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WO1996017081A1 - Evaluation en vue d'un traitement par des agents neuroleptiques - Google Patents

Evaluation en vue d'un traitement par des agents neuroleptiques Download PDF

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Publication number
WO1996017081A1
WO1996017081A1 PCT/GB1995/002748 GB9502748W WO9617081A1 WO 1996017081 A1 WO1996017081 A1 WO 1996017081A1 GB 9502748 W GB9502748 W GB 9502748W WO 9617081 A1 WO9617081 A1 WO 9617081A1
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WO
WIPO (PCT)
Prior art keywords
allele
neuroleptic agent
dna
subject
responsiveness
Prior art date
Application number
PCT/GB1995/002748
Other languages
English (en)
Inventor
David Collier
Robert Kerwin
Original Assignee
Institute Of Psychiatry
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
Application filed by Institute Of Psychiatry filed Critical Institute Of Psychiatry
Priority to AU39312/95A priority Critical patent/AU3931295A/en
Publication of WO1996017081A1 publication Critical patent/WO1996017081A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70571—Receptors; Cell surface antigens; Cell surface determinants for neuromediators, e.g. serotonin receptor, dopamine receptor
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2217/00—Genetically modified animals
    • A01K2217/05—Animals comprising random inserted nucleic acids (transgenic)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers

Definitions

  • the present invention relates to methods of assessing the responsiveness of individuals to neuroleptic agents such as clozapine.
  • Schizophrenia is a devastating neurological disease for which there is currently no cure, although advances are now being made in understanding its causes and controlling its symptoms. In general the age of onset is in late adolescence and it is a lifelong illness with a very poor prognosis.
  • Subjects suffering from schizophrenia may exhibit positive symptoms, for example delusions and hallucinations, and/or negative symptoms such as withdrawal, isolation and demotivation leading ultimately to social decline and suicide.
  • neuroleptics have been available and are used with varying degrees of success to treat the positive symptoms of schizophrenia.
  • neuroleptics typically neuroleptics
  • typical neuroleptics do not alleviate the negative symptoms and furthermore have a number of side effects, the most distressing of which are movement disorders known as extrapyramidal side effects (eps).
  • Examples of typical neuroleptics include haloperidol and sulpiride. Over 90% of patients in the UK are treated with such traditional antipsychotics but some 30% of patients fail to respond.
  • the therapeutic effect of typical antipsychotic agents is believed to be exerted principally via blockade of dopamine D2 receptors; however this mechanism is also thought to be responsible for the extrapyramidal side effects.
  • More recently second generation antipsychotic agents so-called "atypical" neuroleptics, having enhanced efficacy and fewer side effects have been developed. These compounds appear to have a lower affinity for D receptors than do the typical neuroleptics but they also interact with other receptors, notably the serotonin 5-HT2 receptor and the dopamine D 4 receptor.
  • the only currently available drug of this type is clozapine which provides advantages in that it improves both the positive and negative symptoms of schizophrenia and causes virtually no eps.
  • its use has been severely limited by controversy over its propensity to produce neutropenia and its expense; hence it is reserved for the treatment of schizophrenia in subjects who do not respond to other neuroleptics.
  • a test therefore, that helps to predict those patients most likely to benefit would be a valuable clinical decision making tool.
  • risperidone which is a mixed 5-HT 2 /D 2 receptor antagonist.
  • This compound which is currently undergoing clinical trials appears to have a similar therapeutic profile to clozapine but does not cause neutropenia. However, it is unlikely to be selected as the drug of first choice on economic grounds. For this reason also it would be useful to predict those patients most likely to benefit.
  • the human serotonin receptor gene encoding the 5-HT 2A receptor exhibits polymorphism in the TMI region of the gene, comprising two alleles, termed allele Cl and allele C2.
  • the polymorphism is an Mspl polymorphism; it is a C/T polymorphism at position 102.
  • Both alleles code for serine at amino acid #34 but differ in that Cl comprises a thymine residue (T) at position 102 of the coding region whereas C2 comprises a cytosine residue (C) at position 102.
  • T thymine residue
  • C2 comprises a cytosine residue
  • This variation therefore allows assessment of the likelihood whether a subject will be non-responsive or responsive to treatment with a neuroleptic agent, for example, clozapine, by a method comprising detecting the presence or absence of DNA comprising the C2 and/or Cl alleles of the 5-HT 2 ⁇ gene in said subject.
  • a neuroleptic agent for example, clozapine
  • the present invention therefore provides a method for use in assessing the responsiveness to a neuroleptic agent of a subject diagnosed as suffering from schizophrenia, the method comprising testing for and hence detecting the presence or absence of DNA comprising the Cl allele and/or C2 allele of the 5-HT 2A gene in a sample containing DNA obtained from the subject.
  • the presence of DNA comprising the C2 allele only indicates a greater probability of non- responsiveness than the presence of DNA comprising the Cl allele only
  • the presence of DNA comprising both the Cl and the C2 alleles indicates a greater probability of responsiveness than the presence of DNA comprising the Cl allele only. This is the case for clozapine.
  • a second aspect of the invention provides a method of assessing the responsiveness of a subject to treatment with a neuroleptic agent the method comprising (i) testing for DNA comprising the Cl allele and/or C2 allele of the 5-HT 2 ⁇ gene in a sample containing DNA obtained from the subject, and
  • the presence of DNA comprising the C2 allele only indicates a greater probability of non-responsiveness than the presence of DNA comprising the Cl allele only
  • the presence of DNA comprising both the Cl and the C2 alleles indicates a greater probability of responsiveness than the presence of DNA comprising the Cl allele only.
  • the present invention also provides a method of treatment of schizophrenia comprising (a) testing for DNA comprising allele C2 and/or Cl in a sample of biological material containing DNA obtained from a patient, and
  • the method of the present invention does not give a precise or absolute identification of responders and non-responders but rather indicates the degree, probability or likelihood of responsiveness and so can be used to aid and guide the clinical judgement of the physician.
  • a subject found to be homozygous for the C2 allele will not necessarily be excluded from drug therapy; however such a finding may have the benefit that the patient is not subjected to prolonged treatment with an ineffective drug, once it is clear that no clinical response is forthcoming.
  • responders and “non-responders” as used herein are terms well known in the art.
  • rating scales such as the Global Assessment Scale (GAS) or the Brief Psychiatric Rating Scale (BPRS).
  • the step of testing for and hence detecting the presence or absence of DNA encoding C2 and/or Cl alleles may be carried out either directly or indirectly by any suitable means, such as by techniques well known in the art, and is preferably carried out e_ ⁇ vivo. All methods of testing generally involve a preliminary step of collecting a sample of bi-ological material containing DNA from the subject, and then the step of detecting from that sample which alleles the subject possesses.
  • the detecting step may be carried out by collecting a biological sample containing DNA from the subject, and then determining the presence or absence of DNA comprising a C2 and/or Cl allele in the biological sample.
  • Any biological sample which contains DNA of that subject may be employed, including tissue samples and blood samples, with blood cells being a particularly convenient source.
  • Determining the presence or absence of DNA comprising a C2 and/or Cl allele may be carried out with an oligonucleotide probe labelled with a suitable detectable group; by means of an amplification reaction such as a polymerase chain reaction or ligase chain reaction (the product of which amplification reaction may then be detected with a labelled oligonucleotide probe) or by means of restriction nuclease digestion and electrophoretic separation to detect restriction fragment length polymorphism (RLFP) .
  • Methods for detecting single base mutations are well known, for example, the use of synthetic oligonucleotides to detect single base mutations in HIV is described in European Patent No. 0 422 762.
  • Testing for DNA comprising an allele may be carried out by testing for the allele itself or for any appropriate part thereof, that is to say, any part which comprises the mutation.
  • the detecting step may include the step of detecting whether the subject is heterozygous or homozygous for the gene encoding a C2 or Cl allele.
  • Numerous different oligonucleotide probe assay formats are known which may be employed to carry out the present invention.
  • the patient will be either homozygous for Cl, and therefore will have a probability of responsiveness to a neuroleptic agent, for example, clozapine, about the same as that found for a cohort of patients, that is to say, a population of patients having the same condition, for example, schizophrenia, or heterozygous, and therefore will have a greater probability of responsiveness to the neuroleptic agent.
  • a neuroleptic agent for example, clozapine
  • any of the techniques described above may be used to detect either the C2 allele or the Cl allele. If only the C2 allele is detected in the subject, then the subject is homozygous for allele C2; but if allele Cl is detected in the subject, either alone or in addition to allele C2 then the subject is either homozygous for Cl or heterozygous.
  • the present invention has utility in enabling improvements in the clinical management of patients suffering from schizophrenia.
  • the invention provides direct benefits to the patient in terms of indicating the most appropriate therapy as early as possible in the treatment process and is of wider benefit in terms of health economics.
  • the invention has utility in enabling effective and efficient design of clinical trials with neuroleptic agents.
  • patients who are not likely to respond to either or any of the agents can be excluded.
  • the present invention also provides a kit suitable for use in assessing the responsiveness of a subject to a neuroleptic agent, which kit comprises
  • reagents for example, diluents, wash solutions and control solutions, for use in the detection process.
  • the means for testing preferably comprises a labelled probe or a restriction enzyme.
  • the present invention also provides a transgenic animal, in particular a transgenic non-human mammal such as a mouse, which expresses the human 5-HT 2A gene containing the C2 allele.
  • the animal should not generally express the human 5-HT 2A gene containing the Cl allele.
  • Such a transgenic animal may be used to screen for and identify novel antipsychotic agents that are likely to be effective in patients who do not respond to currently available neuroleptics such as clozapine.
  • Transgenic animals homozygous for the C2 allelic variant of the 5-HT 2A gene may be obtained using procedures which are standard in the field of genetic engineering. The sequence of the 5- HT 2A gene is given by Saltzman et al. (Biochemical and
  • Genotyping for Mspl polymorphism was carried out using blood samples obtained from individuals diagnosed as suffering from schizophrenia (DSM III) and undergoing treatment with clozapine. The individuals were also separately assessed for responsiveness to clozapine treatment: non-response is defined as a drop of ⁇ 20 points on GAS or ⁇ 20% on BPRS after six weeks treatment. The results were correlated as shown in the table below.
  • a fragment corresponding to the nucleotides -24 to 318 of the serotonin receptor gene (HTR2) was amplified using the method of Warren et al. (1993), with some modifications.
  • the reactions were 25 ⁇ l in volume and each one contained buffer type II (Perkin Elmer), 2.0mM MgCl 2 , 200 ⁇ M of each dNTP, 2.5 ⁇ M of the respective primers, 1 U of Tag polymerase (Perkin Elmer) and 25ng of patient DNA.
  • the amplification programme included 3 cycles of 3' at 94°C, 45" at 60°C and 1.5' at 72°C, followed by 35 cycles of 1' at 94 ⁇ C, 45" at 60°C and 1.5' at 72°C, with a final elongation step of 10' at 72°C. (" ' " denotes seconds and " " " stands for minutes. )
  • the primers used were:
  • 17 ⁇ l of the PCR product (372bp) was diluted with 2 ⁇ l restriction enzyme buffer and digested with Mspl (New England Biolabs) (lOU/sample) at 37°C for a minimum of 3 hours.
  • the size of the digested samples was analysed by separating them electrophoretically in 2% agarose gels containing Tris-borate EDTA buffer and 50 ⁇ g of ethidium bromide per lOOmls of agarose gel. DNA fragments were visualised by ultraviolet radiation at 260nm, and sized relative to a standard DNA size ladder (Gibco, 1Kb ladder). The Cl allele (372bp) is not cut by the enzyme whereas the C2 allele is cut into two fragments, 156bp and 216bp. Data

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  • Health & Medical Sciences (AREA)
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  • Life Sciences & Earth Sciences (AREA)
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  • Proteomics, Peptides & Aminoacids (AREA)
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Abstract

L'ADN codant pour le récepteur 5-HT2A à la sérotonine présente un polymorphisme T/C en position 102, les deux allèles étant connus respectivement sous la désignation C1 et C2. L'état homozygote ou hétérozygote d'un sujet par rapport aux allèles C1 et C2 est utilisé pour évaluer la réactivité d'un sujet à un agent neuroleptique, en particulier la clozapine. On décrit des procédés pour effectuer cette évaluation de la réactivité d'un sujet.
PCT/GB1995/002748 1994-11-26 1995-11-24 Evaluation en vue d'un traitement par des agents neuroleptiques WO1996017081A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU39312/95A AU3931295A (en) 1994-11-26 1995-11-24 Assessment for treatment with neuroleptic agents

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9423905A GB9423905D0 (en) 1994-11-26 1994-11-26 Novel method
GB9423905.0 1994-11-26

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WO1996017081A1 true WO1996017081A1 (fr) 1996-06-06

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PCT/GB1995/002748 WO1996017081A1 (fr) 1994-11-26 1995-11-24 Evaluation en vue d'un traitement par des agents neuroleptiques

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AU (1) AU3931295A (fr)
GB (2) GB9423905D0 (fr)
IL (1) IL116128A0 (fr)
WO (1) WO1996017081A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000020636A1 (fr) * 1998-10-07 2000-04-13 Acadia Pharmaceuticals Inc. Procede permettant l'identification d'agonistes inverses du recepteur 2a de serotonine
US6358698B1 (en) 1998-10-07 2002-03-19 Acadia Pharmacueticals Inc. Methods of identifying inverse agonists of the serotonin 2A receptor
US7425420B2 (en) 1999-10-07 2008-09-16 Acadia Pharmaceuticals Inc. Identification of ligands by selective amplification of cells transfected with a 5HT2A receptor
US8355927B2 (en) 2010-11-05 2013-01-15 Genomind, Llc Neuropsychiatric test reports

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993014201A1 (fr) * 1992-01-08 1993-07-22 Synaptic Pharmaceutical Corporation Adn codant un recepteur humain 5-ht1f et utilisations de cet adn

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993014201A1 (fr) * 1992-01-08 1993-07-22 Synaptic Pharmaceutical Corporation Adn codant un recepteur humain 5-ht1f et utilisations de cet adn

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
ARRANZ, M. ET AL.: "Association between clozapine response and allelic variation in 5-HT2a receptor gene", THE LANCET, vol. 346, pages 281 - 82 *
BURNET, P. ET AL.: "genetic variation of the 5-HT receptor and response to clozapine", THE LANCET, vol. 346, pages 909 *
COOK, E. ET AL: "Primary structure of the human platelet serotonin 5-HT2a receptor", JOURNAL OF NEUROCHEMISTRY, vol. 63, no. 2, pages 465 - 9 *
MELTZER, H.: "an overview of the mechanism of action of clozapine", J. CLIN PSYCHIARTY, vol. 55, no. 9, suppl b, pages 47 - 52 *
NÖTHEN, M. ET AL.: "genetic variation of the 5-HT receptor response to clozapine", THE LANCET, vol. 346, pages 908 - 9 *
WARREN, J. ET AL: "An MspI polymorphism in the serotonin receptor gene (HTR2): detection by DGGE and RFLP analysis", HUMAN MOLECULAR GENETICS, vol. 2, no. 3, pages 338 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000020636A1 (fr) * 1998-10-07 2000-04-13 Acadia Pharmaceuticals Inc. Procede permettant l'identification d'agonistes inverses du recepteur 2a de serotonine
US6358698B1 (en) 1998-10-07 2002-03-19 Acadia Pharmacueticals Inc. Methods of identifying inverse agonists of the serotonin 2A receptor
US7425420B2 (en) 1999-10-07 2008-09-16 Acadia Pharmaceuticals Inc. Identification of ligands by selective amplification of cells transfected with a 5HT2A receptor
US7452682B2 (en) 1999-10-07 2008-11-18 Acadia Pharmaceuticals, Inc. Identification of 5HT2A receptor ligands by selective amplification of cells transfected with receptors
US7491503B2 (en) 1999-10-07 2009-02-17 Acadia Pharmaceuticals, Inc. Identification of ligands by selective amplification of cells transfected with receptors
US8355927B2 (en) 2010-11-05 2013-01-15 Genomind, Llc Neuropsychiatric test reports
US8706526B2 (en) 2010-11-05 2014-04-22 Genomind, Llc Neuropsychiatric test reports

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GB9423905D0 (en) 1995-01-11
IL116128A0 (en) 1996-01-31
AU3931295A (en) 1996-06-19
GB9507229D0 (en) 1995-05-31

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