WO2001070810A2 - Polymorphismes geniques de transporteur 1 de cassettes de liaison d'atp (abc1) et utilisations de ceux-ci dans le diagnostic et le traitement de troubles lipidiques, de maladies cardio-vasculaires et de maladies inflammatoires - Google Patents

Polymorphismes geniques de transporteur 1 de cassettes de liaison d'atp (abc1) et utilisations de ceux-ci dans le diagnostic et le traitement de troubles lipidiques, de maladies cardio-vasculaires et de maladies inflammatoires Download PDF

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WO2001070810A2
WO2001070810A2 PCT/EP2001/002545 EP0102545W WO0170810A2 WO 2001070810 A2 WO2001070810 A2 WO 2001070810A2 EP 0102545 W EP0102545 W EP 0102545W WO 0170810 A2 WO0170810 A2 WO 0170810A2
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abcl
cholesterol
variants
polymorphisms
lipid
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PCT/EP2001/002545
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WO2001070810A3 (fr
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Gerd Schmitz
Marek Bodzioch
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Bayer Aktiengesellschaft
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Priority claimed from EP00106401A external-priority patent/EP1136554A1/fr
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Priority to AU2001244196A priority Critical patent/AU2001244196A1/en
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Publication of WO2001070810A3 publication Critical patent/WO2001070810A3/fr

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    • 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
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • 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

Definitions

  • ATP binding cassette transporter 1 (ABCl) gene polymorphisms and uses thereof for the diagnosis and treatment of lipid disorders, cardiovascular diseases and inflammatory diseases
  • HDL-C plasma high density lipoprotein cholesterol
  • CHD coronary heart disease
  • HDL deficiency is the most common lipid abnormality observed in patients with premature CHD (5,6), with nearly half of all CHD patients having low concentrations of HDL-C.
  • Genetic factors account for approximately 50% of the variation in HDL-C levels in the general population (7), with several common mutations identified in genes encoding for proteins involved in the regulation of plasma HDL-C concentrations and, ultimately, playing a role in the development of CHD (8).
  • FDH familial HDL deficiency
  • TD Tangier disease
  • familial hypoalphaglycoproteinaemia are rare HDL-deficiencies caused by mutations in the gene encoding the ATP -binding cassette transporter- 1 (ABCl).
  • ABCl is a member of the ATP binding cassette family of proteins that are involved in the transmembrane transport of a variety of different molecules, including bile acids, steroid hormones, ions, amino acids, sugars and vitamins (16-19).
  • TD is characterized by severely diminished plasma HDL-C concentrations, reduced levels of low density lipoprotein cholesterol (LDL-C), the deposition of cholesteryl esters in the reticulo-endothelial system with splenomegaly and enlargement of tonsils and lymph nodes (20), as well as a predisposition to neuropathy and CHD (21,22).
  • LDL-C low density lipoprotein cholesterol
  • the HDL deficiency in these patients has been related to a rapid catabolism of HDL and a decrease in ApoA-I induced lipid efflux from various cells including mononuclear phagocytes (23-25).
  • Familial hypoalphaglycoproteinaemia represents the other clinical phenotype that is characterized by a similar disturbance in ApoA-I metabolism but is associated with an enhanced risk of CHD rather than splenomegalie.
  • ApoA-I mediated cellular cholesterol efflux is the first step in the reverse cholesterol transport and prevents excessive cholesterol accumulation in peripheral cells.
  • this process is suggested to contribute to the formation of mature HDL particles, thereby influencing the pool size of HDL in the plasma.
  • ABCl is a cholesterol-responsive modulator of cellular lipid efflux (10) and, thus, plays a significant role in cholesterol homeostasis.
  • ABCl-knockout mice show massively reduced levels of serum lipids and lipoproteins. The expression of ABCl in mucosa cells of the small intestine and the altered lipoprotein metabolism in ABCl-/- mice allows the conclusion that ABCl plays also a major role in intestinal resorption and translocation of lipids into the lymph-system.
  • the identified polymo ⁇ hisms in the ABCl gene can be used for diagnosis and therapy of lipid disorders, cardiovascular diseases, and inflammatory diseases.
  • MDR1 P-glycoprotein is a lipid translocase of broad specificity, while MDR3 P-glycoprotein specifically translocates phosphatidylcholine. Cell 1996; 87:507-17
  • PCR analysis Data provide the relative percentage of homozygous, heterozygous or wild type individuals at the different polymo ⁇ hic sites, n indicates the number of analyzed individuals.
  • Data represent absolute numbers of subjects with the respective allele combination. Data in parenthesis provide the relative percentage within each group.
  • Hybridization probes are designated as detection (DET) or anchor (ANC) probes. As indicated, they are labeled with LightCycler-Red 640 or 705 and fluorescein, respectively. Phosphorylation (ph) of the 3 '-end prevents the elongation of the detection probe. All detection probes recognize wild-type sequences, with the exception of the probe DET1136/mut. Fluo - fluorescein.
  • Genotype distribution of the ABCl polymorphisms in FOS versus VA-HIT subjects are expressed as a percentage of the total number of subjects within each group.
  • FOS and 1,014 for VA-HIT whereas values in parentheses (%) provide the relative percentage of subjects within each group (FOS or VA-HIT). Significant differences in proportions between FOS and VA-HIT are presented in bold face type.
  • the table shows also the codon exchange and the resultant amino acid exchange together with amino acid position and the exon number.
  • the table shows also the codon exchange and the resultant amino acid exchange together with amino acid position and the exon number.
  • This invention provides the four polymo ⁇ hisms G596A, T1 136C, A2589G, and G3456C in the ABCl gene (ABCl gene see Figures 1 and 2), which affect the primary structure of the gene product.
  • the frequencies of these ABCl polymo ⁇ hisms were determined in a young and healthy population (Example 1).
  • ABCl promotes cellular lipid efflux.
  • ABCl is expressed on the plasma membrane and the Golgi complex, mediates ApoA-I associated export of cholesterol and phospholipids from the cell, and is regulated by cholesterol flux.
  • our results indicate that ABCl is involved in lipid export processes involving vesicular budding between the Golgi and the plasma membrane.
  • ABCl may also be involved in the initiation of signal transduction processes stimulating intracellular lipid transport pathways (40).
  • ABCl as a transporter for IL-l ⁇ identifies this gene as a candidate gene for treatment of inflammatory diseases including rheumatoid arthritis and septic shock (27).
  • the cytokine IL-l ⁇ is a broadly acting proin- flammatory mediator that has been implicated in the pathogenesis of these diseases.
  • glyburide as an inhibitor of IL-l ⁇ secretion inhibits not only Caspase I mediated processing of pro-IL-l ⁇ and release of mature IL-l ⁇ but simultaneously inhibits ceramide formation from sphingomyelin mediated by neutral sphingomyelinase and thereby releases human fibroblasts from G 2 -phase cell cycle arrest.
  • Autoimmune disorders that are associated with the antiphospholipid syndrome can be related to dysregulation of B-cell and T-cell function, aberrant antigen processing, or aberrations in the asymmetric distribution of membrane phospholipids.
  • ABC-transporters are, besides their transport function, candidate genes for phospholipid translocases, floppases and scramblases that regulate phospholipid asymmetry (outer leaflet: PC+SPM; inner leaflet: PS+PE) of biological membranes [11].
  • ABC-cassettes are also candidate genes for a genetic basis of antiphospholipid syndromes such as in Lupus erythematodes.
  • Lipid disorders represent diseases characterized by changes in the lipid- and lipoproteinconcentrations in the organism.
  • Cardiovascular diseases represent diseases of the heart and vessel system including coronary heart disease and atherosclerosis.
  • Inflammatory diseases include diseases such as psoriasis and lupus erythematodes.
  • This invention is directed to the nucleotide sequences of the identified ABCl poly- mo ⁇ hism variants, the corresponding protein sequences, antibodies, pharmaceutical compositions, diagnostic tests, vectors, and vector host systems according to the claims.
  • the identified ABCl polymo ⁇ hisms may create immunogenic protein sites that can be used for the generation of antibodies. These antibodies can be used for the detection of mutated ABCl -protein and can be used for the diagnosis of lipid disorders, cardiovascular diseases, and inflammatory diseases.
  • Therapeutic strategies also include the gene therapy of lipid disorders, cardiovascular diseases, and inflammatory diseases.
  • a polynucleotid consisting of a transcription unit is used.
  • the transcription unit consists of at least 9 consecutive nucleotides that are identical or substantial similiar to the ABCl cDNA sequence.
  • the transcription unit consists of at least 9 consecutive nucleotides leading to the production of antisense RNA of wild type ABCl or ABCl containing one or more of the identified polymo ⁇ hisms.
  • the transcription unit is combined with heterologous transcription regulating sequences, which regulate the transcription in human cells.
  • the heterologous transcription regulating sequences include a promoter that is constitutively active in human cells.
  • the heterologous transcription regulating sequences can contain a promoter that can be induced or repressed in human cells by the addition of a regulatory substance.
  • Another therapeutic approach would be the application of antisense molecules or ribozymes or RNA decoys directed towards the ABCl transcripts resulting in a modulation of the ABCl expression. The methodology has been reviewed in (41).
  • This invention also includes a vector containing the above described transcription unit and transcription regulating sequences.
  • Preferred vector is a virus, e.g. retrovirus, adenovirus, adeno-associated virus, he ⁇ es simplex virus, lentivirus, vaccinia virus, Sindbis virus, semliki forest virus.
  • Preferred vectors are also plasmids.
  • the invention also includes a pharmaceutical preparation that contains the recombinant vectors, e.g. in a colloidal dispersion system.
  • Preferred colloidal dispersion systems are liposomes or polylysin ligands.
  • the invention also includes pharmaceutical compositions that contain the above described recombinant vector constructs in combination with nontoxic, inert, pharmaceutically-suited carrier substances.
  • Application of these pharmaceutical compositions can be locally or systemically (e.g. intravenous, intraarterious, intra- muscular, subcutane, intradermal, anal, vaginal, nasal, transdermal, intraperitoneal, oral, or as aerosol).
  • the invention further includes recombinant host cells, especially recombinant eucaryotic host cells, that contain the above described recombinant vector constructs.
  • Fig. 1 The nucleotide sequence of the complete coding region of the human ABCl gene is shown in Fig. 1.
  • the open reading frame of 6603 bp encodes a 2201 amino acid protein with a predicted molecular weight of 220 kDa.
  • the protein sequence of the human ABCl gene is shown in Fig. 2.
  • Sample collection Study subjects were recruited from healthy blood donors at the Institute for Clinical Chemistry (department of transfusion medicine) at the University of Regensburg. Samples from 516 individuals who gave consent to genetic analysis at the time of recruitment were available for the study. At the day of sample collection lipid parameters were determined and DNA-extraction was performed. A local review committee approved the Sample collection for genetic analysis.
  • Genotype analysis was performed on the LightCycler (Roche Diagnostics) as previously described, with minor modifications (29,30).
  • the amplification primers and hybridization probes are listed in table 4. The latter are designated as detection or anchor probes. They are labeled with LightCycler-Red 640 or 705 and fluorescein, respectively.
  • ABCl gene polymorphisms are associated with impaired ApoA-I mediated cholesterol efflux but not with decreased serum HDL or ApoA-1
  • Lipids and Lipoproteins were taken from all blood donors after a 12-h fast. The samples were obtained in polypropylene tubes, centrifuged at 4000 x g for 10 min. Cholesterol, triglycerides, and HDL-cholesterol was measured by standard clinical chemistry protocols as previously described. LDL cholesterol was calculated by the Friedewald equation. ApoA-I was determined on a BNA nephelometer (Dade- Behring) with reagents from Dade-Behring. Cellular Lipid Efflux. Human peripheral blood cells were isolated from lithium- heparin treated blood samples of adult, healthy volunteers.
  • peripheral blood mononuclear cell fraction was separated by density gradient centrifugation over Ficoll-Histopaque 1.007 (Sigma).
  • Cells positive for CD2, CD7, CD 16, CD 19 and CD56 were removed by appropriate magnetic beads (Dynal) leaving > 80% pure monocytes.
  • Isolated monocytes were then cultured at a density of 1.5x10 5 cells/mL in polystyrene culture dishes (100x15mm Petri dish, Falcon) in a serum-free macro- phage medium (Macrophage-SFM, Gibco Life Technologies) supplemented with 50ng/mL human recombinant M-CSF (R&D Systems). After an overnight incubation cells were cholesterol loaded for 24 hrs by addition of enzymatically modified LDL
  • E-LDL 40 ⁇ g/ml
  • the incubation medium was further supplemented with 14 C-cholesterol (1.5 ⁇ Ci/ml) and 3 H-choline (lO ⁇ Ci/ml) in order to label cellular cholesterol and choline containing phosphohpids.
  • cells were stimulated with 10 ⁇ M forskolin during the labeling period.
  • monocytes were washed and incubated for 17 hrs with or without 10 ⁇ g/ml ApoA-I (Sigma) in macrophage medium containing 0.1 % bovine serum albumin and 50ng/mL M-CSF.
  • Lipid efflux was calculated as percentage of disintegrations per minute (dpm) in medium divided by the sum of dpm recovered from medium and cells. The ApoA-I specific efflux is expressed a percent of basal unstimulated efflux observed in serum-free macrophage medium without ApoA-I.
  • VA-HIT a multicenter study initiated in 1991, was designed to address the hypothesis that increasing HDL- C levels with gemfibrozil therapy would reduce the incidence of death from CHD and nonfatal myocardial infarction in men with established CHD, who had reduced HDL-C concentrations ( ⁇ 40mg/dL; 1 mmol/L) and normal LDL-C levels (33).
  • the characteristics of these two groups are provided in table 7.
  • Men participating in VA- HIT were older, and slightly heavier, than men in FOS. With respect to plasma lipids, men in VA-HIT had significantly lower concentrations of plasma total cholesterol
  • HDL-C (-15%), HDL-C (-27%), and LDL-C (-18%), with the greatest difference between the groups noted in HDL-C levels.
  • the G3456C polymo ⁇ hism was rare in both the FOS and VA-HIT populations; however, a significant increase (P ⁇ 0.032) in the frequency of the mutant C allele was observed in VA-HIT subjects (0.038 vs. 0.026).
  • Subjects were men participating in either the Framingham Offspring
  • VA-HIT study (33). FOS subjects were participants in cycle 4 of FOS and were free of clinical evidence of CHD. For VA-HIT, men were recruited at 20 Veterans Affairs medical centers throughout the United States. Eligibility for the trial required a documented history of CHD, an age of ⁇ 74 years, an absence of coexisting conditions, an HDL-C level of ⁇ 40 mg/dL (1.0 mmol/L), an LDL-C of ⁇ 140 mg/dL (3.6 mmol/L), and a triglyceride level of ⁇ 300 mg/dL (3.4 mmol/L).
  • Genomic DNA was extracted from whole blood samples using either QIAamp mini kits (Qiagen) or Generation Capture Column ® kits (Gentra Systems).
  • Genotype analysis was performed using LightCycler technology
  • Plasma lipids and lipoproteins Blood samples were collected from subjects, after a 12-14 h fast, into tubes containing 0.1%> EDTA. Plasma was isolated and frozen for subsequent analysis of plasma lipid and lipoprotein concentrations. Plasma total cholesterol and triglyceride concentrations were determined using enzymatic assays (37). Plasma HDL-C concentrations were measured after dextran sulfate-magnesium precipitation of apoB-containing lipoproteins (38), and LDL-C levels were calculated with the equation of Friedewald, Levy, and Fredrickson (39).

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Abstract

L'invention concerne quatre polymorphismes courants contenus dans le gène codant pour le transporteur 1 de cassette de liaison d'ATP (ABC1), lesquels sont associés à une sortie de cholestérol réduite induite par apoA-I, dans la première étape du transport inverse du cholestérol. Les données produites peuvent être utilisées comme preuve que les polymorphismes communs contenus dans ABC1 modifient directement l'homéostasie lipidique cellulaire, qui est un facteur dans le procédé athérogène. Les fréquences de trois variantes ABC1 communs sont augmentées de manière significative dans une population d'hommes possédant de faibles niveaux de cholestérol HDL et un CHD est établi par rapport à des sujets témoins sans CHD. L'utilisation de polymorphismes ABC1 dans le diagnostic et le traitement de troubles lipidiques, de maladies cardio-vasculaires et de maladies inflammatoires, telles que le psoriasis et le lupus érythémateux.
PCT/EP2001/002545 2000-03-20 2001-03-07 Polymorphismes geniques de transporteur 1 de cassettes de liaison d'atp (abc1) et utilisations de ceux-ci dans le diagnostic et le traitement de troubles lipidiques, de maladies cardio-vasculaires et de maladies inflammatoires WO2001070810A2 (fr)

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Application Number Priority Date Filing Date Title
AU2001244196A AU2001244196A1 (en) 2000-03-20 2001-03-07 Atp binding cassette transporter 1 (abc1) gene polymorphisms and uses thereof for the diagnosis and treatment of lipid disorders, cardiovascular diseases and inflammatory diseases

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP00105820.5 2000-03-20
EP00105820A EP1136552A1 (fr) 2000-03-20 2000-03-20 Polymorphismes du gène codant le transporteur à cassette de fixation à l'ATP 1 (ABC1), et usages pour le diagnostique et le traitement de désordres lipidiques, de maladies cardiovasculaires et de maladies inflammatoires
EP00106401.3 2000-03-24
EP00106401A EP1136554A1 (fr) 2000-03-24 2000-03-24 Polymorphismes du gène codant le transporteur à cassette de fixation à l'ATP 1 (ABC1), et usages pour le diagnostique et le traitement de désordres lipidiques, de maladies cardiovasculaires et de maladies inflammatoires

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000018912A2 (fr) * 1998-09-25 2000-04-06 Bayer Aktiengesellschaft Genes et proteines de cassette de liaison avec atp, destines au diagnostic et au traitement de desordres lipidiques et maladies inflammatoires
WO2001009314A1 (fr) * 1999-07-30 2001-02-08 Institut National De La Sante Et De La Recherche Medicale-Inserm Nouvelles applications des transporteurs de type abca
WO2001030848A2 (fr) * 1999-10-26 2001-05-03 Aventis Pharma S.A. Acides nucleiques du gene humain abc1 et leurs utilisations therapeutiques et diagnostiques

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000018912A2 (fr) * 1998-09-25 2000-04-06 Bayer Aktiengesellschaft Genes et proteines de cassette de liaison avec atp, destines au diagnostic et au traitement de desordres lipidiques et maladies inflammatoires
WO2001009314A1 (fr) * 1999-07-30 2001-02-08 Institut National De La Sante Et De La Recherche Medicale-Inserm Nouvelles applications des transporteurs de type abca
WO2001030848A2 (fr) * 1999-10-26 2001-05-03 Aventis Pharma S.A. Acides nucleiques du gene humain abc1 et leurs utilisations therapeutiques et diagnostiques

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
BODZIOCH M ET AL: "THE GENE ENCODING ATP-BINDING CASSETTE TRANSPORTER 1 IS MUTATED IN TANGIER DISEASE" NATURE GENETICS,NEW YORK, NY,US, vol. 22, no. 4, August 1999 (1999-08), pages 347-351, XP000889766 ISSN: 1061-4036 cited in the application *
BROOKS-WILSON A ET AL: "MUTATIONS IN ABC1 IN TANGIER DISEASE AND FAMILIAL HIGH-DENSITY LIPOPROTEIN DEFICIENCY" NATURE GENETICS,NEW YORK, NY,US, vol. 22, no. 4, August 1999 (1999-08), pages 336-345, XP000889767 ISSN: 1061-4036 cited in the application *
DATABASE EMBL_HUM EBI, Hinxton, U.K.; Accession Number: AF285167, 9 August 2000 (2000-08-09) SCHWARTZ K ET AL: "ABCA1 gene expression and apoA-I-mediated cholesterol efflux are regulated by LXR" XP002177716 -& DATABASE SWISSPROT EBI. Hinxton, U.K.; Accession Number: AAF98175, 21 September 2000 (2000-09-21) SCHWARTZ K ET AL: "ABCA1 gene expression and apoA-I-mediated cholesterol efflux are regulated by LXR" XP002177717 *
LAWN R M ET AL: "THE TANGIER DISEASE GENE PRODUCT ABC1 CONTROLS THE CELLULAR APOLIPOPROTEIN-MEDIATED LIPID REMOVAL PATHWAY" JOURNAL OF CLINICAL INVESTIGATION,NEW YORK, NY,US, vol. 104, no. 8, October 1999 (1999-10), pages R25-R31, XP000884782 ISSN: 0021-9738 cited in the application *
SCHMITZ G ET AL: "ATP-binding cassette transporter A1 (ABCA1) in macrophages: a dual function in inflammation and lipid metabolism?" PATHOBIOLOGY, vol. 67, no. 5-6, 1999, pages 236-240, XP000971329 *
YOUNG S G ET AL: "THE ABCS OF CHOLESTEROL EFFLUX" NATURE GENETICS,US,NEW YORK, NY, vol. 22, no. 4, August 1999 (1999-08), pages 316-318, XP000889764 ISSN: 1061-4036 *

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