, whether linked or unlinked, can exist in single stranded (ss) or double stranded form (ds) (e.g., ssDNA, dsDNA).
  • the donor fragment to be recombined can be linked or un-linked to the triplex-forming molecules.
  • the linked donor fragment may range in length from 4 nucleotides to 100 nucleotides, preferably from 4 to 80 nucleotides in length.
  • the unlinked donor fragments may have a much broader range, from 20 nucleotides to several thousand nucleotides in length.
  • the oligonucleotide donor is between 25 and 80 nucleobases.
  • the non-tethered donor nucleotide is about 50 to 60 nucleotides in length.
  • the outer surface of the particle may be treated using a mannose amine, thereby mannosylating the outer surface of the particle. This treatment may cause the particle to bind to the target cell or tissue at a mannose receptor on the antigen presenting cell surface.
  • the nanoparticles may further include epithelial cell targeting molecules, such as, antibodies or bioactive fragments thereof that recognize and bind to epitopes displayed on the surface of epithelial cells, or ligands which bind to an epithelial cell surface receptor.
  • epithelial cell targeting molecules such as, antibodies or bioactive fragments thereof that recognize and bind to epitopes displayed on the surface of epithelial cells, or ligands which bind to an epithelial cell surface receptor.
  • suitable receptors include, but are not limited to, IgE Fc receptors, EpCAM, selected carbohydrate specificites, dipeptidyl peptidase, and E-cadherin.
  • the plerixafor is contacted with the target cell prior to the gene editing technology and/or donor oligonucleotide.
  • the plerixafor can be contacted with the target cell, for example, 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, or 24 hours, or 1, 2, 3, 4, 5, 6, or 7 days, or any combination thereof prior to the gene editing technology and/or donor oligonucleotide.
  • somatic cells may be harvested from a host.
  • somatic cells may be harvested from a host.
  • PNA and donor DNA were mixed at a 2:1 molar ratio and added dropwise to the PLGA solution under vortex.
  • DNA was added dropwise at a molar ratio of 2 nmoles/mg of polymer.
  • the resulting mixture was sonicated three times for 10 seconds using an amplitude of 38%.
  • the water-in-oil emulsion was subsequently added dropwise to a surfactant solution containing polyvinyl alcohol (5% w/v). Following the second emulsion, the sonication step was repeated as described.
  • the resulting nanoparticle solution was added to 25 ml of a 0.3% PVA solution and allowed to stir for 3 hours at room temperature.
  • the Townes mouse model was developed by Ryan TM, Ciavatta DJ, Townes TM.,“Knockout-transgenic mouse model of sickle cell disease.” Science. 1997 Oct 31 ;278(5339): 873-6. PMID: 9346487.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Zoology (AREA)
  • Organic Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Wood Science & Technology (AREA)
  • Medicinal Chemistry (AREA)
  • Biotechnology (AREA)
  • General Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Biochemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Microbiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Physics & Mathematics (AREA)
  • Biophysics (AREA)
  • Plant Pathology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des compositions, des techniques et des procédés permettant d'améliorer l'édition de gènes. Dans un procédé préféré, l'édition de gènes implique l'utilisation de Plérixafor en tant qu'agent pour améliorer l'édition ciblée à l'aide une technique d'édition de gènes, telle que l'utilisation d'un ANP, en combinaison avec un oligonucléotide donneur. La modification génomique se produit à une fréquence plus élevée lorsque les cellules sont mises en contact avec du Plérixafor, une technique d'édition de gènes et un oligonucléotide donneur, par comparaison à l'absence du Plérixafor. Les procédés sont appropriés pour des approches in vivo, in vitro ou ex vivo pour l'édition de gènes. Les cellules modifiées selon les procédés décrits peuvent être administrées à un sujet en ayant besoin en une quantité efficace pour traiter un symptôme d'une maladie ou d'un trouble. L'invention concerne également des compositions de nanoparticules pour l'administration intracellulaire des techniques d'édition de gènes.
PCT/US2019/049018 2018-11-30 2019-08-30 Compositions, technologies et procédés d'utilisation de plérixafor pour améliorer l'édition de gènes WO2020112195A1 (fr)

Applications Claiming Priority (2)

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US201862773977P 2018-11-30 2018-11-30
US62/773,977 2018-11-30

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WO2020112195A1 true WO2020112195A1 (fr) 2020-06-04

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