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WO2019113277A1 - Diagnostic d'une maladie par l'intermédiaire d'un profil d'expression génique dans des cellules synchronisées - Google Patents

Diagnostic d'une maladie par l'intermédiaire d'un profil d'expression génique dans des cellules synchronisées Download PDF

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Publication number
WO2019113277A1
WO2019113277A1 PCT/US2018/064180 US2018064180W WO2019113277A1 WO 2019113277 A1 WO2019113277 A1 WO 2019113277A1 US 2018064180 W US2018064180 W US 2018064180W WO 2019113277 A1 WO2019113277 A1 WO 2019113277A1
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Prior art keywords
afflicted
subject
patients
gene
add
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Inventor
Florin Valentin Chirila
Daniel L. Alkon
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Neurodiagnostics LLC
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Neurodiagnostics LLC
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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
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5091—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing the pathological state of an organism
    • 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
    • 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
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/502—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing non-proliferative effects
    • G01N33/5023—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing non-proliferative effects on expression patterns

Definitions

  • This invention provides a method for determining whether a human subject is afflicted with a predetermined disorder comprising the steps of (a)
  • step (b) synchronized cells derived from patients afflicted with the disorder and those derived from non-affiicted patients, whereby the subject is afflicted with the disorder if the expression level measured in step (b) is consistent with that gene’s expression level in corresponding synchronized cells derived from patients afflicted with the disorder, and the subject is not afflicted with the disorder if the expression level measured in step (b) is consistent with that gene’s expression level in corresponding synchronized cells derived from non- afflicted patients.
  • AD Alzheimer’s Disease
  • Non-ADD Non Alzheimer’s Disease Demented
  • symptomatic human subject means determining that there is greater than 50% likelihood that the subject is afflicted with Alzheimer’s disease.
  • “diagnosing Alzheimer’s disease” means determining that there is greater than 60%, 70%, 80% or 90% likelihood that the subject is afflicted with Alzheimer’s disease.
  • the phrase“determining whether the subject is afflicted with Alzheimer’s disease” is synonymous with the phrase“diagnosing Alzheimer’s disease.”
  • “diagnosing non-Alzheimer’s dementia (‘non-ADD’)”, with respect to a symptomatic human subject, means determining that there is greater than 50% likelihood that the subject is afflicted with non-ADD.
  • “diagnosing non-ADD” means determining that there is greater than 60%, 70%, 80% or 90% likelihood that the subject is afflicted with non-ADD.
  • the phrase“determining whether the subject is afflicted with non-ADD” is synonymous with the phrase“diagnosing non-ADD.”
  • “Alzheimer’s disease” means a concurrent affliction with the following three symptoms: (i) dementia; (ii) amyloid plaques; and (iii) neurofibrillary tangles. Dementia can be diagnosed during life. Cerebral amyloid plaques and neurofibrillary tangles can, for example, be diagnosed during autopsy.
  • Alzheimer’s disease is the one provided by the National Institute of Neurological Disorders and Stroke (NINDS) of the National Institutes of Health (NIH), and is known as the“gold standard.” All subjects from whom samples were taken and studied, and for which data are presented herein, are autopsy-confirmed AD and non-ADD patients.
  • NINDS National Institute of Neurological Disorders and Stroke
  • NHI National Institutes of Health
  • a subject afflicted with“non-Alzheimer’s dementia” means a subject showing dementia such as, for example, that which characterizes Parkinson’s disease, Huntington’s disease and frontotemporal dementia.
  • a human subject who is“suspected of being afflicted with AD or non-ADD” is a subject displaying at least one symptom consistent with both AD and non-ADD, e.g., dementia.
  • the“human subject” can be of any age. In one embodiment, the subject is 40 years old or younger. In another embodiment, the subject is 50 years old or younger. In a further embodiment, the subject is over 40 years old. In yet a further embodiment, the subject is over 50 years old, over 60 years old, over 70 years old, over 80 years old, or over 90 years old.
  • a“population” of cells includes any number of ceils permitting the manipulation and study required to assess gene expression.
  • the population of cells includes at least 1 ,000,000 ceils.
  • the population of cells includes between 100,000 cells and 1 ,000,000 cells, between 10,000 cells and 100,000 ceils, between 1 ,000 cells and 10,000 cells, between 100 ceils and 1 ,000 cells, between 10 ceils and 100 cells, and fewer than 10 cells (e.g., one cell).
  • cells“derived” from a subject are cells that arise through culturing and/or other physical manipulation performed on cells directly removed from the subject.
  • cultured skin fibroblasts derived from a subject are those skin fibroblasts that arise through culturing a sample of skin ceils (e.g., contained in a punch biopsy) directly removed from the subject.
  • “synchronizing" a population of cells means placing at least a majority of cells in that population in the same ceil cycle stage (namely, in the G1 , S, G2 or M stage, and preferably in the G1 , S or G2 stage).
  • synchronizing a population of cells means placing at least 60%, at least 70%, at least 80%, at least 90%, at least 95% or preferably at least 99% of cells in that population in the same cell cycle stage.
  • synchronizing a population of cells means placing the cells in that population in the same cell cycle stage that they would be in if cultured to over- confluence and then starved. Cell confluence followed by serum starvation typically arrests the cells in the G0/G1 stage [1 -3]
  • RNA Sequencing (20 million reads, 2x75bp PE)
  • measuring the expression level of a gene is accomplished by measuring the number of RNA transcripts for that gene per million total RNA transcripts (i.e , “TPM” via FastG data, and FPKM estimation per sample) present in the cell- derived RNA population being studied. For example, measuring the number of RNA transcripts for that gene per million total RNA transcripts (i.e , “TPM” via FastG data, and FPKM estimation per sample) present in the cell- derived RNA population being studied. For example, measuring the number of RNA transcripts for that gene per million total RNA transcripts (i.e , “TPM” via FastG data, and FPKM estimation per sample) present in the cell- derived RNA population being studied. For example, measuring the number of RNA transcripts for that gene per million total RNA transcripts (i.e , “TPM” via FastG data, and FPKM estimation per sample) present in the cell- derived RNA population being studied. For example, measuring the number of RNA transcripts for that gene per million total
  • expression level of gene X in a synchronized cell population might yield a result of 50 TPM.
  • a gene is“differentially expressed between corresponding synchronized cells derived from AD patients and those derived from non-ADD patients” if, for example, the gene’s TPM measure in synchronized cells derived from AD patients is different than in the same type of ceils derived from non-ADD patients that are synchronized in the same way.
  • gene X would be differentially expressed between corresponding synchronized cells derived from AD patients and those derived from non-ADD patients if its TPM measure in synchronized cells derived from AD patients were 10 and its TPM measure were 100 in the same type of cells derived from non-ADD patients that are synchronized in the same way.
  • a gene’s expression level is“consistent” with that gene’s expression level in corresponding synchronized cells derived from AD patients if it is the same as, or close to, that expression level.
  • gene X TPM measure in synchronized cells derived from AD patients is 10 and its TPM measure is 100 in the same type of cells derived from non-ADD patients that are synchronized in the same way.
  • a subject’s gene X expression level would be consistent with gene X’s AD expression level if it were, for example, below 50, below 40, below 30, below 20 or, ideally 10 or lower.
  • “culturing” skin fibroblasts is achieved, for example, by conducting the culturing at a temperature and in a growth factor milieu permissive of ceil growth.
  • “culturing” skin fibroblasts is performed under conditions (e.g., those described below for proliferation) that preserve skin fibroblasts viability.
  • the temperature, humidity and protein milieu permissive of cell growth is 37 °C, DMEM Medium with 10% fetal bovine serum (“FBS”) and 1 % penicillin (“PS”).
  • FBS fetal bovine serum
  • PS penicillin
  • the skin fibroblast-culturing step is performed for more than three hours.
  • the skin fibroblast-culturing step is performed for more than six hours (e.g., overnight).
  • Methods for obtaining skin fibroblasts from a subject’s blood include, for example, skin punch biopsy, and growing cells out of explants. When cell confluence reaches 100%, cells are passaged. Typically after two passages, fibroblasts are purified in a proportion greater than 95%. As used herein,“culturing” lymphocytes is achieved, for example, by
  • lymphocytes is performed under conditions (e.g., those described below for proliferation) that preserve lymphocyte viability.
  • the temperature, salinity and protein milieu permissive of cel! growth is 37 °C, RPIVII 1640 Medium with 10% fetal bovine serum (“FBS”) and 1 % penicillin (“PS”).
  • FBS fetal bovine serum
  • PS penicillin
  • the lymphocyte-culturing step is performed for more than three hours.
  • the lymphocyte-culturing step is performed for more than six hours (e.g., overnight).
  • B-lymphocyte can be cultured to over- confluence, i.e. , high density/mI.
  • lymphocytes are starved overnight.
  • Methods for obtaining lymphocytes from a subject’s blood include, for example, flow cytometry, Ficoll (a hydrophilic polysaccharide that separates layers of blood), and gradient centrifugation. Additionally, in the subject methods, the lymphocytes (e.g., B lymphocytes) can be used in immortalized or primary (i.e. , non-immortalized) form.
  • lymphocytes immortalizing lymphocytes
  • B lymphocytes include, for example, treating the lymphocytes with Epstein-Barr virus (“EBV”).
  • EBV Epstein-Barr virus
  • This invention provides a method for determining whether a human subject is afflicted with a predetermined disorder comprising the steps of (a)
  • step (b) synchronized cells derived from patients afflicted with the disorder and those derived from non-afflicted patients, whereby the subject is afflicted with the disorder if the expression level measured in step (b) is consistent with that gene’s expression level in corresponding synchronized cells derived from patients afflicted with the disorder, and the subject is not afflicted with the disorder if the expression level measured in step (b) is consistent with that gene’s expression level in corresponding synchronized cells derived from non- afflicted patients.
  • the predetermined disorder can be any disorder (e.g., cancer or a neurodegenerative disorder) wherein there is a defined gene known to be differentially expressed between corresponding synchronized cells derived from patients afflicted with the disorder and those derived from non-afflicted patients.
  • a disorder e.g., cancer or a neurodegenerative disorder
  • the disorder is AD, wherein a subject suspected of being afflicted with AD or non-ADD is diagnosed as being afflicted with one or the other. It is this preferred embodiment (also referred to herein as the “invention”) to which the remainder of this application is devoted.
  • This invention provides accurate gene-based methods for determining whether a human subject is afflicted with Alzheimer’s disease (“AD”) or non-Alzheimer’s dementia (“non-ADD”) when the subject is suspected of being afflicted with AD or non-ADD.
  • the subject methods are based, at least in part, on the surprising discovery that synchronizing a patient’s suitable cell population and then measuring the expression levels of genes that are differentially expressed between AD and non-ADD cells permits accurately diagnosing the patient as having either AD or non-ADD.
  • this invention provides a method for determining whether a human subject is afflicted with Alzheimer’s disease (“AD”) or non-Alzheimer’s dementia (“non-ADD”) when the subject is suspected of being afflicted with AD or non-ADD, comprising the steps of (a) synchronizing a population of suitable cells derived from the AD or non-ADD, comprising the steps of (a) synchronizing a population of suitable cells derived from the AD or non-ADD, comprising the steps of (a) synchronizing a population of suitable cells derived from the
  • the suitable cells derived from the subject are cultured skin cell fibroblasts.
  • the suitable cells derived from the subject are cultured B lymphocytes (preferably immortalized B lymphocytes).
  • synchronizing the population of suitable cells comprises culturing the cells to over-confluence and then starving the resulting over-confluent cells.
  • the gene is known to be differentially expressed by a significant margin.
  • the gene is known to be differentially expressed by at least 50% between corresponding synchronized ceils derived from AD patients and those derived from non-ADD patients.
  • the gene is known to be differentially expressed by at least 100% between corresponding synchronized cells derived from AD patients and those derived from non-ADD patients.
  • Another way of expressing the degree of differential expression is“% change” or“%Ch”, which is equal to [AD expression Nqh-ADDexpression / NqP-ADDexpression] ⁇
  • the gene is selected from the group consisting of PTCD2, ST20, AC090971.4, EIF4A2P1 , CFAP97, AL157871.3, AC00732.4, NR3C2, C60rf58 and LINC01393.
  • AD-indicative expression levels for each other gene disclosed herein are readily determined based on the data presented.
  • step (b) comprises measuring the expression levels of a plurality of genes, each gene being known to be differentially expressed between corresponding synchronized cells derived from AD patients and those derived from non-ADD patients.
  • the plurality of genes can be of any suitable size, such as at least two genes, at least five genes, at least 20 genes, at least 100 genes, and at least 1 ,000 genes.
  • each gene of the plurality of genes is known to be differentially expressed by at least 50% (and more preferably by at least 100%) between corresponding synchronized ceils derived from AD patients and those derived from non-ADD patients.
  • the plurality of genes comprises two or more genes selected from the group consisting of PTCD2, ST20, AC090971.4, EIF4A2P1 , CFAP97, AL157871.3, AC00732.4, NR3C2, C60rf58 and LINC01393.
  • the expression levels measured in step (b) are“consistent” with those in corresponding synchronized cells derived from AD patients if, for example, for at least a majority of gene expression levels measured, each such level is independently consistent with that gene’s expression level in
  • measuring the expression level of a gene can be accomplished by any suitable method known in the art.
  • measuring the expression level of a gene comprises measuring the number of that gene’s RNA transcripts per number of total transcripts.
  • the subject invention provides a method for determining whether a human subject is afflicted with Alzheimer’s disease (“AD”) or non-Alzheimer’s dementia (“non-ADD”) when the subject is AD.
  • AD Alzheimer’s disease
  • non-ADD non-Alzheimer’s dementia
  • the subject invention provides a method for determining whether a human subject is afflicted with Alzheimer’s disease (“AD”) or non-Alzheimer’s dementia (“non-ADD”) when the subject is suspected of being afflicted with AD or non-ADD, comprising the steps of (a) synchronizing a population of cultured immortalized B
  • lymphocytes derived from the subject wherein the synchronizing comprises culturing the lymphocytes to over-confluence and then starving the resulting over-confluent lymphocytes;
  • measuring the expression level of each gene comprises measuring the number of its RNA transcripts per number of total transcripts, whereby (i) the subject is afflicted with AD if the expression levels measured in step (b) are consistent with the genes’ expression levels in corresponding synchronized ceils derived from AD patients, and (ii) the subject is afflicted with non-ADD if the expression levels measured in step (b) are consistent with the genes’ expression levels in corresponding synchronized cells derived from non-ADD patients.

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Abstract

La présente invention concerne un procédé pour déterminer si un sujet humain est atteint d'un trouble prédéterminé comprenant les étapes de (a) synchronisation d'une population de cellules adaptées dérivées du sujet ; et (b) dans la population de cellules synchronisées résultante, mesure du taux d'expression d'un gène connu pour être exprimé de façon différentielle entre des cellules synchronisées correspondantes dérivées de patients atteints du trouble et celles dérivés de patients non atteints, le sujet étant atteint du trouble si le taux d'expression mesuré dans l'étape (b) est cohérent avec le taux d'expression du gène dans des cellules synchronisées correspondantes dérivées de patients atteints du trouble, et le sujet n'étant pas atteint du trouble si le taux d'expression mesuré dans l'étape (b) est cohérent avec le taux d'expression de ce gène dans des cellules synchronisées correspondantes dérivées de patients non atteints.
PCT/US2018/064180 2017-12-08 2018-12-06 Diagnostic d'une maladie par l'intermédiaire d'un profil d'expression génique dans des cellules synchronisées Ceased WO2019113277A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3735587A4 (fr) * 2017-12-08 2022-04-06 NeuroGX LLC Test d'expression génique de cycle cellulaire synchronisé pour la maladie d'alzheimer et procédés thérapeutiques associés

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040132113A1 (en) * 2001-03-12 2004-07-08 Zsuzanna Nagy Diagnostic screens for alzheimer's disease
WO2008003516A1 (fr) * 2006-07-07 2008-01-10 Universität Leipzig Analyse de sang basée sur le cycle cellulaire permettant de diagnostiquer la maladie d'alzheimer

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040132113A1 (en) * 2001-03-12 2004-07-08 Zsuzanna Nagy Diagnostic screens for alzheimer's disease
WO2008003516A1 (fr) * 2006-07-07 2008-01-10 Universität Leipzig Analyse de sang basée sur le cycle cellulaire permettant de diagnostiquer la maladie d'alzheimer

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3735587A4 (fr) * 2017-12-08 2022-04-06 NeuroGX LLC Test d'expression génique de cycle cellulaire synchronisé pour la maladie d'alzheimer et procédés thérapeutiques associés

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