EP2406375A1 - Molécules à base de siarn actives au niveau de cellules spécifiques et kits d'application pour leur production et utilisation - Google Patents

Molécules à base de siarn actives au niveau de cellules spécifiques et kits d'application pour leur production et utilisation

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Publication number
EP2406375A1
EP2406375A1 EP10718039A EP10718039A EP2406375A1 EP 2406375 A1 EP2406375 A1 EP 2406375A1 EP 10718039 A EP10718039 A EP 10718039A EP 10718039 A EP10718039 A EP 10718039A EP 2406375 A1 EP2406375 A1 EP 2406375A1
Authority
EP
European Patent Office
Prior art keywords
sirna
linker
cell
amino
ampoule
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.)
Ceased
Application number
EP10718039A
Other languages
German (de)
English (en)
Inventor
Diana Imhof
Sandra KÖHN
Tobias PÖHLMANN
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.)
Friedrich Schiller Universtaet Jena FSU
Original Assignee
Friedrich Schiller Universtaet Jena FSU
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.)
Filing date
Publication date
Application filed by Friedrich Schiller Universtaet Jena FSU filed Critical Friedrich Schiller Universtaet Jena FSU
Publication of EP2406375A1 publication Critical patent/EP2406375A1/fr
Ceased legal-status Critical Current

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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
    • 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
    • C12N15/111—General methods applicable to biologically active non-coding nucleic acids
    • 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
    • C12N2310/14—Type of nucleic acid interfering N.A.
    • 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
    • C12N2310/35—Nature of the modification
    • C12N2310/351—Conjugate
    • C12N2310/3513—Protein; Peptide
    • 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
    • C12N2310/35—Nature of the modification
    • C12N2310/352—Nature of the modification linked to the nucleic acid via a carbon atom
    • C12N2310/3527—Other alkyl chain
    • 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
    • C12N2320/32—Special delivery means, e.g. tissue-specific

Definitions

  • the invention relates to special biologically active molecules based on "short interfering RNA” (siRNA) .
  • siRNA short interfering RNA
  • the said biologically active molecules interact after activation with the mRNA of the target gene and together with specific endoribonucleases form an RNA-protein complex named "RISC” (US Pat. RNA induced silencing complex).
  • the RISC complex binds to the target mRNA, with endonucleases cleaving the target mRNA. In this way, gene expression is prevented and thus the emergence of target proteins is inhibited.
  • the cell-specifically activatable, biologically active molecules can be used, for example, for controlling and inhibiting the growth of abnormal cells, in particular in the treatment of tumors, in the treatment of viral infections, in age-specific treatments, etc.
  • the cell-specifically activatable, biologically active molecules can be used to modulate the gene expression of the target cells. Not only can the expression of genes be reduced, but they can also be increased by achieving a reduction in the expression of the negative regulator of the target gene by the biologically active molecules.
  • RNA molecules double-stranded RNA molecules
  • siRNA double-stranded RNA molecules
  • the siRNA molecules can be introduced directly into the cell, in particular via transfection reagents and electroporation (Zhang M et al .: Downregulation-enhanced green fluorescence protein gene expression by RNA interference in mammalian cells, RNA Biol. 2004 May Gilmore IR et al .: Delivery strategies for siRNA-mediated gene silencing, Epub 2004 May 22, Gurr Drag Deliv. 2006 Apr, 3 (2), 147-5, US 6,506,559). ,
  • siRNA is relatively unstable, which can be improved by chemical modifications (US 6,107,094).
  • tissue- or cell-specific-labeled transfection reagents eg antibody / antigen-labeled
  • siRNA molecules by binding fluorochromes in their biological action and to reconvert them into their active form by irradiation with light of a specific wavelength
  • QN Nguyen et al. Light-controllable siRNAs regulate gene suppression and phenotypes in cells, Biochim Biophys Acta, 2006.
  • This activation is initiated from the outside and is in no way cell-specific.
  • the said siRNA molecules after their activation in turn also act unintentionally in all other transfected cells and not only in the intended target cells.
  • siRNA molecules by binding peptides in their biological activity, which are designed so that these peptides in target cells by Zielzeil-specifically active
  • Peptidases are cleaved while they remain inactive in non-target cells (WO002008098569A2). In this way, molecules can be on
  • siRNA are very selectively activated in target cells, without these molecules unfold a negative effect on their cell function in other cells.
  • siRNA molecule is during the Effectively inactivates peptide bond, but influence the investigated linkers that remain after peptide cleavage on the siRNA, and possibly also said peptide residues, the induction of RNA interference negative, whereby the biological activity of the siRNA is inhibited.
  • the invention is based on the object to provide a connection between the siRNA and one or more peptides, in which the siRNA is activated after peptide cleavage, without that by the remaining linker and / or remaining peptide residues, the biological activity of the siRNA activated in the cell appreciably affected.
  • This covalent bond inactivates the biologically active siRNA molecules. There is thus no inhibition of specific gene expression after transfection of such inactive molecules, as long as only one of the bound peptides remains due to the absence of the corresponding target cell-typical enzyme on the siRNA molecules.
  • the peptide or peptides are cleaved off from the siRNA, leaving the amino-Cn linker and possibly a peptide residue on the siRNA.
  • the siRNA-based molecules which are not disrupted by the cell-specific enzymes of the target cell (see WO002008098569A2), remain reliably inactive and are activated upon molecule break-up after transfection into or to the target cell with effective biological activity of the siRNA.
  • the inactivated active substance molecules can be transfected into the target cells in a known manner.
  • said inactivating covalent bonds are cell-typically disrupted by the cell-specific enzyme or enzymes which are relevant to the binding sequences of the coupling peptide (s), thereby activating the biological activity of the molecule now in the target cell and dissolved by peptides. This then binds to the specific mRNA of the target cell and thereby inhibits gene expression in a known manner in this particular cell.
  • the active agent molecules remain reliably inactive because the covalent bonds between the biologically active molecule, in particular siRNA, and the peptide (s) are due to the absence of or the target cell specific enzymes completely (no peptide bond was broken) or partially (not all peptide bonds were broken) remain. Due to the further covalent peptide bond, the biologically active molecule does not bind to the mRNA of this cell or no RISC is initiated.
  • the molecule of the invention to be transfected in its inactive (bound) form not only get into or on tumor-targeted cells, but (which is virtually unavoidable in practice) can also reach healthy cells are selectively exclusively in or on activated the tumor-targeted cells with the local cell-specific enzymes, the said molecule in its biological effect and effectively inhibited the drug-related expression of the target gene.
  • This gene expression and thus the protein formation for the survival of healthy cells remains unaffected by this active substance despite the non-diseased (or not intended for the intended biological effect) cells, but permanently inactive molecule.
  • the biologically inactive molecule complexes to be transfected can be systemically administered with appropriate peptide binding (with defined amino acid combinations).
  • the molecular trays can also be bound to other substances (for example nanoparticles as a carrier system) for better transport into or onto the target cells and for their stabilization.
  • substances for example nanoparticles as a carrier system
  • mis-transfection can not be prevented by use of the invention, the mis-transfected molecules in these other cells than the target cells, although still undesirable, are not biologically active. This status remains unchanged despite the molecule activation in or on the target cells, so that the biological effect is selectively carried out exclusively in the target cells and, in contrast to the known mechanisms, a highly cell-selective modulation of gene expression is achieved.
  • an application kit in which the biologically active molecules to be used are provided with the selectable peptides (see WO002008098569A2), connected via a selectable linker, is advantageous.
  • the application kit should be in ampoule form containing all necessary ingredients, conveniently also a selection of suitable transfection systems (such as nanoparticles or lipids), other additives (such as antibodies, ligands and polyethylene glycol) and one or more probes or syringes with cannula for injection of the mixture of the Ampoule contents in containing the target cells containing medium.
  • suitable transfection systems such as nanoparticles or lipids
  • other additives such as antibodies, ligands and polyethylene glycol
  • probes or syringes with cannula for injection of the mixture of the Ampoule contents in containing the target cells containing medium.
  • the user can assemble and apply appropriate application mixtures for the intended use.
  • an application kit is conceivable with which a biologically active molecule can
  • FIG. 1 inactivated siRNA molecule by coupling the siRNA via the amino C6 linker with the peptide;
  • Fig. 2 cell-specifically activated siRNA molecule in which the peptide bond is broken and the siRNA molecule of the
  • Fig. 3 Enzyme activity of caspase-4 in target and non-target cells
  • a siRNA 2 coupled to a peptide 3 for their biological inactivation (inactivation of the action of siRNA in a cell).
  • the amino C6 linker 1 is connected to it via the 5 'end of the antisense strand of siRNA 2.
  • the siRNA molecule remains biologically inactivated.
  • the peptide bond is disrupted by a cell-specific enzyme of a target cell into which the inactivated siRNA molecule of FIG.
  • siRNA 1 has been transfected (complete cleavage of all peptides 3), biological activation of the remaining siRNA molecule occurs by the per se known ones cell-specific action of the siRNA intended for molecular transfection is activated (see also WO002008098569A2).
  • FIG. 3 shows the cell-specific activity of the cleavage enzyme caspase-4.
  • the enzyme caspase-4 is active in the target cells (Jeg-3 choriocarcinoma cells, dark diagram bars), whereas it is not active in the non-target cells (human embryonic kidney, HEK, bright diagram bar).
  • an siRNA inhibited by binding of the targeting peptide for caspase-4 via the linker structure of Fig. 1 is cleaved and activated in the target cells containing active caspase-4.
  • Fig. 4 shows the detection fluorescence intensities in the introduction of a control siRNA without function, a siRNA for the reduction of

Abstract

L'invention concerne des molécules à base de siARN actives dans des cellules spécifiques et des kits d'application pour leur production et utilisation. Le but de l'invention est de créer une liaison entre le siARN et un ou plusieurs peptides, dans laquelle le siARN est activé après séparation des peptides, sans que l'activité biologique du siARN activé dans la cellule soit entravée de manière notable par le segment de liaison restant et/ou les restes de peptides. Selon l'invention, le ou les peptides (3) sont couplés par un segment de liaison amino-Cn spécial, par exemple un segment de liaison amino-C6 (1), au siARN (2) qui, en dépit de ce qu'il demeure de siARN et de restes de peptides éventuels, ne constitue aucune entrave ou qu'une entrave négligeable à l'activité biologique du siARN. Ces molécules sont utilisées par exemple pour influencer l'expression génique d'organes, voire de cellules, de préférence malades ou infectés, ou pour réduire l'expression de gènes souhaités dans des mélanges cellulaires.
EP10718039A 2009-03-13 2010-03-12 Molécules à base de siarn actives au niveau de cellules spécifiques et kits d'application pour leur production et utilisation Ceased EP2406375A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE102009012871 2009-03-13
DE102009043743.6A DE102009043743B4 (de) 2009-03-13 2009-09-30 Zellspezifisch wirksame Moleküle auf Grundlage von siRNA sowie Applikationskits zu deren Herstellung und Verwendung
PCT/DE2010/000284 WO2010102615A1 (fr) 2009-03-13 2010-03-12 Molécules à base de siarn actives au niveau de cellules spécifiques et kits d'application pour leur production et utilisation

Publications (1)

Publication Number Publication Date
EP2406375A1 true EP2406375A1 (fr) 2012-01-18

Family

ID=42558060

Family Applications (1)

Application Number Title Priority Date Filing Date
EP10718039A Ceased EP2406375A1 (fr) 2009-03-13 2010-03-12 Molécules à base de siarn actives au niveau de cellules spécifiques et kits d'application pour leur production et utilisation

Country Status (6)

Country Link
US (1) US9315808B2 (fr)
EP (1) EP2406375A1 (fr)
JP (1) JP2012520060A (fr)
CN (1) CN102348799A (fr)
DE (1) DE102009043743B4 (fr)
WO (1) WO2010102615A1 (fr)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102009043743B4 (de) 2009-03-13 2016-10-13 Friedrich-Schiller-Universität Jena Zellspezifisch wirksame Moleküle auf Grundlage von siRNA sowie Applikationskits zu deren Herstellung und Verwendung
DE102011009470A1 (de) * 2011-01-21 2012-08-09 Friedrich-Schiller-Universität Jena Biologisch wirksame Nukleotid-Moleküle zur gezielten Abtötung von Zellen, Verwendung derselben sowie Applikationskit
DE102012022596B4 (de) * 2012-11-15 2017-05-04 Friedrich-Schiller-Universität Jena Neue zellspezifisch wirksame Nukleotid-Moleküle und Applikationskit zu deren Anwendung
EP3180033B1 (fr) 2014-08-14 2023-06-07 Friedrich-Schiller-Universität Jena Peptide destinée à être utilisée dans la réduction d'effets secondaires sous forme de réactions/effets immunostimulateurs
DE102019000490A1 (de) 2019-01-23 2020-07-23 HAEMES Verwaltungsgesellschaft mbH Verwendung von Oligonukleotiden für die Behandlung von Tumoren
WO2023122805A1 (fr) 2021-12-20 2023-06-29 Vestaron Corporation Procédé de pression de sélection par sorbitol

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Also Published As

Publication number Publication date
DE102009043743B4 (de) 2016-10-13
CN102348799A (zh) 2012-02-08
US20110319342A1 (en) 2011-12-29
WO2010102615A1 (fr) 2010-09-16
JP2012520060A (ja) 2012-09-06
DE102009043743A1 (de) 2010-09-16
US9315808B2 (en) 2016-04-19

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