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WO1993014188A1 - Virus cible - Google Patents

Virus cible Download PDF

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Publication number
WO1993014188A1
WO1993014188A1 PCT/US1993/000072 US9300072W WO9314188A1 WO 1993014188 A1 WO1993014188 A1 WO 1993014188A1 US 9300072 W US9300072 W US 9300072W WO 9314188 A1 WO9314188 A1 WO 9314188A1
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Prior art keywords
cells
virus
human
envelope protein
gene
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PCT/US1993/000072
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English (en)
Inventor
Michael F. Clarke
Stephen G. Emerson
Bernhard O. Palsson
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The Regents Of The University Of Michigan
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Publication of WO1993014188A1 publication Critical patent/WO1993014188A1/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
    • 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
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • C07K14/54—Interleukins [IL]
    • 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
    • C12N7/00—Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof
    • 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
    • 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
    • C12N2740/16011—Human Immunodeficiency Virus, HIV
    • C12N2740/16041—Use of virus, viral particle or viral elements as a vector
    • C12N2740/16043—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
    • C12N2740/16011—Human Immunodeficiency Virus, HIV
    • C12N2740/16041—Use of virus, viral particle or viral elements as a vector
    • C12N2740/16045—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
    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/16011—Human Immunodeficiency Virus, HIV
    • C12N2740/16211—Human Immunodeficiency Virus, HIV concerning HIV gagpol
    • C12N2740/16222—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
    • 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
    • C12N2810/00—Vectors comprising a targeting moiety
    • C12N2810/50—Vectors comprising as targeting moiety peptide derived from defined protein
    • C12N2810/60—Vectors comprising as targeting moiety peptide derived from defined protein from viruses
    • C12N2810/6045—RNA rev transcr viruses
    • C12N2810/6054—Retroviridae
    • 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
    • C12N2810/00—Vectors comprising a targeting moiety
    • C12N2810/50—Vectors comprising as targeting moiety peptide derived from defined protein
    • C12N2810/80—Vectors comprising as targeting moiety peptide derived from defined protein from vertebrates

Definitions

  • the present invention relates to a virus which has an chimeric envelope protein on its surface that effects the specific binding of the virus to a cell of interest.
  • the present invention also relates to a method of producing such a virus and methods of transducing cells and gene therapy utilizing such a virus.
  • the present invention further relates to stem and/or progenitor cells which have been transduced with such a virus and a packaging cell line which produces such a virus.
  • the principle underlying gene therapy is to, rather than deliver doses of pharmacologic molecules, deliver a functional gene whose RNA or protein product will produce the desired biochemical effect in the target cell or tissue.
  • gene therapy can in principle be permanent within an individual, as the gene will continue to function in the target cells and their progeny.
  • the hematopoietic system is an ideal choice as a delivery system for gene therapy.
  • Hematopoietic cells are readily accessible, simply by bone marrow aspiration or by peripheral blood mononuclear cell harvest. Once the genetic insertion is accomplished in vitro, the treated cells can be reinfused intravenously, after which the genetically transformed cells will home to and develop in the bone marrow. Since mature blood cells circulate throughout the body, the genetically modified cells would deliver the specific gene product to any desired tissue. Most importantly, hematopoietic tissues contain stem cells, which possess extensive (perhaps unlimited) capacities for self-renewal.
  • hematopoietic stem cell gene therapy has broad application, to both diseases specific to the hematopoietic system and to other organ system diseases.
  • both inherited and acquired diseases can be treated by stem cell gene therapy.
  • hemoglobin deficiencies such as ⁇ and ⁇ Thalessemias could be treated by the insertion of the gene coding for the globin ⁇ or ⁇ chain, together with regulatory sequences that confer high level tissue-specific expression of these genes in erythrocytes (Grosveld F, van Assendelft GB, Greaves DR, Kollias G, Cell.
  • sickle cell anemia could be corrected by the genetic insertion of the fetal globin gene into hematopoietic stem cells, as the regulated expression of high levels of fetal hemoglobin are sufficient to prevent sickling in red cells despite the copresence of sickle hemoglobin (Sunshine HR, Hofrichter J, et al. , J. Molec. Biol. 133:435; 1979).
  • lymphocyte immunodeficiency diseases such as severe combined immunodeficiency (SCID) due to adenosine deaminase deficiency.
  • SCID severe combined immunodeficiency
  • Retroviral gene therapy of circulating T cells with the ADA gene has been found to be successful at reducing the clinical immunodeficiency experienced by these patients, but the effects are only temporary, because the transfected T lymphocytes have a finite life span in vivo (Kasid A, Morecki S, Aebersold P, Cornetta K, Culver K, Freeman S, Director E, Lotze MT, Blaese RM, Anderson WF, et al., Proc. Natl. Acad. Sci. U.S.A.
  • the T cell ADA deficiency would be permanently treated by a single gene transfer stem cell treatment (Wilson JM, Danos 0, Grossman M, Raulet DH, Mulligan RC, Proc. Natl. Acad. Sci.. U.S.A.. 87:439-443;1990) .
  • stem cell gene therapy could be useful for protecting stem cells and their progeny from toxic exogenous agents such as viruses or chemotherapy.
  • gene transfer of DNA sequences encoding the TAR binding site of the HIV TAT transactivating factor have been shown to protect T cells from spreading infection by the HIV virus (Sullenger BA, Gallardo HF, Ungers GE, Gilboa E, Cell. 1990;63:601-8). Stable transfection of these sequences into hematopoietic stem cells would result in a pool of T cells, all arising from these stem cells, which would be relatively or absolutely resistant to the spread of HIV.
  • hematopoietic stem cell gene therapy will also be useful for acquired hematopoietic diseases such as leukemia, lymphoma and aplastic anemia. Once the genetic causes of these diseases are discovered, insertion of a gene whose product either overcomes that of the abnormal gene in the cell or corrects it directly (e.g., by splicing out and replacing the gene, via homologous recombination) would correct the abnormality.
  • hematopoietic stem cell gene therapy would be useful for the treatment of diseases outside the hematopoietic system as well.
  • Gene transfer of DNA sequences carrying therapeutic soluble proteins could give rise to mature blood cells which permanently secrete the desired amounts of a therapeutic molecule.
  • this approach could be useful for the treatment of, e.g., diabetes mellitus by the insertion of DNA sequences for insulin along with regulatory DNA sequences that control the proper expression of the transfected insulin gene, perhaps in response to elevated plasma glucose levels.
  • Systemic hypertension could be treated by genetic insertion of stem cells with DNA sequences encoding secretory peptides which act as competitive inhibitors to angiotensin converting enzyme, to vascular smooth muscle calcium channels, or to adrenergic receptors.
  • Alzheimer's disease could possibly be treated by genetic insertion into stem cells of DNA sequences encoding enzymes which break down amyloid plaques within the central nervous system.
  • the major impediments to achieving successful human hematopoietic stem cell gene therapy has been the inability to have cultured stem cells replicate to allow for the stable insertion of genes, and the existence of a retroviral packaging cell line which efficiently infects human stem cells.
  • Successful infection with a retroviral vector requires: binding of the virus to the target cell, penetration into the cell, uncoating of the virus, reverse transcription of viral RNA into DNA, integration of the viral DNA into the host chromosome (using a viral integrase) , and expression of the gene of interest.
  • a retrovirus is an RNA virus consisting of approximately 9,000 bases of RNA. After infection of the host cell, the RNA is converted into double stranded DNA which inserts into the host chromosome.
  • the integrated viral DNA is called the provirus.
  • the provirus consists of two repetitive sequences, called the long terminal repeat (LTR) , at the beginning (5') and the end (3') of the virus sequences.
  • LTR long terminal repeat
  • the 5' LTR directs transcription of virus mRNA's which encode at least two transcripts which encode the viral structural and replication proteins.
  • the first m NA encodes the GAG and POL/INT proteins
  • the second mRNA encodes the envelope proteins.
  • Some viruses also encode transcripts involved in other virus replication functions, for example the HIV REV gene.
  • the host and cell type specificity of the retrovirus is determined in some cases by the ability of the LTR to function in the specific cell and in other cases by the presence of the receptor for the viral envelope on the cell. In the latter case, the cell receptor binds to the viral envelope (ligand) , and the virus enters the cell. It is felt that lentiviruses, such as the HIV retrovirus, enter the cell via virus envelope mediated fusion after the viral envelope binds to the CD4 molecule on the cell surface (Grewe C, Beck A, and Gelderblom HR, J. AIDS. 3, 965-979, 1990).
  • amphotropic murine retroviruses which are used in current packaging cell lines, may enter the host via a pH-independent envelope fusion with endosomal particles (McClure MO, So merfelt MA, Marsh M, and Weiss RA, J. Gen. Virol.. 71, 767-773, 1990).
  • the amphotropic virus envelope binds to a cell surface receptor present on all cells.
  • the virus particle is assembled at the cell membrane.
  • the structural proteins, the GAG proteins in the case of MoMLV, and replication proteins (RT/INT) bind to ⁇ is-acting sequences present in viral RNA, and assemble at the cell surface with the virus envelope proteins and the virus particle buds off the cell surface.
  • the packaging virus In order to accomplish gene therapy, the packaging virus must be able to efficiently infect the host cell.
  • the majority of packaging lines developed to date are based on the mouse MoMLV amphotropic virus. Although this viral coat will bind to human cells, it is very inefficient at infecting human hematopoietic cells (Gruber DE, Finley KD, Hershberg RM, Katzman SS, Laikind PK, Siegmiller JE, Friedmann T, Vee JK and Jolley DJ, Science. 230, 1057-1061, 1985; Hogge DE & Humphries RK, Blood. 69, 611-617, 1987).
  • xenotropic virus a virus which infects species other than mouse packaging cell line
  • 3T3 xenotropic packaging cell lines a virus which infects species other than mouse packaging cell line
  • a Gibbon Ape Leukemia Virus envelope which recognizes a widely distributed cell receptor, has been used to make a 3T3 pseudotype packaging cell line (Miller D et al. , J. Virol.. 65, 2220-4, 1991) .
  • the ideal packaging virus would have an envelope (ligand) which recognizes a receptor present only on the subset of cells which are the intended target for gene therapy.
  • This cell type specificity would have multiple advantages over the present amphotropic and xenotropic packaging cell lines which recognize a receptor present on all cell types.
  • human hematopoietic stem cells probably only represent .01% or less of mononuclear bone marrow cells.
  • these cells appear to grow only when in contact with stromal cells, which represent a large proportion of bone marrow cultures.
  • extremely high viral titers are required to infect a stem cell. These high viral titers are very difficult to obtain.
  • the ideal packaging line would be constructed using a human retrovirus envelope, since these viruses have evolved to efficiently infect human cells.
  • the known human retroviruses HTLV and HIV
  • T-cell specificity is due to the fact that only T-cells express the viral receptor on their cell membranes.
  • studies have shown that the HIV envelope will form virions with the GAG and POL proteins of an amphotropic virus (Wilson K, Reitz MS, Okayama H, and Eiden MB, J. Virol.. 63, 2374-8, 1989).
  • U.S. patent no. 4,731,324 describes a viral lysis assay in which modified viral particles are utilized. Specifically, the virus particles contain on their surface non-viral anti- analyte molecules which are composed of an anti-analyte which is derivatized with a lipid moiety which anchors the molecule to the virus lipid bilayer surface.
  • U.S. patent no. 4,948,590 discloses avidin- or streptavidin-conjugated liposomes which can be utilized as a vehicle for site-specific targeting of encapsulated drugs or other macromolecules, including retrovirus vectors.
  • the conjugated liposomes are prepared by coupling, e.g., the carboxyl residues of streptavidin to the phospholipid amino groups of the liposome.
  • U.S. patent no. 4,786,590 describes the use of monoclonal antibodies which bind to one or more determinant sites of cell surface membrane receptors (CSMR) for directing agents to the site of transformed cells.
  • CSMR cell surface membrane receptors
  • agents include radionuclides, toxins, and factors involved in complement lysis.
  • U.S. patent no. 4,701,416 teaches the use of protein carriers to which is conjugated an amino acid sequence which is homologous to at least a portion of gp70 envelope protein of FeLV as a FeLV immunogen.
  • carrier proteins include keyhole limpet hemocyanin, ovalbumin, porcine thyroglobulin, and bovine serum albumin.
  • U.S. patent no. 4,861,588 describes hepatitis B vaccines containing an amino acid chain corresponding to a chain of amino acids in the pre-S region linked to a carrier. Lipid vesicles are described as the preferred carrier.
  • U.S. patent no. 4,859,769 teaches the use of liposomes which may be tagged with a viral component which recognizes the. second-step receptor on the surface of a cell.
  • the liposome may be used to carry a toxic drug.
  • U.S. patent no. 4,545,985 discloses a method for modifying Pseudomonas exotoxin for conjugating the exotoxin to a monoclonal antibody which binds to a cell surface membrane receptor to form an immunotoxin.
  • viruses which contain, on their surface, proteins specific for receptors found on the membrane of targeted cells. Further, there remains a need for methods and packaging cell lines to prepare such retroviruses.
  • viruses including retroviruses, which possess on their surface at least one chimeric envelope protein which binds specifically to a receptor found on targeted cells. It is another object of the present invention to provide viruses, including retroviruses, which contain on their surface at least one chimeric envelope protein which specifically binds to mammalian, including human, stem and/or progenitor cells.
  • viruses including retroviruses, which possess on their surface at least one chimeric envelope protein which specifically binds to human hematopoietic stem and/or progenitor cells.
  • a genetically engineered virus including a retrovirus, containing a therapeutic gene packaged in a virion with a chimeric envelope protein which specifically binds to a receptor found on the membrane of the stem and/or progenitor cell.
  • viruses including retroviruses
  • the viral membrane contains a chimeric envelope peptide which will specifically bind to a targeted cell and that such retroviruses may be used to transduce specific targeted cells.
  • the present invention relates to the use of a genetically engineered retroviral packaging cell line that has altered the viral envelope such that it contains a peptide which will bind to a molecule on the membrane of the target cell.
  • the present invention can be used for the transfer of any genetic information that can be engineered into a recombinant retrovirus, or any other gene transfer vector that requires a virus for delivery.
  • the present invention also relates to a stromal cell line which supports hematopoiesis and is transfected with the retrovirus packaging vectors.
  • Genetically modified human stem cells produced by the present invention can be applied to a wide variety of clinical diseases, as described in the preceding text. Further, the present invention also provides methodology that enhances the efficiency of genetic transfer into human progenitor cells.
  • the present invention includes a genetically modified human stem cell produced with the use of the present retroviruses and/or packaging cell line.
  • tissue specificity of retrovirus infection can be conferred by virus envelope (ligand) binding to a cell receptor, and both stem and progenitor cell specific ligands and receptors are known
  • virus envelope ligand
  • stem and progenitor cell specific ligands and receptors are known
  • the construction of chimeric viral envelope/stem cell ligand molecules will confer stem and progenitor cell tropism to virus particles.
  • the HIV viral membrane gene has been cloned, and the envelope amino acids which bind to the CD4 antigen on the T-cell membrane are known (Lasky LA, et al. Cell. 50, 975-985, 1987) .
  • This knowledge provides the information needed to substitute into the gene for the HIV envelope CD4 antigen binding site a sequence that encodes the peptide that is known to bind to the cell membrane of any specific targeted cell of interest.
  • virus particles that infect target cells efficiently and selectively, because the virus particles will now encode a chimeric envelope protein which will bind specifically to the stem and/or progenitor cell receptor molecule, and will not bind to cell types which do not have the receptor.
  • CF cystic fibrosis
  • the present invention includes a human stromal cell line derived from, e.g., fetal liver (which supports hematopoiesis) or adult bone marrow for use as the packaging cell line.
  • a retrovirus envelope mRNA usually encodes a protein which is cleaved into two peptides. These peptides are inserted into the cell membrane and are associated as a dimer or tetramer.
  • the viral envelope consists of an intracellular and extracellular domain.
  • the present invention is achieved by genetically engineering the extracellular domain of the retroviral envelope so that it consists of a chimeric molecule which will associate as a dimer with the small envelope peptide.
  • the viral envelope extracellular domain contains a ligand which will specifically bind to the cell membrane of interest.
  • the target cells are human hematopoietic stem cells
  • the genes for the c-kit ligand, the Leukemic Inhibitory Factor (LIF) , the CS-1 peptide of the alternatively spliced non-type III connecting segment (IIICS) of human plasma fibronectin, or any other ligand which recognizes human stem cells may be substituted for the CD4 binding amino acids in the HIV envelope.
  • LIF Leukemic Inhibitory Factor
  • IIICS alternatively spliced non-type III connecting segment
  • the appropriate ligand is selected and substituted for all or a portion of the ligand naturally occurring on the virus envelope. The selection of the appropriate ligand for the target cell of interest is well within the abilities of the artisan of ordinary skill.
  • substitution of a ligand specific for the target cell receptor it is meant that either the entire protein or a portion thereof may be substituted for a portion of the ligand naturally occurring on the virus envelope.
  • the selection of the particular portion of a ligand responsible for the binding to a target cell and the optimization of the size of the portion of both ligand being replaced and the ligand being inserted are within the capabilities of one of ordinary skill in the art.
  • the replacement of the portion of the ligand, naturally occurring on the virus envelope and responsible for binding to a cell surface, with the ligand or portion thereof responsible for binding to the target cell is achieved by altering the sequence of the gene encoding the ligand naturally occurring on the virus envelope using recombinant DNA technology.
  • a portion of the gene which encodes the sequence of the naturally occurring ligand necessary for binding to the natural receptor is excised and replaced with either the DNA sequence encoding the entire ligand which binds to the target cell or any portion of the ligand which results in binding to the target cell.
  • the present invention relates to retroviruses which have been engineered to specifically bind to human stem and/or progenitor cells.
  • Human hematopoietic cells may be isolated from bone marrow, peripheral blood, fetal liver, or umbilical cord blood. It is further preferred that these cells are cultured as described in U.S. Patent Applications Serial Nos. 07/737,024, 07/628,343, and 07/366,639, which are incorporated herein by reference, under conditions in which about 50% of the medium and serum is exchanged daily, and the replacing volume is supplemented with hematopoietic growth factors.
  • Such hematopoietic growth factors may be supplied exogenously by addition of the growth factors to the culture medium or may be present in the medium as a result of the presence of transformed stromal cells in the culture which endogenously produce the growth factors. It should be noted that these conditions result in formation of a stroma during the time of the retroviral infection.
  • the growth factors are GM-CSF (0.1 to 100 ng/ml/day, preferably about 5 ng/ml/day) plus IL-3 (0.1 to 100 ng/ml/day, preferably about 10 ng/ml/day) with or without IL-l ⁇ (10 to 100 U/ml per 3 to 5 day period, preferably about 50 U/ml/4 day period) , with or without c-kit ligand (Mast cell growth factor) (1 to 100 ng/ml/day, preferably about 10 ng/ml/day) , with or without IL-6 (1 to 100 ng/ml/day, preferably about 10 U/ml/day) .
  • GM-CSF 0.1 to 100 ng/ml/day, preferably about 5 ng/ml/day
  • IL-3 0.1 to 100 ng/ml/day, preferably about 10 ng/ml/day
  • IL-l ⁇ 10 to 100 U/ml per 3 to 5 day period, preferably about 50
  • the retroviral infection (transduction) of the cells is preferably carried out as described in U.S. Patent Application Serial No. 07/740,590, which is incorporated herein by reference.
  • transduction it is meant the delivery of genes into cells by means of a viral vector.
  • the retroviral infection is performed by including supernatants produced by retroviral packaging lines infected with recombinant retrovirus, during the first days of the culture, or by culturing the cells directly over the infected retroviral packaging lines themselves. In the preferred embodiment, retroviral supernatants are used, and the period of incubation in the presence of virus is about 14 days.
  • the retrovirus of the present invention used to infect the target cell should of course also contain within its genome the genetic information encoding the desired therapeutic gene and any required regulatory sequence.
  • the choice of therapeutic gene will depend on the particular disease or condition to be treated. Generally speaking, the therapeutic gene and any attendant regulatory sequences should be no more than approximately 6 to 8 kb in size. Examples of therapeutic genes have been discussed above, and the choice of the particular therapeutic gene is within the abilities of those skilled in the art.
  • the present retroviruses may be prepared by the following method, which is described in terms of the HIV envelope protein containing the CD4 binding domain. However, it is to be understood that other envelope proteins for which the binding domain is known may take the place of the exemplified HIV envelope protein.
  • Two plasmids which contain the necessary genes for retrovirus packaging may be constructed.
  • One plasmid may include the GAG, POL, and RT genes, with or without the HTLV TAT and/or REV genes, of either MoMLV, HTLVI, or HIV.
  • the second plasmid may include a genetically modified HIV envelope gene which has the CD4 binding domain (Olshensky U, Helseth E, Furma C, Li J, Haseltine W, Sodroski J, J. Virol.. 64, 5701-5707, 1990) replaced by either the c-kit ligand (Zsebo KM et al. Cell. 63, 195-201, 1990; Anderson KM et al. Cell.
  • human fetal liver stroma or bone marrow stroma may be immortalized with the SV40 large T antigen, and a transformed cell line which supports hematopoiesis may then be selected. These cells may then be transfected with the packaging vectors, and a virus producer cell line selected to act as the packaging line.
  • viruses of the present invention are characterized by the presence, on their envelope, of multiple copies of at least one type of chimeric envelope protein which results in the virus binding specifically to a receptor on a cell surface to which the natural virus would not specifically bind.
  • natural virus it is meant the virus which has on its surface the naturally occurring envelope protein.
  • a ligand (envelope protein) is said to specifically bind to a cell surface receptor, if the ligand binds to that cell surface receptor preferentially in the presence of other cell surface receptors to which it does not specifically bind.
  • ligands which specifically bind to cell surface receptors do so with an affinity constant of 10 ⁇ 6 to 10 ⁇ 12 M.
  • any gene which is inserted into a recombinant retrovirus vector together with suitable promoter and enhancer elements that permit its expression can be incorporated into human hematopoietic stem cells.
  • the achievement of the present invention derives from the conditions that permit stem cell infection through the use of a genetically altered retroviral envelope gene which confers binding specificity for human stem and/or progenitor calls, and the use of a human stromal cell line as the packaging cell line.
  • LIF LIF is known to be found on mouse embryonal stem cells and early hematopoietic cells but not on mature tissue cells. Thus, this protein should have specificity for stem and early progenitor cells. It should be noted that other ligands such as IL1 through 10, GM-CSF, the c-kit ligand, the ligand for Flk 2, etc. can also be used. In addition, just the receptor binding sequences of the ligand may be used, and these sequences may be substituted into different parts of the HIV ENV gene, or into the binding protein (ENV) genes of other retroviruses or other viruses. Furthermore, some or all of the extracellular domain, not including the portion of the extracellular domain which associates with the retrovirus small envelope protein, of the ENV gene may be deleted.
  • ENV binding protein
  • an HIV ENV, LIF chimeric retroviral ENV gene may be made as follows.
  • the HIV ENV coding region may be isolated in two parts by using the polymerase chain reaction (PCR) using specific primers designed to introduce useful restriction endonuclease sites into the ENV gene. Since amino acids 410-421 (Ratner L, et al, Nature. 313, 277-284, 1985), contain sequences essential for CD4 binding (Lasky LA, Cell. 50, 975-985. 1991), they may be deleted to abrogate CD4 binding.
  • the primers may be CCGTCGACATGAGAGTGAAGGAGAAA TATCAGCACTTG and the sequence
  • the HIV clone pBHIO may be used as a template for the PCR amplification of part of the ENV gene. Two more primers,
  • CCGGAATTCAGTGGACAAATTAGATGTTCATCAAATATTACAGGG and CCGTCGACTTATAGCAAAATCCTTTCCAAGCCCTGTCT may be used to amplify the HIV clone pBHIO ENV (Hahn B et al, Nature. 312, 166, 1984) .
  • the two PCR products may be digested with the restriction endonuclease Sal 1 and Eco Rl, and then included in a tripartite ligation reaction containing Sal 1 digested pSub 1, a eukaryotic expression vector (Castle VP, Varani J, Fligiel S, Prochownik EV, and Dixit VM, J. Clin. Inv..
  • the ligation reaction may be transfected into E. coli, and a recombinant plasmid containing the HIV envelope gene with a deletion of the bases encoding amino acids critical for CD4 binding may then be identified. There is now an Eco Rl restriction endonuclease site substituted for the deleted CD4 binding region.
  • a clone containing only the coding sequences of LIF may be isolated by PCR amplification of LIF (Moreau J-F et al. Nature. 336,690-692, 1988)) using the primers CCGAATTCCAGCCCCCTCCCCATCACCCCTGTCAACGCCACCTGT and CCGAATTCGAAGGCCTGGGCCAACACGGCGATGATCTG.
  • the PCR amplified LIF coding sequence is now flanked by an Eco Rl restriction endonuclease site.
  • the PCR product may then be digested with the restriction endonuclease Eco Rl and ligated into the Eco Rl site which was introduced into the HIV ENV gene.
  • a clone with an in-frame substitution of LIF for the CD4 binding region of the HIV ENV gene may be isolated and transfected into a cell line expressing the GAG POL genes of either an amphotropic MoMLV, or another retrovirus. This results in a packaging cell line which produces virions with a chimeric LIF/HIV envelope when transfected with a recombinant retroviral vector.

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Abstract

Virus produits par génie génétique et comprenant un gène produit par génie génétique ainsi qu'une protéine d'enveloppe chimérique qui se lie spécifiquement à un récepteur de cellule cible auquel la protéine d'enveloppe naturelle ne se lie pas. Ces virus peuvent être utilisés pour la thérapie génique à spécificité de type cellulaire. La transduction de cellules précurseurs et/ou de cellules souches humaines à l'aide de ces virus contenant des protéines d'enveloppe chimériques qui se lient spécifiquement aux cellules précurseurs et/ou aux cellules souches humaines s'effectue avec une efficacité et une spécificité élevées, en particulier lorsque de tels virus sont incubés avec des cellules précurseurs et/ou des cellules souches humaines cultivées dans des conditions d'échange de milieu rapide.
PCT/US1993/000072 1992-01-17 1993-01-13 Virus cible WO1993014188A1 (fr)

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