WO2018178071A1 - Procédé de prédiction de la réponse thérapeutique à des médicaments antipsychotiques - Google Patents

Procédé de prédiction de la réponse thérapeutique à des médicaments antipsychotiques Download PDF

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WO2018178071A1
WO2018178071A1 PCT/EP2018/057761 EP2018057761W WO2018178071A1 WO 2018178071 A1 WO2018178071 A1 WO 2018178071A1 EP 2018057761 W EP2018057761 W EP 2018057761W WO 2018178071 A1 WO2018178071 A1 WO 2018178071A1
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expression level
gene
disorder
psychotic disorder
treatment
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PCT/EP2018/057761
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Jesús Vicente SAINZ MAZA
Benedicto CRESPO FACORRO
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Consejo Superior De Investigaciones Cientificas
Universidad De Cantabria
Ciber Centro De Investigacion Biomedica En Red
Servicio Cantabro De Salud
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Publication of WO2018178071A1 publication Critical patent/WO2018178071A1/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
    • 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
    • C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/30—Psychoses; Psychiatry
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/30—Psychoses; Psychiatry
    • G01N2800/302—Schizophrenia
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/30—Psychoses; Psychiatry
    • G01N2800/304—Mood disorders, e.g. bipolar, depression
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • This invention falls within the field of prognosis or predicting methods for identifying which patients suffering from a psychotic disorder will benefit from an antipsychotic treatment.
  • the invention provides genetic biomarkers or genes which expression levels allow predicting, before the treatment, which patients will show sensitivity and an adequate clinical response to an antipsychotic treatment.
  • the invention relates thus to a method for predicting the clinical response to antipsychotic drugs before treatment in individuals diagnosed with a psychotic disorder, such as schizophrenia.
  • Antipsychotic drugs also termed as tranquilizers or neuroleptics, are the cornerstone to treat psychotic disorders such as schizophrenia. They are also majorly used to treat several other psychotic disorders including bipolar disorder, delirium, dementia and psychotic depression and they can be also used to treat severe depression, personality disorders, autism and anxiety. Therefore, antipsychotic medications are among the most common and costly prescribed drugs with significant increases in overall prescription in recent years.
  • the present invention discloses a method for predicting, before treatment, the individual clinical response to antipsychotic medication in subjects suffering from (diagnosed with) psychosis.
  • This method of the invention is based on a gene expression profile that is useful to predict the therapeutic response to antipsychotics in drug-naive patients, /. e. in patients diagnosed with a psychotic disorder who have not received antipsychotic medication yet. This method allows therefore the selection of patients for further or alternative antipsychotic therapies.
  • This predicting method of the present invention is useful for the identification, in early stages before the treatment, of those patients that will or will not respond to the antipsychotic drugs, which allow designing specific individual therapeutic strategies for each patient.
  • the inventors have identified six-genes (SLC9A3, H OX1 , SLC22A16, LOC284581 , PF4V1 and GSTT1 ) which expression profile, preferably measured in blood samples collected from the patient, provides useful information to predict the clinical response to antipsychotics in psychotic patients, more preferably in schizophrenia patients, before treatment.
  • the predicting method of the invention is therefore based on the analysis of the expression level of the gene SLC9A3, or its combination with at least one of the genes HMOX1 , SLC22A16, LOC284581 , PF4V1 and/or GSTT1 .
  • the inventors sequenced total mRNA from biological samples obtained from antipsychotic naive patients (Table 1 ) that, after 3 months of treatment, were in the top 40% with the best clinical response (15 patients) and in the bottom 40% with the poorer clinical response (15 patients) according to the Brief Psychiatric Rating Scale (Lukoff, et al., 1986, Schizophrenia bulletin, 12, 578-602).
  • the transcriptome before treatment of these 30 patients was characterized using next generation sequencing and 130 genes were found with significant differential expression (Padj value ⁇ 0.01 ) between the responders and the poorer responders.
  • Random Forests an ensemble learning method for classification and regression, was used to obtain a list of predictor genes (Koo, et al., 2013, BioMed research international, 432375).
  • predictor genes or new genetic markers identified in the invention showed, before treatment, significantly different expression between those patients that, after the treatment, had a positive response and those patients that had a poorer response to the treatment.
  • the six-gene expression profile identified with this methodology can predict the clinical response with a cross-validation estimate of accuracy of 0.83 and an area under the curve of 0.96 using a logistic regression.
  • the method provided in the present invention allows determining the clinical response to antipsychotic drugs before the treatment in a reliable manner.
  • This method is also simple since it can be performed by means of, for instance but without limitation, sequencing and/or immunohistochemical techniques commonly used in medicine and molecular biology.
  • the method of the invention is non-invasive, as it can be performed on isolated biological samples obtained from the patients through non-invasive techniques, such as blood extraction. Another advantage of this method is that in the proposed six-gene signature each individual gene has high predictive power (based on the Gini value).
  • each single gene provides useful information to predict the clinical response.
  • the preferred gene for the prediction with a single biomarker is the SLC9A3 gene, since it shows the highest Gini value (see Table 6) and therefore the highest predictive capacity.
  • the combination of this SLC9A3 gene with the other five genes also identified in this invention as biomarkers, HMOX1 , SLC22A16, LOC284581 . PF4V1 and GSTT1 improves the prediction value of the gene expression signature proposed herein.
  • these six predictor genes identified in this invention have, before treatment, significantly altered expression in those patients that after the treatment have a positive response compared to the expression before treatment in those patients that after the treatment have a poorer response. For this reason, this six- gene signature is useful to predict the therapeutic response to antipsychotic drugs. However, this significantly differential expression before treatment between responders and non-responders further evidences that these six genes must be direct or indirect targets for the antipsychotic drugs action.
  • this invention also provides a method for the screening of compounds, molecules or compositions useful for the treatment of a psychotic disorder based on the measurement of the expression levels of the SLC9A3 gene or its combination with any of HMOX1 , SLC22A16, LOC284581 , PF4V1 and/or GSTT1 genes, before and after the treatment.
  • This screening method will help, not only to discover and identify those drugs useful for the treatment of psychotic disorders but also, given that these genes are associated to the symptoms improved by the antipsychotics, could be used as targets to improve the existing drugs or to generate new drugs for the psychotic symptoms and, in turns, to select the specific antipsychotics that will produce the best clinical response for each specific patient.
  • a first aspect of the invention refers to the use of the expression level value of the SLC9A3 gene in an isolated biological sample as a biomarker in an in vitro method for predicting the therapeutic response to antipsychotic drugs in a subject suffering from (who has been diagnosed with) a psychotic disorder or as a biomarker in an in vitro method for the screening or identification of compounds, molecules or compositions useful for the treatment of a psychotic disorder.
  • "Predicting the therapeutic response" refers to determining, before administering the treatment, whether the antipsychotic treatment will have a favourable, positive or adequate response in the subject once treated (after administering the treatment).
  • a "positive response" to an antipsychotic treatment or an antipsychotic drug occurs when an improvement or a reduction in the symptoms of the psychotic disorder is observed in the patient.
  • the expression "positive response to the treatment with antipsychotic drugs” means a favourable response to the treatment that can be recognized when a significant reduction, for instance 40% reduction, in the symptoms of the psychotic disorder is observed in the patient according to the Brief Phsychiatric Rating Scale (BPRS) (Overall, JE y Gorham, DR (1962) The Brief Psychiatric Rating Scale. Psychol Rep 10: 799-812).
  • BPRS Brief Phsychiatric Rating Scale
  • in vitro means that the methods of the invention are fully performed outside of the human or animal body.
  • subject refers to a human or a non-human mammal, such as rodents, ruminants, cats or dogs. In a preferred embodiment, the subject is a human.
  • the expression levels of the genes indicated in the present invention may be previously normalized.
  • the "SLC9A3 gene” is the gene known by its identification number 6550 ⁇ Gene ID NCBl) (Solute carrier family 9 member A3).
  • the use further comprises the expression level of the HMOX1 gene.
  • HMOX1 gene is the gene known by its identification number 3162 (Gene ID NCBl) (Heme oxygenase 1 ).
  • the use further comprises the expression level of the SLC22A16 gene.
  • the "SLC22A16 gene” is the gene known by its identification number 85413 (Gene ID NCBI) (Solute carrier family 22 member 16).
  • the use further comprises the expression level of the LOC284581 gene.
  • the "LOC284581 gene” is the gene known by its identification number 284581 (Gene ID NCBI).
  • the use further comprises the expression level of the PF4V1 gene.
  • the "PF4V1 gene” is the gene known by its identification number 5197 (Gene ID NCBI) (Platelet factor 4 variant 1 ).
  • the use further comprises the expression level of the GSTT1 gene.
  • the "GSTT1 gene” is the gene known by its identification number 2952 (Gene ID NCBI) (Glutathione S-transferase theta 1 ).
  • the genes which expression levels are used as a biomarker in an in vitro method for predicting the therapeutic response to antipsychotic drugs in a subject suffering from a psychotic disorder or for the screening of compounds, molecules or compositions useful for the treatment of a psychotic disorder are SLC9A3, HMOX1 , SLC22A16, LOC284581 , PF4V1 and GSTT1 .
  • a "psychotic disorder” is a group of severe mental disorders that cause abnormal thinking and perceptions.
  • Psychotic disorders are a psychopathological condition in which symptoms such as delusions, hallucinations, delirium and altered behaviour are present. Subjects suffering from psychotic disorders have a disturbed reality perception.
  • the psychotic disorder is selected from the list consisting of: schizophrenia, schizophreniform disorder, schizoaffective disorder, bipolar disorder, delusional disorder, delirium, dementia and/or behavioral disorders. More preferably, the psychotic disorder is schizophrenia or bipolar disorder. Even more preferably, the psychotic disorder is schizophrenia.
  • "Schizophrenia" is the brain illness that course with the criteria indicated in Psychiatry American Society DSM-IV for schizophrenia, schizophreniform disorder, schizoaffective disorder or brief psychotic disorder. It is a chronic and severe mental disorder that affects how a person thinks, feels, and behaves. Symptoms of schizophrenia usually start between ages 16 and 30.
  • the symptoms of schizophrenia fall into three categories: positive, negative, and cognitive.
  • “Positive” symptoms are psychotic behaviors not generally seen in healthy people. People with positive symptoms may "lose touch” with some aspects of reality. Positive symptoms include: hallucinations, delusions, thought disorders (unusual or dysfunctional ways of thinking) or movement disorders (agitated body movements).
  • Negative symptoms are associated with disruptions to normal emotions and behaviors. Negative symptoms include: "Flat affect” (reduced expression of emotions via facial expression or voice tone), reduced feelings of pleasure in everyday life, difficulty beginning and sustaining activities or reduced speaking.
  • the cognitive symptoms of schizophrenia are subtle, but for others, they are more severe and patients may notice changes in their memory or other aspects of thinking.
  • Cognitive symptoms include: poor "executive functioning” (the ability to understand information and use it to make decisions), trouble focusing or paying attention or problems with "working memory” (the ability to use information immediately after learning it). It is considered that a subject suffers from schizophrenia when these symptoms last at least six months.
  • the subject suffering from a psychotic disorder is a first-episode psychosis patient.
  • a "first-episode psychosis patient” is a subject who has only experienced his first episode of psychosis and who does not present affective psychosis.
  • a first episode of psychosis is the first time a person experiences a psychotic episode.
  • Antipsychotic drugs is understood as the medication or actions known by the skilled in the art taken in order to palliate, reduce, cure, mitigate, eliminate or the like, a psychotic disorder or episode.
  • the antipsychotic drug as used in the present invention is selected from the list consisting of: aripiprazole (Ability®), risperidone (Risperdal®), olanzapine (Zyprexa®), paliperidone (Invega®), chlorpromazine (Largactil®, Thorapine®), clozapine (Clorazil®), quetiapine (Seroquel®), ziprasidone (Geodon®), asenapine, iloperidone (Zomaril®), zotepine, amisulpride (Solian@), fluphenazine (Prolixin®), haloperidol (Aldol®, Serenace®),
  • expression level refers to the expression level of any genetic expression product of the genes SLC9A3, HMOX1 , SLC22A16, LOC284581 , PF4V1 and GSTT1 .
  • the expression levels are RNA and/or protein.
  • the RNA may be mRNA or microRNA, preferably mRNA.
  • Another aspect of the invention refers to a method for obtaining information or data useful for predicting the therapeutic response to antipsychotic drugs in a subject suffering from a psychotic disorder, comprising measuring the expression level of the SLC9A3 gene in an isolated biological sample collected from the subject suffering from a psychotic disorder before the treatment with antipsychotic drugs, and comparing this expression level value obtained with an standard value.
  • this method further comprises measuring the expression level of at least one of the genes of the list consisting of HMOX1 , SLC22A16, LOC284581 , PF4V1 or GSTT1 , in the isolated biological sample. More preferably, this method comprises measuring the expression level of the SLC9A3, HMOX1 , SLC22A16, LOC284581 , PF4V1 and GSTT1 genes, in the isolated biological sample.
  • Another aspect of the invention refers to an in vitro method for predicting the therapeutic response to antipsychotic drugs in a subject suffering from (who has been diagnosed with) a psychotic disorder, comprising the following steps: a) measuring the expression level of the SLC9A3 gene in an isolated biological sample collected from the subject suffering from a psychotic disorder before the treatment with antipsychotic drugs,
  • step (b) comparing the expression level value obtained after step (a) with an standard value
  • step (a) assigning the subject of step (a) to the group of patients that will positively respond to the treatment with antipsychotic drugs when the expression level value obtained after step (a) is lower than the standard value, wherein the standard value is the mean value obtained after measuring the expression level of the SLC9A3 gene in isolated biological samples collected from a group of subjects suffering from a psychotic disorder who have not been treated with antipsychotic drugs.
  • the standard value is the mean value obtained after measuring the expression level of the SLC9A3 gene in isolated biological samples collected from a group of subjects suffering from a psychotic disorder who have not been treated with antipsychotic drugs.
  • the expression "before the treatment with antipsychotic drugs” or "subjects who have not been treated with antipsychotic drugs” means that the subject has not received prior treatment with antipsychotic medication. These subjects will be also called “antipsychotic drug-naive patients”.
  • the expression level of the genes indicated in this invention may, for example, be measured directly by assessing the protein levels soluble in the samples. For instance, these protein levels can be measured by immunohistochemistry, Western blot, ELISA, lateral flow devices or Luminex®. In another preferred embodiment, the mRNA expression levels can be measured instead. For example, mRNA expression levels can be measured by RT-PCR, Northern blot or array hybridization.
  • the expression levels are RNA and/or protein.
  • the RNA may be mRNA or microRNA, preferably mRNA.
  • the measurement of the expression levels in the present invention refers to the measurement of the quantity or concentration. This measurement may be performed as a direct or an indirect measurement.
  • the direct measurement refers to the measurement of the quantity or concentration of the expression levels based on a signal directly obtained from the expression of the genes to be assessed. This signal is directly correlated with the number of product molecules present in the sample. This signal, also referred to as "intensity signal", may be obtained for instance by measuring an intensity value derived from a physical or chemical property of the product.
  • the indirect measurement refers to the measurement obtained from a secondary component (for example, a component which is different from the gene products) or a measurement derived from, for example, cellular responses, ligands, tags or enzymatic reaction products associated to these molecules or their activities.
  • mRNA levels are measured.
  • mRNA extractions protocols are well known for those skilled in the art. This measurement may be performed, but without limitation, by sequencing, amplification with the polymerase chain reaction (PGR), retrotranscription combined with ligase chain reaction (RTLCR), retrotranscription combined with PGR (RT-PCR), retrotranscription combined with quantitative PGR (qRT-PCR), SAGE or any other method for the amplification of nucleic acids; microarrays made with oligonucleotides deposited by any technique, microarrays made with in situ synthesized oligonucleotides, in situ hybridization using specific labeled probes, electrophoresis gels, membrane transfer and hybridization with a specific probe, RMN or any other image diagnosis technique using paramagnetic nanoparticles or other type of functionalized nanoparticles.
  • PGR polymerase chain reaction
  • RTLCR ligase chain reaction
  • RT-PCR retrotranscription combined with PGR
  • qRT-PCR retrotranscription
  • microarray refers to a solid support to which RNA or protein is bound being thus useful for the gene expression analysis through label and/or antibody hybridization.
  • SAGE refers to the detection and quantification of the gene expression by means of the RNA measurement.
  • SAGE variants may be used, such as SuperS AGE, MicroSAGE or LongSAGE.
  • Protein levels may also be measured in the present invention. This measurement may be performed, but without limitation, by incubation with a specific antibody against the protein or a fragment thereof in assays such as Western blot, electrophoresis gels, immunoprecipitation assays, protein arrays preferably antibodies based microarrays, immunofluorescence, immunohistochemistry, ELISA or any other enzymatic method, by incubation with a specific ligand, RMN or any other image diagnosis technique or by chromatographic techniques preferably combined with mass spectrometry. Protein levels measurement may be performed by the specific recognition of any protein fragment by means of probes and/or antibodies. Proteins or fragments thereof may be quantified by electrophoresis and/or immunoassays. For the immunoassay the antibodies used may be labeled with, for instance, an enzyme, radioisotopes, magnetic tags or fluorescence.
  • isolated biological sample refers, but without limitations, to any biological tissue and/or fluid collected from a subject.
  • Biological samples may be obtained by means of any method known by those skilled in the art.
  • the biological sample referred to in the present invention is a biological fluid, for instance, blood, plasma, serum, lymph, saliva, urine, tears, synovial fluid or the like.
  • the biological sample in the present invention is blood, more preferably peripheral blood.
  • the biological sample comprises RNA and/or protein, preferably mRNA.
  • the biological sample may be fresh, frozen, fixed or fixed and paraffin-embedded.
  • the first method of the invention further comprises: measuring in step (a) the expression level of the HMOX1 gene, comparing in step (b) this expression level value with an standard value, and assigning in step (c) the subject to the group of patients that will positively respond to the treatment with antipsychotic drugs when this expression level value obtained after step (a) is higher than the standard value, wherein this standard value is the mean value obtained after measuring the expression level of the HMOX1 gene in isolated biological samples collected from a group of subjects suffering from a psychotic disorder who have not been treated with antipsychotic drugs.
  • the first method of the invention further comprises: measuring in step (a) the expression level of the SLC22A16 gene, comparing in step (b) this expression level value with an standard value, and assigning in step (c) the subject to the group of patients that will positively respond to the treatment with antipsychotic drugs when this expression level value obtained after step (a) is higher than the standard value, wherein this standard value is the mean value obtained after measuring the expression level of the SLC22A16 gene in isolated biological samples collected from a group of subjects suffering from a psychotic disorder who have not been treated with antipsychotic drugs.
  • the first method of the invention further comprises: measuring in step (a) the expression level of the LOC284581 gene, comparing in step (b) this expression level value with an standard value, and assigning in step (c) the subject to the group of patients that will positively respond to the treatment with antipsychotic drugs when this expression level value obtained after step (a) is lower than the standard value, wherein this standard value is the mean value obtained after measuring the expression level of the LOC284581 gene in isolated biological samples collected from a group of subjects suffering from a psychotic disorder who have not been treated with antipsychotic drugs.
  • the first method of the invention further comprises: measuring in step (a) the expression level of the PF4V1 gene, comparing in step (b) this expression level value with an standard value, and assigning in step (c) the subject to the group of patients that will positively respond to the treatment with antipsychotic drugs when this expression level value obtained after step (a) is higher than the standard value, wherein this standard value is the mean value obtained after measuring the expression level of the PF4V1 gene in isolated biological samples collected from a group of subjects suffering from a psychotic disorder who have not been treated with antipsychotic drugs.
  • the first method of the invention further comprises: measuring in step (a) the expression level of the GSTT1 gene, comparing in step (b) this expression level value with an standard value, and assigning in step (c) the subject to the group of patients that will positively respond to the treatment with antipsychotic drugs when this expression level value obtained after step (a) is lower than the standard value, wherein this standard value is the mean value obtained after measuring the expression level of the GSTT1 gene in isolated biological samples collected from a group of subjects suffering from a psychotic disorder who have not been treated with antipsychotic drugs.
  • said method comprises measuring in step (a) the expression levels of the SLC9A3, HMOX1 , SLC22A16, LOC284581 , PF4V1 and GSTT1 genes.
  • the term "mean value” refers to the arithmetic mean of the gene expression level value considering every member of the sample population or group.
  • the mean gene expression level of the sample population or group is equal to the sum of the gene expression levels of every individual divided by the total number of individuals in the sample group.
  • the "group of subjects suffering from a psychotic disorder who have not been treated with antipsychotic drugs" from which the mean value is obtained comprises at least 15, more preferably at least 30 individuals, and includes individuals of both conditions responders and non-responders to antipsychotic drugs once this medication is administered.
  • the mean value for the SLC9A3 gene is 564
  • the mean value for the HMOX1 gene is 2923
  • the mean value for the SLC22A16 gene is 101
  • the mean value for the LOC284581 gene is 149
  • the mean value for the PF4V1 gene is 153
  • the mean value for the GSTT1 gene is 158.
  • step (a) of the method of the invention means that the value obtained after step (a) of the method of the invention is significantly lower or significantly higher than the standard value.
  • the signification level may be calculated by statistical methods well known by those skilled in the art, such as confidence intervals, p-value, Student test or Fisher discriminant analysis.
  • Steps (a) and (b) of the first method of the invention may be total or partially computerized. Furthermore, the first method of the invention may comprise other additional steps, for example, related to the pre-treatment of the biological samples prior to the analysis.
  • the psychotic disorder is selected from the list consisting of: schizophrenia, schizophreniform disorder, schizoaffective disorder, bipolar disorder, delusional disorder, delirium, dementia and/or behavioral disorders. More preferably, the psychotic disorder is schizophrenia or bipolar disorder. Even more preferably, the psychotic disorder is schizophrenia.
  • the subject suffering from a psychotic disorder is a first-episode psychosis patient.
  • the antipsychotic drug is selected from the list consisting of: aripiprazole (Ability®), risperidone (Risperdal®), olanzapine (Zyprexa®), paliperidone (Invega®), chlorpromazine (Largactil®, Thorapine®), clozapine (Clorazil®), quetiapine (Seroquel®), ziprasidone (Geodon®), asenapine, iloperidone (Zomaril®), zotepine, amisulpride (Solian@), fluphenazine (Prolixin®), haloperidol (Aldol®, Serenace®), loxapine (Loxapac®, Loxitane®), perphenazine, pimozide (Orap®), zuclopenthixol (Clopixol®), or any combination thereof. More preferably, aripiprazole (Ability
  • Another aspect of the present invention refers to an in vitro method for the screening or identification of compounds, molecules or compositions useful for the treatment of a psychotic disorder that comprises: i) measuring the expression level of at least one gene of those included in Table 4 of the present invention or of the SLC9A3 gene in an isolated biological sample obtained from a subject suffering from a psychotic disorder before the administration of the compound, molecule or composition to be tested, ii) measuring the expression level of the same gene/s as that measured in step (i) in an isolated biological sample obtained from the same subject after the administration of the compound, molecule or composition to be tested, (iii) comparing the expression level values obtained in (i) and (ii), and (iv) classifying the compound, molecule or composition as useful for the treatment of a psychotic disorder when a significant difference in the expression level values has been detected in step (iii).
  • This method will be also referred to as "the second method of the invention" and allows the discovery and identification of new drugs useful for the treatment of psychotic disorders as well as the improvement of the existing drugs in terms of, for instance, administering route, dosage regime, etc.
  • This method also allows the selection of the specific antipsychotic drug that will produce the best clinical response for each specific patient. This method represents thus a tool to select the antipsychotic that is expected to provide the best response.
  • said method further comprises measuring in step (i) the expression level of at least one gene selected from the list consisting of: HMOX1 , SLC22A16, LOC284581 , PF4V1 and/or GSTT1 . More preferably, this second method comprises measuring in step (i) the expression level of the following genes: SLC9A3, HMOX1 , SLC22A16, LOC284581 , PF4V1 and GSTT1 .
  • the psychotic disorder is selected from the list consisting of: schizophrenia, schizophreniform disorder, schizoaffective disorder, bipolar disorder, delusional disorder, delirium, dementia and/or behavioral disorders. More preferably, the psychotic disorder is schizophrenia.
  • the expression levels are RNA and/or protein, preferably mRNA.
  • the isolated biological sample is peripheral blood.
  • kits comprising compounds capable of specifically binding SLC9A3 gene or its expression products.
  • This kit comprises all those necessary elements for predicting the therapeutic response to antipsychotic drugs in a subject suffering from a psychotic disorder according to the first method of the invention or for the screening of compounds, molecules or compositions useful for the treatment of a psychotic disorder according to the second method of the invention. That is, this kit comprises all the elements needed for measuring the gene expression levels as explained before.
  • this kit will be referred to as the "kit of the invention”.
  • the kit further comprises compounds capable of specifically binding HMOX1 , SLC22A16, LOC284581 , PF4V1 and/or GSTT1 genes or their expression products.
  • the compounds comprised in the kit are labels, antibodies and/or primers, preferably primers capable of detecting and amplyfing the genes indicated in this invention or fragments thereof.
  • the kit of the invention consists of labels, antibodies and/or primers capable of specifically binding SLC9A3, HMOX1 , SLC22A16, LOC284581 , PF4V1 and GSTT1 genes or their expression products.
  • primer refers to a nucleic acid sequence capable of acting as the starting point for the DNA synthesis when it hybridizes with the template nucleic acid.
  • the primer is a deoxyribose primer.
  • Primers may be designed for instance by direct chemical synthesis. Primers may be designed to hybridize with specific sequences within the genes indicated in this invention (specific primers) or they may be randomly synthetized (arbitrary primers).
  • primers comprised in the kit of the invention may be labeled with detectable tags, such as radioactive isotopes, fluorescence tags, chemiluminescent or bioluminescent tags or enzymatic tags.
  • detectable tags such as radioactive isotopes, fluorescence tags, chemiluminescent or bioluminescent tags or enzymatic tags.
  • at least one of the antibodies comprised in the kit of the invention is labeled or immobilized.
  • the antibody may be labeled with, for example, a tag selected from the list consisting of a radioisotope (such as 32P, 35S or 3H), a fluorescent or luminescent marker (such as fluorescein (FITC), rhodamine, texas red, ficoeritrine (PE), aloficocianine, 6-carboxyfluorescein (6-FAM), 2 ' ,7'-dimetoxi-4',5'- dichlore-6-carboxyfluorescein (JOE), 6-carboxy-X-rhodamine (ROX), 6-carboxy- 2',4',7',4,7-hexachlorefluorescein (HEX), 5-carboxyfluorescein (5-FAM) o ⁇ , ⁇ , ⁇ ', ⁇ '- tetramethyl-6-carboxyrhodamine (TAMRA)), a secondary antibody, an antibody fragment (such as F(ab)2), an affinity tag (such as biot
  • the antibody may be immobilized without losing its activity in, for example, a matrix (preferably a nylon or latex matrix), a microtiter plate or a similar plastic support, beads, glass support, gel, cellulosic support, adsorption resin, or the like.
  • the kit of the invention comprises all those reactives needed to perform the methods of the invention.
  • the kit may further comprise elements such as buffers, enzymes, such as polymerases, cofactors needed to obtain an optimal activity of said enzymes, etc.
  • the kit may comprise all those supports and recipients needed for the implementation of the methods of the invention.
  • the kit may comprise other molecules, genes, proteins or probes suitable as positive or negative controls.
  • the kit of the invention further comprises instructions explaining how to perform the methods of the invention.
  • kits of the invention for predicting the therapeutic response to antipsychotic drugs in a subject suffering from a psychotic disorder or for the screening of compounds, molecules or compositions useful for the treatment of a psychotic disorder, preferably for performing the first or the second method of the invention.
  • Another aspect of the present invention refers to a method of treating a subject suffering from a psychotic disorder comprising: selecting a subject as responding or non-responding to the antipsychotic treatment in accordance with the first method of the invention; and administering an antipsychotic therapy to the patient.
  • the antipsychotic therapy is an antipsychotic drug as those defined herein, psychosocial treatment, coordinated specialty care (CSC), or any other antipsychotic treatment of those known in the art.
  • Gini variable importance measures reflect the mean decrease in impurity by splits of a given variable in the classification tree, weighted by the proportion of samples reaching that node. A greater "mean decrease Gini" indicates that the gene plays a greater role in partitioning the data into the defined classes.
  • FIG. 2 Receiver operating characteristic (ROC) curves, a) Using the best two genes (SCL9A3, HMOX1 ) for training the predictor it was obtain a ROC with an area under the curve (AUC) of 0.92. b) Using the best three genes (SCL9A3, HMOX1 , SLC22A16) for training the predictor it was obtain a ROC with an AUC of 0.96. c) Using the best four genes (SCL9A3, HMOX1 , SLC22A16, LOC284581 ) for training the predictor it was obtain a ROC with an AUC of 0.97.
  • ROC Receiver operating characteristic
  • FIG. 3 Predicted probability of response to antipsychotics. Scatter plot which represent the predicted probability of response (y-axis) for each input sample (x-axis) in the logistic regression predictor. Grey points represent no responder patients and black points represent responder patients.
  • BPRS Brief Psychiatric Rating Scale
  • VWF a glycoprotein with levels increased in plasma of not medicated patients and in bipolar disorder and schizophrenia compared to control individuals
  • UGT1 A1 a gene with promoter variations in patients with schizophrenia that result in lower serum bilirubin levels
  • HMOX1 an enzyme that has anti-inflammatory properties and mediates the first step of heme catabolism, is over-expressed in transgenic mice with schizophrenia-like features
  • IL8 known also as CXCL8
  • NTNG2 a gene with haplotypes associated with schizophrenia and isoform expression significantly different between schizophrenic and control brains
  • PTGDS a prostaglandin that acts as neuromodulator as
  • the differential expression genes between responders and non-responders after 3 months of medication indicates that 5 out the 1 1 genes involved in "drug processing" with differential expression before medication still have differential expression and similar expression profile after medication.
  • These 5 genes are: GSTM1 , a glutathione S- transferase involved in detoxification of electrophilic compounds, such as therapeutic drugs, by conjugation with glutathione, with genetic variations that affect the toxicity and efficacy of certain drugs; THBS1 , an adhesive glycoprotein that mediates cell-to- cell and cell-to-matrix interactions and related to drug resistance; PRAME, an antigen related to cytotoxic drug sensitivity; GSTT1 , a glutathione S-transferase that functions as a drug metabolizing enzyme; and SLC22A16, a solute carrier reported to be involved in response to drugs. These genes could be good candidates to be involved in the different clinical response of both groups of patients.
  • AUC area under the curve
  • the gene with the highest predictive value, SLC9A3, is a Na/H exchanger and belongs to several pathways involved in transmembrane transportation of small molecules.
  • the second best predictor is HMOX1 , an essential enzyme in heme catabolism that is involved in the production of carbon monoxide, a putative neurotransmitter, belongs to a pathway for transmembrane transport of small molecules, and has been related to schizophrenia and to drug resistance in acute myeloid leukemia.
  • the third predictor, SLC22A16 encodes a protein that been shown to be involved in the transport and response to anticancer drugs like bleomycin or others and is located within a schizophrenia susceptibility locus in chromosome 6q.
  • the fourth gene, LOC284581 is not annotated but locates within a Parkinson disease locus of 15.8 Mb. This data have allowed generating a simple test (expression level of at least 1 gene) to predict the response to antipsychotics, one of the most prescribed type of drugs worldwide, and provide a tool to select the antipsychotic that is expected to provide the best response.
  • the cohort analyzed in this study was obtained from an ongoing epidemiological and three-year longitudinal intervention program of first-episode psychosis (PAFIP) conducted at the outpatient clinic and the inpatient unit at the University Hospital Marques de Valdecilla, Cantabria, Spain. Conforming to international standards for research ethics, the research in this study was approved by the Cantabria Ethics Institutional Review Board (IRB). Patients meeting inclusion criteria and their families provided written informed consent to be included in the PAFIP. The biological samples of patients included in the study were provided by the Valdecilla biobank.
  • Age of onset of psychosis was defined as the age when the emergence of the first continuous (present most of the time) psychotic symptom occurred.
  • Duration of untreated illness (DUI) was defined as the time from the first unspecific symptoms related to psychosis (for such a symptom to be considered, there should be no return to previous stable level of functioning) to initiation of adequate antipsychotic drug treatment.
  • the dose and type of antipsychotic medication could be changed based on clinical efficacy and the profile of side effects during the follow-up period.
  • Antimuscarinic medication, lormetazepam and clonazepam were permitted for clinical reasons. No antimuscarinic agents were administered prophylactically.
  • Mean daily dose of antipsychotics at baseline was 189.19 (51 .55) mg/day chlorpormazine (CPZ) equivalent doses.
  • Mean daily dose of antipsychotics at 3 months was 361 .43 (179.50) mg/day CPZ equivalent doses.
  • CGI Clinical Global Impression
  • BPRS Brief Psychiatric Rating Scale
  • SAPS Scale for the Assessment of Positive symptoms
  • SANS Scale for the Assessment of Negative symptoms
  • CDSS Calgary Depression Scale for Schizophrenia
  • YMRS Young Mania Rating Scale
  • Blood samples were assessed for biochemical and hematological parameters. To minimize the effects of diet and technique, blood samples were obtained from fasting subjects from 8:00 to 10:00 a.m. by the same personnel, in the same setting. No patient had a chronic inflammation or infection, or was taking medication that may apparently influence the results of blood tests. RNA extraction
  • RNA was extracted from blood using the TempusTM Blood RNA Tube and TempusTM Spin RNA Isolation Kit (Applied Biosystems, Foster City, CA, USA) using the manufacturer protocols. To define expression profiles, a key factor is that the RNA is intact. To select only RNA with good quality, the RNA Integrity Number (RIN) was characterized with a Bioanalyzer (Agilent Technologies, Santa Clara, CA, USA) and samples with a RIN of at least 7.2 were selected. The selected samples have RINs that range from 8 to 10 with an average of 9.1 1 . RNA Next Generation Sequencing. Total RNA was extracted from peripheral blood of each individual.
  • RNA Integrity Number RIN
  • the mRNA obtained from blood was sequenced at the Centra Nacional de Analisis Genomico (CNAG) using lllumina HiSeq instruments (San Diego, CA, USA).
  • the mRNA was isolated from the total RNA and was fragmented once transformed in cDNA. Fragments of 300 bp on average were selected to construct the libraries for sequencing. Pair-end sequences of 70 nucleotides for each end were produced. Alignment of reads to the human genome reference
  • Tophat Alignment of the reads was performed in an SLURM HPC server running Tophat 2.0.6 with default options. Tophat aligns RNA-Seq reads to genomes using the Bowtie 2.0.2 alignment program, and then analyzes the mapping results to identify splice junctions between exons.
  • Bedtools 2.17.0 (multicov option) was used to count the amount of reads mapped to each gene.
  • the Reference Sequence (RefSeq) gene coordinates were defined using the RefFlat file from the UCSC Genome Bioinformatics Site (as February 28th, 2014).
  • Gene selection was performed with the implementation of Random Forest method in the the RandomForest 4.6-12 package (Breiman, L, 2001 , Mach Learn, 45, 5-32) of R. Expression values of the 130 genes with significantly different expression between the responders and no responders was used as input with default parameters. Genes with the best Gini were selected for the predictor. It was trained using Logistic regression (Cox, D. R., 1958, J Roy Stat Soc B, 20, 215-242) with the glm function of R 3.2.3 and the calculation of the estimated cross-validation was performed with the cv.glm function of boot package which implements bootstrapping methods (Hinkley, D. V., 1988, J Roy Stat Soc B Met, 50, 321 -337).
  • Table 1 Characteristics of the patients assessed.

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Abstract

La présente invention concerne un procédé de prédiction, avant le traitement, de la réponse clinique individuelle à un médicament antipsychotique chez des sujets souffrant de psychose. Ce procédé est basé sur un profil d'expression génique qui est utile pour prédire la réponse thérapeutique à des antipsychotiques chez des patients non encore traités. En particulier, la signature génique proposée dans l'invention comprend six gènes (SLC9A3, HMOX1, SLC22A16, LOC284581, PF4V1 et GSTT1), lequel profil d'expression, de préférence mesuré dans des échantillons de sang recueillis à partir du patient, fournit des informations utiles pour prédire la réponse clinique à des antipsychotiques chez des patients psychotiques, plus préférablement chez des patients atteints de schizophrénie, avant le traitement.
PCT/EP2018/057761 2017-03-29 2018-03-27 Procédé de prédiction de la réponse thérapeutique à des médicaments antipsychotiques WO2018178071A1 (fr)

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