WO2009074331A2 - Test diagnostique precoce et differentiel de la maladies d'alzheimer - Google Patents

Test diagnostique precoce et differentiel de la maladies d'alzheimer Download PDF

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Publication number
WO2009074331A2
WO2009074331A2 PCT/EP2008/010552 EP2008010552W WO2009074331A2 WO 2009074331 A2 WO2009074331 A2 WO 2009074331A2 EP 2008010552 W EP2008010552 W EP 2008010552W WO 2009074331 A2 WO2009074331 A2 WO 2009074331A2
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gene
marker
disease
marker gene
gene product
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PCT/EP2008/010552
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English (en)
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WO2009074331A3 (fr
Inventor
Edna Gruenblatt
Peter Riederer
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Julius-Maximilians-Universität Würzburg
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Publication of WO2009074331A2 publication Critical patent/WO2009074331A2/fr
Publication of WO2009074331A3 publication Critical patent/WO2009074331A3/fr

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    • 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
    • G01N33/6896—Neurological disorders, e.g. Alzheimer's disease
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers
    • 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
    • G01N2800/2814—Dementia; Cognitive disorders
    • G01N2800/2821—Alzheimer

Definitions

  • the present invention is related to an in vitro method for diagnosing Alzheimer's disease.
  • AD Alzheimer's disease
  • amyloid plaques which are extracellular deposits consisting mainly of aggregated ⁇ -amyloid peptide
  • NFT neurofibrillary tangles
  • AD Alzheimer's disease
  • susceptibility genes include genetic mutations, susceptibility genes and environmental factors such as aluminum that promote formation and accumulation of insoluble amyloid-beta (A- ⁇ ) and hyperphosphorylated tau (R. A. Yokel, Neurotoxicology 21, 813 (2000)).
  • A- ⁇ amyloid-beta
  • PS presenilin
  • Apolipoprotein E is a fourth genetic factor involved in the development of AD. Unlike the three deterministic genes, APOE is a susceptibility locus that accounts for approximately half of the late onset AD (A. M. Saunders, J Neuropathol Exp Neurol 59, 751 (2000), C. L. Masters, K. Beyreuther, Bmj 316, 446 (1998)) .
  • IL-I interleukin-1
  • Fig. 1 recapitulates that current diagnosis options either provide a late diagnosis when the degeneration of the neurons already occurred or act as confirmatory methods in post-mortem material according to Braak and Braak or the CERAD methodology (Fig 1).
  • a problem underlying the present invention is to provide a non-invasive and cost- efficient method to diagnose Alzheimer's disease that can be applied at an early stage of the disease.
  • a further problem underlying the present invention is to detect in an early stage of the degeneration, either before subjects will become MCI or during MCI phase, whether this person will develop AD and provide respective means therefore.
  • the problem underlying the present invention is solved in a first aspect which is also a first embodiment of the first aspect, by the use of a marker gene or a gene product thereof or a combination of marker genes or a combination of the gene products thereof, wherein the marker gene(s) is/are selected from the group comprising SLC 1A7, SLC 1A2, TF, GRIK4, CNR2, IGF-IR, CHAK2, GRINLlA, CHRNAl, GSTMl, FTHl, NDUFS3, LYST, SYNII, COG2, PEX5, STX5A, HIST1H3E, IRS4, RPL36A, GFAP, IDE and DEFAl; as a peripheral marker for diagnosing a neurodegenerative disease.
  • the marker gene(s) is/are selected from the group comprising SLC 1A7, SLC 1A2, TF, GRIK4, CNR2, IGF-IR, CHAK2, GRINLlA, CHRNAl, GSTMl, FTHl, NDUFS
  • the neurodegenerative disease is Alzheimer's disease.
  • the marker gene is HISTH3E.
  • the marker or marker gene is increased with decreased MMSE scores.
  • the marker gene is CNR2.
  • the marker or marker gene is increased with decreased MMSE score.
  • the combination of marker genes or combination of the gene products thereof comprises at least HISTH3E or CNR2.
  • the combination of marker genes or combination of the gene products thereof comprise at least HISTH3E and CNR2.
  • the marker gene or gene product thereof or combination of marker genes or combination of gene products thereof is used as a marker for diagnosing the neurodegenerative disease at an early stage of the neurodegenerative disease.
  • the problem underlying the present invention is solved in a second aspect which is also a first embodiment of the second aspect, by the use of a detector molecule that binds to a marker gene or a gene product thereof, whereby the marker gene is as defined in connection with any embodiment of the first aspect, for diagnosing a neurodegenerative disease, preferably Alzheimer's disease.
  • the detector molecule consists of at least two species of detector molecule, whereby each species binds to a marker gene or a gene product thereof and whereby the marker gene or gene product thereof is different for each species of detector molecule.
  • the detector molecule is a nucleic acid selected from the group comprising oligonucleotides, deoxyribonucleic acids, ribonucleic acids, aptamers and spiegelmers.
  • the detector molecule is selected from the group comprising peptides, proteins, antibodies, anticalines, peptide-aptamers and small molecules.
  • a third aspect which is also a first embodiment of the third aspect, by a method for the diagnosis of a disease comprising the following steps:
  • the presence, concentration and/or activity of said one or more marker gene(s) or product(s) thereof correlate(s) or is/are correlated with the disease.
  • the said one or more marker gene product(s) is a/are RNA molecule(s).
  • said marker gene(s) product(s) thereof is a/are peptide(s) or protein(s).
  • a fifth embodiment of the third aspect which is also an embodiment of the first, second, third and fourth embodiment of the third aspect, the presence, concentration and/or activity of said one or more marker gene(s) or gene product(s) thereof is/are assessed using PCR-related techniques.
  • the PCR-related techniques comprise real-time, reverse transcriptase PCR techniques and RNA protection assays.
  • a seventh embodiment of the third aspect which is also an embodiment of the first, second, third and fourth embodiment of the third aspect, the presence, concentration and/or activity of said one or more marker gene(s) or gene product(s) thereof is/are assessed using blotting techniques and/or chip-based techniques.
  • the presence, concentration and/or activity of said one or more marker gene(s) or gene product(s) thereof is/are assessed using enzymatic assays or binding assays.
  • the presence, concentration and/or activity of said one or more marker gene(s) or gene product(s) thereof is/are assessed using detection methods, whereby such detection methods are selected from the group comprising chromatography, mass spectrometry, electrophoresis, GS-MS and LC-MS.
  • the presence, concentration and/or activity of said one or more marker gene(s) or gene product(s) thereof is/are assessed using an interaction partner of such a molecule/ such molecules, whereby the interaction partner is selected from the group comprising antibodies, anticalines, peptide-aptamers, aptamers and spiegelmers.
  • said assessing is performed using a technique selected from the group comprising blotting techniques, enzymatic assays, binding assays and chip-based techniques.
  • the disease is a neurodegenerative disease.
  • the neurodegenerative disease is Alzheimer's disease.
  • the subject is a mammal.
  • the mammal is a human being.
  • the sample is derived from one or more body fluids.
  • the body fluid is selected from the group comprising blood, whole blood, peripheral blood, plasma, blood cells, CSF and saliva.
  • the present invention is based on the surprising finding that peripheral markers exist the expression of which, as detectable in vitro using material from sources other than brain tissue, indicates, at an early stage, affliction with Alzheimer's disease.
  • a marker gene or a gene product thereof which is also referred to herein as a marker gene product, or a combination of such marker or marker gene products thereof may be used as (a) peripheral marker(s) for diagnosing a disease, more preferably a neurodegenerative disease and most preferably Alzheimer's disease.
  • the marker gene(s) is/are SLC1A7, SLC1A2, TF, GRIK4, CNR2, IGF-IR, CHAK2, GRINLlA, CHRNAl, GSTMl, FTHl, NDUFS3, LYST, SYNII, COG2, PEX5, STX5A, HIST1H3E, IRS4, RPL36A, GFAP, IDE DEFAl as depicted in Table 1.
  • the marker gene is HIST3H3E.
  • These genes comprise genes from groups of transporter and Channel related genes; receptor and channels related genes; vesicle, synapse and protein transport related genes; oxidative-stress and toxin metabolism related genes; transcription, translation and signal transduction related genes; and structural proteins and enzymes related genes.
  • marker genes and marker gene products are used as peripheral markers of a disease such as a neurodegenerative disease, including, but not limited to Alzheimer's disease.
  • a disease such as a neurodegenerative disease, including, but not limited to Alzheimer's disease.
  • the presence, concentration and/or activity of the marker genes and/or the marker gene products may differ in the diseased state compared to a healthy subject as a result of intracellular events associated with Alzheimer's disease, such as, for example, elevated levels of reactive oxygen species.
  • Samples indicative of the affliction of a subject suffering from or suspected of suffering from Alzheimer's disease may be derived from any tissue and body fluid other than the brain and CSF for the purpose of diagnosing Alzheimer's disease in accordance with the present invention, despite the fact that the brain is separated from the blood through barriers such as the blood-brain-barrier, at least in a healthy subject.
  • peripheral blood refers to blood circulating through the body as well as any component thereof such as cellular components, with non-limiting examples being red blood cells, white blood cells and platelets.
  • the peripheral blood may comprise molecules such as electrolytes, metabolites, peptide proteins, carbohydrates, liquids, nucleic acids or combinations thereof, which may or may not originate from other tissues or other parts of the body, i.e. tissues and parts of the body different from the brain.
  • the term "peripheral blood”, as used herein comprises fractions of the peripheral blood.
  • peripheral blood comprises a preparation of red blood cells.
  • whole blood refers to peripheral blood from which no fractions or components have been removed or separated, although the blood may have been processed, for example through the addition of chemicals.
  • peripheral blood refers to peripheral blood from which no fractions or components have been removed or separated, although the blood may have been processed, for example through the addition of chemicals.
  • peripheral blood refers to peripheral blood from which no fractions or components have been removed or separated, although the blood may have been processed, for example through the addition of chemicals.
  • peripheral blood may be used synonymously.
  • the term ,,metabolites refers to molecules that are products and intermediates of the metabolism.
  • Non-limiting examples include, but are not limited to sugars, organic acids, amino acids, nucleotides, lipids, fatty acids and the like.
  • nucleic acid refers to a polymer comprising at least two nucleotide units attached to each other, preferably via phosphodiester bonds. Nucleotide units typically include a sugar moiety, for example ribose or deoxyribose, attached to a nitrogen base, for instance adenine, guanine, thymine, cytosine or uracil, although the scope of the invention includes alternative sugar moiety, bases and backbones such as the ones incorporated through the use of artificial nucleotide in chemical syntheses including phosphothioates.
  • a nucleic acid is deoxyribonucleic acid (DNA), in another preferred embodiment of the present invention, the nucleic acid is a ribonucleic acid (RNA).
  • a nucleic acid is an aptamer.
  • the term "aptamer”, as used herein, refers to a D-nucleic acid which is either single-stranded or double-stranded and which specifically interact with a target molecule.
  • the manufacture or selection of aptamers is, e. g., described in European patent EP 0 533 838.
  • the length of aptamers typically ranges from as little as 15 to as much as 80 nucleotides, and preferably ranges from about 20 to about 50 nucleotides.
  • a nucleic acid is a aptamer.
  • the term "aptamer”, as used herein, refers to a are molecule similar to an aptamer.
  • spiegelmers consist either completely or mostly of L- nucleotides rather than D-nucleotides in contrast to aptamers. Otherwise, particularly with regard to possible lengths of aptamers, the same applies to aptmers as outlined in connection with aptamers. The manufacture of aptmers is described in international patent application WO 98/08856.
  • the term "peptide”, as used herein, refers to any polymer consisting of at least two amino acids which are covalently linked to each other, preferably through a peptide bond. More preferably, a peptide consists of two to ten amino acids. A particularly preferred embodiment of the peptide is an oligopeptide which even more preferably comprises from about 10 to about 100 amino acids.
  • Amino acids typically include the natural proteinogenic L-amino acids, in particular glycine, alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, cystein, methionine, serine, threonine, lysine, arginine, histidine, aspartate, glutamate, asparagine and glutamine, but also any other kind of amino acid that can be chemically or enzymatically synthesised.
  • the term "amino acid”, as used herein also comprises derivatives and isomers of the proteinogenic L-amino acids, for example D-amino acids.
  • the term "proteins”, as used herein, refers to polymers consisting of a plurality of amino acids which are covalently linked to each other, preferably through a peptide bond. Preferably, such proteins comprise about at least 100 amino acids or amino acid residues.
  • the peptide or protein is a so-called “anticaline” which is, among others, described in German patent application DE 197 42 706.
  • the peptide is a peptide-aptamer.
  • peptide aptamer refers to a high affinity binding peptide which can be identified from random sequence peptide libraries comprising 10 to 10 peptides differing in their amino acid sequence in a manner similar to aptamers.
  • the term "marker”, as used herein, refers to any kind of molecule that is, directly or indirectly, for example by itself or through precursors, derivatives or products thereof, or interactions with other molecules, organelles, cells, tissues or the like, associated with and, preferably, indicative of a certain physiological state of an organism.
  • the physiological state is a disease.
  • the marker can be used to diagnose a disease.
  • the term "marker gene”, as used herein, is a gene that is differentially expressed in a disease or a diseased organism compared to the healthy organism, and the disease can be diagnosed by way of analysis of the differential expression of said marker gene. In a particularly preferred embodiment of the present invention, such differential expression, but also other mechanisms lead to changes concerning the presence, concentration and/or activity of a gene product of such marker gene.
  • peripheral marker is a marker that can support a diagnosis comprising the analysis of peripheral blood based on or making use of a sample which is preferably different from neuronal tissue and/or cerebrospinal fluid.
  • a sample which is preferably different from neuronal tissue and/or cerebrospinal fluid.
  • the sample contains or is derived from a body fluid.
  • the body fluid is different from cerebrospinal fluid.
  • the term "gene product”, as used herein, refers to any molecule that is the result of a transcription process of the gene of interest or fragments thereof and all forms derived thereof, comprising, but not limited to transcripts or fragments thereof, including, but not limited to truncated, spliced, fused, rearranged, cleaved and covalently modified forms thereof and the like; as well as any molecule that is the result of a translation process of the gene or fragments thereof, comprising, but not limited to peptides, proteins, cleaved, rearranged, fused, covalently modified, oxidised, reduced, truncated forms thereof.
  • the gene product is a mature mRNA transcript or polypeptide or a protein.
  • a fragment gene product has the essential features of the respective full length gene.
  • the term "marker gene product”, as used herein, refers to the gene product of a marker gene.
  • a gene product may, among others, as a consequence of its differential expression or any other mechanism, affect the metabolism, so that the presence, concentration and/or activity of metabolites in the brain and/or in any body fluid may be altered.
  • the presence of metabolites in fluids of the body may be altered in an indicative manner, thus, in a preferred embodiment of the invention, such changes of the presence, concentration and/or activity of a metabolite could be detected for the purpose of supporting a diagnosis.
  • detection is based or performed on a on a sample as defined herein.
  • neurodegenerative disease refers to a disease that is associated with an altered, preferably decreasing degree of neuronal viability and/or activity.
  • Non-limiting examples of neurodegenerative disease include, but are not limited to Alzheimer's disease, Parkinson's disease, Huntington disease, Lewy body dementia, Prion diseases.
  • the marker gene or a gene product thereof or a combination of marker genes or a combination of gene products thereof may be released into the peripheral blood, where their presence, concentration and/or activity directly correlate with the disease and can be detected.
  • even minute concentrations of such marker gene or gene product thereof or combination of marker genes or combination of gene products thereof released into the peripheral blood may trigger signal transduction cascades, affect the activity of peripheral enzymes, receptors, ion channels, transport molecules or the like to the effect that the presence, concentrations and/or activities of downstream molecules will be affected, thus contributing directly or indirectly to the symptoms of such neurodegenerative disease.
  • detector molecules are used so as to detect the marker gene and/or a gene product thereof, whereby the interaction between the detector molecule and the marker gene and the gene product thereof, respectively is used in order to diagnose the disease.
  • a detector molecule is any type of molecule that interacts with or detects a marker gene or marker gene product, which may be used for diagnosing the disease.
  • the disease is a neurodegenerative disease and preferably Alzheimer's disease and is diagnosed as a result of the detector molecule binding to a marker gene or marker gene product.
  • the term "to bind" means any contact between at least two molecules beyond any random interaction.
  • the binding involves the formation of a stable complex characterized by dissociation constants in the range of 1 fM - 100 ⁇ M, preferably 1 pM - 100 nM, more preferably 0,1 nM — 10 nM.
  • the detector molecule is a nucleic acid such as a primer or probe and the marker gene and/or gene product thereof is another nucleic acid such as a DNA or RNA molecule
  • the binding involves the formation of a double stranded piece of nucleic acid based on specific base pairing such as the formation of Watson-Crick base pairs.
  • specific base pairing such as the formation of Watson-Crick base pairs.
  • the person skilled in the art knows how to design such molecules, how to synthesize such molecules, either through synthetic or recombinant approaches, and how to evaluate their ability to act as detector molecules.
  • the detector molecule is a nucleic acid selected from the group comprising oligonucleotides, deoxyribonucleic acids, ribonucleic acids, aptamers and spiegelmers.
  • oligonucleotide is a relatively short pieces of any type of nucleic acid; typically a oligonucleotide, irrespective of whether it is an oligoribonucleic acid or a deoxyribonucleic acid, comprises about 10 - 100 pairs.
  • the terms "primers” and “probes” are oligonucleotides used for analytical purposes.
  • a probe is a deoxyribonucleic acid of about 20 - 30 bases used to detect an RNA transcript of a gene through a stable hybridization.
  • a primer is a deoxyribonucleic acid of the same length used to perform an analytical or preparative PCR reaction.
  • the detector molecule is selected from the group comprising peptides, proteins, antibodies, anticalines, and peptide-aptamers.
  • the term "antibody”, as used herein, comprises any construct, fragment, derivate, fusion or the like including at least one binding domain of an antibody.
  • the person skilled in the art is aware of procedures to identify peptides, proteins, antibodies, anticalines, and peptide-aptamers that bind to a molecule of interest and how to obtain peptides, proteins, antibodies, anticalines, and peptide-aptamers, either through synthetic or recombinant approaches, and how to evaluate their ability to act as detector molecules.
  • the detector molecule is a small molecule.
  • the term "small molecule”, as used herein, refers to a compound of any chemical identity having a molecular weight of approximately 1000 Dalton and following the Lepinsky Rules of Five. Small molecules are typically provided in the form of chemical libraries comprising thousands of different species. The person skilled in the art knows how to synthesize small molecules and how to evaluate their ability to act as detector molecules.
  • the term "the detector molecule consists of at least two species of detector molecule”, as used herein, means that the detector molecule consists of at least two separate entities of detector molecules, whereby the first entity detects a first marker gene or product thereof, the second entity detects a second marker gene or products thereof other than the first marker gene or gene product thereof, and so on. Consequently, the detector molecule comprises at least one entity for each marker gene or gene product thereof to be detected.
  • the detector molecule may consist of two probes that have been separately synthesized and are not physically associated with each other, and the first probe detects an mRNA transcript of one marker gene and the second probe detects an mRNA transcript of another marker gene.
  • marker genes and or gene products thereof for the diagnosis of a neurodegenerative disease, preferably Alzheimer's disease, by detecting a combination of marker genes and/or gene products thereof and by using, accordingly, a combination of detector molecules to detect the presence, concentration and/or activity of each marker gene or gene product thereof.
  • 23 detector molecules are used to detect 23 marker genes or gene products thereof for the diagnosis of a neurodegenerative disease, preferably Alzheimer's disease. Typically, this involves the use of 23 different probes to detect the presence of 23 marker gene transcripts.
  • marker genes and/or gene products thereof can be plausibly implemented in methods that are straightforward to perform and known to a person skilled in the art and are suitable to support or allow the diagnosis of a neurodegenerative disease, preferably Alzheimer's disease. Such methods have the potential for routine use and for use on a high- throughput scale.
  • a state that is usually associated with the presence, elevated concentrations and/or activities of the marker gene or gene products thereof, the presence, elevated concentration and/or activity of said marker gene or gene product thereof detected in samples derived from him or her indicate that a subject suspected of suffering from said neurodegenerative disease, preferably Alzheimer's disease, actually suffers from said neurodegenerative disease.
  • a marker gene the absence or normal or decreased concentration and/or activity of said marker gene or gene product thereof in a sample derived from a subject would indicate that he or she does not suffer from said neurodegenerative disease, preferably Alzheimer's disease.
  • the expression of the gene encoding for channel kinase 2 is up-regulated in subjects suffering from Alzheimer's disease. Therefore, the presence, elevated concentration and/or activity of the channel kinase 2 gene or gene products thereof in a sample derived from a subject suspected of suffering from Alzheimer's disease indicates that said subject actually suffers from Alzheimer's disease.
  • the expression of a known marker gene is known to be down-regulated in a diseased subject, a state that is usually associated with the absence or a decreased concentration and/or activity of the marker gene, the absence or decreased concentration and/or activity detected in samples derived from him or here, indicate that a subject suspect of suffering from said neurodegenerative disease, preferably Alzheimer's disease, actually suffers from said neurodegenerative disease.
  • the expression of the gene encoding for transferrin is down-regulated in subjects suffering from Alzheimer's disease. Therefore, the absence, decreased concentration and/or activity of the transferrin gene or gene products thereof in a sample derived from a subject suspected of suffering from Alzheimer's disease indicates that said subject actually suffers from Alzheimer's disease.
  • the nature of the marker gene product(s) is diverse.
  • the marker gene product(s) is/are RNA molecule(s).
  • the marker gene product(s) is/are peptide(s) or protein(s).
  • the methods according to the present invention are applicable following the derivation of a sample from a subject.
  • all steps comprised by the methods according to the present invention are performed in vitro.
  • the provision of the sample explicitly excludes any interaction with the body of a subject.
  • a method for the diagnosis of a neurodegenerative disease preferably Alzheimer's disease, by detecting a combination of marker genes and/or gene products thereof preferably using a combination of detector molecules to detect the presence, concentration and/or activity of each marker gene or gene product thereof.
  • the method for diagnosing a neurodegenerative disease preferably Alzheimer's disease makes use of 23 detector molecules to detect 23 marker genes or gene products thereof.
  • a step of the method comprises the analysis of a whole blood sample with respect to the presence, concentration and/or activity of 23 marker genes or gene products thereof.
  • sample contains or is suspected to contain one or more of the marker genes or gene products means that one or more marker genes and/or gene products thereof may be detected in the sample in order to support or allow the diagnosis of a disease.
  • the sample is based on or derived from a body fluid or from a skin biopsy.
  • body fluid refers to any material comprising a liquid component that is obtainable from an organism of interest. Non- limiting examples include, but are not limited to cerebrospinal fluid (CSF), saliva, peripheral blood or whole blood.
  • CSF cerebrospinal fluid
  • body fluids comprise fractions or processed forms of any material comprising a liquid component that is obtainable from an organism of interest.
  • body fluids comprise preparations of blood cells.
  • the term ,,derived as used herein, comprises obtained by way of biopsy.
  • a sample that can be used to support the diagnosis of a disease, preferably a neurodegenerative disease, most preferably Alzheimer's disease
  • a multitude of different approaches may be used or followed for the detection of the presence, the concentration and/or the activity of a marker gene or a product thereof.
  • said marker gene product is a nucleic acid molecule and a technique selected from the group comprising PCR-related techniques, spotted arrays, Northern blotting, Southern blotting, chip-based techniques or the like, is used for the detection.
  • PCR-related techniques refers to any technique, process, method or methodology that makes use, in some form, of a polymerase chain reaction (PCR), reagents, products or intermediates thereof.
  • PCR polymerase chain reaction
  • Non-limiting examples include, but are not limited to real time PCR, reverse transcriptase PCR, RNA protection assays or the use of primers or probes attached to fluorescent dyes for the purpose of monitoring binding or product formation using fluorescence.
  • blotting techniques involve the permanent or transient attachment of a molecule to a surface and a detection step that results in a readout.
  • a multitude of molecules can be detected using blotting techniques, with non-limiting examples including proteins, peptides, RNA, DNA, carbohydrates and combinations thereof.
  • chip-based techniques involved the attachment of a detector molecule to a chip and the subsequent exposure to a sample, with interactions between the detector molecule with the target to be detected being recorded.
  • chips include peptide chips, protein chips such as antibody chips, nucleic acid chips and the like.
  • enzymatic assays may also be used for the gene, gene products and interaction partners thereof such as the detector molecule for assessing the presence, concentration and/or activity thereof.
  • the term "enzymatic assay”, as used herein, refers to any method that can be used to determine an enzymatic activity of interest.
  • Non-limiting examples include, but are not limited to continuous assays, typically involving the use of UV/vis spectroscopy to monitor the turnover of chromogenic substrate molecules in the presence of enzyme molecules or the use of a light detector to record the activity of an enzyme that emits light upon turning over substrate, or discontinuous assays, wherein the concentration of substrate molecules is determined in regular intervals, for example through the use of High Pressure Liquid Chromatography, Western blotting or other quantitative methods.
  • the term "enzymatic assays” comprises the use of ELISA (enzyme-linked immunosorbent assay) approaches and all variations thereof.
  • proteomic approaches refers to any kind of method that allows for the detection of changes with respect to the protein composition of a sample, both in terms of the concentration and/or activity of one or more proteins.
  • such approaches include the use of mass spectrometry, electrophoretic techniques, one or two dimensional protein gels, NMR (nuclear magnetic resonance) spectroscopy, protein chips, chromatographic methods including Liquid Chromatography Mass Spectrometry (LC-MS), Gas Source Mass Spectrometry (GS - MS) and the like, all of which are known to a person skilled in the art.
  • a Multiplex particle assay refers to a method based on flow cytometry that makes use of antigen-coated beads in a multiplex test system, allowing for the use of more than one antibody to detect antigens in a single sample (Leinfelder et al. (2007) LABO (April 2007), pages 54-56).
  • the marker gene or gene product thereof or combination of marker genes or combination of gene products thereof affect the presence, concentration and/or activity of a small molecule, preferably a metabolite, and metabolomic approaches or enzymatic assays are used to detect its presence, concentration and/or activity. Therefore, in a preferred embodiment, the presence, concentration and/or activity of a small molecule, which correlates with the presence, concentration and/or activity of a marker gene or gene product thereof, is detected to support or allow the diagnosis of a disease rather than the marker gene or gene product thereof itself.
  • the term "metabolomic approach”, as used herein, comprises the use of NMR spectroscopy and mass spectrometry to detect a small molecule or combinations of small molecules.
  • a disease preferably a neurodegenerative disease, and most preferably Alzheimer's Disease, can be diagnosed at any stage of the disease, preferably at an early stage of the disease.
  • the term "early stage of a disease”, as used herein, refers to a state of an individual, wherein the individual suffers, knowingly or unknowingly, from said disease prior to the onset of clinical symptoms.
  • the term "early stage of a disease”, as used herein, refers to a stage where symptoms are considered as MCI (mild cognitive impaired).
  • MCI mimild cognitive impaired
  • the term “MCI”, as used herein, refers to a state of cognitive functioning that is below defined norms, yet falls short of dementia in severity, and exists across a cognitive continuum with borders that are difficult to define precisely.
  • MMSE refers to a scale that can be used for the determination of a cognitive deficit
  • a score in the range of 27- 30 score is assigned to a cognitive healthy subject
  • a score in the range of 24-26 is a assigned to a mild-cognitive-impaired (MCI) subject
  • MCI mild-cognitive-impaired
  • a score in the range of 19-23 is assigned to a slightly demented subject
  • a score in the range of 12-18 score is assigned to a subject suffering from medium dementia
  • a score in the range of 0-11 score is assigned to a severely demented subject.
  • the term "subject”, as used herein, refers to any being which may or may not be ridden with a disease.
  • the subject is a bird or a mammal.
  • the subject is a human.
  • Table 1 Gene markers useful to diagnose Alzheimer's disease Transporter and Channel related genes
  • Oxidative-stress ana toxin metabolism related genes Oxidative-stress ana toxin metabolism related genes
  • Affy ID represents the Affymetrix ID number as used in the microarray (gives the whole information on the gene, such as annotations, sequences etc.); Gene Name: the whole name of the protein/gene; Symbol: the consensus symbol of the gene; Expected expression: the alteration of expression expected compared to a healthy control; Gene Bank Accession No.: the number assigned to the sequence in NCBI; Function: the functional group the gene belongs to; Protein family: the protein family to which the gene belongs to.
  • Fig. 1 depicts various timings of diagnosis and treatment in relation to the time course of a patient's mental capacities/accomplishments.
  • Fig. 2 lists the genes investigated; house keeping genes are in bold.
  • Fig. 3 depicts a time course (every 3 months in a period of 1 year) for each subject for gene expression and MMSE. Each line represents one subject. Time 1- February to March; Time 2- May to June; Time 3- August to September; Time 4- November to December. The t-Test p-values are given under each schema.
  • Fig. 4 lists the descriptive statistics for the 33 gene expressions.
  • Fig. 5 lists Pearson correlation coefficients and univariate p-values of the linear regression analysis between MMSE and the 33 genes. Significant results are in bold, and the lowest p- values in italics.
  • Fig. 6 Scatter plot describing the correlation between MMSE scores and HIST1H3E mRNA expression in all four time points.
  • Example 1 Peripheral blood mononuclear cells gene expression profile in Alzheimer's disease
  • Fig. 2 In order to investigate the influence of gene expression alterations on MMSE, 33 genes (Fig. 2) were investigated separately. Figs. 3A and 3B show the time course for each gene where each line represents one patient. A very large variation between the time points (every 3 months, up to 4 times in a period of one year) could be found.
  • Pearson correlation coefficients between the gene and MMSE were calculated in order to investigate the influence of time (up to 4 recruitments). T-tests were used if these correlation coefficients differed from zero, which would mean that the MMSE and the gene expression in a patient change over time in the same manner.
  • CNRl are expressed primarily in the brain and in some peripheral tissues, while CNR2 are thought to be expressed primarily by immune cells in peripheral tissues, but nowadays are found to be expressed also in the brain (Onaivi, E.S., Ishiguro, H., Gong, J.P., Patel, S., Perchuk, A., Meozzi, P.A., Myers, L., Mora, Z., Tagliaferro, P., Gardner, E., et al., Ann N Y Acad Sci 1074:514-536 (2006)).
  • histone proteins play key roles in the regulation of transcription. Transcription becomes active when histones are acetylated by histone acetyltransferase (HATs), silenced when histones are deacetylated by histone deacetylases (HDACs) and silenced or activated when methylated by histone methyltransferases (HMTs) (Berger, S. L. Curr Opin Genet Dev 12:142-148 (2002)). Soon as early as 1993 Mecocci et al.
  • HATs histone acetyltransferase
  • HDACs histone deacetylases
  • HMTs histone methyltransferases
  • Phosphorylated histone H3 a key component involved in chromosome compaction during cell division, was found to be increased in the cytoplasma of hippocampal neurons in AD subjects (Ogawa, O., Zhu, X., Lee, H.G., Raina, A., Obrenovich, M.E., Bowser, R., Ghanbari, H.A., Castellani, R.J., Perry, G., and Smith, M.A., Acta Neuropathol (Berl) 105:524-528 (2003)). Therefore, the aberrant cytoplasmic localization of phosphorylated histone H3 indicates a mitotic disruption that leads to neuronal dysfunction and neurodegeneration in AD. Accordingly the present inventors found in peripheral blood samples a significant increase of HIST1H3E mRNA with decreased MMSE scores, which points to the progress of the dementia stage.
  • the inventors of the present invention confronted these points by using a larger group of subjects with one ethnical background (total 52 subjects, white Caucasian). Regarding gender, the inventors of the present invention had nearly 1:1 female to male in order to eliminate these variations (30:22, respectively).
  • the present inventors used four time points for withdrawal of samples over the period of one year.
  • the circadian and seasonal environment may influence gene expression and processes in the CNS as well as the periphery (Hofman, M.A., and Swaab, D.F., Prog Brain Res 138:255-280 (2002)).
  • the present inventors did not find any significant correlation between the withdrawal time point and gene expression profile, but still some tendencies toward seasonal effects can be observed.
  • RNA and the expression profile was shown to be strongly influence by the blood collection technique.
  • the effects in gene expression alterations as a consequence of blood withdrawal and isolation methodology were eliminated by using the newly PAXgene methodology containing preserving fluid in order to "freeze" the RNA profile and eliminate extractions' variations and RNA degradation (Whitney, A.R., Diehn, M., Popper, S.J., Alizadeh, A.A., Boldrick, J.C., Relman, D.A., and Brown, P.O., Proc Natl Acad Sci U S A 100:1896-1901 (2003), Rainen, L., Oelmueller, U., Jurgensen, S., Wyrich, R., Ballas, C, Schram, J., Herdman, C, Bankaitis-Davis, D., Nicholls, N., Trollinger,
  • Example 2 Studies on gene expression alterations in living humans with and without Alzheimer's disease
  • Alzheimer's Disease and Related Disorders Association criteria McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (1984) Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology 34, 939-944.)- Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS- cog) (Pena-Casanova J (1997) Alzheimer's Disease Assessment Scale— cognitive in clinical practice.
  • ADAS- cog Alzheimer's Disease Assessment Scale— cognitive in clinical practice.
  • the MMSE was used for following up the progression, while the other two were used for rough estimation of the diagnosis assessment. Further information was obtained by Unified Parkinson Scale. Depressive and anxiety symptoms were assessed with Hamilton Depression Scale, Short Geriatric Depression Scale and State Trait Anxiety Inventory (Xl, X2) (for details see Table 4). These scales were used in order to rule out subjects with sever neurologic of psychiatric disorders. In addition detailed information on medication and smoking habits were collected. Subjects were retested every 3 months in a period of one year for all parameters (4 recruitments, see Table 4).
  • MMSE ⁇ 24 52 subjects from both genders (30 females and 22 males) aged between 54.5-95 years were recruited for this study. 34 were non-demented control subjects with no cognitive deficits and MMSE scores 25-30 and 18 subjects were diagnosed as demented with AD (multiple cognitive deficits with significant psychosocial impairment) (MMSE ⁇ 24).
  • Whole blood was collected with PAXgeneTM Blood RNA system (Becton Dickinson GmbH, Heidelberg, Germany). The blood samples were frozen at -20 0 C until further process for RNA isolation.
  • RNA isolation reagents were prepared from 0.2 ⁇ M filtered, diethyl pyrocarbonate (DEPC) -treated water (Fermentas Inc., Hanover, MD, USA) throughout the isolation procedure.
  • Total RNA samples were spectrophotometrically scanned (Experion, BioRad Co., Hercules, CA, USA) from 220 to 320 nm; the A260/A280 of total RNA was typically >1.9. 3.
  • RNA (1 ⁇ g) from each sample was reverse transcribed with random hexamer & oligo-dT primer mix using iScript (BioRad Co., Hercules, CA, USA).
  • Quantitative real-time PCR was performed in the iCycler iQ system (BioRad Co., Hercules, CA, USA) as described previously (Gr ⁇ nblatt E, Zander N, Bartl J, Jie L, Monoranu CM, Arzberger T, Ravid R, Roggendorf W, Gerlach M, Riederer P (2007) Comparison Analysis of Gene Expression Patterns between Sporadic Alzheimer's and Parkinson's Disease. J Alzheimers Dis 12, 291-311).
  • the genes were normalized to the 5 most stable house-keeping genes: ACTB, RPL13A, PPIA, GAPDH and R18S.
  • Standard curves for each amplification product were generated from 10-fold dilutions of pooled PCR-amplicons (isolated using MiniElute Gel Extraction Kit (Qiagen, Hilden, Germany) to determine primer efficiency and quantization. Data was analyzed with Microsoft Excel 2000 to generate raw expression values.
  • Diazepam binding inhibitor GABA receptor modulator, acyl- DBI NM_020548 Coenzyme A binding protein
  • Transient receptor potential cation channel, subfamily M, member 6 TRPM6 AF350881 Cannabinoid receptor 2 CNR2 NMJ)01841 amyloid beta (A4) precursor protein APP BC004369
  • Table 3 Pearson correlation coefficients and univariate p-values of the linear regression analysis between MMSE and the 33 genes.
  • Subject Age Gender Diagnose (a) MMSE MMSE MMSE MMSE
  • Int Psychogeriatr 9 Suppl 1, 173-176; discussion 177-178. were administered to all subjects.
  • the MMSE was used for following up the progression, while the other two were used for rough estimation of the diagnosis assessment. Further information was obtained by Unified Parkinson Scale (Goetz CG, Stebbins GT, Shale HM, Lang AE, Chernik DA, Chmura TA, Ahlskog JE, Dorflinger EE (1994) Utility of an objective dyskinesia rating scale for Parkinson's disease: inter- and intrarater reliability assessment. Mov Disord 9, 390-394.). Depressive and anxiety symptoms were assessed with Hamilton Depression Scale (Hamilton M (1960) A rating scale for depression.
  • Subject A6 and subject Al 1 showed at assessment period-Ill and subject Al 7 showed at assessment period-II unspecific symptoms of physical diseases.
  • Subject A9 underwent surgery some days before assessment. At assessment period-I and -II the same 10 subjects took anticholinergic drugs only 2 of them have increased dosage. At assessment period-II, additional 4 subjects that were assessed the first time took anticholinergic drugs. At assessment period-Ill, again, 14 subjects took anticholinergic drugs two of these subjects have discontinued anticholinergic medication, two have started medication and one has decreased dosage. At assessment period-IV, one of these subjects has discontinued anticholinergic medication, and one has decreased dosage. At all four assessment periods all the subjects underwent any pharmacological treatment with the exception of 2 healthy controls.
  • cDNA (1 :10 diluted final amount of 10-30ng) and gene specific primers (probes, when assays with probes) were used in each reaction with total volume of 25 ⁇ l.
  • gene specific primers probes, when assays with probes
  • the same amount of cDNA was used for analysis, high abundant genes were assayed with the lower amount of cDNA while the lower abundant genes were assayed with the higher amount of cDNA.
  • QuantiTect assays we used QuantiTectTM Custome Assay (Qiagen Inc., Valencia, CA, USA) (Supplementary Table 2) were added to QuantiTect (Probe/SYBR Green) PCR Master Mix (Qiagen Inc., Valencia, CA, USA).
  • the assays with designed primers we used the iQ-SYBR Green Supermix (BioRad, Hercules, California, USA).
  • Amyloid beta APBA3 CAGGCAAGGGATGAGGTG SYBR 170 40 67 91 8 precursor CTTGAGATCAATGGGCAGAG protein-binding, family A, member 3 (AI141541) beta-site APP- BACEl QuantiTect Primer Assay SYBR 146 40 manual 95 3 cleaving enzyme 1 (NM_012104)
  • Insulin-like IGF-IR QuantiTect Primer Assay SYBR 106 40 manual 98 5 growth factor 1 receptor (NM_000875)
  • Transferrin TF QuantiTect P ⁇ mer Assay SYBR 190 40 manual 96 8 (NM_ 00106 3) ferritin, heavy CTGGAGCTCTACGCCTCCTA SYBR 232 30 64 882 polypeptide 1 FTHl CACACTCCATTGCATTCAGC (NM_002032) glutathione S- GSTMl CCTCCTCGTTCCTTTCTCCT SYBR 28 5 40 63 882 transferase Ml, ACCAGTCAATGCTGCTCCTT transcript variant 1 (X08020)
  • Heme HMOX 1 GCCAGGTGACCCGAGACG SYBR 120 40 60 99 oxygenase GGAAGTAGACAGGGGCGAAGA C (decycling) 1 (NM_002133)
  • the mean values and standard deviations are calculated over all time points and patients.

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Abstract

L'invention concerne l'utilisation d'un gène marqueur ou d'un produit génique de celui-ci ou d'une combinaison de gènes marqueurs ou de produits géniques de ceux-ci, ce(s) gène(s) marqueur(s) étant sélectionné(s) dans le groupe constitué par SLC1A7, SLC1A2, TF, GRIK4, CNR2, IGF-1R, CHAK2, GRINL1A, CHRNA1, GSTM1, FTH1, NDUFS3, LYST, SYNII, COG2, PEX5, STX5A, HIST1H3E, IRS4, RPL36A, GFAP, IDE et DEFA1. Ce(s) gène(s) sert/servent de marqueur(s) périphérique(s) dans le diagnostic d'une maladie neurodégénérative.
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EP3171174A1 (fr) 2015-11-20 2017-05-24 Geroa Diagnostics, S.L Lactoferrine pour utilisation dans le diagnostic ou le pronostic de la maladie d'alzheimer
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US10934588B2 (en) 2008-01-18 2021-03-02 President And Fellows Of Harvard College Methods of detecting signatures of disease or conditions in bodily fluids
WO2009144424A3 (fr) * 2008-03-28 2010-02-25 Exonhit Therapeutics Sa Procede et methodes de diagnostic de la maladie d'alzheimer
US8481701B2 (en) 2008-03-28 2013-07-09 Exonhit Therapeutics Sa Process and method for diagnosing Alzheimer's disease
WO2009144424A2 (fr) * 2008-03-28 2009-12-03 Exonhit Therapeutics Sa Procede et methodes de diagnostic de la maladie d'alzheimer
WO2012012725A2 (fr) 2010-07-23 2012-01-26 President And Fellows Of Harvard College Méthodes de dépistage de maladies ou d'affections à l'aide de cellules phagocytaires
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US10961578B2 (en) 2010-07-23 2021-03-30 President And Fellows Of Harvard College Methods of detecting prenatal or pregnancy-related diseases or conditions
WO2013188828A1 (fr) 2012-06-15 2013-12-19 Harry Stylli Méthodes de détection de maladies ou d'états au moyen de cellules infectées en circulation
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US10494675B2 (en) 2013-03-09 2019-12-03 Cell Mdx, Llc Methods of detecting cancer
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US10626464B2 (en) 2014-09-11 2020-04-21 Cell Mdx, Llc Methods of detecting prostate cancer
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