WO2008125805A1 - Profilage métabolique d'amides d'acides gras et leur utilisation dans le diagnostic et le criblage de médicaments pour la schizophrénie - Google Patents

Profilage métabolique d'amides d'acides gras et leur utilisation dans le diagnostic et le criblage de médicaments pour la schizophrénie Download PDF

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Publication number
WO2008125805A1
WO2008125805A1 PCT/GB2008/001180 GB2008001180W WO2008125805A1 WO 2008125805 A1 WO2008125805 A1 WO 2008125805A1 GB 2008001180 W GB2008001180 W GB 2008001180W WO 2008125805 A1 WO2008125805 A1 WO 2008125805A1
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Prior art keywords
biomarker
sample
subject
fatty acid
schizophrenia
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PCT/GB2008/001180
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English (en)
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Emanuel Schwarz
Sabine Bahn
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Cambridge Enterprise Limited
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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
    • G01N33/92—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving lipids, e.g. cholesterol, lipoproteins, or their receptors
    • 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
    • G01N2800/302—Schizophrenia

Definitions

  • This invention relates to the metabolic profiling of serum from patients with schizophrenia and affective disorder.
  • it is related to the metabolic profiling of fatty acid amides and its use in the diagnosis and screening of drugs for schizophrenia.
  • Schizophrenia is a major psychiatric disorder, affecting as many as one percent of the population, with similar prevalence between the sexes and throughout diverse cultures and geographic areas [Reference 1; see list of References, below].
  • the endocannabinoid system plays a major role in the modulation of functions of the central and peripheral nervous system [2]. Its possible involvement in schizophrenia pathology is based on several findings.
  • ⁇ 9 - tetrahydrocannabinol a major active ingredient in cannabis, acts on the two known endocannabinoid receptors CB1 and CB2, and that consumption of relatively large amounts of cannabis can precipitate a schizophrenia-like state with hallucinations, delusions and emotional liability [3-6].
  • the density distribution of endocannabinoid receptor expression overlaps with the brain areas that have been reported to be involved in schizophrenia pathology [7,8], and several neuronal functions modulated by the endocannabinoid system have also been reported to be altered in schizophrenia [9].
  • Endocannabinoid concentrations are elevated in cerebrospinal fluid
  • CSF CSF of schizophrenia patients [10,11]. Whilst 'typical' endocannabinoids like anandamide or 2-arachidonyl glycerol bind to the two endocannabinoid receptors CB1 and CB2, molecules like several primary fatty acid amides that are connected to the endocannabinoid system do not or only negligibly show affinity to these receptors [12,13,14]. Oleamide, the primary amide of oleic acid, was shown to induce effects similar to cannabinoids, as it induces the triad of reduction of body temperature, hypolocomotion and reduction in pain perception [15].
  • fatty acid amides and endocannabinoids are degraded by the same enzyme, i.e. fatty acid amide hydrolase (FAAH) [18,19].
  • FAAH fatty acid amide hydrolase
  • a possible function of fatty acid amides lies in the competition with endocannabinoids for binding to the active site of the enzyme and thus in increasing the concentration of endocannabinoids, by preventing their degradation [20].
  • the present invention is based on a study in which the serum metabolites of drug-na ⁇ ve patients with first onset, paranoid schizophrenia, drug-treated acute paranoid schizophrenia patients, affective disorder patients, sleep-deprived healthy volunteers, and demographically matched controls were profiled. Analysing the interactions between the metabolites based on their correlation, this 'bottom up' approach was used to identify a metabolic network of fatty acid amides. The abnormalities of this metabolic network in schizophrenia and affective disorder, and the effect of antipsychotic drug treatment on this network have been analysed.
  • An aspect of the present invention is the use of one or more fatty acid amides as a marker of disease in subjects, e.g. first-onset, drug-naive patients; the disease may be, for example, schizophrenia, paranoid schizophrenia or an affective disorder.
  • this invention is based on the finding that fatty acids are useful as biomarkers, and may be used as such, e.g. as described in WO2007/045865.
  • fatty acid amides such as those described herein, or other substrates of FAAH, may be used in diagnosis, to determine the condition of a subject.
  • the level of such individual compounds or a profile of two or more may be determined, e.g. with respect to those found in a normal subject.
  • one or more fatty acid amides cam be used to monitor the efficacy of therapy for a disorder or disease as described above. Yet another aspect lies in monitoring one or more fatty acid amides in an animal model, as a means of determining the suitability of a test agent as a therapeutic candidate.
  • Figure 1 comprises (A) a graph showing correlation of spectrometric peaks, (B) peaks identifying analyte, and (C) a plot of p-values.
  • Figures 2 to 5 each show one or more PLS-DA plots. Description of Preferred Embodiments
  • diagnosis encompasses identification, confirmation, and/or characterisation of a psychotic disorder, in particular a schizophrenic disorder, bipolar disorder, related psychotic disorder, or predisposition thereto.
  • predisposition it is meant that a subject does not currently present with the disorder, but is liable to be affected by the disorder in time.
  • Monitoring methods of the invention can be used to monitor onset, progression, stabilisation, amelioration and/or remission of an affective disorder.
  • the invention relates to schizophrenia disorder. Identification of differences between responses in samples from a subject having or being predisposed to an affective disorder, and those not affected by or predisposed to an affective disorder, can therefore be used to diagnose or monitor disease. Methods of the invention may comprise comparing a response in a test sample from a subject with a response in a control. Suitable controls include normal controls derived from individuals not affected by or predisposed to affective disorder and controls derived from individuals with an affective disorder, preferably a schizophrenic disorder.
  • Methods of the invention may comprise detecting a difference in a response between the test sample and a control sample. Differences in response may be detected as a presence, absence, increase or decrease of fatty acid amides.
  • suitable methods for determining the level of biomarkers include immunological methods, involving an antibody, or an antibody fragment capable of specific binding to the protein of interest.
  • Suitable immunological methods include sandwich immunoassays, such as sandwich ELISA in which detection of the peptide is performed using two antibodies which recognize different epitopes; radioimmunoassays (RIA), direct or competitive enzyme-linked immunosorbent assays (ELISA), enzyme- immuno assays (EIA), Western blotting, immunoprecipitation and any particle-based immunoassay (e.g. using gold, silver, latex or magnetic particles or Q-dots).
  • Immunological methods may be performed, for example, in microtitre plate or strip format.
  • spectral analysis such as NMR spectroscopy and high resolution NMR spectroscopy ( 1 H NMR)
  • mass spectrometry such as Surface Enhanced Laser/Desorption Ionization (SELDI) (-TOF) and/or MALDI (-TOF)
  • 1-D gel-based analysis 2-D gel-based analysis
  • LC-MS- based technique iTRAQTM.
  • a suitable cohort of patients and controls may be selected including first onset and/or minimally treated individuals, and these can be compared with chronically ill patients having a more established clinical history. This allows comparison of both disease progression and the effects of drug treatment.
  • Methods of the invention may comprise comparing samples by assessing variation in one or more biomarkers in response to stimulation of the sample.
  • biomarker means a distinctive biological or biologically-derived indicator of a process, event, or condition. Biomarkers can be used in methods of diagnosis (e.g. clinical screening), prognosis assessment, in monitoring the results of therapy, identifying patients most likely to respond to a particular therapeutic treatment, drug screening and development. The biomarker may be quantified. Biomarkers and uses thereof are valuable for identification of new drug treatments and for discovery of new targets for drug treatment. Quantifying the amount of the biomarker present in a sample may include determining the concentration of the peptide biomarker present in the sample.
  • Detecting and/or quantifying may be performed directly on the sample, or indirectly on an extract therefrom, or on a dilution thereof. Detecting and/or quantifying can be performed by any method suitable to identify the presence and/or amount of a specific protein in a biological sample.
  • the control sample comprises a normal control sample.
  • the control sample comprises an affective disorder control sample.
  • the method may also comprise classifying proliferative responses of a sample as having a normal profile, disorder profile, or disorder predisposition profile.
  • serum samples may be taken on two or more occasions from a test subject.
  • Stimulatory responses from samples taken on two or more occasions from a test subject can be compared to identify differences between the responses in samples taken on different occasions.
  • Methods may include analysis of stimulatory responses from biological samples taken on two or more occasions from a test subject to quantify the level of one or more biomarkers present in the biological samples, and comparing the level of the one or more biomarkers present in samples taken on two or more occasions.
  • Diagnostic and monitoring methods of the invention are useful in methods of assessing prognosis of an affective disorder, in methods of monitoring efficacy of an administered therapeutic substance in a subject having, suspected of having, or of being predisposed to, a disorder and in methods of identifying a therapeutic candidate.
  • Such methods may comprise comparing the level of the one or more biomarkers in a test biological sample taken from a test subject with the level present in one or more samples taken from the test subject prior to administration of the substance, and/or one or more samples taken from the test subject at an earlier stage during treatment with the substance. Additionally, these methods may comprise detecting a change in the level of the one or more biomarkers in biological samples taken from a test subject on two or more occasions.
  • a method of diagnosis of or monitoring according to the invention may comprise quantifying the one or more biomarkers in a test biological sample taken from a test subject and comparing the level of the one or more biomarkers present in said test sample with one or more controls.
  • the control can be selected from a normal control and/or a disorder control.
  • the control used in a method of the invention can be selected from: the level of biomarker found in a normal control sample from a normal subject, a normal biomarker level; a normal biomarker range, the level in a sample from a subject with a schizophrenic or related disorder; and a schizophrenic or related disorder marker level.
  • the level or ratio of one or more biomarkers is detected.
  • a sensor e.g. a biosensor comprising one or more enzymes, binding, receptor or transporter proteins, antibody, synthetic receptors or other selective binding molecules for direct or indirect detection of the biomarkers.
  • the sensor may be coupled to an electrical, optical, acoustic, magnetic or thermal transducer.
  • antibody as used in this embodiment includes, but is not limited to, polyclonal, monoclonal, bispecific, humanised or chimeric antibodies, single chain antibodies, Fab fragments and F (ab') 2 fragments, fragments produced by a Fab expression library, anti-idiotypic (anti-Id) antibodies, and epitope-binding fragments of any of the above.
  • antibody as used herein also refers to immunoglobulin molecules and immunologically-active portions of immunoglobulin molecules, i.e., molecules that contain an antigen binding site that specifically binds an antigen.
  • the immunoglobulin molecules of the invention can be of any class (e.
  • Biomarkers identified using a method of the invention can be used as biomarkers for a disorder or predisposition thereto. They are thus useful in methods for monitoring or diagnosing disease.
  • the present invention may be used identify a potential therapeutic agent for the prevention, treatment or amelioration of an affective disorder.
  • the invention comprises comparing a response in a test sample to a response in a control sample.
  • responses in test and normal control samples exposed to a candidate therapeutic agent may be compared, identifying the candidate as a potential therapeutic agent if one or more responses in the test sample are modulated such that a normal response is restored.
  • a candidate therapeutic agent is identified if the candidate therapeutic agent is capable of modulating a response in a subject having an affective disorder, in particular such that one or more responses are restored to the response characteristic of normal individuals.
  • the response can be assessed using the methods described herein, in particular by assessing biomarkers of response identified as described herein.
  • Animal models suitable for use in the invention are known to those skilled in the art. Examples include metabolically induced models, such as phencyclidine (PCP) or methylazoxymetanolacetate (MAM), "social” models, such as prenatal stress model or early social isolation model, and genetic models, such as NRG1 mice model or DISC1-1 mice model.
  • metabolically induced models such as phencyclidine (PCP) or methylazoxymetanolacetate (MAM)
  • “social” models such as prenatal stress model or early social isolation model
  • genetic models such as NRG1 mice model or DISC1-1 mice model.
  • kits according to the invention may comprise one or more components selected from: instructions for use of the kit, one or more normal and/or disorder controls, a sensor or biosensor suitable and/or adapted for detecting a biomarker according to the invention and a ligand, e.g. nucleic acid, antibody, aptamer, or the like, capable of specifically binding a biomarker according to the invention or specifically binding a substance derived from the biomarker or from the action of the biomarker.
  • the ligand may be provided immobilised on a solid support such as bead or surface, for example in the form of an array adapted for use in a method of the invention
  • Fig. 1A Undirected graph showing the correlation between 29 mass spectrometric peaks corresponding to 8 different molecules. Each node represents a mass spectrometric peak, each edge a Pearson's correlation coefficient greater than or equal to 0.8. The graph was generated based on the Kamada Kawai algorithm that is incorporated into the free software Pajek.
  • B Confirmation of the identification of oleamide. The intensity of the peak with m/z 282.28 is increased after addition of oleamide to a serum sample (I) as compared to the same sample without standard (II, red numbers indicate intensity). Ill) shows the pure internal standard oleamide. The retention times of internal standard and oleamide in the sample are the same.
  • FIG. 2A PLS-DA scores plot showing separation between drug na ⁇ ve first onset schizophrenia patients and healthy volunteers.
  • B PLS-DA scores plot showing predicted scores of schizophrenia patients treated with typical and atypical antipsychotic medication. Patients treated with typical medication show a much stronger normalization to healthy volunteers than patients treated with atypical antipsychotics.
  • Fig. 3 PLS-DA scores plot showing separation between affective disorder patients and healthy volunteers.
  • Fig. 4 PLS-DA scores plot of sleep deprived healthy volunteers and controls showing a different alteration as compared to first onset schizophrenia and affective disorder.
  • Fig. 5 PLS-DA scores plot showing that cannabis consumption did not affect the serum level of the reported fatty acid amides. Colours are defined according to how often cannabis was consumed by the patient (no: 0 times; light: 1-99 times; moderate: 100 - 999 times; heavy: > 1000 times) Materials and methods Clinical samples
  • Antipsychotic medication was either 'typical' (D 2 -antagonistic) or 'atypical' (5HT 2 A/D2 antagonistic).
  • Glucose levels in serum and Cerebrospinal fluid were measured immediately after collection using a NOVA BioProfile analyser (Nova Biomedical, Waltham, USA). Preparation of serum samples Acetonitrile (120 ⁇ L, Sigma Aldrich) was added to a 30 ⁇ l_ aliquot of each serum sample in 1.5 mL Eppendorf tubes. The tubes were vortexed and spun down at 13000 rpm for 15 min at room temperature in a Sanyo Micro Centaur centrifuge.
  • the LC system used was a Acquity UPLC (Waters Corporation).
  • An Acquity UPLC BEH C18 (1.7 ⁇ m, 2.1 x 100 mm, Waters Corporation) was used as analytical column.
  • 5 ⁇ l serum was injected to LC and a three-step linear gradient (0-95% acetonitrile with 0.1% formic acid (Fisher Chemicals)) was applied within 11 min at a flow rate of 0.6 mL per min. After acquiring the raw data of all samples, the run was repeated.
  • the analytical column was coupled directly to a liquid chromatography time-of-flight mass spectrometer (LCT, Waters Corporation).
  • the sensitivity of the system was optimised by infusing a known standard of 200 pg/ ⁇ L Leucin- Enkephalin solution.
  • the capillary voltage was set to 3000 V at a source temperature of 120 s C. Every 30 spectra, the Leucin-Enkephalin solution was injected through the reference needle to acquire a lock mass spectrum and to correct for mass accuracy changes along the run.
  • the mass accuracy was calibrated using a source spray of 10 ⁇ L per min of Naformate (1 mL 0.5 M NaOH, 5% Aristar formic acid (BDH) in 9 mL 70/30 acetonitrile/ H 2 O ).
  • the data quality was controlled by repeated measurement of a system test mix (Waters corporation) containing 5 compounds with known concentration and mass and of a quality control serum sample.
  • PCA Principal Component Analysis
  • the data were exported to the free software R and after, filtering for non-zero intensity measurements in at least 80% of the samples in at least one sample group (drug naive first onset, paranoid schizophrenia and healthy volunteers) in the first cluster, the metabolic network of interest was extracted from a complete Pearson's correlation matrix using a correlation cut-off of 0.8. As the extracted metabolic network was not affected by sensitivity changes along the experiment, further analysis was carried out considering all samples.
  • SIMCA-P was further used for Partial Least Squares Discriminant Analysis (PLS-DA) to assess the discriminative power of the extracted metabolic network and to predict the scores of drug treated patients in the space of drug na ⁇ ve first onset, paranoid schizophrenia patients and healthy volunteers.
  • PLS-DA Partial Least Squares Discriminant Analysis
  • each molecule is represented by the sum of all corresponding peaks in the extracted metabolic network.
  • the fold change for each molecule was calculated as the ratio of the average intensity in the drug na ⁇ ve, first onset, paranoid schizophrenia group and the average of the healthy volunteers group and was based on the first replicate.
  • Effects of antipsychotic treatment and cannabis consumption on the extracted metabolic network Interestingly, PLS-DA scores plots of the metabolic network identified in this study showed normalization of the profile after short term treatment with typical antipsychotic medication for an average of nine days. This normalization was not visible, or visible to a far smaller extent, after treatment with atypical antipsychotics (Figure 2B).
  • CSF cerebrospinal fluid
  • PLS-DA scores showed that the metabolic network of primary fatty acid amides is more severely altered in affective disorder than in first onset, paranoid schizophrenia. It is well known that sleep deprivation is one of the most frequent symptoms in depression; significant negative correlations of the serum concentrations of certain fatty acids (amongst others, myristic, palmitic, palmitoleic, oleic and linoleic acid) with the degree of sleep disturbance have been reported [21]. This is interesting, as oleic acid and linoleic acid are precursors of the well known sleep inducing molecules oleamide and linoleamide.

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Abstract

L'invention concerne une méthode permettant de diagnostiquer ou de surveiller un trouble affectif, ou une prédisposition à celui-ci, qui comprend la détection et/ou la quantification, dans un échantillon d'un sujet testé, du taux d'un ou plusieurs amides d'acides gras en tant que biomarqueur.
PCT/GB2008/001180 2007-04-11 2008-04-03 Profilage métabolique d'amides d'acides gras et leur utilisation dans le diagnostic et le criblage de médicaments pour la schizophrénie WO2008125805A1 (fr)

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GB0707001.4 2007-04-11

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011101666A1 (fr) 2010-02-16 2011-08-25 Loxbridge Research Llp Procédé de détection d'analyte à base d'oligonucléotide
CN108195987A (zh) * 2018-01-15 2018-06-22 黄河三角洲京博化工研究院有限公司 一种分析硬脂酸盐中硬脂酸含量的方法
CN108562679A (zh) * 2018-04-17 2018-09-21 安徽润安信科检测科技有限公司 一种白酒中八种生物胺的uplc-ms/ms检测方法
EP3307413A4 (fr) * 2015-06-15 2018-12-05 Rush University Medical Center Ligands de ppar dérivés du cerveau

Citations (1)

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WO2003011220A2 (fr) * 2001-07-31 2003-02-13 The Scripps Research Institute Modele animal pour comportements neurologiques associes a l'amide d'acide gras

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WO2003011220A2 (fr) * 2001-07-31 2003-02-13 The Scripps Research Institute Modele animal pour comportements neurologiques associes a l'amide d'acide gras

Non-Patent Citations (2)

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DE MARCHI N ET AL: "Endocannabinoid signalling in the blood of patients with schizophrenia", LIPIDS IN HEALTH AND DISEASE 20030819 GB, vol. 2, 19 August 2003 (2003-08-19), pages 1 - 9, XP002485926, ISSN: 1476-511X *
GIUFFRIDA ANDREA ET AL: "Cerebrospinal anandamide levels are elevated in acute schizophrenia and are inversely correlated with psychotic symptoms.", November 2004, NEUROPSYCHOPHARMACOLOGY : OFFICIAL PUBLICATION OF THE AMERICAN COLLEGE OF NEUROPSYCHOPHARMACOLOGY NOV 2004, VOL. 29, NR. 11, PAGE(S) 2108 - 2114, ISSN: 0893-133X, XP002485927 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011101666A1 (fr) 2010-02-16 2011-08-25 Loxbridge Research Llp Procédé de détection d'analyte à base d'oligonucléotide
EP3307413A4 (fr) * 2015-06-15 2018-12-05 Rush University Medical Center Ligands de ppar dérivés du cerveau
US11344524B2 (en) 2015-06-15 2022-05-31 Rush University Medical Center Brain derived PPARα ligands
CN108195987A (zh) * 2018-01-15 2018-06-22 黄河三角洲京博化工研究院有限公司 一种分析硬脂酸盐中硬脂酸含量的方法
CN108562679A (zh) * 2018-04-17 2018-09-21 安徽润安信科检测科技有限公司 一种白酒中八种生物胺的uplc-ms/ms检测方法
CN108562679B (zh) * 2018-04-17 2019-11-15 安徽润安信科检测科技有限公司 一种白酒中八种生物胺的uplc-ms/ms检测方法

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