WO2008107700A1 - Diagnostic de troubles psychotiques - Google Patents

Diagnostic de troubles psychotiques Download PDF

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Publication number
WO2008107700A1
WO2008107700A1 PCT/GB2008/000829 GB2008000829W WO2008107700A1 WO 2008107700 A1 WO2008107700 A1 WO 2008107700A1 GB 2008000829 W GB2008000829 W GB 2008000829W WO 2008107700 A1 WO2008107700 A1 WO 2008107700A1
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WIPO (PCT)
Prior art keywords
peptide
biomarker
subject
sample
quantifying
Prior art date
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PCT/GB2008/000829
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English (en)
Inventor
Sabine Bahn
Rachel Marie Craddock
Original Assignee
Cambridge Enterprise Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GB0704512A external-priority patent/GB0704512D0/en
Priority claimed from GB0720548A external-priority patent/GB0720548D0/en
Application filed by Cambridge Enterprise Limited filed Critical Cambridge Enterprise Limited
Publication of WO2008107700A1 publication Critical patent/WO2008107700A1/fr

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • G01N33/6896—Neurological disorders, e.g. Alzheimer's disease
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/46—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
    • G01N2333/47—Assays involving proteins of known structure or function as defined in the subgroups
    • G01N2333/4701—Details
    • G01N2333/4721—Cationic antimicrobial peptides, e.g. defensins
    • 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

  • the invention relates to the use of alpha-defensin (peptide biomarker) as a biomarker for schizophrenia or major depressive disorders.
  • the invention also relates to method to monitor and diagnose schizophrenia or a major depressive disorder.
  • the invention relates to methods to monitor the efficacy of a therapy in a subject suspected of having, or of being predisposed to schizophrenia or a major depressive disorder.
  • Psychosis is a symptom of severe mental illness. Although it is not exclusively linked to any particular psychological or physical state, it is particularly associated with schizophrenia, bipolar disorder (manic depression) and severe clinical depression. These conditions, their characterisation and categorisation, including DSM IV diagnosis criteria, are described in WO2007/045865, the content of which is incorporated herein by reference.
  • WO01 /63295 describes methods and compositions for screening, diagnosis and determining prognosis of neuropsychiatric or neurological conditions (including bipolar affective disorder, schizophrenia and vascular dementia), for monitoring the effectiveness of treatment in these conditions and for use in drug development.
  • DSM IV Diagnostic and Statistical Manual of Mental Disorders fourth edition published by the American Psychiatric Association, Washington D.C., 1994, has proven to be an authoritative reference handbook for health professionals both in the United Kingdom and in the United States in categorizing and diagnosing mental health problems. This describes the diagnostic criteria, subtypes, associated features and criteria for differential diagnosis of mental health disorders, including major depressive disorder.
  • a person who suffers from a major depressive disorder must either have a depressed mood or a loss of interest or pleasure in daily activities consistently for at least a two week period.
  • This mood must represent a change from the person's normal mood; social, occupational, educational or other important functioning must also be negatively impaired by the change in mood.
  • a depressed mood caused by substances is not considered a major depressive disorder, nor is one which is caused by a general medical condition.
  • Major depressive disorder cannot be diagnosed if a person has a history of manic, hypomanic, or mixed episodes (e.g., a bipolar disorder) or if the depressed mood is better accounted for by schizoaffective disorder and is not superimposed on schizophrenia, a delusional or psychotic disorder. Further, the symptoms are not better accounted for by bereavement, i.e., after the loss of a loved one, the symptoms persist for longer than two months or are characterized by marked functional impairment, morbid preoccupation with worthlessness, suicidal ideation, psychotic symptoms, or psychomotor retardation.
  • Major depressive disorder is characterized by the presence of the majority of these symptoms: a depressed mood most of the day, nearly every day, as indicated by either subjective report (e.g., feels sad or empty) or observation made by others (e.g., appears tearful). In children and adolescents, this may be characterized as an irritable mood.
  • the ⁇ -defensins are a group of cationic peptides that comprise 30-50% of the total protein in azurophilic granules of human neutrophils. They include the human neutrophil peptides (HNP) 1, 2 and 3 which have almost identical amino acid sequences but differ in their biological activities.
  • HNP human neutrophil peptides
  • WO2004/082455 and U S2004/0142388 disclose biomarkers for Alzheimer's disease.
  • WO2006/085121 (not published at the priority date of this case) discloses biomarkers for schizophrenia and bipolar disorder. Summary of the Invention The present invention relates to peptide biomarkers for major depressive disorders. In particular, the present invention provides the use of an ⁇ -defensin peptide, as a biomarker for schizophrenia or a major depressive disorder, or predisposition thereto.
  • the invention provides a method of diagnosing or monitoring schizophrenia or a major depressive disorder, or predisposition thereto, comprising detecting and/or quantifying the peptide biomarker present in a biological sample from a test subject.
  • a further aspect of the invention provides ligands, such as naturally occurring or chemically synthesised compounds, capable of specific binding to the peptide biomarker.
  • a ligand according to the invention may comprise a peptide, an antibody or a fragment thereof, or an aptamer or oligonucleotide, capable of specific binding to the peptide biomarker.
  • the antibody can be a monoclonal antibody or a fragment thereof capable of specific binding to the peptide biomarker.
  • a ligand according to the invention may be labelled with a detectable marker, such as a luminescent, fluorescent or radioactive marker; alternatively or additionally a ligand according to the invention may be labelled with an affinity tag, e.g. a biotin, avidin, streptavidin or His (e.g. hexa-His) tag.
  • Biosensors according to the invention may comprise a ligand or ligands, as described herein, capable of specific binding to the peptide biomarker. Such biosensors are useful in detecting and/or quantifying a peptide of the invention.
  • a biosensor according to the invention may comprise the peptide biomarker or a structural/shape mimic thereof capable of specific binding to an antibody against the peptide biomarker. Also provided is an array comprising a ligand or mimic as described herein.
  • kits for performing methods of the invention.
  • Such kits will suitably comprise a ligand according to the invention, for detection and/or quantification of the peptide biomarker, and/or a biosensor, and/or an array as described herein, optionally together with instructions for use of the kit.
  • ligands as described herein, which may be naturally occurring or chemically synthesised, and is suitably a peptide, antibody or fragment thereof, aptamer or oligonucleotide, or the use of a biosensor of the invention, or an array of the invention, or a kit of the invention to detect and/or quantify the peptide.
  • the detection and/or quantification can be performed on a biological sample such as from the group consisting of CSF, whole blood, blood serum, plasma, urine, saliva, or other bodily fluid, breath, e.g. as condensed breath, or an extract or purification therefrom, or dilution thereof.
  • Biomarkers for schizophrenia or major depressive disorders are essential targets for discovery of novel targets and drug molecules that retard or halt progression of the disorder.
  • the biomarker is useful for identification of novel therapeutic compounds in in vitro and/or in vivo assays.
  • Biomarkers of the invention can be employed in methods for screening for compounds that modulate the activity of the peptide.
  • a ligand as described, which can be a peptide, antibody or fragment thereof or aptamer or oligonucleotide according to the invention; or the use of a biosensor according to the invention, or an array according to the invention; or a kit according to the invention, to identify a substance capable of promoting and/or of suppressing the generation of the biomarker. Also there is provided a method of identifying a substance capable of promoting or suppressing the generation of the peptide in a subject, comprising administering a test substance to a subject animal and detecting and/or quantifying the level of the peptide biomarker present in a test sample from the subject.
  • ⁇ -defensin peptide biomarker includes the mature full-length human peptide.
  • biomarker means a distinctive biological or biologically derived indicator of a process, event, or condition.
  • Peptide biomarkers can be used in methods of diagnosis, e.g. clinical screening, and prognosis assessment and in monitoring the results of therapy, identifying patients most likely to respond to a particular therapeutic treatment, drug screening and development. Biomarkers and uses thereof are valuable for identification of new drug treatments and for discovery of new targets for drug treatment.
  • major depressive disorder refers to certain types of depression.
  • the diagnostic category major depressive disorder appears in the
  • Major Depression or, more properly, Major Depressive Disorder (MDD)
  • Major Depressive Disorder is characterized by a severely depressed mood that persists for at least two weeks.
  • Major Depressive Disorder is specified as either "a single episode” or “recurrent”; periods of depression may occur as discrete events or as recurrent events over the lifespan of a subject.
  • Episodes of major depression may be further divided into mild, major or severe.
  • a diagnosis of bipolar disorder also called bipolar affective disorder
  • depression without periods of elation or mania is therefore sometimes referred to as unipolar depression because their mood remains on one pole.
  • the diagnosis also usually excludes cases where the symptoms are a normal result of bereavement.
  • ICD-10 does not specify a melancholic subtype, but does distinguish on presence or absence of psychosis- Depression with Catatonic Features - This subtype can be applied to Major Depressive episodes as well as to manic episodes, though it is rare, and rarer in mania. Catatonia is characterized by motoric immobility evidenced by catalepsy or stupor. This MDD subtype may also manifest excessive, non- prompted motor activity (akathjsja), extreme negativism or mutism, and peculiarities in movement, including stereotypical movements, prominent mannerisms, and prominent grimacing. There may also be evidence of echolalia or echopraxia. It is very rarely encountered, and may not be a useful category.
  • Melancholia is characterized by a loss of pleasure (anhedonia) in most or all activities, a failure of reactivity to pleasurable stimuli, a quality of depressed mood more pronounced than that of grief or loss, a worsening of symptoms in the morning hours, early morning waking, psychomotor retardation, anorexia (excessive weight loss, not to be confused with Anorexia Nervosa), or excessive guilt.
  • Depression with Atypical Features - Atypicality is characterized by mood reactivity (paradoxical anhedonia) and positivity, significant weight gain or increased appetite, excessive sleep or somnolence (hypersomnia), leaden paralysis, or significant social impairment as a consequence of hypersensitivity to perceived interpersonal rejection. People with this can react with interest or pleasure to some things, unlike most depressed individuals.
  • Depression with Psychotic Features Some people with a Major Depressive or Manic episode may experience psychotic features. They may be presented with hallucinations or delusions that are either mood-congruent (content coincident with depressive themes) or non-mood-congruent (content not coincident with depressive themes). It is clinically more common to encounter a delusional system as an adjunct to depression than to encounter hallucinations, whether visual or auditory. Other categories of depression which are not encompassed by the term major depressive disorder include:
  • Dvsthvmia a long-term, mild depression that lasts for a minimum of two years. There must be persistent depressed mood continuously for at least two years. By definition the symptoms are not as severe as with Major Depression, although those with Dysthymia are vulnerable to co-occurring episodes of Major Depression. This disorder often begins in adolescence and may persist for life. People who are diagnosed with major depressive episodes and dysthymic disorder are diagnosed with double depression. Dysthymic disorder develops first and then one or more major depressive episodes happen later. Bipolar I Disorder is an episodic illness in which moods may cycle between mania and depression. In the United States, Bipolar Disorder was previously called Manic Depression. This term is no longer favoured by the medical community, however, even though depression plays a much stronger (in terms of disability and potential for suicide) role in the disorder. "Manic Depression” is still often used in the non-medical community.
  • Bipolar Il Disorder is an episodic illness that is defined primarily by depression but evidences episodes of hypomania.
  • Postpartum Depression or Post-Natal Depression is clinical depression that occurs within two years of childbirth, largely due to physical, mental and emotional exhaustion combined with sleep-deprivation.
  • Premenstrual dysphoria is a pattern of recurrent depressive symptoms tied to the menstrual cycle.
  • the premenstrual decline in brain serotonin function is strongly correlated with the concomitant worsening of self-rated cardinal mood symptoms.
  • Major depressive disorder does not encompass schizophrenic disorders, bipolar disorders and related psychotic disorders such as neuropsychiatric (psychotic depression and other psychotic episodes) and neurodevelopmental disorders (especially Autistic spectrum disorders) which can present with psychotic or other schizophrenia-like symptoms.
  • Monitoring methods of the invention can be used to monitor onset, progression, stabilisation, amelioration and/or remission.
  • detecting and/or quantifying the peptide biomarker in a biological sample from a test subject may be performed on two or more occasions. Comparisons may be made between the level of biomarker in samples taken on two or more occasions. Assessment of any change in the level of the peptide biomarker in samples taken on two or more occasions may be performed. Modulation of the peptide biomarker level is useful as an indicator of the state of the major depressive disorder or predisposition thereto. An increase in the level of the biomarker, over time is indicative of onset or progression, i.e. worsening of this disorder, whereas a decrease in the level of the peptide biomarker indicates amelioration or remission of the disorder, or vice versa.
  • a method of diagnosis of or monitoring according to the invention may comprise quantifying the peptide biomarker in a test biological sample from a test subject and comparing the level of the peptide present in said test sample with one or more controls.
  • the control used in a method of the invention can be one or more control(s) selected from the group consisting of: the level of biomarker peptide found in a normal control sample from a normal subject, a normal biomarker peptide level; a normal biomarker peptide range, the level in a sample from a subject with a major depressive disorder, or a diagnosed predisposition thereto; a major depressive disorder biomarker peptide level, or a major depressive disorder biomarker peptide range.
  • a preferred method of diagnosing schizophrenia or a major depressive disorder, or predisposition thereto comprises: (a) quantifying the amount of the peptide biomarker in a test biological sample; and
  • diagnosis encompasses identification, confirmation, and/or characterisation of schizophrenia or a major depressive 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.
  • Methods of monitoring and of diagnosis according to the invention are useful to confirm the existence of a disorder, or predisposition thereto; to monitor development of the disorder by assessing onset and progression, or to assess amelioration or regression of the disorder.
  • Methods of monitoring and of diagnosis are also useful in methods for assessment of clinical screening, prognosis, choice of therapy, evaluation of therapeutic benefit, i.e. for drug screening and drug development.
  • Efficient diagnosis and monitoring methods provide very powerful "patient solutions” with the potential for improved prognosis, by establishing the correct diagnosis, allowing rapid identification of the most appropriate treatment (thus lessening unnecessary exposure to harmful drug side effects), reducing "downtime” and relapse rates.
  • test samples may be taken on two or more occasions.
  • the method may further comprise comparing the level of the biomarker(s) present in the test sample with one or more control(s) and/or with one or more previous test sample(s) taken earlier from the same test subject, e.g. prior to commencement of therapy, and/or from the same test subject at an earlier stage of therapy.
  • the method may comprise detecting a change in the level of the biomarker(s) in test samples taken on different occasions.
  • the invention provides a method for monitoring efficacy of therapy for schizophrenia or major depressive disorder in a subject, comprising:
  • a decrease in the level of the peptide biomarker in the test sample relative to the level in a previous test sample taken earlier from the same test subject is indicative of a beneficial effect, e.g. stabilisation or improvement, of said therapy on the disorder, suspected disorder or predisposition thereto.
  • Methods for monitoring efficacy of a therapy can be used to monitor the therapeutic effectiveness of existing therapies and new therapies in human subjects and in non-human animals (e.g. in animal models). These monitoring methods can be incorporated into screens for new drug substances and combinations of substances.
  • the time elapsed between taking samples from a subject undergoing diagnosis or monitoring will be 3 days, 5 days, a week, two weeks, a month, 2 months, 3 months, 6 or 12 months. Samples may be taken prior to and/or during and/or following an anti-depressant therapy. Samples can be taken at intervals over the remaining life, or a part thereof, of a subject.
  • detecting means confirming the presence of the peptide biomarker present in the sample.
  • 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.
  • the presence of the peptide biomarker is assessed by detecting and/or quantifying antibody or fragments thereof capable of specific binding to the biomarker that are generated by the subject's body in response to the peptide and thus are present in a biological sample from a subject having major depressive disorder or a predisposition thereto.
  • 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 from a patient or a purification or extract of a biological sample or a dilution thereof.
  • quantifying may be performed by measuring the concentration of the peptide biomarker in the sample or samples.
  • Biological samples that may be tested in a method of the invention include cerebrospinal fluid (CSF), whole blood, blood serum, plasma, urine, saliva, or other bodily fluid (stool, tear fluid, synovial fluid, sputum), breath, e.g. as condensed breath, or an extract or purification therefrom, or dilution thereof.
  • CSF cerebrospinal fluid
  • Biological samples also include tissue homogenates, tissue sections and biopsy specimens from a live subject, or taken post-mortem. The samples can be prepared, for example where appropriate diluted or concentrated, and stored in the usual manner.
  • Detection and/or quantification of peptide biomarkers may be performed by detection of the peptide biomarker or of a fragment thereof, e.g. a fragment with C-terminal truncation, or with N-terminal truncation. Fragments are suitably greater than 4 amino acids in length, preferably 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acids in length.
  • the biomarker may be directly detected, e.g. by SELDI or MALDI-TOF.
  • the biomarker may be detected directly or indirectly via interaction with a ligand or ligands such as an antibody or a biomarker-binding fragment thereof, or other peptide, or ligand, e.g. aptamer, or oligonucleotide, capable of specifically binding the biomarker.
  • the ligand may possess a detectable label, such as a luminescent, fluorescent or radioactive label, and/or an affinity tag.
  • detecting and/or quantifying can be performed by one or more method(s) selected from the group consisting of: SELDI (-TOF), MALDI (-TOF), a 1-D gel-based analysis, a 2-D gel-based analysis, Mass spec (MS), reverse phase (RP) LC, size permeation (gel filtration), ion exchange, affinity, HPLC, UPLC and other LC or LC MS-based techniques.
  • SELDI SELDI
  • MALDI MALDI
  • MS mass spec
  • RP reverse phase
  • size permeation gel filtration
  • ion exchange affinity
  • HPLC HPLC
  • UPLC UPLC
  • LC MS-based techniques e.g.
  • Methods of diagnosing or monitoring according to the invention may comprise analysing a sample of cerebrospinal fluid (CSF) by SELDI TOF or MALDI TOF to detect the presence or level of the peptide biomarker. These methods are also suitable for clinical screening, prognosis, monitoring the results of therapy, identifying patients most likely to respond to a particular therapeutic treatment, for drug screening and development, and identification of new targets for drug treatment.
  • CSF cerebrospinal fluid
  • Detecting and/or quantifying the peptide biomarkers may be performed using an immunological method, involving an antibody, or a fragment thereof capable of specific binding to the peptide biomarker.
  • Suitable immunological methods include sandwich immunoassays, such as sandwich ELISA, in which the detection of the peptide biomarkers is performed using two antibodies which recognize different epitopes on a peptide biomarker; radioimmunoassays (RIA), direct, indirect or competitive enzyme linked immunosorbent assays (ELISA), enzyme immuno assays (EIA), Fluorescence immunoassays (FIA), western blotting, immunoprecipitation and any particle-based immunoassay (e.g. using gold, silver, or latex particles, magnetic particles, or Q-dots).
  • Immunological methods may be performed, for example, in microtitre plate or strip format.
  • Immunological methods in accordance with the invention may be based, for example, on any of the following methods.
  • lmmunoprecipitation is the simplest immunoassay method; this measures the quantity of precipitate, which forms after the reagent antibody has incubated with the sample and reacted with the target antigen present therein to form an insoluble aggregate, lmmunoprecipitation reactions may be qualitative or quantitative.
  • Radioimmunoassay methods employ radioactive isotopes such as
  • I 125 to label either the antigen or antibody.
  • the isotope used emits gamma rays, which are usually measured following removal of unbound (free) radiolabel.
  • the major advantages of RIA compared with other immunoassays, are higher sensitivity, easy signal detection, and well-established, rapid assays.
  • the major disadvantages are the health and safety risks posed by the use of radiation and the time and expense associated with maintaining a licensed radiation safety and disposal program. For this reason, RIA has been largely replaced in routine clinical laboratory practice by enzyme immunoassays.
  • EIA Enzyme immunoassays were developed as an alternative to radioimmunoassays (RIA). These methods use an enzyme to label either the antibody or target antigen. The sensitivity of EIA approaches that for RIA, without the danger posed by radioactive isotopes.
  • One of the most widely used EIA methods for detection is the enzyme-linked immunosorbent assay (ELISA). ELISA methods may use two antibodies one of which is specific for the target antigen and the other of which is coupled to an enzyme, addition of the substrate for the enzyme results in production of a chemoluminescent or fluorescent signal.
  • Fluorescent immunoassay refers to immunoassays which utilize a fluorescent label or an enzyme label which acts on the substrate to form a fluorescent product. Fluorescent measurements are inherently more sensitive than colorimetric (spectrophotometric) measurements. Therefore, FIA methods have greater analytical sensitivity than EIA methods, which employ absorbance (optical density) measurement. Chemiluminescent immunoassays utilize a chemiluminescent label, which produces light when excited by chemical energy; the emissions are measured using a light detector.
  • Immunological methods according to the invention can thus be performed using well-known methods. Any direct (e.g., using a sensor chip) or indirect procedure may be used in the detection of peptide biomarkers of the invention.
  • Biotin-Avidin or Biotin-Streptavidin systems are generic labelling systems that can be adapted for use in immunological methods of the invention.
  • One binding partner hapten, antigen, ligand, aptamer, antibody, enzyme etc
  • biotin is labelled with avidin or streptavidin.
  • avidin or streptavidin is conventional technology for immunoassays, gene probe assays and (bio)sensors, but is an indirect immobilisation route rather than a direct one.
  • a biotinylated ligand e.g.
  • antibody or aptamer) specific for a peptide biomarker of the invention may be immobilised on an avidin or streptavidin surface, the immobilised ligand may then be exposed to a sample containing or suspected of containing the peptide biomarker in order to detect and/or quantify a peptide biomarker of the invention. Detection and/or quantification of the immobilised antigen may then be performed by an immunological method as described herein.
  • antibody as used herein 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.
  • biosensors g., IgG, IgE, IgM, IgD and IgA
  • detecting and quantifying can be performed using a biosensor, microanalytical system, microengineered system, microseparation system, immunochromatography system or other suitable analytical devices.
  • the biosensor may incorporate an immunological method for detection of the biomarker(s), electrical, thermal, magnetic, optical (e.g. hologram) or acoustic technologies. Using such biosensors, it is possible to detect the target biomarker(s) at the anticipated concentrations found in biological samples.
  • biomarker(s) of the invention can be detected using a biosensor incorporating technologies based on "smart" holograms, or high frequency acoustic systems, such systems are particularly amenable to "bar code” or array configurations.
  • a holographic image is stored in a thin polymer film that is sensitised to react specifically with the biomarker.
  • the biomarker reacts with the polymer leading to an alteration in the image displayed by the hologram.
  • the test result read-out can be a change in the optical brightness, image, colour and/or position of the image.
  • a sensor hologram can be read by eye, thus removing the need for detection equipment.
  • a simple colour sensor can be used to read the signal when quantitative measurements are required. Opacity or colour of the sample does not interfere with operation of the sensor.
  • the format of the sensor allows multiplexing for simultaneous detection of several substances. Reversible and irreversible sensors can be designed to meet different requirements, and continuous monitoring of a particular biomarker of interest is feasible.
  • biosensors for detection of one or more biomarkers of the invention combine biomolecular recognition with appropriate means to convert detection of the presence, or quantitation, of the biomarker in the sample into a signal.
  • Biosensors can be adapted for "alternate site" diagnostic testing, e.g. in the ward, outpatients' department, surgery, home, field and workplace.
  • Biosensors to detect one or more biomarkers of the invention include acoustic, plasmon resonance, holographic and microengineered sensors. Imprinted recognition elements, thin film transistor technology, magnetic acoustic resonator devices and other novel acousto-electrical systems may be employed in biosensors for detection of the one or more biomarkers of the invention.
  • Methods involving detection and/or quantification of one or more peptide biomarkers of the invention can be performed on bench-top instruments, or can be incorporated onto disposable, diagnostic or monitoring platforms that can be used in a non-laboratory environment, e.g. in the physician's office or at the patient's bedside.
  • Suitable biosensors for performing methods of the invention include "credit" cards with optical or acoustic readers. Biosensors can be configured to allow the data collected to be electronically transmitted to the physician for interpretation and thus can form the basis for e-neuromedicine.
  • Any suitable animal may be used as a subject non-human animal, for example a non-human primate, horse, cow, pig, goat, sheep, dog, cat, fish, rodent, e.g. guinea pig, rat or mouse; insect (e.g. Drosophila), amphibian (e.g. Xenopus) or C. elegans.
  • the test substance can be a known chemical or pharmaceutical substance, such as, but not limited to, an anti-depressive disorder therapeutic; or the test substance can be novel synthetic or natural chemical entity, or a combination of two or more of the aforesaid substances.
  • a method of identifying a substance capable of promoting or suppressing the generation of the peptide biomarker in a subject comprising exposing a test cell to a test substance and monitoring the level of the peptide biomarker within said test cell, or secreted by said test cell.
  • the test cell could be prokaryotic, however it is preferred that a eukaryotic cell be employed in cell-based testing methods.
  • the eukaryotic cell is a yeast cell, insect cell, Drosophila cell, amphibian cell (e.g. from Xenopus), C. elegans cell or is a cell of human, non-human primate, equine, bovine, porcine, caprine, ovine, canine, feline, piscine, rodent or murine origin.
  • non- human animals or cells can be used that are capable of expressing the peptide. Screening methods also encompass a method of identifying a ligand capable of binding to the peptide biomarker according to the invention, comprising incubating a test substance in the presence of the peptide biomarker in conditions appropriate for binding, and detecting and/or quantifying binding of the peptide to said test substance.
  • High-throughput screening technologies based on the biomarker, uses and methods of the invention, e.g. configured in an array format, are suitable to monitor biomarker signatures for the identification of potentially useful therapeutic compounds, e.g. ligands such as natural compounds, synthetic chemical compounds (e.g. from combinatorial libraries), peptides, monoclonal or polyclonal antibodies or fragments thereof, which may be capable of binding the biomarker.
  • potentially useful therapeutic compounds e.g. ligands such as natural compounds, synthetic chemical compounds (e.g. from combinatorial libraries), peptides, monoclonal or polyclonal antibodies or fragments thereof, which may be capable of binding the biomarker.
  • Methods of the invention can be performed in array format, e.g. on a chip, or as a multiwell array. Methods can be adapted into platforms for single tests, or multiple identical or multiple non-identical tests, and can be performed in high throughput format. Methods of the invention may comprise performing one or more additional, different tests to confirm or exclude diagnosis, and/or to further characterise a condition.
  • the invention further provides a substance, e.g. a ligand, identified or identifiable by an identification or screening method or use of the invention.
  • a substance e.g. a ligand, identified or identifiable by an identification or screening method or use of the invention.
  • Such substances may be capable of inhibiting, directly or indirectly, the activity of the peptide biomarker, or of suppressing generation of the peptide biomarker.
  • the term "substances" includes substances that do not directly bind the peptide biomarker and directly modulate a function, but instead indirectly modulate a function of the peptide biomarker.
  • Ligands are also included in the term substances; ligands of the invention (e.g. a natural or synthetic chemical compound, peptide, aptamer, oligonucleotide, antibody or antibody fragment) are capable of binding, preferably specific binding, to the peptide.
  • the invention further provides the use of a substance according to the invention in the treatment of a major depressive disorder, or predisposition thereto.
  • a substance according to the invention as a medicament.
  • a substance according to the invention in the manufacture of a medicament for the treatment of a major depressive disorder, or predisposition thereto.
  • kits for diagnosing or monitoring a major depressive disorder, or predisposition thereto may contain one or more components selected from the group: a ligand specific for the peptide biomarker or a structural/shape mimic of the peptide biomarker, one or more controls, one or more reagents and one or more consumables; optionally together with instructions for use of the kit.
  • a ligand specific for the peptide biomarker or a structural/shape mimic of the peptide biomarker one or more controls, one or more reagents and one or more consumables; optionally together with instructions for use of the kit.
  • the identification of biomarkers for major depressive disorder permits integration of diagnostic procedures and therapeutic regimes.
  • many anti-depressant therapies have required treatment trials lasting weeks to months for a given therapeutic approach.
  • Detection of a peptide biomarker of the invention can be used to screen subjects prior to their participation in clinical trials.
  • the biomarkers provide the means to indicate therapeutic response, failure to respond, unfavourable side-effect profile, degree of medication compliance and achievement of adequate serum drug levels.
  • the biomarkers may be used to provide warning of adverse drug response. Biomarkers are useful in development of personalized brain therapies, as assessment of response can be used to fine-tune dosage, minimise the number of prescribed medications, reduce the delay in attaining effective therapy and avoid adverse drug reactions.
  • biomarker of the invention can be used to titrate the optimal dose, predict a positive therapeutic response and identify those patients at high risk of severe side effects.
  • Biomarker-based tests provide a first line assessment of 'new' patients, and provide objective measures for accurate and rapid diagnosis, in a time frame and with precision, not achievable using the current subjective measures.
  • diagnostic biomarker tests are useful to identify family members or patients at high risk of developing major depressive disorder. This permits initiation of appropriate therapy, or preventive measures, e.g. managing risk factors. These approaches are recognised to improve outcome and may prevent overt onset of the disorder.
  • Biomarker monitoring methods, biosensors and kits are also vital as patient monitoring tools, to enable the physician to determine whether relapse is due to worsening of the disorder, poor patient compliance or substance abuse. If pharmacological treatment is assessed to be inadequate, then therapy can be reinstated or increased; a change in therapy can be given if appropriate.
  • the biomarkers are sensitive to the state of the disorder, they provide an indication of the impact of drug therapy or of substance abuse.
  • the present invention is based on the Study, below. This shows that ⁇ - defensin expression is higher in the plasma of schizophrenia patients. An aspect of this invention may therefore be considered as a method of diagnosing, predicting or monitoring a psychotic disorder in a subject by assessing the level of ⁇ -defensin in plasma. Study
  • T-cell lysates were profiled using SELDI-TOF to investigate differential protein expression. Proteins of molecular weight 3375 Da and 3450 Da were found to be over-expressed in schizophrenia. Subsequent experiments and sequencing suggested that these were oc-defensins. These changes were also found to be present in patient plasma, by the following procedure. Patient plasma is a more accessible tissue for diagnostic purposes.
  • Heparinised plasma was sampled from 21 pairs of monozygotic twins discordant for schizophophrenia and 8 pairs of completely unaffected twins. Expression of ⁇ -defensin was assayed using a commercially available defensin ELISA kit (Hycult Biotechnology).

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Abstract

L'invention concerne l'utilisation d'un biomarqueur peptidique qui est une α-défensine ou un fragment de celle-ci comme biomarqueur de la schizophrénie ou un trouble dépressif majeur, ou d'une prédisposition à ceux-ci.
PCT/GB2008/000829 2007-03-08 2008-03-10 Diagnostic de troubles psychotiques WO2008107700A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB0704512.3 2007-03-08
GB0704512A GB0704512D0 (en) 2007-03-08 2007-03-08 Diagnosing psychotic disorders
GB0720548.7 2007-10-19
GB0720548A GB0720548D0 (en) 2007-10-19 2007-10-19 Diagnosing psychotic disorders

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WO2008107700A1 true WO2008107700A1 (fr) 2008-09-12

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010041069A1 (fr) 2008-10-10 2010-04-15 Cambridge Enterprise Limited Biomarqueurs
WO2010064030A1 (fr) * 2008-12-01 2010-06-10 Cambridge Enterprise Limited Biomarqueurs
WO2011101666A1 (fr) 2010-02-16 2011-08-25 Loxbridge Research Llp Procédé de détection d'analyte à base d'oligonucléotide

Citations (4)

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Publication number Priority date Publication date Assignee Title
US20040091498A1 (en) * 2002-05-31 2004-05-13 Aaron Diamond Aids Research Center Defensins: use as antiviral agents
US20060099593A1 (en) * 2002-09-27 2006-05-11 Japan Science And Technology Agency Method of diagnosing integration dysfunction syndrome using blood
DE102005023748A1 (de) * 2005-05-18 2006-11-23 Friedrich-Schiller-Universität Jena Verwendung der Peptide HNP 1-3 als Marker für den Nachweis von malignen Lymphomen, insbesondere von kutanen T-Zell Lymphomen aus Blut
WO2007063333A1 (fr) * 2005-12-02 2007-06-07 Cambridge Enterprise Limited Procedes pour surveiller, diagnostiquer et identifier des biomarqueurs de troubles psychotiques

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040091498A1 (en) * 2002-05-31 2004-05-13 Aaron Diamond Aids Research Center Defensins: use as antiviral agents
US20060099593A1 (en) * 2002-09-27 2006-05-11 Japan Science And Technology Agency Method of diagnosing integration dysfunction syndrome using blood
DE102005023748A1 (de) * 2005-05-18 2006-11-23 Friedrich-Schiller-Universität Jena Verwendung der Peptide HNP 1-3 als Marker für den Nachweis von malignen Lymphomen, insbesondere von kutanen T-Zell Lymphomen aus Blut
WO2007063333A1 (fr) * 2005-12-02 2007-06-07 Cambridge Enterprise Limited Procedes pour surveiller, diagnostiquer et identifier des biomarqueurs de troubles psychotiques

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CRADDOCK R.M. ET AL.: "Increased alpha-defensins as a blood marker for schizophrenia susceptibility", MOL. CELL. PROTEOMICS, vol. 7, no. 7, July 2008 (2008-07-01), pages 1204 - 1213, XP009102761 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010041069A1 (fr) 2008-10-10 2010-04-15 Cambridge Enterprise Limited Biomarqueurs
WO2010064030A1 (fr) * 2008-12-01 2010-06-10 Cambridge Enterprise Limited Biomarqueurs
WO2011101666A1 (fr) 2010-02-16 2011-08-25 Loxbridge Research Llp Procédé de détection d'analyte à base d'oligonucléotide

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