US20050158741A1 - Self-cleaving ribozymes and uses thereof - Google Patents

Self-cleaving ribozymes and uses thereof Download PDF

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Publication number
US20050158741A1
US20050158741A1 US10/990,355 US99035504A US2005158741A1 US 20050158741 A1 US20050158741 A1 US 20050158741A1 US 99035504 A US99035504 A US 99035504A US 2005158741 A1 US2005158741 A1 US 2005158741A1
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Prior art keywords
nucleic acid
cleaving
self
rna
schistosome
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US10/990,355
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English (en)
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Richard Mulligan
Laising Yen
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Childrens Medical Center Corp
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Childrens Medical Center Corp
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Priority to US10/990,355 priority Critical patent/US20050158741A1/en
Assigned to CHILDREN'S HOSPITAL reassignment CHILDREN'S HOSPITAL ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MULLGAN, RICHARD, YEN, LAISING
Publication of US20050158741A1 publication Critical patent/US20050158741A1/en
Assigned to CHILDREN'S MEDICAL CENTER CORPORATION reassignment CHILDREN'S MEDICAL CENTER CORPORATION RE-RECORD TO CORRECT THE NAME OF THE ASSIGNEE, PREVIOUSLY RECORDED ON REEL 015919 FRAME 0709. Assignors: MULLIGAN, RICHARD, YEN, LAISING
Priority to US12/715,104 priority patent/US20110061120A1/en
Priority to US13/471,255 priority patent/US20150056174A1/en
Priority to US15/397,210 priority patent/US10233447B2/en
Abandoned 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • 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
    • 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
    • C12N2310/11—Antisense
    • 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
    • C12N2310/12—Type of nucleic acid catalytic nucleic acids, e.g. ribozymes

Definitions

  • grafting can be outside of the normal secondary structure of the self-cleaving schistosome RNA mutant motif in a manner similar to the loop III modifications.
  • an aptamer can be grafted onto stem II, stem III, loop I, loop II, loop III, the nucleotide core or a combination of two or more of the aforementioned structural elements of the self-cleaving schistosome RNA mutant motif.
  • the present invention relates to nucleic acids, constructs (DNA or RNA) which encode the novel self-cleaving schistosome RNA mutant motifs and schistosome RNA, described and illustrated herein.
  • Constructs, such as DNA constructs can be used alone or in a vector, such as a plasmid or a viral vector.
  • an mRNA of the nucleic acid product and the self-cleaving schistosome RNA mutant motif are produced. Self-cleavage of the mRNA by the self-cleaving schistosome RNA mutant motif prevents expression of the nucleic acid product.
  • the invention provides DNA constructs comprising: (a) a promoter; (b) nucleic acid encoding a nucleic acid product operably linked to the promoter; and (c) nucleic acid encoding a self-cleaving schistosome RNA mutant motif of the invention which includes an aptamer grafted onto the self-cleaving schistosome RNA mutant motif at a location such that the cleaving activity of the self-cleaving schistosome RNA mutant motif can be controlled (is regulatable) by binding of an effector to the aptamer.
  • the inhibitor is an antisense oligonucleotide, including a modified antisense oligonucleotide (e.g., morpholino, phosphorothioate RNA, 2′-O-methyl RNA, or phosphorothioate 2′-O-methoxyethyl RNA).
  • a modified antisense oligonucleotide e.g., morpholino, phosphorothioate RNA, 2′-O-methyl RNA, or phosphorothioate 2′-O-methoxyethyl RNA.
  • the ribozyme of the invention can be other self-cleaving ribozymes, such as a hepatitis delta virus (HDV) ribozyme, a hairpin ribozyme, and a Neurospora Varkud satellite (VS) ribozyme (see, e.g., FIG. 10 ).
  • HDV hepatitis delta virus
  • VS Neurospora Varkud satellite
  • these three self-cleaving ribozymes are found in viral, virusoid, or satellite RNA genomes, and process the products of rolling circle replication into genome-length strands (Doherty et al., 2001, Annu Rev Biophys Biomol Struct. 30:457-75; Branch et al., 1984, Science 223:45055).
  • the mRNA Under conditions which are appropriate for expression of the self-cleaving RNA mutant motif, the mRNA is cleaved and as a result, the desired nucleic acid product encoded by the mRNA is not produced ( FIG. 1A ).
  • the present invention relates to a self-cleaving schistosome RNA motif modified to include a loop on stem III.
  • a “loop,” as used herein, refers to a secondary structure in an RNA sequence in which a single-stranded RNA sequence is flanked by RNA sequences which are capable of pairing with each other to form a “stem” structure.
  • a loop comprises at least three nucleotides, and preferably from about 3-40 nucleotides.
  • a “loop” can include nucleotides which can base pair and result in non-loop structures.
  • a loop can include nucleotides which can base pair and optionally elongate the stem from which it branches.
  • DNA constructs encoding a self-cleaving ribozyme (naturally occurring or mutants such as schistosome ribozyme mutants) of the present invention can be manufactured according to methods generally known in the art.
  • nucleic acids encoding a self-cleaving ribozyme can be manufactured by chemical synthesis or recombinant DNA/RNA technology (see, e.g., Sambrook et al., Eds., Molecular Cloning: A Laboratory Manual, 2nd edition, Cold Spring Harbor University Press, New York (1989); and Ausubel et al., Eds., Current Protocols In Molecular Biology, John Wiley & Sons, New York (1997)).
  • the DNA construct is present in cells under conditions which permit expression of the two nucleotide components, the mRNA molecule comprising the self-cleaving ribozyme and mRNA encoding the nucleic acid product is produced, the encoded self-cleaving ribozyme is spontaneously cleaved and, as a result, the nucleic acid product is not produced.
  • an agent such as a drug (e.g., an antibiotic), which inhibits (totally or partially) cleaving activity of the encoded self-cleaving ribozyme, the desired nucleic acid product is produced.
  • the invention relates to packaging cell lines useful for generating recombinant viral vectors and viruses comprising a recombinant genome which includes a nucleotide sequence (RNA or DNA) which represents a DNA construct of the present invention; construction of such cell lines; and methods of using the recombinant viral vectors to modulate production of a desired nucleic acid product in vitro, in vivo and ex vivo.
  • RNA or DNA nucleotide sequence
  • a DNA construct encoding a self-cleaving ribozyme is inserted into a nucleic acid vector, e.g., a DNA plasmid, virus or other suitable replicon (e.g., viral vector).
  • a nucleic acid vector e.g., a DNA plasmid, virus or other suitable replicon (e.g., viral vector).
  • Viral vectors include retrovirus, adenovirus, parvovirus (e.g., adeno-associated viruses), coronavirus, negative strand RNA viruses such as orthomyxovirus (e.g., influenza virus), rhabdovirus (e.g., rabies and vesicular stomatitis virus), paramyxovirus (e.g.
  • the cleaving activity of a self cleaving ribozyme can be inhibited (partially or totally) using an agent such as a drug (e.g., an antibiotic) or other molecule or composition, which inhibits (partially or totally) the cleaving activity of the self-cleaving ribozyme.
  • an agent such as a drug (e.g., an antibiotic) or other molecule or composition, which inhibits (partially or totally) the cleaving activity of the self-cleaving ribozyme.
  • Inhibition of spontaneous cleavage of the corresponding mRNA results in the efficient induction of expression of the nucleic acid product of interest.
  • viruses of the methods include, but are not limited to, hepatitis virus (e.g., C, B, and delta), human immunodeficiency virus (HIV), herpes virus, and human papillomavirus (HPV).
  • pathogenic microorganisms of the methods include, but are not limited to, Notophthalmus viddescens, Ambystoma talpoideum, Amphiuma tridactylum , and Schistosoma mansoni .
  • Cells of the methods can be animal cells (e.g., mammalian cells such as human cells) or plant cells (e.g., tobacco).
  • the cells can be obtained commercially or from a depository or obtained directly from an individual, such as by biopsy.
  • the cells used can be obtained from an individual to whom they will be returned or from another/different individual of the same or different species.
  • nonhuman cells such as pig cells
  • the cell need not be isolated from the individual where, for example, it is desirable to deliver the vector to the individual in gene therapy.
  • the DNA construct which comprises: (a) DNA encoding the desired nucleic acid product; (b) a promoter operably linked to the DNA encoding the desired nucleic acid product; and (c) DNA encoding a self-cleaving ribozyme.
  • the DNA encoding the desired nucleic acid product and the DNA encoding the self-cleaving ribozyme are downstream of the promoter.
  • the DNA encoding the self-cleaving ribozyme can be 5′ or 3′ of the DNA encoding the desired nucleic acid product. Transcription of the two DNA components in the construct produces a mRNA comprising the self-cleaving ribozyme and mRNA encoding the desired nucleic acid product.
  • RNA-based mechanisms for controlling gene expression involve the modulation of translation, transcription termination, or RNA self-cleavage through the direct interaction of specific intracellular metabolites and RNA sequences (Winkler, et al., 2002, Nature 419, 952-6; Winkler, et al., 2004, Nature 428, 281-6; Mandal, et al., 2004, Nat Struct Mol Biol 11, 29-35; Cech, et al., 2004, Nature 428, 263-4).
  • AAV adeno-associated virus

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  • Genetics & Genomics (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Chemical & Material Sciences (AREA)
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  • Wood Science & Technology (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • AIDS & HIV (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
US10/990,355 2003-11-14 2004-11-15 Self-cleaving ribozymes and uses thereof Abandoned US20050158741A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
US10/990,355 US20050158741A1 (en) 2003-11-14 2004-11-15 Self-cleaving ribozymes and uses thereof
US12/715,104 US20110061120A1 (en) 2003-11-14 2010-03-01 Self-cleaving ribozymes and uses thereof
US13/471,255 US20150056174A1 (en) 2003-11-14 2012-05-14 Self-cleaving ribozymes and uses thereof
US15/397,210 US10233447B2 (en) 2003-11-14 2017-01-03 Self-cleaving ribozymes and uses thereof

Applications Claiming Priority (2)

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US51994103P 2003-11-14 2003-11-14
US10/990,355 US20050158741A1 (en) 2003-11-14 2004-11-15 Self-cleaving ribozymes and uses thereof

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US10/990,355 Abandoned US20050158741A1 (en) 2003-11-14 2004-11-15 Self-cleaving ribozymes and uses thereof
US12/715,104 Abandoned US20110061120A1 (en) 2003-11-14 2010-03-01 Self-cleaving ribozymes and uses thereof
US13/471,255 Abandoned US20150056174A1 (en) 2003-11-14 2012-05-14 Self-cleaving ribozymes and uses thereof
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US13/471,255 Abandoned US20150056174A1 (en) 2003-11-14 2012-05-14 Self-cleaving ribozymes and uses thereof
US15/397,210 Active US10233447B2 (en) 2003-11-14 2017-01-03 Self-cleaving ribozymes and uses thereof

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US (4) US20050158741A1 (fr)
EP (3) EP2476707B1 (fr)
AU (2) AU2004291911A1 (fr)
CA (1) CA2545697C (fr)
ES (2) ES2638274T3 (fr)
WO (1) WO2005049817A2 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007007326A2 (fr) * 2005-07-14 2007-01-18 Gryphonet Ltd. Systeme et procede de detection de defaillance et de recuperation dans des dispositifs mobiles
US9701706B2 (en) 2015-08-06 2017-07-11 Chimerix, Inc. Pyrrolopyrimidine nucleosides and analogs thereof
WO2021076563A1 (fr) * 2019-10-15 2021-04-22 The Scripps Research Institute Commutateurs d'arn efficaces et systèmes d'expression associés
US11111264B2 (en) 2017-09-21 2021-09-07 Chimerix, Inc. Morphic forms of 4-amino-7-(3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide and uses thereof

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104962560B (zh) * 2015-06-16 2017-07-21 湖南大学 一种检测日本血吸虫卵的核酸适配体及其在制备检测制剂中的应用
BR112018015815A2 (pt) * 2016-02-02 2019-01-02 Meiragtx Uk Ii Ltd regulação da expressão gênica através do controle mediado por aplicação de ribozimas auto-cleavantes
WO2022150773A2 (fr) * 2021-01-11 2022-07-14 The Regents Of The University Of California Constructions d'arn activées par un ribozyme et leurs utilisations

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US3675970A (en) * 1970-02-10 1972-07-11 Sigmund Bereday Seat construction
US3833242A (en) * 1972-12-29 1974-09-03 Original Plastic Bike Bicycle frame
US4332419A (en) * 1979-01-23 1982-06-01 Ignaz Vogel Seat
US6221661B1 (en) * 1988-09-20 2001-04-24 The Of Regents For Northern Illinois University Of Dekalb Hairpin ribozymes
US5016941A (en) * 1990-03-13 1991-05-21 Tachi-S Co. Ltd. Structure of vehicle seat
US5722729A (en) * 1990-05-21 1998-03-03 Carilli; Brian D. Multi-layer high impact seating
US5076601A (en) * 1990-05-25 1991-12-31 Duplessis Delano A High strength composite bicycle frame and method for its manufacture
US5236247A (en) * 1992-02-14 1993-08-17 Hoover Universal, Inc. Insert molded composite plastic seat cushion frame
US5544937A (en) * 1995-01-25 1996-08-13 Hanagan; Michael W. Motorcycle seat and method of making same
US5988757A (en) * 1996-08-29 1999-11-23 Lear Corporation Vehicle seat assembly
US20020166132A1 (en) * 2000-08-18 2002-11-07 Daniel Scherman System for regulating in vivo the expression of a transgene by conditional inhibition
US20030228455A1 (en) * 2002-06-06 2003-12-11 Foamex L.P. Foam laminate for mold in place seating component

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007007326A2 (fr) * 2005-07-14 2007-01-18 Gryphonet Ltd. Systeme et procede de detection de defaillance et de recuperation dans des dispositifs mobiles
WO2007007326A3 (fr) * 2005-07-14 2009-05-22 Gryphonet Ltd Systeme et procede de detection de defaillance et de recuperation dans des dispositifs mobiles
US9701706B2 (en) 2015-08-06 2017-07-11 Chimerix, Inc. Pyrrolopyrimidine nucleosides and analogs thereof
US9708359B2 (en) 2015-08-06 2017-07-18 Chimerix, Inc. Pyrrolopyrimidine nucleosides and analogs thereof
US10407457B2 (en) 2015-08-06 2019-09-10 Chimerix, Inc. Pyrrolopyrimidine nucleosides and analogs thereof
US10941175B2 (en) 2015-08-06 2021-03-09 Chimerix, Inc. Pyrrolopyrimidine nucleosides and analogs thereof
US11981700B2 (en) 2015-08-06 2024-05-14 Chimerix, Inc. Pyrrolopyrimidine nucleosides and analogs thereof
US11111264B2 (en) 2017-09-21 2021-09-07 Chimerix, Inc. Morphic forms of 4-amino-7-(3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide and uses thereof
WO2021076563A1 (fr) * 2019-10-15 2021-04-22 The Scripps Research Institute Commutateurs d'arn efficaces et systèmes d'expression associés

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Publication number Publication date
EP2476707A1 (fr) 2012-07-18
ES2488641T3 (es) 2014-08-28
EP1689784A2 (fr) 2006-08-16
WO2005049817A3 (fr) 2006-01-26
US20110061120A1 (en) 2011-03-10
US10233447B2 (en) 2019-03-19
EP3279328A1 (fr) 2018-02-07
AU2010201034A1 (en) 2010-04-08
ES2638274T3 (es) 2017-10-19
CA2545697A1 (fr) 2005-06-02
CA2545697C (fr) 2016-12-20
US20170253872A1 (en) 2017-09-07
EP1689784B1 (fr) 2014-07-16
WO2005049817A2 (fr) 2005-06-02
EP2476707B1 (fr) 2017-05-24
AU2004291911A1 (en) 2005-06-02
US20150056174A1 (en) 2015-02-26

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