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WO1987003451A1 - Arn anti-detection pour le traitement de maladies retrovirales - Google Patents

Arn anti-detection pour le traitement de maladies retrovirales Download PDF

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Publication number
WO1987003451A1
WO1987003451A1 PCT/US1986/002604 US8602604W WO8703451A1 WO 1987003451 A1 WO1987003451 A1 WO 1987003451A1 US 8602604 W US8602604 W US 8602604W WO 8703451 A1 WO8703451 A1 WO 8703451A1
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Prior art keywords
cell
cells
rna
retrovirus
infection
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PCT/US1986/002604
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English (en)
Inventor
Paul E. Neiman
Richard Yue-Leung To
Shane C. Booth
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Fred Hutchinson Cancer Center
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Fred Hutchinson Cancer Center
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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
    • C12N15/1131—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 against viruses
    • 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
    • C12N15/1131—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 against viruses
    • C12N15/1132—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 against viruses against retroviridae, e.g. HIV

Definitions

  • This invention relates to genetic engineering methods of treating retroviral disease states.
  • Retroviruses are widespread in nature, and infection with these agents is associated with neoplastic and other disease states in many vertebrate species.
  • the infectious retroviral agent is called a virion.
  • Envelope glycoprotein on the surface of the virion recognizes receptors that mediate entry (l) of two copies of the retroviral genome, each an RNA molecule of between about 8,000 and 10,000 nucleotides, into a target cell.
  • the two genomic virion RNA molecules are copied (2) by a viral reverse transciptase enzyme into duplex linear and circular, supercoiled viral DNA (v-DNA) molecules.
  • the virion RNA first serves as a template for the transcription of a complementary DNA nucleotide sequence (minus strand), and a second-strand DNA copy (plus strand) is then made using the reverse transcribed minus-strand DNA as a template.
  • v-DNA can be transcribed (dashed arrow)
  • some of the circular DNA molecules integrate (3) into the cellular genome at a precise point on the viral DNA molecule and a random, or near random, site on host chromosomal DNA.
  • the integrated viral DNA copy is called a provirus.
  • LTRs Long terminal repeats containing sequences copied from both ends of viral genomic RNA are located at each end of the DNA provirus and linked directly to host DNA. These LTRs contain regulatory sequences for the expression of the genes required for viral replication: gag, internal structural protein; pol, reverse transcriptase; and env, viral envelope glycoprotein.
  • the LTR regulatory sequences include promoters for the initiation and signals for the termination of transcription.
  • the LTRs usually also include powerful enhancer sequences which amplify the rate of transcription of the viral genes to the point that proviral RNA transcripts may comprise as much as 0.1 to 1% of total cellular messenger RNA.
  • the transcriptional promoter/enhancer apparatus associated with some retroviruses appears to function only when introduced into particular cell types, resulting in a tissue specific expression of the viral genes.
  • the integrated provirus is transcribed (4) into both messenger RNA and full-length genomic virion RNA.
  • the viral messenger RNA is expressed into viral proteins on cellular polyso es (5).
  • the virion RNA contains specific sequences serving as packaging signals for virion assembly (6).
  • Virion RNA and viral proteins are assembled into new virions which bud from the infected host cell.
  • retroviruses usually do not lyse their host cell; and so their life cycle constitutes an efficient mechanism for the introduction and high level expression of genes in living host cells.
  • the replication and/or viral gene expression of some retroviruses can have cytotoxic and even cytopathic effects on some types of infected target cells. These pathogenic effects of retroviral infection may lead to systemic disorders associated with disease states.
  • HTLV human T-cell lymphotrophic viruses
  • HTLV-II retroviral family
  • retroviruses i.e., encoding the gag, pol, and env genes; but not oncogenes
  • pathogenesis of retrovirus-induced diseases in Molecular Biology of Tumor Viruses: RNA tumor viruses, 2nd Ed., R. eis, N. Teich, H. Varmus and J. Coffin (eds), New York, Cold Spring Harbor Laboratory, 1984, pp. 785-998, hereby incorporated by reference.
  • Ly phoid leukosis viruses including the aetiological agent of avian leukosis, severely impact the poultry industry.
  • Bovine leukemia virus which is related to HTVL-I, infects dairy herds causing the disease known as enzootic bovine leukosis or lymphosarcoma in cattle.
  • the retroviral agent (FeLV) of feline leukemia is also of veterinary concern.
  • a method for conferring resistance to infection by pathogenic retroviruses such as those associated with adult T-cell leukemia and acquired immunodeficiency syndrome (AIDS) in humans and with avian leukosis, bovine leukosis and feline leukemia in domestic animals.
  • pathogenic retroviruses such as those associated with adult T-cell leukemia and acquired immunodeficiency syndrome (AIDS) in humans and with avian leukosis, bovine leukosis and feline leukemia in domestic animals.
  • cells susceptible to infection by a pathogenic retrovirus are trans ⁇ formed with a polynucleotide directing transcription of RNA that is complementary to a region of the retroviral genome and that is effective to interrupt retroviral replication by substantially preventing formation of patho ⁇ genic virions in the treated cell and its progeny.
  • the therapeutic transformation may be achieved with a DNA vector or an RNA vector.
  • the transforming polynucleotide may be selected from the genome of retroviruses known to be the aetiological agents of disease states, including but not limited to HTLV -I, HTLV- II, HTLV- ⁇ i (LAV, ARV), LLV, BLV, and FeLV.
  • the therapeutically transformed cells may include those susceptible to infection, e.g., T-cells in the case of T- lymphotrophic retroviruses, and also progenitors of such cells, e.g., lymphocytes and hematopoietic stem cells.
  • the therapeutically transformed cells and their progeny are also considered within the scope of the invention.
  • the cells are explanted during the therapeutic transformation step, then introduced into the treated host.
  • FIGURE 1 depicts the pertinent features of retroviral replication
  • FIGURE 2 depicts the pertinent structural elements of a typical provirus
  • FIGURE 3 depicts a representative anti-sense retroviral vector of the invention
  • FIGURE 4 shows a representative Northern blot-hybridization of cellular RNA from A-l cells, as described in Example 1;
  • FIGURE 5 shows representative dot-blot hybridizations of viral
  • FIGURE 6 shows representative dot-blot hybridizations of viral RNAs as described in Example 4.
  • RNA transcripts from the cellular gene being anti-sense to the incoming retroviral RNA, markedly inhibit infec ⁇ tion by the retroviral vector.
  • a cell susceptible to infection by a pathogenic retrovirus is transformed with a polynucleotide directing transerip- tion of RNA that is complementary to part of the genomic virion RNA of the targeted pathogenic retrovirus and that effectively interrupts retroviral replica ⁇ tion in the transformed cell and its progeny.
  • polynucleotide is meant a relatively small natural or synthetic nucleic acid polymer containing from many thousand to a minimum of about 10 to 20 nucleotide bases.
  • transformation is meant the process of changing the genotype of a recipient cell mediated by the introduction of DNA, RNA, or nucleotide analogue polymer.
  • the transforming polynucleotide can be a double-stranded DNA molecule whose sense strand is homologous to a region of the targeted virion RNA.
  • the cell can be treated by transformation with an RNA vector containing a polynucleotide that is complementary to a region of the targeted virion RNA.
  • the RNA vector can be a therapeutic retroviral construct, in which case the v-DNA reverse transcribed from the latter polynucleotide, once integrated into the cellular genome, will transcribe RNA that is complementary to the targeted virion RNA.
  • the RNA transcript directed by the transforming polynucleotide must contain base sequences complementary to the virion RNA of the pathogenic retrovirus, that is, the (anti-sense) RNA directed by the transforming poly ⁇ nucleotide and the targeted virion RNA must be capable of forming molecular hybrids.
  • the RNA directed by the transforming polynucleotide must in addition interrupt replication of the targeted pathogenic retrovirus in the transformed cell, that is, the transforming polynucleotide must confer resistance to infection by preventing or reducing the formation of pathogenic virions in the transformed cell. It is considered therapeutically efficacious to select a transforming polynucleotide that will interrupt replication by substantially preventing formation of pathogenic virions in the treated cell and its progeny.
  • the anti-sense RNA directed by the transforming polynucleotide is preferably selected to interrupt retroviral replication by disrupting the formation and/or processing of viral DNA and thereby prevent its integration into the cellular genome.
  • a transforming polynucleotide effective to therapeutically interrupt retroviral replication is achievable by standard genetic engineering manipulations such as those described below.
  • the therapeutically transformed cell synthesizes the anti-sense RNA transcripts at a continuous rate, and so a steady-state level of resistance to infection is conferred on the cell and its progeny.
  • a series of discrete segments are inserted, in an anti-sense orientation, into a prepared cloning site of an engineered vector, for example, one recently developed from murine ecotropic and amphotropic retroviruses for use in a wide range of animal cells including human cells.
  • an engineered vector for example, one recently developed from murine ecotropic and amphotropic retroviruses for use in a wide range of animal cells including human cells.
  • a suitable vector is described by Miller, Law and Verne in Mol. Cell Biol. 5:431-432, 1985, hereby incorporated by reference.
  • a representative anti-sense retroviral vector is shown in FIGURE 3.
  • the vector may be constructed in the form of a bacterial plas id for efficient production in large quantities.
  • the bacterial region (indicated by oblique hatching) includes a replication region (o) and an antibiotic drug resistant gene (cross- hatched region) for effective selection.
  • the remaining retroviral region includes the 5' LTR (u3 and u5) that provides the enhancer and promoter sequences for RNA transcription, the tRNA primer attachment site (PR), the packaging sequences (PK), the polypurine tract (PPT) important for reverse transcription, and the 3' LTR (u3 and u5) that provides the termination signals of RNA transcription.
  • An engineered polylinker region (transversely hatched regions) provides convenient restriction enzyme sites for inserting any specific anti-sense polynucleotide (dotted region).
  • the anti-sense poly ⁇ nucleotide should not be homologous to the retroviral replicative genes in a helper virus or packaging cell line used to rescue the resistance-conferring segment(s), below.
  • the engineered vector is introduced by standard gene transfer technology into cell lines that are potentially susceptible to infection by the pathogenic retrovirus, and transformants are selected, e.g., with a drug resistance marker within the retroviral construct or contransf erred with the construct. Transformants are tested and selected for high steady state levels of
  • RNA molecules anti-sense with respect to the targeted retroviral genomic RNA are anti-sense with respect to the targeted retroviral genomic RNA.
  • RNA anti-sense to various segments of the pathogenic retroviral genome are tested for their resistance to infection by the AIDS inducing retroviruses, e.g., as described for the model viruses below.
  • Cell lines containing retroviral constructs most effective in inhibiting retroviral replication are identified.
  • the identified anti-sense RNA containing constructs are then rescued as replication defective viruses using available packaging systems such as that referenced above which provide high titer virus stocks of both the helper virus free and helper virus containing varieties.
  • Clinical trials using the selected anti-sense polynucleotides can follow two general strategies.
  • a first strategy involves inoculating patients having AIDS or pre-AIDS with vector stocks containing helper virus.
  • the vector would infect patient T-cells not yet harboring the AIDS virus, and expression of the anti-sense polynucleotide would render the therapeutically transformed cells resistant to infection by the pathogenic retrovirus.
  • This strategy would stop or retard the progression of the disease, and the resistant T-cells or other stem cells might serve to reconstitute the patient's immune system.
  • T-cells e.g., marrow stem cells, fetal thymus
  • Precursors to T-cells are explanted from the patient (or from allogeneic or isogeneic donors), infected at high multiplicity by helper virus free stocks of the anti-sense vector, and transplanted into the patient using available transplanta ⁇ tion technology.
  • Cells successfully infected with the anti-sense vector could reconstitute the patient's immune system with T-cells resistant to infection by residual pathogenic AIDS virus.
  • the use of a cytotoxic drug resistance gene within the vector may enhance the immune reconstitution by permitting in-vivo selection of cells carrying the anti-sense vector.
  • This transplantation therapy avoids the risk of vector or helper virus induced pathogenicity because the anti- sense vector cannot spread outside of the initially infected cells and their progeny.
  • the following Examples are provided to illustrate the advantages of the present invention and to assist one of ordinary skill in making and using the same.
  • the Examples also indicate how the seminal observation that the anti ⁇ viral activity of anti-sense RNA molecules resident in host cells does not work primarily through the anti-sense inhibition of (viral) gene expression resulted from a failed experiment.
  • the Examples are not intended in any way to otherwise limit the scope of the disclosure and the protection granted by Letters Patent her eon.
  • EXAMPLE 1 Cell test system. To test the effects of anti-sense RNA molecules on the expression of genes such as oncogenes that are typically expressed at very high levels, the gene neo R , which confers on eukaryotic cells resistance to the cytotoxic effects of the neomycin analog G418 (Southern and Berg, J.Mol.App.Genetics 1:327-341,
  • FIGURE 4 shows a representative Northern blot-hybridization analysis of cellular RNA from the A-l cells.
  • RNA from G418 resistant A-l cells (lane b) and from control quail QT35 cells (lane a) were extracted, then denatured and subjected to formaldehyde- agarose gel electrophoresis. The RNAs separated on the gel were blotted onto nitrocellulose filters and hybridized to neo probes.
  • Retroviral vectors containing the neo gene in either the sense or anti-sense orientation were prepared using the 779NC TAQ26 system described by Hughes and Kosik in Virology 136:89-99, 1984.
  • the 779NC TAQ26 system consists of an infectious DNA clone of the Schmidt-Rupin strain of Rous sarcoma virus subgroup A (SR-TSV-A) from which the src gene has been deleted.
  • SR-TSV-A Rous sarcoma virus subgroup A
  • Sense and anti-sense neo R vectors were then recovered as virions from supernatant fluids of chick embryo fibroblasts (CEF) transfected with the engineered constructs. The replication of ⁇ > the recovered viruses on fresh cultured cells was assayed by detection of neo sense or anti-sense sequences in virion RNA released from infected cells using strand specific hybridization probes.
  • the sense neo vector was designated N-10, and the anti-sense neo vector was designated ct N-10.
  • FIGURE 5 shows representative dot-blot hybridizations of viral RNA from different sets (rows a-f) of cultured chick fibroblasts.
  • Supernatant fluid from each culture was collected and virions purified through sucrose gradients and pelleted by centrifugation.
  • Viral RNA was extracted, serially diluted and then blotted on nitrocellulose filters and hybridized to strand specific probes designed to detect either the anti-sense neo R gene (plate A) or the sense p neo gene (plate B) in the viral genomes.
  • Rows a-c are viruses from chronically infected chick fibroblasts, specifically: a, N-10; b, N-10 + G418 treatment; c, ⁇ N-10.
  • Rows d-f are the original stocks of virus from transfected fibroblasts, specifically: d, ex N-10; e, N-10; f, virus derived from the vector (only) as a control.
  • anti-sense neo e.g., viral long terminal repeat or LTR sequences
  • Rows a-c represent viruses harvested from G418 treated quail
  • Rows a-f are original viral stocks from chicken fibroblasts transfected with: d, N-10; e, vector control; and f, ⁇ N-10.
  • R R sense neo sequences from N-10 by neo sense RNA molecules would suggest that the affected replication step is early in the viral life cycle, most probably during the formation and/or processing of viral DNA molecules before their integration into chromosomal DNA.
  • Hybrids between anti-sense RNA molecules and complementary virion RNA sequences or plus strand v-DNA sequences provide a plausible substrate for the excision of specific sequences we have observed.
  • Other steps in retroviral replication could also be inhibited by the anti-sense RNA, but presumably not viral gene expression.

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Abstract

Le procédé ci-décrit permet de développer une résistance à une infection provoquée par des rétrovirus pathogènes. Des cellules susceptibles d'être infectées par un rétrovirus pathogène sont transformées avec un polynucléotide dirigeant la transcription d'ARN qui est complémentaire vers une région du génome rétroviral et qui est efficace pour interrompre la réplication rétrovirale en empêchant sensiblement la formation de virions pathogènes dans la cellule traitée et sa lignée. Les cellules sont de préférence explantées pendant l'étape de transformation thérapeutique, puis introduites dans l'hôte traité.
PCT/US1986/002604 1985-12-05 1986-11-26 Arn anti-detection pour le traitement de maladies retrovirales Ceased WO1987003451A1 (fr)

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US80597685A 1985-12-05 1985-12-05
US805,976 1985-12-05

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WO1988010311A1 (fr) * 1987-06-26 1988-12-29 Syntro Corporation Cytomegalovirus humain recombinant contenant des genes etrangers et son utilisation
EP0310229A1 (fr) * 1987-07-31 1989-04-05 The Board Of Trustees Of The Leland Stanford Junior University Amplification sélective de séquences de cible oligonucléotide
FR2622207A1 (fr) * 1987-10-21 1989-04-28 Agronomique Inst Nat Rech Vecteurs d'integration et d'expression d'un gene heterologue, cellules infectees avec ces vecteurs et procede de production d'une proteine ou de modification genetique d'animaux
EP0215907A4 (fr) * 1985-03-21 1989-06-26 Univ Duke Resistance derivee d'un parasite.
WO1989008146A1 (fr) * 1988-02-26 1989-09-08 Worcester Foundation For Experimental Biology Inhibition du htlv-iii par des oligonucleotides exogenes
WO1990008832A1 (fr) * 1989-01-27 1990-08-09 National Research Development Corporation Vecteur retroviral et son utilisation dans la production d'animaux transgeniques
EP0300687A3 (fr) * 1987-07-14 1990-10-03 City Of Hope Méthode pour l'inhibition du virus immunodéficient humain
EP0374503A3 (fr) * 1988-11-25 1990-11-14 Tadatsugu Prof. Dr. Taniguchi Régulation de l'expression de gène
EP0331939A3 (fr) * 1988-02-16 1991-10-30 Greatbatch Gen-Aid, Ltd Procédé et compositions pour conférer de la résistance aux infections rétrovirales
US5087617A (en) * 1989-02-15 1992-02-11 Board Of Regents, The University Of Texas System Methods and compositions for treatment of cancer using oligonucleotides
WO1992013090A1 (fr) * 1991-01-17 1992-08-06 The General Hospital Corporation Ribozymes de trans-epissage
WO1992013089A1 (fr) * 1991-01-17 1992-08-06 The General Hospital Corporation Ablation de cellules a l'aide de ribozymes de trans-epissage
US5194428A (en) * 1986-05-23 1993-03-16 Worcester Foundation For Experimental Biology Inhibition of influenza virus replication by oligonucleotide phosphorothioates
US5316930A (en) * 1986-04-02 1994-05-31 Pioneer Hi-Bred International, Inc. Virus resistant plants having antisense RNA
US5541291A (en) * 1984-12-31 1996-07-30 Duke University Methods and compositions useful in the diagnosis and treatment of autoimmune diseases
US5580761A (en) * 1988-02-16 1996-12-03 Greatbatch Gen-Aid Ltd. Method of conferring resistance to immunodeficiency viral infection
US5637573A (en) * 1986-05-23 1997-06-10 Agrawal; Sudhir Influenza virus replication inhibiting oligonucleotide analogues and their pharmaceutical compositions
US6010904A (en) * 1995-06-07 2000-01-04 The General Hospital Corporation Cell ablation using trans-splicing ribozymes
US6034233A (en) * 1990-05-04 2000-03-07 Isis Pharmaceuticals Inc. 2'-O-alkylated oligoribonucleotides and phosphorothioate analogs complementary to portions of the HIV genome
US6776986B1 (en) 1996-06-06 2004-08-17 Novartis Ag Inhibition of HIV-1 replication by antisense RNA expression
US7056689B1 (en) 1993-04-30 2006-06-06 Wellstat Biologics Corporation Methods of treating and detecting cancer using viruses

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Cited By (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5541291A (en) * 1984-12-31 1996-07-30 Duke University Methods and compositions useful in the diagnosis and treatment of autoimmune diseases
EP0215907A4 (fr) * 1985-03-21 1989-06-26 Univ Duke Resistance derivee d'un parasite.
US5316930A (en) * 1986-04-02 1994-05-31 Pioneer Hi-Bred International, Inc. Virus resistant plants having antisense RNA
US5194428A (en) * 1986-05-23 1993-03-16 Worcester Foundation For Experimental Biology Inhibition of influenza virus replication by oligonucleotide phosphorothioates
US5637573A (en) * 1986-05-23 1997-06-10 Agrawal; Sudhir Influenza virus replication inhibiting oligonucleotide analogues and their pharmaceutical compositions
WO1988010311A1 (fr) * 1987-06-26 1988-12-29 Syntro Corporation Cytomegalovirus humain recombinant contenant des genes etrangers et son utilisation
EP0300687A3 (fr) * 1987-07-14 1990-10-03 City Of Hope Méthode pour l'inhibition du virus immunodéficient humain
EP0310229A1 (fr) * 1987-07-31 1989-04-05 The Board Of Trustees Of The Leland Stanford Junior University Amplification sélective de séquences de cible oligonucléotide
WO1989003877A1 (fr) * 1987-10-21 1989-05-05 Institut National De La Recherche Agronomique (Inr Vecteurs viraux d'integration et d'expression
US5252465A (en) * 1987-10-21 1993-10-12 Institut National De La Recherche Agronomique (Impa) Avian erythroblastosis virus vectors for integration and expression of heterologous genes in avian cells
FR2622207A1 (fr) * 1987-10-21 1989-04-28 Agronomique Inst Nat Rech Vecteurs d'integration et d'expression d'un gene heterologue, cellules infectees avec ces vecteurs et procede de production d'une proteine ou de modification genetique d'animaux
EP0331939A3 (fr) * 1988-02-16 1991-10-30 Greatbatch Gen-Aid, Ltd Procédé et compositions pour conférer de la résistance aux infections rétrovirales
US5580761A (en) * 1988-02-16 1996-12-03 Greatbatch Gen-Aid Ltd. Method of conferring resistance to immunodeficiency viral infection
US5324643A (en) * 1988-02-16 1994-06-28 Greatbatch Gen-Aid, Ltd. Method of conferring resistance to retroviral infection
WO1989008146A1 (fr) * 1988-02-26 1989-09-08 Worcester Foundation For Experimental Biology Inhibition du htlv-iii par des oligonucleotides exogenes
EP0374503A3 (fr) * 1988-11-25 1990-11-14 Tadatsugu Prof. Dr. Taniguchi Régulation de l'expression de gène
US5157115A (en) * 1988-11-25 1992-10-20 Tadatsugu Taniguchi Regulation of expression
WO1990008832A1 (fr) * 1989-01-27 1990-08-09 National Research Development Corporation Vecteur retroviral et son utilisation dans la production d'animaux transgeniques
US5087617A (en) * 1989-02-15 1992-02-11 Board Of Regents, The University Of Texas System Methods and compositions for treatment of cancer using oligonucleotides
US6034233A (en) * 1990-05-04 2000-03-07 Isis Pharmaceuticals Inc. 2'-O-alkylated oligoribonucleotides and phosphorothioate analogs complementary to portions of the HIV genome
US6071730A (en) * 1991-01-17 2000-06-06 The General Hospital Corporation Cell ablation using trans-splicing ribozymes
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EP0252940A4 (fr) 1989-07-27
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