WO2001027254A2 - Gentransfervektoren zur therapie von autoimmunerkrankungen und erkrankungen mit immunpathogenese - Google Patents

Gentransfervektoren zur therapie von autoimmunerkrankungen und erkrankungen mit immunpathogenese Download PDF

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WO2001027254A2
WO2001027254A2 PCT/DE2000/003608 DE0003608W WO0127254A2 WO 2001027254 A2 WO2001027254 A2 WO 2001027254A2 DE 0003608 W DE0003608 W DE 0003608W WO 0127254 A2 WO0127254 A2 WO 0127254A2
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cells
nucleic acid
apoptosis
vectors
acid sequence
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PCT/DE2000/003608
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German (de)
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French (fr)
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WO2001027254A3 (de
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Fritz Schwarzmann
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Fritz Schwarzmann
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Priority to AU21479/01A priority Critical patent/AU782255B2/en
Priority to JP2001530459A priority patent/JP2003513619A/ja
Priority to EP00984828A priority patent/EP1220900A2/de
Priority to IL14880500A priority patent/IL148805A0/xx
Priority to CA002387146A priority patent/CA2387146A1/en
Priority to DE10083095T priority patent/DE10083095D2/de
Publication of WO2001027254A2 publication Critical patent/WO2001027254A2/de
Publication of WO2001027254A3 publication Critical patent/WO2001027254A3/de

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    • A61K39/0005—Vertebrate antigens
    • A61K39/0008—Antigens related to auto-immune diseases; Preparations to induce self-tolerance
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    • 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
    • A—HUMAN NECESSITIES
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    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70575—NGF/TNF-superfamily, e.g. CD70, CD95L, CD153, CD154
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    • 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
    • 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
    • A61K2035/124—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells the cells being hematopoietic, bone marrow derived or blood cells
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • 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
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    • C12N2800/00—Nucleic acids vectors
    • C12N2800/40—Systems of functionally co-operating vectors
    • C—CHEMISTRY; METALLURGY
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    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • FIG. 4 graphically shows the result of the reduction in inflammation in the lungs, kidneys and liver in mouse cytomegalovirus-infected mice which were treated before infection with AdFasL-infected antigen presenting cells (APC).
  • B6-gld / gld- and B6- lprllpr-MM.se. were infected with mouse cytomegalovirus and treated 28 days after infection with APCs, either with Ad-CMVLacZ (FasL negative control), with mouse cytomegalovirus (APC + MCMV), with AdFasL (FasL positive control) or with mouse cytomegalovirus and AdFasL (MCMV + AdFasL) were infected.
  • Ad-CMVLacZ FesL negative control
  • APC + MCMV mouse cytomegalovirus
  • AdFasL FesL positive control
  • MCMV + AdFasL mouse cytomegalovirus and AdFa
  • eukaryotic promoter elements such as the CMV promoter and the SV40 promoter are represented by dark arrows, prokaryotic promoters such as the SP6 and the T7 promoter are represented by thin angled arrows.
  • Interfaces for selected restriction endonucleases such as Bam ⁇ l, EcoRI, Xh ⁇ l and HincfiR are marked with the identification of the nuclease. are marked by thin bars regulatory nucleic acid sequences such as the polyadenylation sequence of the SV40 virus (SV40polyA) and the LRES, the internal ribosome binding site.
  • the cells modified by means of the vectors according to the invention comprising the combination of nucleic acid sequences according to the invention, express antigens which are recognized by immunopathogenic immune cells.
  • immunopathogenic immune cells play a special role in the pathogenesis of a defined disease, since they specifically recognize (endogenous) antigens and coordinate an immune reaction against these antigens and the antigen-expressing cells.
  • the antigens introduced into the cells with the vectors according to the invention can be specific for certain diseases or specific for the attacked organ, tissue or the attacked cell type.
  • the vectors according to the invention additionally code for ligands which trigger apoptosis. These ligands that trigger apoptosis induce natural cell death in the immunopathogenic immune cells that recognize the antigens.
  • Retroviruses particularly suitable for the production of retroviral gene transfer vectors include representatives from the group of avian leukemia viruses, bovine leukemia viruses, mouse leukemia viruses, Mink-ce // ocw5-inducing viruses, mouse sarcoma viruses, Gibbon viruses. Leukemia viruses, feline leukemia viruses, reticuloendothelial viruses and Rous sarcoma viruses. Mouse leukemia viruses such as representatives 4070A and 1504A, Abelson (ATCC No. VR-999), Friend (ATCC No. VR-245), Graffi, Gross (ATCC No. VR-590), Kirsten, are particularly suitable. Harvey's Sarcoma Virus and Rauscher (ATCC No.
  • the nucleic acids can include retroviral gene transfer vectors
  • the expanded packaging signal from Mo-MLV contains sequences beyond nucleotide 567, the start of the Gag / Pol gene (nucleotide 621) and ends beyond nucleotide 1560. Therefore, deletion of the sequence beyond nucleotide 567 allows a retroviral from the Mo-MLV
  • Rheumatoid artritis was one of the first systemic diseases that was attributed to autoimmune mechanisms. Essentially two aspects of rheumatoid artritis suggest a fundamental immune system disorder as the cause of the disease. First, the often very massive infiltration of lymphocytes, including CD4 + T cells, in the inflamed hypertrophic synovial tissue, and second, the production of large amounts of rheumatoid factor from B cells and plasma cells in the synovium. Rheumatoid factors are antibodies that are directed against structuring regions of the IgG heavy chain.
  • Antibodies against various autoantigens have been detected in prediabetic patients and those with recently diagnosed diabetes.
  • CD4 + and CD8 + T cells with different specificity were detected.
  • the gene therapy vectors within the scope of the invention described here carry functional areas or genes which code and express for antigenic proteins, protein fragments or epitopes and combinations of epitopes which represent targets for CD4 + and / or CD8 + T cells.
  • Antigenic proteins in the sense of this invention are those proteins which are recognized by T cells of persons with diabetes in connection with MHC class I or MHC class II on syngeneic cells.
  • the heat shock protein Hsp60 represents another target for activated immune cells in type I diabetes.
  • the vectors encode and express, for example, the area of AS 437-460
  • Caspases are a group of cysteine proteases. So far, 14 caspases have been identified in mammals (including humans). Caspases recognize motifs consisting of 4 amino acids, which they cut on the carboxyl side of the amino acid aspartate. Caspases are synthesized as zymogens, i.e. they are precursor proteins with a very low activity, which are activated by proteolytic cleavage. The activated enzymes are heterotetramers, each consisting of two identical cleaved subunits. Some caspases are activated by autoproteolytic cleavage, others by additional caspases.
  • the vectors according to the invention can comprise nucleic acid sequences which code for the protein TRAIL (APO-2L) which binds to the specific receptor molecules TRAIL-Rl (DR4), TRAIL-R2 (KILLER, DR5, TRICK2), TRAIL-R3 (LIT, DcRl ) and TRAIL-R4 (TRUNDD, DcR2) binds.
  • TRAIL has been detected naturally on a number of cells, such as type II interferon-stimulated monocytes, cytomegalovirus-infected fibroblasts, type I interferon and antigen-stimulated T cells or NK cells.
  • the vectors according to the invention either synthesize a single antisense RNA or a combination of different antisense RNAs which are specifically directed against individual adapter proteins.
  • the vectors express an antisense RNA which contains individual regions which are in each case specific for an adapter protein and, in combination, prevents the expression of several adapter proteins.
  • the prodrugs used must have significantly lower toxicity than the activated substances and must be good substrates for the activating enzymes. In addition, these substances must be sufficiently chemically stable under physiological conditions and have good pharmacological and pharmacokinetic properties. Depending on the type, some prodrugs are absorbed into the cells and converted intracellularly into the toxic substance. Other prodrugs are activated extracellularly. Accordingly, the prodrugs or the activated toxic substances must be easily absorbed by the cells.
  • sequences and functional regions can also be transcription termination and polyadenylation sequences.
  • Some very efficient poly-A signals for use in mammalian expression vectors are derived, for example, from the bovine growth hormone, the mouse ⁇ -globin, the SV40 early transcription unit and the herpes simplex thymidine kinase gene. Prokaryotic transcription terminators are described in detail and their incorporation shows diverse positive effects on gene expression. In eukaryotes identified a consensus sequence with the nucleotide sequence ATC AAA (A7T) TAG GAA GA in the termination region of 9 genes.
  • An internal ⁇ bosomal entry point can be used to express two or more genes under the transcriptional control of a consumable or regulable promoter.
  • IRES internal ⁇ bosomal entry point
  • the IRES of picornaviruses and the hepatitis C virus, the BiP (immunoglobulin heavy chain binding protein) are used.
  • retroviral 7i? ES sequences are used
  • Lymphocytes accessory cells and effector cells are the most prominent representatives of the acquired immune system. Lymphocytes are able to specifically recognize foreign antigens and to stimulate a specific humoral and cell-mediated immune response. Different subpopulations of lymphocytes are known which differ in the type of antigen recognition and the specific effector functions. B lymphocytes are the producers of antibodies. They recognize extracellular and antigens presented on the surface of cells and differentiate into antibody-secreting plasma cells after contact with an antigen. T lymphocytes, the mediators of the cell-mediated immune response, can be divided into several subtypes, of which the CD4 + T helper cells and the CD8 ⁇ cytotoxic T cells are most significant. Helpers and cytotoxic T cells have a restricted specificity for antigens.
  • the region coding for the thymidine kinase was first cloned into the vector pcDNA3 via the interfaces for Hz «dIII and BamKl. Then the fragment coding for crmA was used via them interfaces of Bam ⁇ l and Xhol. Finally, the nucleic acid fragment comprising the ERES was cloned between FasL and PLP via the recognition sequence for Bam ⁇ l.
  • the nucleic acid sequences of the two vectors pcDNA3-FasL-ERES-crmA and pcDNA3-TK-ERES-PLP are listed as SEQ ED NO: 1 and SEQ ID NO: 2, respectively.

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PCT/DE2000/003608 1999-10-12 2000-10-12 Gentransfervektoren zur therapie von autoimmunerkrankungen und erkrankungen mit immunpathogenese WO2001027254A2 (de)

Priority Applications (6)

Application Number Priority Date Filing Date Title
AU21479/01A AU782255B2 (en) 1999-10-12 2000-10-12 Gene transfer vectors for treating autoimmune diseases and diseases with immunopathogenesis by therapy
JP2001530459A JP2003513619A (ja) 1999-10-12 2000-10-12 自己免疫疾患および免疫病因を含む疾患を治療するための遺伝子導入ベクター
EP00984828A EP1220900A2 (de) 1999-10-12 2000-10-12 Gentransfervektoren zur therapie von autoimmunerkrankungen und erkrankungen mit immunpathogenese
IL14880500A IL148805A0 (en) 1999-10-12 2000-10-12 Gene transfer vectors
CA002387146A CA2387146A1 (en) 1999-10-12 2000-10-12 Gene transfer vectors for treating autoimmune diseases and diseases with immunopathogenesis by therapy
DE10083095T DE10083095D2 (de) 1999-10-12 2000-10-12 Gentransfervektoren zur Therapie von Autoimmunerkrankungen und Erkrankungen mit Immunpathogenese

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DE19948983.1 1999-10-12
DE19948983 1999-10-12

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WO2001027254A3 WO2001027254A3 (de) 2002-02-28

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WO2001057228A1 (en) * 2000-02-02 2001-08-09 Genzyme Corporation Methods for treatment of restenosis using adenoviral vectors and transgene products
JP2005501917A (ja) * 2001-09-07 2005-01-20 ザ トラスティーズ オブ ボストン ユニバーシティ 免疫複合体関連疾患を処置するための方法および組成物
CN101875920B (zh) * 2009-12-29 2012-04-18 中国人民解放军第三军医大学 DcR3和GAD65双基因共表达重组腺病毒及其制备方法和应用

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JP2007195440A (ja) * 2006-01-25 2007-08-09 Bachtech Kk バキュロウイルスベクターを利用したｈｉｖ感染症治療薬
GB0706631D0 (en) * 2007-04-04 2007-05-16 King S College London Nucleic acids and libraries
AU2017244108B2 (en) * 2016-03-29 2021-03-18 University Of Southern California Chimeric antigen receptors targeting cancer
KR101671361B1 (ko) * 2016-08-08 2016-11-01 에스씨엠생명과학 주식회사 TYMP(thymidine phosphorylase) 단백질을 유효성분으로 포함하는 탈모 예방 또는 치료용 약학적 조성물
AU2022418605A1 (en) * 2021-12-22 2024-06-20 Memorial Hospital For Cancer And Allied Diseases Cells expressing fas ligand and cflip polypeptides and uses thereof

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WO2000073477A1 (en) * 1999-05-27 2000-12-07 Genzyme Corporation Methods for induction of tolerance to adenoviral vectors and transgene products

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WO2001057228A1 (en) * 2000-02-02 2001-08-09 Genzyme Corporation Methods for treatment of restenosis using adenoviral vectors and transgene products
JP2005501917A (ja) * 2001-09-07 2005-01-20 ザ トラスティーズ オブ ボストン ユニバーシティ 免疫複合体関連疾患を処置するための方法および組成物
CN101875920B (zh) * 2009-12-29 2012-04-18 中国人民解放军第三军医大学 DcR3和GAD65双基因共表达重组腺病毒及其制备方法和应用

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AU782255B2 (en) 2005-07-14
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