WO2016020573A1 - Procédé de surveillance de traitement antiseptique - Google Patents

Procédé de surveillance de traitement antiseptique Download PDF

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WO2016020573A1
WO2016020573A1 PCT/ES2015/070608 ES2015070608W WO2016020573A1 WO 2016020573 A1 WO2016020573 A1 WO 2016020573A1 ES 2015070608 W ES2015070608 W ES 2015070608W WO 2016020573 A1 WO2016020573 A1 WO 2016020573A1
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expression
genes
quantification
treatment
detection
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Spanish (es)
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Jseús Vicente SAINZ MAZA
Benedicto CRESPO FACORRO
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Fundación "Instituto De Investigaciones Marques De Valdecilla"
Consejo Superior De Investigaciones Científicas (Csic)
Universidad De Cantabria
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    • 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

Definitions

  • the present invention relates to a method for monitoring an antipsychotic treatment in a subject diagnosed with psychosis comprising the detection and / or quantification of the expression of the RPPH1 gene. Therefore, the present invention could be framed in the field of medicine. STATE OF THE TECHNIQUE
  • Psychotic diseases also called psychotic disorders, have common pathological and symptomatic features, with psychosis. These diseases include schizophrenia, bipolar disorder, depression, alcoholism, drug addiction and alcohol or drug withdrawal syndrome, with schizophrenia considered as representative of this group.
  • Schizophrenia is a serious mental illness characterized by positive (hallucinations, delusions, behavioral alterations) and negative symptoms (flattened affection, alogia, anergy, associability), and cognitive malfunction already from the initial stages of the disease (Pelayo-Terán JM et al. Eariyinterv. Psychiatry 2008 2: 178-187).
  • all these manifestations are associated with very negative effects on the functioning and personality of the affected individual.
  • the onset of symptoms normally occurs in young adulthood, with a lifetime prevalence of around 0.3-0.7%. (van Os J et al.
  • RNA ribonucleic acid
  • CHRNA7 7-acetylcholine receptor
  • a method for the monitoring of antipsychotic treatments is described as well as to indicate the clinical response to said treatment in individuals with psychosis.
  • This invention identifies new genetic markers that are useful for monitoring an antipsychotic treatment and / or indicate the favorable or not response to the treatment of patients with psychosis, including patients with schizophrenia.
  • genes with significant differential expression are identified between individuals with psychosis and control individuals and also between individuals with psychoses treated and not treated with antipsychotics (cases / controls; medicated / non-medicated). Genes have been identified, among which RPPH1 stands out, whose expression is altered due to the effects of antipsychotic drugs.
  • mRNA messenger RNA
  • group 1 healthy controls
  • group 2 patients with disease without medication (have never received any antipsychotic treatment)
  • group 3 those same patients in group 2 after three months of treatment and with changes in their clinical symptoms
  • the differential expression profiles performed have allowed us to characterize new genes involved in the therapeutic action of antipsychotics that have not been detected using others.
  • RPPH1 the genes that demonstrate its usefulness for the monitoring of antipsychotic treatments as well as to indicate the clinical response to such treatment in individuals with psychosis is the RPPH1 gene and also its combination with any of the genes ALPL, CRISP3, ABCA13, CEACAM8, MMP8, OLFM4, OLR1, LTF, GPER, MIR3198, ADAMTS2, UNC45B, CD177, RFX2, CNTNAP3 and ENTPD2.
  • a first aspect of the present invention relates to a method of obtaining useful data for the monitoring of an antipsychotic treatment in a subject diagnosed with psychosis comprising the detection and / or quantification of the expression of the RPPH1 gene in a isolated biological sample from said subject before and after the administration of antipsychotic treatment and / or to indicate the favorable clinical response or not to an antipsychotic treatment.
  • first method of the invention we will refer to this as the "first method of the invention”.
  • Monitoring of a treatment means the indication of whether the patient is properly medicated with said treatment; i.e. who is following the prescribed medication properly (abandonment of treatment is common in these patients).
  • RPPH 1 is understood as the gene known by its identification number 85495 (Gene ID of the NCBI) [Ribonuclease P RNA Component H1).
  • Treatment means the set of means used to cure or alleviate a disease.
  • Antipsychotic treatment means the measures known by the person skilled in the art taken to alleviate psychosis, preferably the administration of antipsychotic drugs, such as, but not limited to, clozapine (Clorazil®), risperidone (Risperdal®), olanzapine (Zyprexa®), quetiapine (Seroquel®), ziprasidone (Geodon®), aripiprazole (Abilify®), paliperidone (Invega®), asenapine, iloperidone (Zomaril®), zotepine, amisulpride, chlorpromazine (Largapine®) , fluphenazine (Prolixin®), haloperidol (Aldol®, Serenace®), loxapine (Loxapac®, Loxitane®), perphenazine, pi
  • the term "subject”, “individual” and “patient” are used interchangeably.
  • the subject is a human.
  • Psychosis means any psychopathological condition in which symptoms appear as hallucinations, delusions and behavioral alterations that are associated with an alteration of the reality judgment and without altering the level of consciousness.
  • biological sample in the present invention refers to any sample that makes it possible to detect and / or quantify the expression of the gene or genes of the individual from which said sample was obtained, and includes, but is not limited to, any of the biological fluids of an individual, obtained by any method known to a person skilled in the art that serves this purpose.
  • the biological sample comprises RNA and / or protein, preferably messenger RNA.
  • the biological sample could be, for example, but not limited to, a sample of fluid, such as blood, plasma, serum, saliva, urine, synovial fluid or lymph. It can also be a tissue sample.
  • the biological sample can also come from routine extractions in analyzes that can be performed periodically to patients.
  • the biological sample in the present invention can be fresh, frozen, fixed, or fixed and embedded in paraffin.
  • the method further comprises the detection and / or quantification of the expression of at least one of the genes that are selected from the list comprising: ALPL, CRISP3, ABCA13, CEACAM8, MMP8, OLFM4 , OLR1, LTF, GPER, MIR3198, ADAMTS2, UNC45B, CD177, RFX2, CNTNAP3 and ENTPD2, or any combination thereof.
  • the genes are ALPL, CRISP3, ABCA13, CEACAM8, MMP8, OLFM4, OLR1, LTF, GPER, MIR3198, ADAMTS2, UNC45B, CD177, RFX2, CNTNAP3 and ENTPD2.
  • ALPL alkaline phosphatase, liver / bone / kidney, referred to the identification number gene or geneID 249), CRISP3 ⁇ cysteine-rich secretor / protein 3, geneID 10321), ABCA13 ⁇ ATP-binding cassette, sub-family A (ABC1), member 13, geneID 154664), CEACAM8 (carcinoembryonic antigen-related cell adhesion molecule 8, geneID 1088), MMP8 (matrix metallopeptidase 8 (neutrophil collagenase), geneID 4317) , OLFM4 (olfactomedin 4, geneID 10562), OLR1 (oxidized low density lipoprotein (lectin-like) receptor 1, geneID 4973), LTF (lactotransferrin, geneID 4057), GPER (G protein-coupled estrogen receptor 1, geneID 2852), MIR3198 ⁇ microRNA 3198-1, geneID 100423025), ADAMTS2 ⁇
  • identification numbers are those of the NCBI database ⁇ National Center for Biotechnology Information).
  • the method further comprises the detection and / or quantification of the expression of the ALPL gene.
  • the method further comprises the detection and / or quantification of the expression of at least one of the genes that are selected from the list comprising: CRISP3, ABCA13, CEACAM8, MMP8, OLFM4, OLR1, LTF, GPER and MIR3198, or any combination thereof.
  • the genes are CRISP3, ABCA13, CEACAM8, MMP8, OLFM4, OLR1, LTF, GPER and MIR3198.
  • the method further comprises the detection and / or quantification of ADAMTS2 gene expression.
  • the method further comprises the detection and / or quantification of the expression of the UNC45B gene. In another even more preferred embodiment, the method further comprises the detection and / or quantification of the expression of at least one of the genes that are selected from the list comprising: CD177, RFX2, CNTNAP3 and ENTPD2 or any combination thereof. Preferably the genes are CD177, RFX2, CNTNAP3 and ENTPD2.
  • a second aspect of the present invention relates to an in vitro method for the monitoring of an antipsychotic treatment and / or the indication of the clinical response to an antipsychotic treatment in a subject diagnosed with psychosis comprising: a. detecting and / or quantifying the levels of an RPPH1 gene expression product in an isolated biological sample from said subject before the administration of the treatment;
  • step (b) detecting and / or quantifying the level of the gene expression product described in step (a) in an isolated biological sample from the same subject after the administration of the treatment;
  • in vitro refers to the method of the invention being performed outside the subject's body.
  • the levels of the expression product in the present invention may be previously normalized.
  • “Favorable response” means the significant reduction, for example of 40%, of the symptoms of the psychosis of the patient according to the Brief Phsychiatric Rating Scale (BPRS) scale (Overall, JE and Gorham, DR (1962) The Brief Psychiatric Rating Scale. Psychol Rep 10: 799-812).
  • BPRS Brief Phsychiatric Rating Scale
  • the method further comprises the detection and / or quantification of the expression in step (a) and in step (b) is at least one of the genes that are selected from the list that It includes: ALPL, CRISP3, ABCA13, CEACAM8, MMP8, OLFM4, OLR1, LTF, GPER, MIR3198, ADAMTS2, UNC45B, CD177, RFX2, CNTNAP3 and ENTPD2, or any combination thereof; preferably the genes are ALPL, CRISP3, ABCA13, CEACAM8, MMP8, OLFM4, OLR1, LTF, GPER, MIR3198, ADAMTS2, UNC45B, CD177, RFX2, CNTNAP3 and ENTPD2; and where in step (d) a significant decrease in the expression of RPPH1 and a significant decrease in the expression of ALPL, GPER, MIR3198, ADAMTS2, UNC45B, CD177, RFX2, CNTNAP3 and ENTPD2; and where in step (d)
  • step (d) a significant decrease in the expression of RPPH1 is associated, ALPL, GPER, MIR3198, ADAMTS2, UNC45B, CD177, RFX2, CNTNAP3 and ENTPD2; and a significant increase in the expression of CRISP3, ABCA13, CEACAM8, MMP8, OLFM4, OLR1 and LTF, with the follow-up of the treatment and / or a favorable response to the antipsychotic treatment.
  • the method further comprises the detection and / or quantification in step (a) and in step (b) of the expression of the ALPL gene; and in step (d) the association of a significant decrease in ALPL expression with treatment follow-up and / or a favorable response to antipsychotic treatment.
  • the method further comprises the detection and / or quantification in step (a) and in step (b) of the expression of at least one of the genes that are selected from the list comprising: CRISP3, ABCA13, CEACAM8, MMP8, OLFM4, OLR1, LTF, GPER and MIR3198, or any combination thereof; and in step (d) a significant decrease in the expression of GPER, MIR3198, is associated; or a significant increase in the expression of CRISP3, ABCA13, CEACAM8, MMP8, OLFM4, OLR1 or LTF, or any combination thereof, with treatment follow-up and / or a favorable response to antipsychotic treatment.
  • the detection and / or quantification in step (a) and in step (b) is of the genes CRISP3, ABCA13, CEACAM8, MMP8, OLFM4, OLR1, LTF, GPER and MIR3198; and in step (d) a significant decrease in the expression of GPER and MIR3198 is associated; or a significant increase in the expression of CRISP3, ABCA13, CEACAM8, MMP8, OLFM4, OLR1 and LTF, with the follow-up of the treatment and / or a favorable response to the antipsychotic treatment.
  • the method further comprises the detection and / or quantification in step (a) and in step (b) of ADAMTS2 gene expression; and in step (d) the association of a significant decrease in ADAMTS2 expression with treatment follow-up and / or a favorable response to antipsychotic treatment.
  • the method further comprises the detection and / or quantification in step (a) and in step (b) of the level of expression of the UNC45B gene; and in step (d) the association of a significant decrease in the expression of UNC45B with the follow-up of the treatment and / or a favorable response to the antipsychotic treatment.
  • step (a) also comprises the detection and / or quantification in step (a) and in step (b) of the expression of at least one of the genes that are selected from the list comprising: CD177, RFX2, CNTNAP3 and ENTPD2 or any combination thereof; and in step (d) the association of a significant decrease in the expression of the CD177, RFX2, CNTNAP3 and ENTPD2 genes, or any combination thereof, with the follow-up of the treatment and / or a favorable response to the antipsychotic treatment.
  • the detection and / or quantification in step (a) and in step (b) is of the CD177, RFX2, CNTNAP3 and ENTPD2 genes; and in step (d) a significant decrease in the expression of CD177, RFX2, CNTNAP3 and ENTPD2 is associated with treatment follow-up and / or a favorable response to antipsychotic treatment.
  • the detection and / or quantification in the present invention can be carried out by any technique known to the person skilled in the art, for example by sequencing, amplification by polymerase chain reaction (PCR), microarray or SAGE. Detection can be carried out using primers and / or probes.
  • PCR polymerase chain reaction
  • Detection can be carried out using primers and / or probes.
  • the detection and / or quantification is carried out by sequencing, PCR, microarray or by serial analysis of gene expression (SAGE).
  • sequencing refers to the determination of the nucleotides of a template nucleic acid and its order.
  • Conditions under which sequencing is performed generally include (a) contacting a template nucleic acid with a polymerase in a mixture that further comprises a primer, a bivalent cation (eg, Mg 2+ ), and nucleotides, generally, dNTPs and at least one ddNTP (dideoxynucleotidotrifostat), and (b) subjecting said mixture to a temperature sufficient for the polymerase to initiate the incorporation of the nucleotides into the primer by complementing bases with the template nucleic acid, and giving rise to a population of complementary DNA molecules of different sizes.
  • the separation of said population from complementary DNA molecules generally, by electrophoresis, allows the nucleotide sequence to be determined.
  • amplification refers to the increase in the number of copies of a template nucleic acid.
  • the conditions in which amplification is performed generally include (a) contacting a template nucleic acid with a polymerase in a mixture that further comprises at least one primer (usually two primers), a bivalent cation (eg, Mg 2+ ), and nucleotides, generally, dNTPs, and (b) subjecting said mixture to a temperature sufficient for the polymerase to initiate the incorporation of the nucleotides into the primer by complementing bases with the template nucleic acid, and giving rise to a population of complementary DNA molecules Usually the same size.
  • the PCR can also be quantitative real-time PCR.
  • template nucleic acid refers to a single or double stranded nucleic acid molecule that is to be amplified or sequenced.
  • primer also called “first” or “oligo”
  • oligo refers to an oligonucleotide capable of acting as the starting point of DNA synthesis when hybridized with the template nucleic acid.
  • the primer is a deoxyribose oligonucleotide.
  • Primers can be prepared by any suitable method, including, but not limited to, cloning and restriction of appropriate sequences and direct chemical synthesis.
  • the primers can be designed to hybridize with specific nucleotide sequences in the template nucleic acid (specific primers) or can be synthesized at random (arbitrary primers).
  • a "primer” can be labeled or labeled by techniques well known in the state of the art.
  • Detectable labels include, for example, radioactive isotopes, fluorescent labels, chemiluminescent labels, bioluminescent labels or enzymatic labels.
  • microarray or “chip” in the present invention refers to a solid support to which the RNA or protein is bound for gene expression analysis by hybridization with probes or antibody detection.
  • SAGE refers to the detection and quantification of gene expression by RNA measurement.
  • the variants can be used SAGE known to those skilled in the art, such as SuperSAGE, MicroS AGE and LongSAGE.
  • a third aspect of the present invention relates to the use of the expression of the RPPH1 gene as a biomarker for monitoring an antipsychotic treatment and / or the indication of the clinical response to said antipsychotic treatment in a subject diagnosed with psychosis.
  • a preferred embodiment of the third aspect of the invention further comprises the use of the expression of at least one of the genes that are selected from the list comprising: ALPL, CRISP3, ABCA13, CEACAM8, MMP8, OLFM4, OLR1, LTF, GPER, MIR3198, ADAMTS2, UNC45B, CD177, RFX2, CNTNAP3 and ENTPD2, or any combination thereof.
  • the genes are RPPH 1, ALPL, CRISP3, ABCA13, CEACAM8, MMP8, OLFM4, OLR1, LTF, GPER, MIR3198, ADAMTS2, UNC45B, CD177, RFX2, CNTNAP3 and ENTPD2.
  • Another preferred embodiment of the third aspect of the invention further comprises the use of ALPL gene expression. More preferably it also includes the use of the expression of at least one of the genes that are selected from the list comprising: CRISP3, ABCA13, CEACAM8, MMP8, OLFM4, OLR1, LTF, GPER and MIR3198 or any combination thereof; preferably the genes are CRISP3, ABCA13, CEACAM8, MMP8, OLFM4, OLR1, LTF, GPER and MIR3198.
  • Another preferred embodiment of the third aspect of the invention further comprises the use of ADAMTS2 gene expression. More preferably it also comprises the use of the expression of the UNC45B gene. Even more preferably it also comprises the use of the expression at least one of the genes that are selected from the list comprising: CD177, RFX2, CNTNAP3 and ENTPD2, or any combination thereof; preferably from CD177, RFX2, CNTNAP3 and ENTPD2.
  • psychosis is caused by at least one of the diseases that are selected from the list comprising: schizophrenia, bipolar disorder, depression, alcoholism, drug addiction and withdrawal syndrome of alcohol or drugs.
  • the disease is schizophrenia.
  • "Schizophrenia” means that disease in which there is a sensory and perceptual alteration that lasts more than six months without other psychopathological alterations (affective and level of consciousness) that are associated with the appearance of the picture. Its duration must be at least six months (according to the American Psychiatric Association, DSM-V).
  • the antipsychotic treatment is selected from the list comprising: clozapine, risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, paliperidone, asenapine, iloperidone, zotepine, amisulpride, Chlorpromazine, fluphenazine, haloperidol, loxapine, perphenazine, pimozide and zuclopenthixol.
  • the expression is of RNA and / or protein.
  • the RNA can be messenger RNA (mRNA) or a microRNA.
  • the present invention also relates to the use of the expression of the genes described in the present invention (RPPH1; RPPH1 and at least ALPL, CRISP3, ABCA13, CEACAM8, MMP8, OLFM4, OLR1, LTF, GPER, MIR3198, ADAMTS2, UNC45B, CD177, RFX2, CNTNAP3 or ENTPD2, or any combination thereof; RPPH1, ALPL, CRISP3, ABCA13, CEACAM8, MMP8, OLFM4, OLR1, LTF, GPER, MIR3198, ADAMTS2, UNC45B, CD177, RFX2, CNTNAP3 and ENTP2; ALPL; RPPH1, ALPL and at least CRISP3, ABCA13, CEACAM8, MMP8, OLFM4, OLR1, LTF, GPER,
  • a fourth aspect of the present invention relates to a kit comprising primers, probes or antibodies specific for the detection and / or quantification of the expression of the RPPH1 gene.
  • the kit further comprises primers, probes or antibodies specific for the detection and / or quantification of the expression of at least one of the genes that are selected from the list comprising: ALPL, CRISP3, ABCA13, CEACAM8, MMP8, OLFM4, OLR1, LTF, GPER, MIR3198, ADAMTS2, UNC45B, CD177, RFX2, CNTNAP3 and ENTPD2, or any combination thereof.
  • the kit comprises primers, probes or antibodies specific for the detection and / or quantification of the expression of the RPPH1, ALPL, CRISP3, ABCA13, CEACAM8, MMP8, OLFM4, OLR1, LTF, GPER, MIR3198, ADAMTS2, UNC45B, CD177 genes , RFX2, CNTNAP3 and ENTPD2.
  • the kit further comprises primers, probes or antibodies specific for the detection and / or quantification of the expression of the ALPL gene.
  • it also comprises primers, probes or antibodies specific for the detection and / or quantification of at least one of the genes that are selected from the list comprising: CRISP3, ABCA13, CEACAM8, MMP8, OLFM4, OLR1, LTF , GPER and MIR3198 or any combination thereof; preferably from CRISP3, ABCA13, CEACAM8, MMP8, OLFM4, OLR1, LTF, GPER and MIR3198.
  • the kit further comprises primers, probes or antibodies specific for the detection and / or quantification of ADAMTS2 gene expression. In an even more preferred embodiment, it also comprises primers, probes or antibodies specific for the detection and / or quantification of the expression of the UNC45B gene. More preferably, the kit also comprises specific primers, probes or antibodies for the detection and / or quantification of the expression of at least one of the genes that are selected from the list comprising: CD177, RFX2, CNTNAP3 and ENTPD2, or any combination thereof ; preferably the genes are CD177, RFX2, CNTNAP3 and ENTPD2.
  • the kit consists of specific primers, probes or antibodies for the detection and / or quantification of the expression of the genes and combinations described previously.
  • a fifth aspect of the present invention relates to the use of the kit of the fourth aspect of the invention for the monitoring of an antipsychotic treatment and / or the indication of the clinical response favorable or not to an antipsychotic treatment in a subject diagnosed with psychosis.
  • psychosis is caused by at least one of the diseases that are selected from the list comprising: schizophrenia, bipolar disorder, depression, alcoholism, drug addiction and alcohol or drug withdrawal syndrome.
  • the disease is schizophrenia.
  • the antipsychotic treatment is selected from the list comprising: clozapine, risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, paliperidone, asenapine, iloperidone, zotepine, amisulpride, chlorpromazine, fluphenazine, fluphenazine, fluphenazine, fluphenazine, fluphenazine, fluphenazine , perphenazine, pimozide and zuclopenthixol.
  • FIG. 1 Graph representing the level of expression, obtained by massive sequencing of the transcritptoma, of ADAMTS2, CD177, CNTNAP3, ENTPD2, RFX2 and UNC45B.
  • the level of expression of the untreated cases "1" was obtained in our previous study of a group of 36 patients with schizophrenia, the levels of the untreated cases "2" correspond to the subsequent study with data from 22 of the treated patients previously.
  • Example 1 Differential expression in 22 patients with unmedicated schizophrenia (have never previously received treatment) and medicated (those same patients after being treated for three months).
  • the transcriptome of 22 of the 36 schizophrenia patients analyzed in said previous study before and after antipsychotic medication was analyzed.
  • the decreased expression genes are the genes: RPPH1, ALPL, GPER, MIR3198, ADAMTS2, UNC45B, CD177, RFX2, CNTNAP3 and ENTPD2; while the genes whose expression is The genes are increased: CRISP3, ABCA13, CEACAM8, MMP8, OLFM4, OLR1 and LTF.
  • Six genes of these 17 genes have significantly greater expression in schizophrenics than in control individuals according to the publication of Sainz J et al.
  • ADAMTS2, CD177, CNTNAP3, ENTPD2, RFX2, UNC45B genes with differential expression are common with the document by Sainz J et al. 2013 among non-medicated / medicated schizophrenics, they also have differential expression in non-medicated schizophrenics / healthy controls. Specifically, in patients six of the genes that have altered expression in schizophrenia, their expression is reverted back to levels of expression of control subjects, when they take antipsychotic medication (Table 3).
  • Schizophrenia is considered as a combination of genetic variants that in each individual case causes the disease uniquely. That is why the analysis of the values of genes with differential expression characteristic of schizophrenia (table 3) must be accompanied by the assessment of the genes altered by the medication (table 2) in order to better identify the patient's adherence to treatment. In this sense, the genes in table 2 that best identify the patients who follow the treatment are RPPH1 and ALPL (with 81% of the patients identified with these genes).
  • the combination of ALPL with any of the genes identified in Table 3 is the least informative since there is at least one patient (identified as 51 1) that would only have higher values before the medication later in one of the genes (UNC45B) and not in the others, when said decrease caused by the treatment is key in all these genes: RPPH1, ALPL, ADAMTS2, CD177, CNTNAP3, ENTPD2, RFX2 and UNC45B (Table 1 ); therefore, the combination ALPL, ADAMTS2, CD177, CNTNAP3, ENTPD2, RFX2 and UNC45B could underrepresent the follow-up of the treatment and its effects on the progress of the schizophrenic patient.
  • the RRPH1 combination together with the genes identified in Table 3 does identify at least two genes whose expression decreases with treatment, improving the information obtained with the combination mentioned above. ;
  • the present invention demonstrates the usefulness of the expression of the RPPH1 gene for the monitoring of an antipsychotic treatment and / or for knowing the clinical response to an antipsychotic treatment, as well as that of its combination with the expression of the genes described in the present invention for the same purpose.
  • Example 3 Genes with reversed expression by antipsychotics
  • BaseMean is the average expression of the individuals in the group.
  • BaseMean No med is the mean expression in non-medicated individuals in the case / control study.
  • BaseMean No med2 is the mean expression in non-medicated individuals in the medicated / non-medicated study.
  • BaseMeanMed is the mean expression in medicated individuals Example 4. Enrichment in Gene Ontoloqy categories
  • the GWAS catalog includes associations to traits / diseases for 4,828 genes of the 22,278 we have analyzed in our expression studies, or a fraction equivalent to 21.67% of the total.
  • the fraction of genes with differential expression noted in GWAS is somewhat higher (35.29%), therefore we observe an enrichment, although not significant, of genes associated with diseases in genes whose expression is modulated by antipsychotics.
  • ABCA13 has been related to schizophrenia (although it has not been related to the therapeutic effect of antipsychotic drugs), bipolar disorder and depression (Knight HM et al. Am. J. Hum. Genet. 200985 (6): 833-46) and the LTF and OLR1 genes with the immune system in several studies (Guillen C et al. J Immunol. 2002 168 (8): 3950 -7; Huang D et al. J. Cardiovasc. Pharmacol. 2012 60: 133-9), LTF with wound response (Engelmayer J et al. J. Surg. Res.
  • the patients recruited in this study were obtained from a consecutive sample of non-affective psychotic patients enrolled in the program of first episode of psychosis (PAFIP) from May 2010 to May 2012. Patients had to meet the following criteria: 1) age 15-60 years, 2) live in the catchment area, 3) that was his first episode of psychosis 4) never having been treated with antipsychotic medications, 5) meet the DSM-IV criteria for short-term psychosis, disorder schizophreniform, schizophrenia, or schizoaffective disorder, 6) who have understood the nature of the study and signed an informed consent document.
  • PAFIP program of first episode of psychosis
  • the antipsychotic drugs with which patients were treated are second generation antipsychotics that are characterized by having a common action of antagonism at the level of 5-HT2 and D2 receptors and represent the Most of the second generation antipsychotics used today.
  • a relatively potent action of serotonin 5-HT2A receptor antagonism associated with a milder antagonism of D2 dopamine receptors is the common central feature of second generation antipsychotics.
  • the only one of those drugs used that has a differentiated action is aripiprazole that has an associated action of partial agonist of the high affinity D2 dopamine receptors.
  • BPRS Brief Psychiatric Rating Scale
  • CDSS Calgary Depression Scale for Schizophrenia
  • SANS Scale of the Assessment of Negative Symptoms
  • SAPS Scale of the Assessment of Positive Symptom
  • CGI Clinical Global Impression
  • Mean average. SD, standard deviation.
  • Venous blood samples were obtained under the same conditions with people (patients and controls) fasting and were collected between 08: 00-10: 00 a.m. This extraction protocol was similar in the initial (baseline) extraction and three months later. The patients were without antipsychotic treatment at the time of blood collection from baseline.
  • a key factor is that the RNA is as intact as possible, that is, with the least possible degradation.
  • the "IntegrityNumber RNA” was obtained using a Bioanalyzer (Agilent Technologies, Santa Clara, CA, USA). Samples with an RIN of ⁇ 6.9 were selected. The set of selected samples have RINs ranging from 6.9 to 9.4 with an average of 8.4. Next generation sequencing RNA ("next generation sequencinq").
  • Sequences (readings) of single fragments of 35 nucleotides were obtained using the GenomeAnalyzerlIx mass sequencing platform (lllumina Inc.). The sequences obtained were filtered using quality criteria (reliability of the reading of each base provided by the software of the platform used, llluminallx). The quality filters passed an average of 76% of the readings obtained. The sequence readings that passed the quality filters were aligned with the human reference genome [hg19, February 2009 human referencesequence (GRCh37), Genome Reference Consortium] obtained from UCSC Genome Bioinformatics. The alignment of the readings was carried out using the ⁇ Ilumina Casava 1 .8.1 software package, with software specifically configured to process RNA-Seq data.
  • the length of the sequences read varies between 35 base pairs (bp) to 38bp, so the alignment was configured to mask the sequences until a uniform length of 35 nucleotides was obtained. This masking was done in order to avoid the alignment biases in the genome that we observed when the sequences analyzed varied in length.
  • the Bedtools 2.15.0 (“bedtoolscoverage”) tool was used to compute the amount of readings (sequences) assigned to each gene.
  • the DESeq 1 .9.6 package (Anders S and Huber JS Genome Biology 2010 1 1: R106)) for R in Bioconductor was used to analyze the differential expression of the human reference genes (22,278 RefSeqs) according to the computed number of sequences obtained for each gene
  • the "fit-only" configuration was used as the adjustment method.
  • Casava 1 .8.1 was used to calculate RPKMs (readings per kilobase per million readings mapped in the reference genome). RPKM values allow comparison of gene expression data obtained in different experiments and of different genes when normalized.

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Abstract

La présente invention concerne un procédé de surveillance de traitement antiseptique et/ou d'indication de réponse à celui-ci chez un patient diagnostiqué avec une psychose, ledit procédé comprenant au moins la détection et/ou la quantification de l'expression du gène RPPH1. L'invention concerne également l'utilisation de l'expression du gène RPPH1 comme biomarqueur à des fins susmentionnées. En outre, ladite invention concerne un kit pour la détection de l'expression du gène RPPH1 et son utilisation à des fins décrites dans l'invention.
PCT/ES2015/070608 2014-08-04 2015-08-04 Procédé de surveillance de traitement antiseptique WO2016020573A1 (fr)

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US11160758B2 (en) 2019-06-04 2021-11-02 Sunovion Pharmaceuticals Inc. Modified release formulations and uses thereof
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Cited By (19)

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US11337932B2 (en) 2016-12-20 2022-05-24 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene
US10980753B2 (en) 2016-12-20 2021-04-20 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
US10898449B2 (en) 2016-12-20 2021-01-26 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
WO2018178071A1 (fr) * 2017-03-29 2018-10-04 Consejo Superior De Investigaciones Cientificas Procédé de prédiction de la réponse thérapeutique à des médicaments antipsychotiques
US11033512B2 (en) 2017-06-26 2021-06-15 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and silicone acrylic hybrid polymer
US10874639B2 (en) 2017-12-05 2020-12-29 Sunovion Pharmaceuticals Inc. Nonracemic mixtures and uses thereof
US11517558B2 (en) 2017-12-05 2022-12-06 Sunovion Pharmaceuticals Inc. Nonracemic mixtures and uses thereof
US11767293B2 (en) 2017-12-05 2023-09-26 Sunovion Pharmaceuticals Inc. Crystal forms and production methods thereof
US10660875B1 (en) 2017-12-05 2020-05-26 Sunovion Pharmaceuticals Inc. Nonracemic mixtures and uses thereof
US10577317B2 (en) 2017-12-05 2020-03-03 Sunovion Pharmaceuticals Inc. Crystal forms and production methods thereof
US10576058B2 (en) 2017-12-05 2020-03-03 Sunovion Pharmaceuticals Inc. Nonracemic mixtures and uses thereof
US10377708B2 (en) 2017-12-05 2019-08-13 Sunovion Pharmaceuticals Inc. Crystal forms and production methods thereof
US10800738B2 (en) 2017-12-05 2020-10-13 Sunovion Pharmaceuticals Inc. Crystal forms and production methods thereof
US10369134B2 (en) 2017-12-05 2019-08-06 Sunovion Pharmaceuticals Inc. Nonracemic mixtures and uses thereof
US11370753B2 (en) 2017-12-05 2022-06-28 Sunovion Pharmaceuticals Inc. Crystal forms and production methods thereof
US11648213B2 (en) 2018-06-20 2023-05-16 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
WO2020216832A1 (fr) * 2019-04-24 2020-10-29 INSERM (Institut National de la Santé et de la Recherche Médicale) Procédé de prédiction de la réponse thérapeutique à des médicaments antipsychotiques
US11160758B2 (en) 2019-06-04 2021-11-02 Sunovion Pharmaceuticals Inc. Modified release formulations and uses thereof
US11654113B2 (en) 2019-06-04 2023-05-23 Sunovion Pharmaceuticals Inc. Modified release formulations and uses thereof

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