WO1997021833A1 - Procede de prediction, chez un sujet, de la reponse de celui-ci a des agents neuroleptiques - Google Patents
Procede de prediction, chez un sujet, de la reponse de celui-ci a des agents neuroleptiques Download PDFInfo
- Publication number
- WO1997021833A1 WO1997021833A1 PCT/EP1996/005734 EP9605734W WO9721833A1 WO 1997021833 A1 WO1997021833 A1 WO 1997021833A1 EP 9605734 W EP9605734 W EP 9605734W WO 9721833 A1 WO9721833 A1 WO 9721833A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- drug
- allele
- subject
- treatment
- dna
- Prior art date
Links
Classifications
-
- 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
- C07K14/775—Apolipopeptides
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
- C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
-
- 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
-
- 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
- C12Q2600/172—Haplotypes
Definitions
- the present invention relates to methods of assessing the responsiveness of individuals to neuroleptic agents such as clozapine.
- Schizophrenia is a devastating psychiatric 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 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 withdrawl. There are 600,000 schizophrenics at any one time in the UK and their care has been reported to cost approximately 1.6% of the total healthcare budget.
- Atypical neuroieptics provide advantages in that they improve both the positive and negative symptoms of schizophrenia and cause virtually no eps.
- An example of this type of drug is clozapine.
- clozapine and other atypical neuroleptic agents to treat schizophrenia is reserved for those mdividuals who have failed to respond to treatment with other neuroleptic agents, such as haioperidol.
- the method may be used more generally to predict whether a patient is likely to respond to any of the existing typical or atypical neuroleptic agents.
- the present invention therefore provides an objective method of assessing in a subject the likelihood whether said subject will be non-responsive or responsive to treatment with neuroieptics such as clozapine, the method comprising detecting the presence or absence of DNA comprising the E2 allele of the ApoE gene . or the protein expressed by said DNA, in said subject.
- responders and “non-responders” as used herein are terms well known in the art.
- GAS Global Assessment Scale
- BPRS Brief Psychiatric Rating Scale
- the present invention provides a method for use in assessing whether a subject suffering from a condition which may be treated with a neuroleptic agent will be responsive to treatment with said neuroleptic agent, said method comprising the steps of:
- the predetermined correlation utilised in step (ii) may itself be obtained by the following series of steps: selecting a population or cohort of subjects diagnosed as suffering from a specified condition suitable for treatment with a neuroleptic agent; treating said cohort with a specified neuroleptic agent; monitoring the outcome of said treatment and identifying responders and non-responders to the said treatment, taking from said cohort biological samples containing DNA or protein and testing this for the presence or absence of the ApoE E2 allele; analysing the presence or absence of the ApoE E2 allele as between responders and non- responders; making a comparison with the distribution of the ApoE E2 alleles in a control group of subjects, not suffering from said condition; performing a statistical analysis to determine if there is a statistically significant association between presence or absence of the ApoE E2 allele and response to treatment.
- the invention thus also provides a method for assessing whether a sub j ect suffering from a condition which may be treated with a neuroleptic agent will be responsive to treatment with a specified neuroleptic agent, said method comprising the steps of: (i) correlating the presence or absence of the ApoE E2 aliele in a population of subjects suffering from a specified condition requiring treament with a neuroleptic agent with observed clinical response to said neuroleptic agent; (ii) testing for the presence or absence of DNA comprising the E2 allele of the ApoE gene or the protein expressed by said gene in a sample containing DNA or protein obtained from said subject, and
- the invention provides a method for generating a model to assess whether a subject is likely to be responsive to treatment with a neuroleptic agent which method comprises:
- a cohort of patients diagnosed as suffering from a specified condition eg schizophrenia
- a neuroleptic agent eg clozapine
- assessing the outcome of treatment so as to define responders and non-responders according to pre-determined criteria
- the invention also provides a method for assessing whether a subject suffering from a condition which may be treated with a neuroleptic agent will be responsive to treatment with a specified neuroleptic agent, which comprises comparing said subject's genotype with the model described above.
- a computer-contolled system may be carried out by a computer-controlled robotic system.
- a computer-controlled system may also be configured to make the comparison between the subject to be assessed and a pre-determined correlation or model.
- a computer controlled system may also be configured to give either a positive or negative readout depending on the outcome ofthe comparison. The present invention therefore extends to such computer-controlled or computer-implemented methods.
- the steps of testing for and detecting the presence or absence of DNA encoding the ApoE E2 allele or the protein expressed by said gene 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 ex vivo All generally involve the step of collecting a sample of biological material containing DNA or protein from the subject, and then detecting which alleles or protein the subject possesses from that sample.
- 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 the E2 allele in the biological sample.
- Any biological sample which contains the DNA or protein 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 the E2 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).
- 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).
- 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
- 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 basis of the present invention namely that patients possessing an E2 allele of the ApoE gene are less likely to respond to clozapine.
- the present invention provides a method for assessing in a subject the likelihood whether said subject will be non-responsive or responsive to treatment with a drug whose primary mode of action is via a process of altered synaptic activity, the method comprising testing for an detecting the presence or absence of DNA comprising the E2 allele of the ApoE gene, or the protein expressed by said DNA
- the present invention may also be utilised in screening for drugs whose primary mode of action is via a process of altered synaptic activity, eg antipsychotic, anti- epileptic or antidepressant agents
- screening may be useful to identify therapeutic agents which may be potentially useful in patients who are not responsive to existing drugs
- Screening may be effected using in vitro methods or in vivo methods eg utilising transgemc animals, eg mammals such as mice, which express the E2 allehc variant of the ApoE gene
- transgenic animals may be obtained using procedures which are standard in the field of genetic engineering EXAMPLE
Abstract
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU13762/97A AU1376297A (en) | 1995-12-13 | 1996-12-11 | Method of predicting a subjects response to neuroleptic agents |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9525481.9 | 1995-12-13 | ||
GBGB9525481.9A GB9525481D0 (en) | 1995-12-13 | 1995-12-13 | Novel method |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1997021833A1 true WO1997021833A1 (fr) | 1997-06-19 |
Family
ID=10785365
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP1996/005734 WO1997021833A1 (fr) | 1995-12-13 | 1996-12-11 | Procede de prediction, chez un sujet, de la reponse de celui-ci a des agents neuroleptiques |
Country Status (4)
Country | Link |
---|---|
AU (1) | AU1376297A (fr) |
GB (1) | GB9525481D0 (fr) |
WO (1) | WO1997021833A1 (fr) |
ZA (1) | ZA9610458B (fr) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6280763B1 (en) | 1999-05-10 | 2001-08-28 | Pierce Management, Llc | Apparatus and method for transdermal delivery of bupropion |
EP2514840A1 (fr) * | 2008-01-02 | 2012-10-24 | Suregene Llc | Système de génération d'énergie éolienne et procédé d'installation supplémentaire de générateur d'énergie éolienne dans celui-ci |
EP2581455A3 (fr) * | 2008-01-17 | 2013-07-10 | Suregene LLC | Marqueurs génétiques de maladie mentale |
GB2524519A (en) * | 2014-03-25 | 2015-09-30 | Pelago Bioscience AB | Method for identifying a biomarker indicative of a reduced drug response using a thermal shift assay |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1995025793A1 (fr) * | 1994-03-21 | 1995-09-28 | Rhône-Poulenc Rorer S.A. | Lapin transgenique sensibilise aux dyslipoproteinemies |
WO1995029257A2 (fr) * | 1994-04-27 | 1995-11-02 | Mcgill University | Polymorphisme de l'apolipoproteine e et traitement de la maladie d'alzheimer |
-
1995
- 1995-12-13 GB GBGB9525481.9A patent/GB9525481D0/en active Pending
-
1996
- 1996-12-11 AU AU13762/97A patent/AU1376297A/en not_active Abandoned
- 1996-12-11 WO PCT/EP1996/005734 patent/WO1997021833A1/fr active Application Filing
- 1996-12-12 ZA ZA9610458A patent/ZA9610458B/xx unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1995025793A1 (fr) * | 1994-03-21 | 1995-09-28 | Rhône-Poulenc Rorer S.A. | Lapin transgenique sensibilise aux dyslipoproteinemies |
WO1995029257A2 (fr) * | 1994-04-27 | 1995-11-02 | Mcgill University | Polymorphisme de l'apolipoproteine e et traitement de la maladie d'alzheimer |
Non-Patent Citations (1)
Title |
---|
Dialog Information Service, file 154, Medline, Dialog accession no. 08723289, Medline accession no. 96379828, Harrington CR et al: "Apolipoprotein E type epsilon 4 allele frequency is increased in patients with schizophrenia", Neurosci Lett (IRELAND) Dec 29 1995, 202 (1-2) p101-4 * |
Cited By (24)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6280763B1 (en) | 1999-05-10 | 2001-08-28 | Pierce Management, Llc | Apparatus and method for transdermal delivery of bupropion |
EP2514840A1 (fr) * | 2008-01-02 | 2012-10-24 | Suregene Llc | Système de génération d'énergie éolienne et procédé d'installation supplémentaire de générateur d'énergie éolienne dans celui-ci |
EP2570494A1 (fr) * | 2008-01-02 | 2013-03-20 | Suregene Llc | Marqueurs génétiques de maladie mentale |
EP2570493A1 (fr) * | 2008-01-02 | 2013-03-20 | Suregene LLC | Marqueurs génétiques de maladie mentale |
EP2570495A1 (fr) * | 2008-01-02 | 2013-03-20 | Suregene Llc | Marqueurs génétiques de maladie mentale |
EP2570498A3 (fr) * | 2008-01-02 | 2013-03-27 | Suregene Llc | Marqueurs génétiques de maladie mentale |
EP2570497A3 (fr) * | 2008-01-02 | 2013-03-27 | Suregene Llc | Marqueurs génétiques de maladie mentale |
EP2570496A3 (fr) * | 2008-01-02 | 2013-03-27 | Suregene Llc | Marqueurs génétiques de maladie mentale |
EP2570500A3 (fr) * | 2008-01-02 | 2013-04-03 | Suregene Llc | Marqueurs génétiques de maladie mentale |
EP2570499A3 (fr) * | 2008-01-02 | 2013-04-03 | Suregene Llc | Marqueurs génétiques de maladie mentale |
EP2570501A3 (fr) * | 2008-01-02 | 2013-04-10 | Suregene Llc | Marqueurs génétiques de maladie mentale |
EP2581453A3 (fr) * | 2008-01-17 | 2013-07-10 | Suregene Llc | Marqueurs génétiques de maladie mentale |
EP2581455A3 (fr) * | 2008-01-17 | 2013-07-10 | Suregene LLC | Marqueurs génétiques de maladie mentale |
EP2581454A3 (fr) * | 2008-01-17 | 2013-07-10 | Suregene LLC | Marqueurs génétiques de maladie mentale |
EP2581457A3 (fr) * | 2008-01-17 | 2013-07-17 | Suregene LLC | Marqueurs génétiques de maladie mentale |
EP2581459A3 (fr) * | 2008-01-17 | 2013-07-17 | Suregene LLC | Marqueurs génétiques de maladie mentale |
EP2581458A3 (fr) * | 2008-01-17 | 2013-07-17 | Suregene LLC | Marqueurs génétiques de maladie mentale |
EP2581460A3 (fr) * | 2008-01-17 | 2013-07-17 | Suregene LLC | Marqueurs génétiques de maladie mentale |
EP2581456A3 (fr) * | 2008-01-17 | 2013-07-17 | Suregene Llc | Marqueurs génétiques de maladie mentale |
US9040241B2 (en) | 2008-01-17 | 2015-05-26 | Suregene Llc | Genetic markers of mental illness |
US9738934B2 (en) | 2008-01-17 | 2017-08-22 | Clinical Reference Laboratory, Inc. | Genetic markers of mental illness |
GB2524519A (en) * | 2014-03-25 | 2015-09-30 | Pelago Bioscience AB | Method for identifying a biomarker indicative of a reduced drug response using a thermal shift assay |
GB2524519B (en) * | 2014-03-25 | 2019-11-06 | Pelago Bioscience AB | Methods for identifying a biomarker indicative of a reduced drug response using a thermal shift assay |
US11480578B2 (en) | 2014-03-25 | 2022-10-25 | Pelago Bioscience AB | Method for identifying a biomarker indicative of a reduced drug response using a thermal shift assay |
Also Published As
Publication number | Publication date |
---|---|
ZA9610458B (en) | 1998-06-12 |
GB9525481D0 (en) | 1996-02-14 |
AU1376297A (en) | 1997-07-03 |
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