EP2627783A2 - Séquences de marqueur pour la sclérose en plaques et leur utilisation - Google Patents

Séquences de marqueur pour la sclérose en plaques et leur utilisation

Info

Publication number
EP2627783A2
EP2627783A2 EP11784434.0A EP11784434A EP2627783A2 EP 2627783 A2 EP2627783 A2 EP 2627783A2 EP 11784434 A EP11784434 A EP 11784434A EP 2627783 A2 EP2627783 A2 EP 2627783A2
Authority
EP
European Patent Office
Prior art keywords
multiple sclerosis
marker sequences
case
marker
seq
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP11784434.0A
Other languages
German (de)
English (en)
Inventor
Angelika Lueking
Axel Kowald
Heike GÖHLER
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Protagen GmbH
Original Assignee
Protagen GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Protagen GmbH filed Critical Protagen GmbH
Publication of EP2627783A2 publication Critical patent/EP2627783A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • C12N15/10—Processes for the isolation, preparation or purification of DNA or RNA
    • C12N15/1034—Isolating an individual clone by screening libraries
    • C12N15/1086—Preparation or screening of expression libraries, e.g. reporter assays
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/28—Neurological disorders
    • G01N2800/285—Demyelinating diseases; Multipel sclerosis

Definitions

  • the present invention relates to novel marker sequences for multiple sclerosis and their diagnostic use, including a method for screening potential drugs for multiple sclerosis disorders by means thereof
  • the invention relates to a
  • diagnostic device containing such marker sequences for multiple sclerosis, in particular a protein biochip and its use.
  • Protein biochips are gaining an increasing industrial
  • Protein biochips require the necessary proteins to be available. In particular,
  • GATEWAY recombinational cloning application to the cloning of large numbers of open reading frames or ORFeems. Methods Enzymol, 328, 575-592).
  • ORFeems open reading frames
  • Methods Enzymol, 328, 575-592 are strongly related to the progress of genome sequencing projects and the annotation of these gene sequences.
  • determination of the expressed sequence is due
  • the cDNA of a particular tissue in a bacterial or a eukaryotic expression vector, such as yeast, is cloned.
  • the vectors used for the expression are generally characterized by the fact that they carry inducible promoters, with which the timing of protein expression can be controlled.
  • expression vectors have sequences for so-called
  • Affinity epitopes or proteins on the one hand for the specific detection of the recombinant fusion proteins by means of a directed against the affinity epitope
  • Antibody on the other hand becomes the specific one
  • the object of the present invention is to provide improved marker sequences and their diagnostic
  • the invention relates to the use of
  • Marker sequences for the diagnosis of multiple sclerosis wherein at least one marker sequence of a cDNA selected from the group SEQ 1-81 or in each case a protein coding therefor or in each case a partial sequence or fragment thereof
  • marker sequences according to the invention to or from a patient to be examined.
  • an improved bioinformatic evaluation is strained and the samples are particularly preferably taken from the cerebrospinal fluid (CSF).
  • CSF cerebrospinal fluid
  • specially selected samples are used that meet the high sensitivity of a protein biochip.
  • multiple sclerosis (MS), also encephalomyelitis disseminata) refers to an autoimmune inflammatory /
  • demyelinating and degenerative disease of central nervous system disease (definition, for example, according to Pschyrembel, de Gruyter, 261st edition (2007), Berlin).
  • Essential to the invention is that the samples are not taken from conventional blood banks, but from MS patients
  • the complex sample selection method allows, for example, a sufficient advantageous delimitation of diseases such as MS symptom-like neuroborelliosis. Furthermore, false-positive results are excluded, on the one hand due to the strict bioinformatory evaluation (see examples) and by comparing the results on a protein biochip according to the invention with eg sera from Neuroborelliosis patients who do not have multiple sclerosis
  • the invention therefore also relates to such indication-specific protein biochips according to the invention for the diagnosis of
  • Sclerosis patients can be normalized and in this way false-positive proteins can be removed. Remaining non-false positive proteins can be reassembled on a protein biochip, called rearraying. This also allows the exclusion of autoantibodies that are positive for E. coli. This is another qualitative
  • the marker sequences according to the invention can also be combined, supplemented or extended with known biomarkers for this indication.
  • the determination of the marker sequences takes place outside the human body and the determination is made in an ex vivo / in vitro diagnosis.
  • the invention relates to the use of marker sequences as diagnostics, wherein at least one marker sequence of a cDNA is selected from the group SEQ 1-81 or in each case a protein coding therefor or in each case a partial sequence or fragment thereof.
  • the invention relates to a method for the diagnosis of multiple sclerosis, wherein a.) At least one marker sequence of a cDNA selected from the group SEQ 1-81 or a respective coding protein or a partial sequence or fragment thereof is applied to a solid support and b .) with body fluid or tissue extract one
  • the invention also relates to diagnostics for
  • the detection of such an interaction can, for example, by a probe, in particular by an antibody
  • the invention also relates to the task of providing a diagnostic device or an assay, in particular a protein biochip, which allows a diagnosis or examination for multiple sclerosis. Furthermore, the invention relates to a method for
  • Stratification in particular for the risk stratification and / or therapy control of a patient with multiple sclerosis, wherein at least one marker sequence of a cDNA selected from the group SEQ 1-81 or a protein coding therefor is determined on a patient to be examined.
  • therapy control also includes the classification of patients into responders and non-responders with regard to a therapy or its course of therapy.
  • Diagnosis in the sense of this invention means the positive finding of multiple sclerosis by means of
  • Marker sequences of the invention and the assignment of patients to the disease of multiple sclerosis.
  • diagnosis includes medical diagnostics and
  • diagnosis also includes the
  • the term "stratification" includes in particular the
  • patient means any subject - human or mammal - with the proviso that the subject is being examined for multiple sclerosis.
  • marker sequences in the sense of this invention means that the cDNA or the respective polypeptide or protein obtainable therefrom are significant for multiple sclerosis
  • the cDNA or the respectively obtainable polypeptide or protein can interact with substances from the body fluid or tissue extract of a Patients with multiple sclerosis (eg antigen
  • At least one marker sequence of a cDNA selected from the group SEQ 1-81 or in each case a protein coding therefor or in each case a partial sequence or fragment thereof to or from a patient to be examined is determined" that an interaction between the Body fluid or tissue extract of a patient and the marker sequences of the invention is detected.
  • Such an interaction is for example a bond, in particular a binding substance on at least one invention
  • Marker sequence or, in the case of a cDNA, hybridization with a suitable substance under selected conditions, in particular stringent conditions (for example, as usual
  • Hybridization conditions are hybridization in 4 x SSC at 37 ° C followed by several washes in 1 x SSC at room temperature.
  • Body fluid in particular blood, whole blood, blood plasma, blood serum, patient serum, urine, cerebrospinal fluid, synovial fluid or a tissue extract of the patient.
  • the marker sequences according to the invention may be present in a significantly higher or lower expression rate or concentration, which points to multiple sclerosis.
  • the relative expression rates ill / healthy of the invention may be present in a significantly higher or lower expression rate or concentration, which points to multiple sclerosis.
  • Marker sequences for multiple sclerosis are determined.
  • the marker sequences have a recognition signal which is addressed to the substance to be bound (for example antibodies,
  • the recognition signal is preferably an epitope and / or paratope and / or hapten and, for a cDNA, a hybridization or hybridization protein
  • the marker sequences of the invention are the subject of Table A and can by the respective cited
  • the invention also relates to the full-length sequences of the markers according to the invention and indeed as defined in Table A on the known database entry, hereinafter called SEQ -a 81a (cDNA) or SEQ ID-81b (protein).
  • SEQ 1-81 according to the invention again represent partial sequences, at least with high homology.
  • the specific ones are identical to
  • marker sequences SEQ 1-81 are in accordance with the invention.
  • the marker sequences also include such
  • Amino acid sequence such as chemical modification, such as
  • marker sequences In particular, those partial sequences which have an identity of 95%, 90%, in particular 80% or 70% with the marker sequences according to the invention.
  • Partial sequences are also those sequences having 50 to 81 nucleotides, 70-120 nucleotides of a sequence of SEQ 1-81, or peptides obtainable therefrom.
  • Marker sequences are functionally defined and include those sequences which have the same inventive diagnostic function.
  • Marker sequence can be represented in different amounts in one or more areas on a solid support. This allows a variation of the sensitivity.
  • the regions may each comprise a total of marker sequences, i. a sufficient number of different marker sequences, in particular 2 to 5 or 10 or more and optionally further nucleic acids and / or proteins, in particular biomarkers.
  • Biomarkers Further preferred are more than 2,500, more preferably 10,000 or more different or the same
  • Marker sequences and optionally other nucleic acids and / or proteins, in particular biomarkers are optionally other nucleic acids and / or proteins, in particular biomarkers.
  • Another object of the invention relates to an array of marker sequences containing at least one marker sequence a cDNA selected from the group SEQ 1-81 or in each case a protein coding therefor.
  • a cDNA selected from the group SEQ 1-81 or in each case a protein coding therefor.
  • “arrangement” synonymously means “array” and insofar as this "array” is used to identify substances on marker sequences, this is to be understood as meaning an “assay” or a diagnostic device.
  • the arrangement is designed such that those represented on the assembly
  • Marker sequences are in the form of a grid on a solid support. Furthermore, such arrangements are preferred which include a high density array of protein binders
  • Such high density spotted assemblies are disclosed, for example, in WO 99/57311 and WO 99/57312, and may be advantageously used in a robotic automated high throughput method.
  • test or diagnostic device also includes such
  • Embodiments of a device such as ELISA, bead-based assay, line assay, Western blot, immunochromatographic
  • Invention is the systematic arrangement of proteins on a solid support.
  • the marker sequences of the assembly are fixed to a solid support, but preferably spotted or immobilized imprinted, ie applied reproducible.
  • One or more marker sequences can be present multiple times in the totality of all marker sequences and be present in different amounts relative to one spot.
  • the marker sequences can be standardized on the solid support (eg by serial dilution series of eg
  • the invention relates to an assay or protein biochip consisting of an array containing marker sequences according to the invention.
  • the marker sequences are present as clones.
  • Such clones can be obtained, for example, by means of a cDNA expression library according to the invention (Büssow et al., 1998 (supra)).
  • such expression libraries become
  • Obtained marker sequences are obtained. These expression vectors preferably contain inducible promoters. The induction of
  • Expression can e.g. by means of an inductor, such as IPTG.
  • IPTG inductor
  • Suitable expression vectors are described in Terpe et al. (Terpe T Appl Microbiol Biotechnol 2003 Jan; 60 (5): 523-33).
  • Expression libraries are known to the person skilled in the art, these can be prepared according to standard works, such as Sambrook et al., Molecular Cloning, Laboratory Handbook, 2nd edition (1989), CSH press, Cold Spring Harbor, New York Further preferred are such expression libraries
  • tissue specific eg human tissue, in particular human organs
  • expression libraries are also included according to the invention, which can be obtained by exon trapping. Instead of expression library can be spoken synonymously from an expression bank.
  • protein biochips or corresponding expression libraries which have no redundancy (so-called: Uniclone® library) and can be prepared, for example, according to the teachings of WO 99/57311 and WO 99/57312. These preferred Uniclone libraries have a high content of non-defective, fully expressed proteins of a cDNA expression library.
  • the clones may not be such as transformed bacteria, recombinant phage or transformed cells of mammals, insects, fungi, yeasts or plants.
  • the clones are fixed on a solid support, spotted or immobilized.
  • the invention relates to an arrangement, wherein the
  • Marker sequences are present as clones.
  • the marker sequences may be in the form of a fusion protein in the particular form
  • At least one affinity epipope or "tag” contains.
  • the tag may be one such as c-myc, His-tag, Arg-tag, FLAG, alkaline phosphatase, V5 tag, T7 tag or Strep tag, HAT tag, NusA, S-tag, SBP tag , Thioredoxin, DsbA, a fusion protein, preferably a cellulose-binding one
  • solid support includes embodiments such as a filter, a membrane, a magnetic or fluorophore-labeled bead
  • Silicon wafer, glass, metal, plastic, a chip, a mass spectrometric target or a matrix Silicon wafer, glass, metal, plastic, a chip, a mass spectrometric target or a matrix.
  • a filter is preferred according to the invention.
  • the filter is PVDF, nitrocellulose or nylon (e.g., Immobilon P Millipore, Protran Whatman, Hybond N + Amersham).
  • nitrocellulose e.g., Immobilon P Millipore, Protran Whatman, Hybond N + Amersham.
  • this corresponds to a grid having the order of a microtiter plate (8-12 wells strips, 96 wells, 384 wells or more), a silicon wafer, a chip, a mass spectrometric target or a matrix.
  • the invention relates to an assay or protein biochip for identifying and
  • Characterizing a substance for multiple sclerosis characterized in that an arrangement or assay according to the invention is brought into contact with a.) At least one substance to be investigated and b.) A binding success is detected.
  • the invention relates to a method for identifying and characterizing a substance for multiple sclerosis, characterized in that an arrangement or assay according to the invention is brought into contact with a.) At least one substance to be investigated and b.) A binding success
  • the substance to be tested may be any native or non-native biomolecule, a synthetic chemical
  • Antigen / antibody or corresponding "means for detecting the binding success" can, for example, by means of
  • reporter enzymes such as alkaline
  • a readout is e.g. by means of a microarray laser scanner, a CCD camera or visually.
  • the invention relates to a drug / prodrug or prodrug developed for multiple sclerosis and obtainable through the use of the
  • the invention also relates to the use of an arrangement according to the invention or an assay for the screening of drugs for multiple sclerosis.
  • the invention also relates to a target for the treatment and therapy of multiple sclerosis, each selected from the group SEQ 1-81 or in each case a protein coding therefor.
  • the invention also relates to the use of the invention
  • Marker sequences preferably in the form of an arrangement, as
  • Affinity material for performing an apheresis or iwS. a blood wash wherein substances from body fluids of a patient with multiple sclerosis, such as blood or plasma, bind to the marker sequences of the invention and thus the body fluid can be selectively withdrawn.
  • Ten or more patient samples were individually screened against a cDNA expression library. Multiple sclerosis - specific expression clones were identified by comparison with ten or more healthy specimens. The identity of the marker sequences was determined by DNA sequencing.
  • FIG. 1 shows the differential screening between two protein biochips from in each case one cDNA expression bank of a patient and one healthy subject.
  • Differential clones are detected by fluorescence labeling and evaluated bioinformatorisch.
  • bioinformatic analyzes In the context of biomarker identification various bioinformatic analyzes are carried out. For each serum, microarray reactivities against about 2000 measured different antigens. These data are used for a ranking of the spotted antigens regarding their
  • Intensity data performed.
  • an internal standard is used, which is spotted on each chip. Since a p-value is calculated for each antigen, methods for correcting the multiple testing are used. As a very conservative approach, a Bonferroni correction is performed and, in addition, the less restrictive False Discovery Rate (FDR) is calculated according to Benjamini & Hochberg.
  • FDR False Discovery Rate
  • the data are used to classify the sera.
  • different multivariate methods are used. These are methods from the statistical
  • Threshold method which is suitable for both classification and visual representation of the data. To avoid overfitting, a 10-fold cross-validation of the data is performed.
  • mannosidase alpha
  • class 2A member 2 [Homo gi
  • mannosidase alpha
  • class 2A member 2 [Homo gi
  • gi 22027541 g 22027540 programmed cell death 7 [Homo sapiens] gi 5902122 g 15902121 spectrin, beta, non-erythrocytic 2 [Homo sapiens] gi 5902122 g 5902121 spectrin, beta, non-erythrocytic 2 [Homo sapiens] gi 5902122 g 5902121 spectrin, non-erythrocytic 2 [Homo sapiens] gi 71361682 g 171361681 nuclear mitotic apparatus protein 1 [Homo sapiens] gi 71361682 g 71361681 nuclear mitotic apparatus protein 1 [Homo sapiens] gi 71361682 g 171361681 nuclear mitotic apparatus protein 1 [Homo sapiens] triple functional domain (PTPRF interacting) [Homo gi
  • gi 53759122 adenomatous polyposis coli Homo sapiens] gi 53759122 gi 53759121 adenomatous polyposis coli gi 53759122 gi
  • 53759121 adenomatous polyposis coli Homo sapiens] gi 40548332 gi 149363677 coiled-coil domain containing 137 [Homo sapiens]

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  • Life Sciences & Earth Sciences (AREA)
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  • Biomedical Technology (AREA)
  • Molecular Biology (AREA)
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  • Hematology (AREA)
  • Immunology (AREA)
  • Urology & Nephrology (AREA)
  • Genetics & Genomics (AREA)
  • Physics & Mathematics (AREA)
  • Microbiology (AREA)
  • General Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • General Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • Pathology (AREA)
  • Analytical Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Food Science & Technology (AREA)
  • Cell Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • General Physics & Mathematics (AREA)
  • Bioinformatics & Computational Biology (AREA)
  • Plant Pathology (AREA)
  • Biophysics (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Peptides Or Proteins (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Investigating Or Analysing Biological Materials (AREA)

Abstract

La présente invention concerne des séquences de marqueur pour la sclérose en plaques et leur utilisation diagnostique ainsi qu'un procédé pour cribler des principes actifs potentiels pour des pathologies liées à la sclérose en plaques, au moyen de ces séquences de marqueur. L'invention a également pour objet un dispositif diagnostique comprenant des telles séquences de marqueur pour la sclérose en plaques, notamment une biopuce protéique et son utilisation.
EP11784434.0A 2010-10-12 2011-10-12 Séquences de marqueur pour la sclérose en plaques et leur utilisation Withdrawn EP2627783A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102010042359A DE102010042359A1 (de) 2010-10-12 2010-10-12 Markersequenzen für Multiple Sklerose und deren Verwendung
PCT/EP2011/067845 WO2012049228A2 (fr) 2010-10-12 2011-10-12 Séquences de marqueur pour la sclérose en plaques et leur utilisation

Publications (1)

Publication Number Publication Date
EP2627783A2 true EP2627783A2 (fr) 2013-08-21

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP11784434.0A Withdrawn EP2627783A2 (fr) 2010-10-12 2011-10-12 Séquences de marqueur pour la sclérose en plaques et leur utilisation

Country Status (4)

Country Link
US (1) US20140018245A1 (fr)
EP (1) EP2627783A2 (fr)
DE (1) DE102010042359A1 (fr)
WO (1) WO2012049228A2 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3586866A1 (fr) * 2018-06-28 2020-01-01 Universität Zürich Protéines et fragments immunodominants dans la sclérose en plaques

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100112583A1 (en) * 2008-10-31 2010-05-06 Yokogawa Electric Corporation Blood diagnosis method for dialysis patient and dialysis machine

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DE1073771T1 (de) 1998-04-30 2002-06-13 Max-Planck-Gesellschaft Zur Foerderung Der Wissenschaften E.V. Neue methode zur selektion von klonen einer expressionsbibliothek mittels "rearraying"
WO1999057311A2 (fr) 1998-04-30 1999-11-11 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Nouveau procede permettant l'identification de clones conferant une propriete biologique desiree dans une banque d'expression
US20070031841A1 (en) * 2001-02-28 2007-02-08 Choong-Chin Liew Method for the detection of gene transcripts in blood and uses thereof
AU7073800A (en) * 1999-08-25 2001-03-19 Regents Of The University Of California, The Novel plexins and uses thereof
WO2005027733A2 (fr) * 2003-09-18 2005-03-31 Ppd Biomarker Discovery Sciences, Llc Marqueurs biologiques destines au diagnostic de la sclerose en plaques
WO2005113831A2 (fr) * 2004-05-19 2005-12-01 Ppd Biomarker Discovery Sciences, Llc Biomarqueurs pour la sclerose en plaques et procedes d'utilisation correspondants
US7608395B2 (en) * 2005-09-15 2009-10-27 Baylor Research Institute Systemic lupus erythematosus diagnostic assay
US7919240B2 (en) * 2005-12-21 2011-04-05 Children's Hospital Medical Center Altered gene expression profiles in stable versus acute childhood asthma
EP1892303A1 (fr) * 2006-08-22 2008-02-27 Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. Méthodes d'identification de cibles thérapeutiques de tumeurs et méthodes de la détermination et du traitement de l'angiogenèse et de l'hémostase associés d'adénocarcinome pulmonaire
WO2008092442A1 (fr) * 2007-02-01 2008-08-07 Protagen Aktiengesellschaft Stratification et commande thérapeutique d'un patient au moyen de biopuces protéiniques
DE102007041657A1 (de) 2007-09-03 2009-03-05 Protagen Ag Markersequenzen für Multiple Sklerose und deren Verwendung

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100112583A1 (en) * 2008-10-31 2010-05-06 Yokogawa Electric Corporation Blood diagnosis method for dialysis patient and dialysis machine

Also Published As

Publication number Publication date
WO2012049228A3 (fr) 2012-08-30
DE102010042359A1 (de) 2012-04-12
WO2012049228A2 (fr) 2012-04-19
US20140018245A1 (en) 2014-01-16

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