WO2005049863A2 - Identification de marqueurs diagnostic pour les encephalopathies subaiguës spongiformes transmissibles - Google Patents
Identification de marqueurs diagnostic pour les encephalopathies subaiguës spongiformes transmissibles Download PDFInfo
- Publication number
- WO2005049863A2 WO2005049863A2 PCT/FR2004/002892 FR2004002892W WO2005049863A2 WO 2005049863 A2 WO2005049863 A2 WO 2005049863A2 FR 2004002892 W FR2004002892 W FR 2004002892W WO 2005049863 A2 WO2005049863 A2 WO 2005049863A2
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- nucleic acid
- sequence
- seq
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- 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
Definitions
- the present application relates to biological markers of transmissible spongiform encephalopathies and their uses in diagnostic methods. It also relates to tools and / or kits which can be used for the implementation of these methods (reagents, probes, primers, antibodies, chips, cells, etc.), their preparation and their uses.
- the invention can be used to detect the presence of an infection in mammals, including in the early phase.
- Prion diseases also called transmissible spongiform subacute encephalopathies or diseases with unconventional transmissible agents (CNTA) are diseases of the central nervous system encountered in certain mammals, including humans.
- the infectious agent is not yet definitively determined, but the most accepted hypothesis is that these diseases are associated with the accumulation in the brain of a prion protein (PrP) of abnormal conformation compared to the conformation observed in healthy individuals.
- PrP prion protein
- DATAS identifies qualitative differences in gene expression and provides a systematic analysis of spliced RNA between two conditions: healthy / infected. DATAS leads to the identification of functionally distinct RNA variants.
- the DATAS technique comprises three distinct stages: the collection of tissue, the isolation of RNAs and the construction of a repertoire containing qualitative differences and identifying new gene fragments, which cannot be isolated by other genetic techniques.
- the markers contained in these directories were selected and validated according to two approaches:
- the different clones of the two DATAS experiments were deposited on glass slides.
- the slides were hybridized with probes produced from biological material from cows infected naturally or experimentally and from healthy cows used as control.
- SAM Signal Analysis of Microarray
- PAM Prediction analysis of Microarray
- the present application thus provides a set of biological markers which can be used, alone or in combination (s), to detect, characterize or follow a transmissible spongiform encephalopathy in a mammal.
- the invention is useful in particular for detecting the presence of prion diseases in mammalian subjects, in particular sheep, cattle or humans. It is particularly advantageous insofar as it can be carried out on living mammals, from biological fluids such as blood, plasma, platelets, etc.
- An object of the present application relates to a method for detecting the presence or the risk of developing encephalopathy in a mammal, comprising determining the presence (or absence), in a biological sample of the mammal, of a target molecule chosen from: a) a nucleic acid comprising a sequence chosen from SEQ ID NOs: 1 to 26 or a fragment thereof having at least 5, preferably 6, 7, 8, 9 or 10 consecutive bases, b) an acid nucleic acid having a sequence complementary to a sequence according to a), c) a functional analog of a nucleic acid according to a) or b), or d) a polypeptide encoded by a nucleic acid according to a) to c), the presence ( or the absence) of such a target molecule in the sample being an indication of the presence or risk of developing encephalopathy in this mammal.
- a target molecule chosen from: a) a nucleic acid comprising a sequence chosen from SEQ ID NOs: 1 to 26 or
- the method comprises the determination (simultaneous) of the presence or absence of at least 2, 3, 4, 5, 6, 7, 8, 9, 10 or more of the target molecules such as defined above.
- the invention indeed makes it possible to establish and determine a hybridization profile on a set of markers, in order to assess the presence or the risk of developing encephalopathy in a mammal.
- the hybridization profile is typically carried out using a combination of several markers chosen by the targets indicated above, for example containing all of these targets.
- the target molecule may be the complete sequence of the gene or of the RNA or of the protein corresponding to the sequences SEQ ID NOs: 1-26, or a fragment thereof, for example a fragment comprising a domain of variability (splicing, deletion, polymorphism, etc.).
- a functional analogue more particularly designates an analogue originating from another species (for example man, sheep, etc.), or a natural variant resulting for example from polymorphism, splicing, etc.
- the method comprises determining the presence of at least one nucleic acid according to a) to c).
- Different techniques which can be used to detect a species of nucleic acid in a sample can be used in the present invention, such as, for example, Northern Blot, selective hybridization, the use of supports coated with probe oligonucleotides, the amplification of nucleic acid such as for example by RT-PCR, quantitative PCR and ligation-PCR, etc.
- These methods may include the use of a nucleic probe (eg, an oligonucleotide) capable of selectively or specifically detecting the target nucleic acid in the sample.
- Amplification can be carried out according to various methods known per se to those skilled in the art, such as PCR, LCR, transcription-mediated amplification (TMA), strand displacement amplification (SDA), NASBA, use of allele specific oligonucleotides (ASO), allele specific amplification, Southern blot, SSCA conformational analysis, in situ hybridization (eg, FISH), gel migration, heteroduplex analysis, etc.
- TMA transcription-mediated amplification
- SDA strand displacement amplification
- NASBA use of allele specific oligonucleotides (ASO), allele specific amplification, Southern blot, SSCA conformational analysis, in situ hybridization (eg, FISH), gel migration, heteroduplex analysis, etc.
- the method comprises the detection of the presence or absence of a nucleic acid according to a) to c) by selective hybridization or selective amplification.
- nucleic acid probes preferably immobilized on a support, such as a solid or semi-solid support having at least one surface, flat or not, allowing the immobilization of nucleic probes.
- a support such as a solid or semi-solid support having at least one surface, flat or not.
- Such supports are for example a blade, ball, membrane, filter, column, plate, etc. They can be made of any compatible material, such as glass, silica, plastic, fiber, metal, polymer, etc.
- the nucleic acid probes can be any nucleic acid (DNA, RNA, PNA, etc.), preferably single-stranded, comprising a specific sequence of a target molecule as defined in a) to c) above.
- the probes typically comprise from 5 to 400 bases, preferably from 8 to 200, more preferably less than 100.
- the probes can be synthetic oligonucleotides, produced on the basis of the sequences of target molecules of the invention according to conventional synthesis techniques .
- the probes can also be synthesized directly in situ, on the support, according to methods known per se to those skilled in the art.
- the probes can also be manufactured by genetic techniques, for example by amplification, recombination, ligation, etc.
- Such a probe constitutes another object of the present application, as well as its use (essentially in vitro) for the detection of encephalopathy in a subject.
- we uses a set of nucleic probes comprising all or a fragment of at least 5 consecutive bases of each of the sequences SEQ ID NO: 1-26, or of a strand complementary to these, advantageously immobilized on a support.
- Hybridization can be carried out under conventional conditions, known to those skilled in the art and adjustable by the latter (Sambrook et al). In particular, hybridization can be carried out under conditions of high, medium or low stringency, depending on the level of sensitivity sought, the amount of material available, etc. For example, suitable hybridization conditions include a temperature between 62 and 67 ° C for 2 to 18 hours. After hybridization, various washes can be carried out to remove the non-hybridized molecules, typically in SSC buffers comprising SDS, such as a buffer comprising 0.1 to 10 ⁇ SSC and 0.1% SDS.
- the nucleic acids are pre-hybridized in a hybridization buffer (Rapid Hybrid Buffer, Amersham) typically containing 100 ⁇ g / ml of salmon sperm DNA to 65 ° C for 30 min.
- a hybridization buffer typically containing 100 ⁇ g / ml of salmon sperm DNA to 65 ° C for 30 min.
- the nucleic acids in the sample are then brought into contact with the probes
- the nucleic acids of the sample are labeled beforehand, by any known labeling (radioactive, enzymatic, fluorescent, luminescent, etc.).
- the supports are then washed in a 5X SSC buffer, 0.1% SDS at 65 ° C for 30 min, then in a 0.2X SSC buffer, 0.1% SDS.
- the hybridization profile is analyzed according to conventional techniques, such as for example by measuring the marking on the support by means of a suitable instrument (for example Instantlmager, Packard Instruments).
- the hybridization conditions can naturally be adjusted by a person skilled in the art, for example by modifying the hybridization temperature and / or the salt concentration of the buffer.
- the selective amplification is preferably carried out using a primer or a pair of primers allowing the amplification of all or part of one of the target nucleic acids in the sample, when the latter is present there.
- the primer can be specific for a target sequence according to SEQ ID NO: 1-26, or for a region flanking the target sequence in a nucleic acid of the sample.
- the primer typically includes a nucleic acid single-stranded, of a length advantageously between 5 and 50 bases, preferably between 5 and 30.
- Such a primer constitutes another object of the present application, as well as its use (essentially in vitro) for the detection of a encephalopathy in a subject.
- the method comprises determining the presence of a polypeptide according to d).
- the demonstration of a polypeptide in a sample can be carried out by any technique known per se, such as in particular by means of a specific ligand, for example an antibody or a fragment or derivative of antibody.
- the ligand is an antibody specific for the polypeptide, or a fragment of such an antibody (for example a Fab, Fab ', CDR, etc.), or a derivative of such an antibody (for example a simple antibody). chain, ScFv).
- the ligand is typically immobilized on a support, such as a blade, ball, column, plate, etc.
- the presence of the target polypeptide in the sample can be detected by detecting a complex between the target and the ligand, for example by using a labeled ligand, by using a second labeled revealing ligand, etc.
- Immunological techniques which can be used and which are well known are ELISA, RIA, etc.
- Antibodies specific for the target polypeptides can be produced by conventional techniques, in particular by immunization of a non-human animal with an immunogen comprising the polypeptide (or an immunogenic fragment thereof), and recovery of the antibodies (polyclonal) or producer cells (to produce monoclonals). Techniques for producing poly- or monoclonal antibodies, ScFv fragments, human or humanized antibodies are described for example in Harlow et al., Antibodies: A laboratory Manual, CSH Press, 1988; Ward et al., Nature 341 (1989)
- the immunogen can be manufactured by synthesis, or by expression, in an appropriate host, of a target nucleic acid as defined above.
- a target nucleic acid as defined above.
- the method of the invention is applicable to any biological sample from the mammal tested, in particular any sample comprising nucleic acids or polypeptides. Mention may advantageously be made of a sample of blood, plasma, platelet, saliva, urine, stool, etc., more generally any tissue, organ or, advantageously, biological fluid comprising nucleic acids or polypeptides.
- the sample is a blood or plasma sample.
- the sample can be obtained by any technique known per se, for example by sampling, by non-invasive techniques, from collections or banks of samples, etc.
- the sample can also be pre-treated to facilitate the accessibility of the target molecules, for example by lysis (mechanical, chemical, enzymatic, etc.), purification, centrifugation, separation, etc.
- the sample can also be labeled, to facilitate the determination of the presence of the target molecules (fluorescent, radioactive, luminescent, chemical, enzymatic, etc. labeling).
- the invention is applicable to any mammal, preferably chosen from cattle, sheep and humans.
- the method of the invention is particularly useful for the detection of scrapie in sheep, Bovine Spongiform Encephalopathy (BSE) in cattle, and Creutzfeld-Jakob disease (CJD), kuru and l fatal family insomnia in men.
- BSE Bovine Spongiform Encephalopathy
- CJD Creutzfeld-Jakob disease
- a particular subject of the present application relates to a method for detecting the presence or the risk of developing BSE in a bovine animal, comprising determining the presence (or absence), in a biological sample of the bovine animal, of one or more several target molecules chosen from: a) a nucleic acid comprising a sequence chosen from SEQ ID NO: 1 to 26 or a fragment thereof having at least 5, preferably 6, 7, 8, 9 or 10 consecutive bases, b ) a nucleic acid having a sequence complementary to a sequence according to a), c) a polypeptide encoded by a nucleic acid according to a) or b).
- Another particular object of the present application relates to a method for detecting the presence or the risk of developing BSE in a bovine or ovine, comprising bringing a biological sample from bovine or ovine containing nucleic acids into contact with a product comprising a support on which is immobilized at least one nucleic acid comprising a sequence chosen from SEQ ID NO: 1 to 26, a fragment thereof having at least 5 consecutive bases, or a nucleic acid having a sequence complementary to these, and determining the hybridization profile, the profile indicating the presence or the risk of developing BSE in cattle or sheep.
- the product comprises at least 2, 3, 4, 5, 6, 7, 8, 9, 10 different nucleic acids chosen from the nucleic acids mentioned above.
- the product each comprises nucleic acids of sequence SEQ ID NO: 1 to 26, a fragment thereof having at least 5 consecutive bases, or a nucleic acid having a sequence complementary to these this.
- a product comprising a support on which is immobilized at least one nucleic acid comprising a sequence chosen from SEQ ID NO: 1 to 26, a fragment thereof having at least 5 consecutive bases, an acid nucleic acid having a sequence complementary thereto or a functional analog thereof.
- the product comprises at least 2, 3, 4, 5, 6, 7, 8, 9, 10 different nucleic acids chosen from the nucleic acids mentioned above.
- the product each comprises nucleic acids of sequence SEQ ID NO: 1 to 26, a fragment thereof having at least 5 consecutive bases, or a nucleic acid having a sequence complementary to these this
- Another subject of the present application relates to a product comprising a support on which is immobilized at least one polypeptide encoded by a nucleic acid comprising a sequence chosen from SEQ ID NO: 1 to 26, a fragment thereof having at least 15 bases consecutive, a nucleic acid having a sequence complementary thereto or a functional analog thereof.
- the product comprises at least 2, 3, 4, 5, 6, 7, 8, 9, 10 different polypeptides chosen from the polypeptides mentioned above.
- the support can be any solid or semi-solid support having at least one surface, flat or not, allowing the immobilization of nucleic acids or polypeptides.
- Such supports are for example a blade, ball, membrane, filter, column, plate, etc. They can be made of any compatible material, such as in particular glass, silica, plastic, fiber, metal, polymer, polystyrene, teflon, etc.
- the reagents can be immobilized on the surface of the support by known techniques, or, in the case of nucleic acids, synthesized directly in situ on the support. Immobilization techniques include passive adsorption (Inouye et al., J. Clin. Microbiol. 28 (1990) 1469), covalent bonding.
- the reagents immobilized on the support can be ordered according to a pre-established scheme, to facilitate the detection and identification of the complexes formed, and according to a variable and adaptable density.
- the product of the invention comprises a plurality of synthetic oligonucleotides, of a length between 5 and 100 bases, specific for one or more target nucleic acids defined in a) to c).
- the products of the invention typically include control molecules, making it possible to calibrate and / or standardize the results.
- kits comprising a compartment or container comprising at least one nucleic acid comprising a sequence chosen from SEQ ID NO: 1 to 26, a fragment thereof having at least 5 consecutive bases, a nucleic acid having a sequence complementary to these or a functional analog thereof.
- the product comprises at least 2, 3, 4, 5, 6, 7, 8, 9, 10 different nucleic acids chosen from the nucleic acids mentioned above.
- the product each comprises nucleic acids of sequence SEQ ID NO: 1 to 26, a fragment thereof having at least 5 consecutive bases, or a nucleic acid having a sequence complementary to these this.
- the kit can also include reagents for a hybridization or immunological reaction, as well as, if necessary, controls and / or instructions.
- Another object of the invention relates to the use of a product or kit as defined above for the detection of encephalopathy in a mammalian subject.
- Another subject of the invention relates to a nucleic acid comprising a sequence chosen from SEQ ID NO: 1-26, or a fragment thereof comprising at least 5 consecutive bases, or a nucleic acid having a sequence complementary to these , or a functional analog thereof, in particular an analog from another species.
- the invention also relates to a cloning or expression vector comprising these nucleic acids, as well as any recombinant cell comprising such a vector or nucleic acid.
- Another subject of the invention relates to the use of a nucleic acid comprising a sequence chosen from SEQ ID NO: 1-26, or a fragment thereof comprising at least 5 consecutive bases, or a nucleic acid having a sequence complementary to these, or a functional analog thereof, in particular an analog from another species, for the detection (essentially in vitro) of encephalopathy in a mammalian subject.
- a blood sample from a mammal to be tested is taken.
- the blood sample is processed to make the nucleic acids more accessible, and these are labeled.
- the nucleic aids are then applied to a product as defined above and the hybridization profile is determined, making it possible to diagnose the presence or not of an encephalopathy in the subject.
- the method of the invention is simple, practiced ex vivo, on living animals, and allows the early detection of a prion disease.
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Abstract
Description
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Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA002545098A CA2545098A1 (fr) | 2003-11-13 | 2004-11-10 | Identification de marqueurs diagnostic pour les encephalopathies subaigues spongiformes transmissibles |
EP04805435A EP1692310A2 (fr) | 2003-11-13 | 2004-11-10 | Identification de marqueurs diagnostic pour les encephalopathies subaigu s spongiformes transmissibles |
US10/578,672 US20070292850A1 (en) | 2003-11-13 | 2004-11-10 | Identification of Diagnostic Markers for Communicable Subacute Spongiform Encephalopathies |
BRPI0416552-7A BRPI0416552A (pt) | 2003-11-13 | 2004-11-10 | método para detectar a presença ou risco de desenvolver uma encefalopatia em um mamìfero, utilização de uma sonda nucleica, de um iniciador nucleico e de um ácido nucleico, produto e kit |
AU2004291700A AU2004291700A1 (en) | 2003-11-13 | 2004-11-10 | Identification of diagnostic markers for communicable subacute spongiform encephalopathies |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR0313275 | 2003-11-13 | ||
FR0313275A FR2862314A1 (fr) | 2003-11-13 | 2003-11-13 | Identification de marqueurs diagnostic pour les encephalopathies subaigues spongiformes transmissibles |
FR0314486A FR2867485B1 (fr) | 2003-12-10 | 2003-12-10 | Identification de marqueurs diagnostics pour les encephalopathies subaigues spongiformes transmissibles |
FR0314486 | 2003-12-10 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2005049863A2 true WO2005049863A2 (fr) | 2005-06-02 |
WO2005049863A3 WO2005049863A3 (fr) | 2005-10-20 |
Family
ID=34621624
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/FR2004/002892 WO2005049863A2 (fr) | 2003-11-13 | 2004-11-10 | Identification de marqueurs diagnostic pour les encephalopathies subaiguës spongiformes transmissibles |
Country Status (6)
Country | Link |
---|---|
US (1) | US20070292850A1 (fr) |
EP (1) | EP1692310A2 (fr) |
AU (1) | AU2004291700A1 (fr) |
BR (1) | BRPI0416552A (fr) |
CA (1) | CA2545098A1 (fr) |
WO (1) | WO2005049863A2 (fr) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1749892A1 (fr) * | 2005-08-02 | 2007-02-07 | Roche Diagnostics GmbH | Séquence nucléotidique permettant d'évaluer TSE |
EP1762618A1 (fr) | 2005-09-07 | 2007-03-14 | Roche Diagnostics GmbH | Procédé de préparation d'acides nucléiques à partir du sang total et son utilisation dans le diagnostic d'EST par PCT temps réel |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1997027317A1 (fr) * | 1996-01-23 | 1997-07-31 | Affymetrix, Inc. | Evaluation rapide de difference d'abondance d'acides nucleiques, avec un systeme d'oligonucleotides haute densite |
WO1999015635A1 (fr) * | 1997-09-19 | 1999-04-01 | Zeneca Limited | Serine/threonine kinase humaine de type ste20 activee par un stress |
WO1999046403A1 (fr) * | 1998-03-11 | 1999-09-16 | Exonhit Therapeutics S.A. | Criblage differentiel qualitatif |
WO2002074986A2 (fr) * | 2001-03-21 | 2002-09-26 | Exonhit Therapeutics S.A. | Test sanguin de diagnostic precoce pre-symptomatique pour les encephalopathies |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20030073623A1 (en) * | 2001-07-30 | 2003-04-17 | Drmanac Radoje T. | Novel nucleic acid sequences obtained from various cDNA libraries |
-
2004
- 2004-11-10 CA CA002545098A patent/CA2545098A1/fr not_active Abandoned
- 2004-11-10 WO PCT/FR2004/002892 patent/WO2005049863A2/fr active Application Filing
- 2004-11-10 AU AU2004291700A patent/AU2004291700A1/en not_active Abandoned
- 2004-11-10 EP EP04805435A patent/EP1692310A2/fr not_active Withdrawn
- 2004-11-10 BR BRPI0416552-7A patent/BRPI0416552A/pt not_active IP Right Cessation
- 2004-11-10 US US10/578,672 patent/US20070292850A1/en not_active Abandoned
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1997027317A1 (fr) * | 1996-01-23 | 1997-07-31 | Affymetrix, Inc. | Evaluation rapide de difference d'abondance d'acides nucleiques, avec un systeme d'oligonucleotides haute densite |
WO1999015635A1 (fr) * | 1997-09-19 | 1999-04-01 | Zeneca Limited | Serine/threonine kinase humaine de type ste20 activee par un stress |
WO1999046403A1 (fr) * | 1998-03-11 | 1999-09-16 | Exonhit Therapeutics S.A. | Criblage differentiel qualitatif |
WO2002074986A2 (fr) * | 2001-03-21 | 2002-09-26 | Exonhit Therapeutics S.A. | Test sanguin de diagnostic precoce pre-symptomatique pour les encephalopathies |
Non-Patent Citations (2)
Title |
---|
DATABASE EMBL EBI; 17 mars 2004 (2004-03-17), XP002288571 Database accession no. CK946384 * |
See also references of EP1692310A2 * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1749892A1 (fr) * | 2005-08-02 | 2007-02-07 | Roche Diagnostics GmbH | Séquence nucléotidique permettant d'évaluer TSE |
EP1762618A1 (fr) | 2005-09-07 | 2007-03-14 | Roche Diagnostics GmbH | Procédé de préparation d'acides nucléiques à partir du sang total et son utilisation dans le diagnostic d'EST par PCT temps réel |
US7569367B2 (en) | 2005-09-07 | 2009-08-04 | Roche Diagnostics Operations, Inc. | Nucleic acid preparation from whole blood for use in diagnosis of transmissible spongiform encephalopathy |
Also Published As
Publication number | Publication date |
---|---|
WO2005049863A3 (fr) | 2005-10-20 |
AU2004291700A1 (en) | 2005-06-02 |
BRPI0416552A (pt) | 2007-01-23 |
US20070292850A1 (en) | 2007-12-20 |
EP1692310A2 (fr) | 2006-08-23 |
CA2545098A1 (fr) | 2005-06-02 |
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