WO2002094989A2 - Vecteurs retroviraux et utilisations de ceux-ci - Google Patents

Vecteurs retroviraux et utilisations de ceux-ci Download PDF

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Publication number
WO2002094989A2
WO2002094989A2 PCT/US2002/015816 US0215816W WO02094989A2 WO 2002094989 A2 WO2002094989 A2 WO 2002094989A2 US 0215816 W US0215816 W US 0215816W WO 02094989 A2 WO02094989 A2 WO 02094989A2
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WO
WIPO (PCT)
Prior art keywords
cell
vector plasmid
retroviral vector
seq
regulatory element
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PCT/US2002/015816
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English (en)
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WO2002094989A3 (fr
Inventor
Gerald M. Edelman
Geoffrey Owens
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The Scripps Research Institute
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Priority to AU2002303804A priority Critical patent/AU2002303804A1/en
Publication of WO2002094989A2 publication Critical patent/WO2002094989A2/fr
Publication of WO2002094989A3 publication Critical patent/WO2002094989A3/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
    • 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
    • C12N15/86—Viral vectors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A61K48/005—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
    • A61K48/0058—Nucleic acids adapted for tissue specific expression, e.g. having tissue specific promoters as part of a contruct
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • 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
    • 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
    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/13011—Gammaretrovirus, e.g. murine leukeamia virus
    • C12N2740/13041—Use of virus, viral particle or viral elements as a vector
    • C12N2740/13043—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector
    • 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
    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/13011—Gammaretrovirus, e.g. murine leukeamia virus
    • C12N2740/13041—Use of virus, viral particle or viral elements as a vector
    • C12N2740/13045—Special targeting system for viral vectors
    • 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
    • C12N2830/008—Vector systems having a special element relevant for transcription cell type or tissue specific enhancer/promoter combination
    • 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
    • C12N2830/15—Vector systems having a special element relevant for transcription chimeric enhancer/promoter combination
    • 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
    • C12N2830/46—Vector systems having a special element relevant for transcription elements influencing chromatin structure, e.g. scaffold/matrix attachment region, methylation free island
    • 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
    • C12N2830/48—Vector systems having a special element relevant for transcription regulating transport or export of RNA, e.g. RRE, PRE, WPRE, CTE
    • 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
    • C12N2830/80—Vector systems having a special element relevant for transcription from vertebrates
    • C12N2830/85—Vector systems having a special element relevant for transcription from vertebrates mammalian
    • 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
    • C12N2840/00—Vectors comprising a special translation-regulating system
    • C12N2840/20—Vectors comprising a special translation-regulating system translation of more than one cistron
    • C12N2840/203—Vectors comprising a special translation-regulating system translation of more than one cistron having an IRES

Definitions

  • a retroviral vector plasmid of the invention and, therefore, a retroviral vector or retroviral vector genome derived therefrom, is characterized, in part, in that it substantially lacks a translation start codon between the R region and the cloning site in the transcribed strand.
  • the cloning site in a retroviral vector plasmid can be any nucleotide sequence that facilitates insertion of an exogenous polynucleotide into the vector plasmid in an operatively linked manner.
  • the cloning site can be a restriction endonuclease recognition site, including a multiple cloning site containing a plurality of restriction endonuclease recognition sites, can be a recombinase recognition site such as a lox site or an att site, or can include a combination of restriction endonuclease recognition sites and recombinase recognition sites.
  • the plurality of transcriptional regulatory elements can include promoters, enhancers, silencers, insulators, or a combination thereof, and can be viral transcriptional regulatory elements, eukaryotic transcriptional regulatory elements, or a combination thereof.
  • a kit of the invention also can contain at least one expressible polynucleotide, which can be monocistronic or polycistronic, and can be inserted into the cloning site of the viral vector plasmid.
  • the kit can contain a plurality of such expressible polynucleotides.
  • the present invention also relates to a method of producing a retroviral vector.
  • a method of producing a retroviral vector can be performed, for example, by introducing a refroviral vector plasmid of the invention into a helper cell, which expresses trans acting factors necessary for packaging a retroviral vector genome encoded by the retroviral vector plasmid.
  • the present invention provides a refroviral vector produced by such a method, and also provides a cell transduced with such a retroviral vector.
  • the particular characteristics of the refroviral vector will depend, in part, on the characteristics of the retroviral vector plasmid, which, for example, can contain an expressible polynucleotide inserted into the cloning site, or can contain a mutated, inactivated retroviral splice site.
  • a method of producing a retroviral vector can further include a step of isolating the retroviral vector. Accordingly, the present invention also provides an isolated retroviral vector produced by the method, as well as a cell fransduced by such an isolated retroviral vector.
  • a method of producing a retroviral vector also can include a step of isolating a retroviral vector genome from the retroviral vector. Accordingly, an isolated retroviral vector genome also is provided.
  • transcriptional regulatory element is an inducible regulatory element
  • expression from the element can be induced by contacting the cell with an appropriate inducing agent, which can be an exogenous inducing agent that is contacted with the cell or an endogenous inducing agent that is produced by the cell or in an organism containing the cell.
  • the present invention also relates to a method of ameliorating a pathological condition in a subject.
  • a method can be performed, for example, by contacting a cell of the subject with the retroviral vector of the invention, wherein the retroviral vector is derived from a retroviral vector plasmid that contains an expressible polynucleotide that can be expressed in the cell in the subject.
  • the subject can be any subject susceptible to transduction by a refroviral vector, particularly a vertebrate subject including a human, a domesticated or commercially valuable mammal, and the like.
  • Figure 8B provides schematic illustrations showing the insertion site for the various enhancer constructs of the vectors used in Figure 8 A (see, also, Figure 7B).
  • the retroviral vectors are useful for expressing a heterologous polyribonucleotide sequence or polypeptide in a neural cell, including a neural stem cell or a differentiated neuronal cell derived therefrom, and, therefor, can be useful for treating a pathological condition of the nervous system, including, for example, Parkinson's disease, Alzheimer's disease, and other neurodegenerative disorders.
  • Retroviral vector plasmids are exemplified herein by the refroviral vector plasmids shown in Figures IE to IL, including those having the nucleotide sequences set forth in SEQ ID NOS:l to 5, as well as derivatives thereof having nucleotide sequences as set forth in SEQ ID NOS:20 to 24.
  • An expressible polynucleotide also can encode a polypeptide, which can be a polypeptide useful for a gene therapy procedure or can be a reporter polypeptide.
  • a reporter polypeptide can be any polypeptide that provides a means to detect or isolate a cell in which the reporter polypeptide is expressed.
  • the expressible polynucleotide encoding a reporter polypeptide can in a form that can be easily manipulated by recombinant DNA methods.
  • an anti-c-myc epitope antibody can be immobilized on a solid matrix and cells, some of which express the tagged polypeptide, can be contacted with the matrix under conditions that allow selective binding of the antibody to the epitope. Unbound cells can be removed by washing the matrix, and bound cells, which express the reporter molecule, can be eluted and collected.
  • a second expressible polynucleotide encoding a polypeptide of interest for example, a therapeutic protein
  • cells can be transfected with the vector plasmid, or transduced with a retroviral vector derived from the vector plasmid, and selected for expression of EGFP, thereby also identifying cells expressing the polypeptide of interest.
  • a method of expressing a polynucleotide in a cell can be performed by contacting the cell with the retroviral vector plasmid, which contains a transcriptional regulatory element in the U3 region and an expressible polynucleotide inserted in the cloning site, under conditions suitable for entry of the retroviral vector plasmid into the cell.
  • the method can be performed by contacting the cell with a retroviral vector of the invention under conditions suitable for entry of the retroviral vector into the cell and integration of a proviral form of the refroviral vector genome into the cellular genome.
  • Such a method is particularly useful where the product of the expressible polynucleotide is secreted from the cell such that it can effect its activity in the subject, for example, an immunostimulatory polypeptide, or a hormone, growth factor or chemokine, or where the product of the expressible polynucleotide corrects the defect in a sufficient number of cells such that, upon readministration of the cells to the subject, the severity of the pathologic condition is ameliorated, for example, bone ma ⁇ ow cells where a gene co ⁇ ecting a defect such as a thalessemia is introduced.
  • the retroviral vectors also can be used for gene activation studies (see, for example, Harrington et al, Nat. Biotech. 19:440-445, 2001, which is inco ⁇ orated herein by reference).
  • the retroviral vector is constructed such that it contains a strong promoter in the U3 region. Following contact with a eukaryotic cell and integration into the genome, cells exhibiting novel phenotypes are identified and examined for newly activated genes due to integration of the retroviral vector.
  • the activated gene can be identified and isolated using the integrated retroviral vector as a tag.
  • MESV is a C-type retrovirus that was modified to remove sequences that are necessary for independent replication. Consequently, the virus can only replicate with the assistance of helper genes that encode the proteins required for retroviral genome packaging and insertion into the host genome.
  • This example provides a method for determining the transcriptional efficiency of a retroviral vectors of the invention.
  • Vectors were constructed by substituting one or more regulatory elements, including a nestin enhancer (SEQ ID NO: 26), a synapsin enhancer (SEQ ID NO:25), or the proximal portion of the synapsin enhancer, refe ⁇ ed to as Synl (SEQ ID NO:26) linked to the truncated Pgkl enhancer, alone or in combination with an island element (SEQ ID NO:28), into the Nsi I/Bgl II site (see Figures 7A and 8B).
  • a nestin enhancer SEQ ID NO: 26
  • SEQ ID NO:25 synapsin enhancer
  • Synl SEQ ID NO:26
  • SEQ ID NO:28 island element

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  • Health & Medical Sciences (AREA)
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Abstract

L'invention concerne un plasmide de vecteur rétroviral qui contient une longue répétitions terminale de rétrovirus, comprenant une région U5, une région R et une région U3, et contenant un élément régulateur de transcription ou un site permettant l'insertion d'un tel élément, un élément constitutif de transport, hétérologue à la région U5 et ne contenant aucun codon d'initiation de traduction, et un site de clonage, ce plasmide de vecteur ne contenant sensiblement aucun codon d'initiation de traduction entre la région R et le site de clonage. L'invention concerne également un vecteur rétroviral dérivé de ce plasmide de vecteur rétroviral, et un génome de vecteur rétroviral, ainsi qu'une cellule contenant ce plasmide de vecteur rétroviral ou ce vecteur rétroviral. L'invention concerne en outre un ensemble de matériel comprenant un tel plasmide de vecteur rétroviral ou vecteur rétroviral. L'invention concerne encore des procédés de préparation et des procédés d'utilisation de tels plasmides de vecteurs rétroviraux ou vecteurs rétroviraux, notamment des procédés comprenant l'utilisation de ce vecteur ou plasmide de vecteur pour introduire un polynucléotide pouvant être exprimé dans une cellule telle qu'une cellule souche neurale.
PCT/US2002/015816 2001-05-18 2002-05-17 Vecteurs retroviraux et utilisations de ceux-ci WO2002094989A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2002303804A AU2002303804A1 (en) 2001-05-18 2002-05-17 Retroviral vectors and methods of using same

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US29220101P 2001-05-18 2001-05-18
US60/292,201 2001-05-18
US33497201P 2001-11-30 2001-11-30
US60/334,972 2001-11-30

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WO2002094989A2 true WO2002094989A2 (fr) 2002-11-28
WO2002094989A3 WO2002094989A3 (fr) 2005-03-10

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009146668A2 (fr) * 2008-06-03 2009-12-10 Ustav Molekulami Genetiky Av Cr, V.V.I. Élément de gène régulateur comprenant un promoteur ou un activateur de transcription protégé contre la méthylation d'adn et le silençage de l'expression génique
EP2639303A1 (fr) * 2010-11-08 2013-09-18 JCR Pharmaceuticals CO., LTD. Nouveau vecteur d'expression

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6312686B1 (en) * 1993-11-19 2001-11-06 Eisai Co., Ltd. Modulating the permeability of a physiological barrier with an agent that modulates tyrosine phosphorylation

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6312686B1 (en) * 1993-11-19 2001-11-06 Eisai Co., Ltd. Modulating the permeability of a physiological barrier with an agent that modulates tyrosine phosphorylation

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009146668A2 (fr) * 2008-06-03 2009-12-10 Ustav Molekulami Genetiky Av Cr, V.V.I. Élément de gène régulateur comprenant un promoteur ou un activateur de transcription protégé contre la méthylation d'adn et le silençage de l'expression génique
WO2009146668A3 (fr) * 2008-06-03 2010-01-28 Ustav Molekulami Genetiky Av Cr, V.V.I. Élément de gène régulateur comprenant un promoteur ou un activateur de transcription protégé contre la méthylation d'adn et le silençage de l'expression génique
EP2639303A1 (fr) * 2010-11-08 2013-09-18 JCR Pharmaceuticals CO., LTD. Nouveau vecteur d'expression
EP2639303A4 (fr) * 2010-11-08 2014-05-28 Japan Chem Res Nouveau vecteur d'expression

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AU2002303804A1 (en) 2002-12-03

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