WO1996000795B1 - Method of amplification for increasing the sensitivity of detecting nucleic acid-probe target hybrids - Google Patents
Method of amplification for increasing the sensitivity of detecting nucleic acid-probe target hybridsInfo
- Publication number
- WO1996000795B1 WO1996000795B1 PCT/CA1995/000369 CA9500369W WO9600795B1 WO 1996000795 B1 WO1996000795 B1 WO 1996000795B1 CA 9500369 W CA9500369 W CA 9500369W WO 9600795 B1 WO9600795 B1 WO 9600795B1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- probe
- sequence
- nucleic acid
- label
- target
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract 24
- 230000003321 amplification Effects 0.000 title claims abstract 18
- 238000003199 nucleic acid amplification method Methods 0.000 title claims abstract 18
- 108020004711 Nucleic Acid Probes Proteins 0.000 title claims 3
- 239000002853 nucleic acid probe Substances 0.000 title claims 3
- 230000035945 sensitivity Effects 0.000 title abstract 3
- 239000000523 sample Substances 0.000 claims abstract 64
- 150000007523 nucleic acids Chemical group 0.000 claims abstract 31
- 238000002372 labelling Methods 0.000 claims abstract 16
- 230000000295 complement effect Effects 0.000 claims abstract 15
- 108020004707 nucleic acids Proteins 0.000 claims abstract 15
- 102000039446 nucleic acids Human genes 0.000 claims abstract 15
- 238000001514 detection method Methods 0.000 claims abstract 13
- 108091028043 Nucleic acid sequence Proteins 0.000 claims abstract 10
- 108020004414 DNA Proteins 0.000 claims abstract 7
- 238000003556 assay Methods 0.000 claims abstract 4
- 238000007899 nucleic acid hybridization Methods 0.000 claims abstract 3
- 230000002708 enhancing effect Effects 0.000 claims abstract 2
- 239000000126 substance Substances 0.000 claims 11
- 238000009007 Diagnostic Kit Methods 0.000 claims 8
- 108090000790 Enzymes Proteins 0.000 claims 8
- 102000004190 Enzymes Human genes 0.000 claims 8
- 239000003153 chemical reaction reagent Substances 0.000 claims 8
- 229940088598 enzyme Drugs 0.000 claims 8
- 239000002773 nucleotide Substances 0.000 claims 5
- 108091033319 polynucleotide Proteins 0.000 claims 5
- 102000040430 polynucleotide Human genes 0.000 claims 5
- 239000002157 polynucleotide Substances 0.000 claims 5
- 125000003729 nucleotide group Chemical group 0.000 claims 4
- 239000000758 substrate Substances 0.000 claims 4
- 239000012472 biological sample Substances 0.000 claims 3
- 235000019162 flavin adenine dinucleotide Nutrition 0.000 claims 3
- 239000011714 flavin adenine dinucleotide Substances 0.000 claims 3
- 108010006591 Apoenzymes Proteins 0.000 claims 2
- 108010015776 Glucose oxidase Proteins 0.000 claims 2
- 239000004366 Glucose oxidase Substances 0.000 claims 2
- 108010025076 Holoenzymes Proteins 0.000 claims 2
- -1 cofactor Substances 0.000 claims 2
- VWWQXMAJTJZDQX-UYBVJOGSSA-N flavin adenine dinucleotide Chemical compound C1=NC2=C(N)N=CN=C2N1[C@@H]([C@H](O)[C@@H]1O)O[C@@H]1CO[P@](O)(=O)O[P@@](O)(=O)OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C2=NC(=O)NC(=O)C2=NC2=C1C=C(C)C(C)=C2 VWWQXMAJTJZDQX-UYBVJOGSSA-N 0.000 claims 2
- 229940093632 flavin-adenine dinucleotide Drugs 0.000 claims 2
- 229940116332 glucose oxidase Drugs 0.000 claims 2
- 235000019420 glucose oxidase Nutrition 0.000 claims 2
- 230000003100 immobilizing effect Effects 0.000 claims 2
- 239000003112 inhibitor Substances 0.000 claims 2
- 230000002687 intercalation Effects 0.000 claims 2
- 238000009830 intercalation Methods 0.000 claims 2
- 239000003446 ligand Substances 0.000 claims 2
- 241000186779 Listeria monocytogenes Species 0.000 claims 1
- 241000293871 Salmonella enterica subsp. enterica serovar Typhi Species 0.000 claims 1
- 241000700605 Viruses Species 0.000 claims 1
- 230000001580 bacterial effect Effects 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 238000004925 denaturation Methods 0.000 claims 1
- 230000036425 denaturation Effects 0.000 claims 1
- 229920001519 homopolymer Polymers 0.000 claims 1
- 239000000138 intercalating agent Substances 0.000 claims 1
- 229940115931 listeria monocytogenes Drugs 0.000 claims 1
- 244000005700 microbiome Species 0.000 claims 1
- 238000009396 hybridization Methods 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 238000005406 washing Methods 0.000 abstract 1
Abstract
The present invention provides a method for simplifying and significantly enhancing the sensitivity of nucleic acid hybridization assays. A method is described whereby a single-stranded primary nucleic acid sequence that includes a region of sequences complementary to a single-stranded target nucleic acid sequence is hybridized to the target molecule. Stability of the double-stranded complex thereby formed can be enhanced by using RNA as the probe if DNA is the target or DNA as the probe if RNA is the target. The probe-target complex is subsequently immunocaptured for detection. After washing away extraneous material, a secondary nucleic acid sequence containing many repeating sequence units is hybridized to the probe component of the immobilized probe-target complex. Detection occurs following hybridization of many labelled nucleic acid sequence probes to each of the repeating sequence units of a nucleic acid amplification probe. Thus, attachment of multiple labelling probes to an amplification probe that is hybridized to an immobilized probe-target complex, provides a simplified method for amplifying the detection signal and therefore the sensitivity of nucleic acid hybridization assays.
Claims
1. An amplification probe comprising two regions of nucleic acid sequences: a first region including a homopolymeric nucleotide tail and a second region including a plurality of discretely labelable sequence units, said units ranging from two to fifty in number.
2. An amplification probe as claimed in Claim 1 , wherein the number of nucleotide molecules ranges from ten to sixty in number.
3 . An amplif ication probe as claimed in Claim 1 , wherein each said discretely labelable sequence unit comprises a sequence of nucleotide bases hybridizable to complementary sequence on a labelling probe , said labelling probe covalently attached to a detectable chemicle label .
4 . An ampl if ication probe as claimed in Claim 3 , wherein the length of each sequence unit ranges from 16 to 100 nucleot ides .
5. A method for enhancing detectable labeling of probe-target complexes in nucleic acid hybridization assays comprising hybridizing a complex of a selected nucleic acid target and a selected primary probe with [incorporating] an amplification probe adapted to permit enhanced detectable labelling of [a] said selected nucleic acid target, [such] said probe comprising at least two regions of nucleic acid sequences: a first region including a sequence complementary to a sequence on [a] said selected primary probe which also contains a sequence complimentary to a sequence of said selected nucleic acid target, and a second region including a plurality of discretely labelable sequence units.
6. A method as claimed in Claim 5 wherein each said discretely labelable sequence unit comprises a sequence of nucleotide bases hybridizable to a complementary sequence on a labelling probe, said labelling probe covalently attached to a detectable chemical label.
7. A method as claimed in claim 6 wherein the detectable chemical label is selected from an enzymatically active group, a fluorescer, a chromophore, a luminescer, a specifically bindable ligand, or a radioisotope.
8. A method as claimed in Claim 5 wherein a label attached to each said discretely labelable sequence units interacts with a reagent member of a label detection system to provide the detectable response.
9. The method as claimed in Claim 8 wherein the detectable chemical label is a substrate, cofactor, or inhibitor of an enzyme which is the member of the label detection system with which the label interacts to provide the detectable response.
10. The method as claimed in Claim 9 wherein the label is a substrate which is acted on by the enzyme to produce a colori etric, fluorescent or luminescent signal.
11. The method as claimed in Claim 9 wherein the label is a prosthetic group of an enzyme and wherein the apoenzy e of such enzyme is the member of the label detection system with which the label interacts to produce the catalytically active holoenzyme.
12. The method as claimed in Claim 11 wherein the prosthetic group is [PAD] flavin adenine dinucleotide and the apoenzyme is apo(glucose oxidase) .
13. A method for detecting specific nucleic acid sequences comprising:
(a) hybridizing a first sequence of a primary polynucleotide probe to a selectable target nucleic acid sequence wherein the primary probe has a means for binding to an amplification probe comprising a nucleic acid sequence adapted to permit enhanced detectable labelling, the amplification probe being capable of hybridizing to at least one labelling probe comprising a nucleic acid sequence conjugated to a chemical label;
(b) immobilizing the targe -probe complex;
(c) exposing the immobilized target-probe complex to said amplification probe, such probe comprising at least two regions of nucleic acid sequences: a first region including a sequence complementary to a sequence on a selected primary probe which also contains a sequence complementary to a sequence of said selected nucleic acid target, and a second region including a plurality of discretely labelable sequence units, under conditions that allows the amplification probe to hybridize to the target-probe complex;
(d) exposing the hybridized amplification probe to a labelling probe covalently attached to a detectable chemical label, such probe comprising sequences complementary to sequences on the amplification probe, under conditions that allow many labelling probes to hybridize to the amplification probe;
(e) observing the presence or absence of the detectable chemical label, covalently attached to said labelling probe, in association with the sample as indicating the presence or absence of the target sequence.
14. A method as claimed in Claim 13 wherein the means for immobilizing the probe-target complex involves an antibody reagent capable of binding to DNA/DNA, DNA/RNA or RNA/RNA duplexes formed between the selectable target sequence and the complementary primary probe sequence .
15. A method as claimed in Claim 14 wherein the antibody reagent is:
(i) selective for binding DNA/RNA hybrids wherein one of the probe and the sequence to be detected is DNA and the other is RNA; (ii) selective for binding RNA/RNA hybrids wherein both the probe and the sequence to be detected are RNA; or (iii) selective for binding intercalation complexes wherein the duplexes formed in the assay comprise a nucleic acid intercalator bound thereto in the form of intercalation complexes.
16. A method as claimed in Claim 13 wherein the detectable chemical label is selected from a enzymatically active group, a [flourescer] fluorescer, a chromophere, a luminescer, a specifically bindable ligand, or a radioscope.
17. A method as claimed in Claim 13 wherein a label attached to each said discretely labelable sequence units interacts with a reagent member of a label detection system to provide the detectable response.
18. The method as claimed in Claim 17 wherein the label is a substrate, cofactor, or inhibitor of an enzyme which is the [ember] member of the label detection system with which the label interacts to provide the detectable response.
19. The method as claimed in Claim 18 wherein the label is a substrate which is acted on by the enzyme to produce a colorimetric, fluorescent or luminescent signal.
20. The method as claimed in Claim 18 wherein the label is a prosthetic group of an enzyme and wherein the apoenzy e of such an enzyme is the [ember] member of the label detection system with which the label interacts to produce the catalytically active holoenzyme.
21. The method as claimed in Claim 20 wherein the prosthetic group is [FAD] flavin adenine dinucleotide and the apoenzyme is apo(glucose oxidase) .
22. The method as claimed in Claim 13 applied to the detection of a particular nucleic acid sequence in a test medium wherein the test medium comprises a biological sample which has been subjected to conditions to release and denature nucleic acids present therein.
23. A method as claimed in Claim 22 wherein the biological sample includes food substances and the target nucleic acid sequence is of a bacterial microorganism.
24. A method as claimed in Claim 22 wherein the biological sample includes food substances and the target nucleic acid sequence is of a virus. 53
25. A reagent for detecting a particular polynucleotide sequence in a test sample, comprising:
(i) a primary nucleic acid probe comprising at least one single stranded base sequence that is substantially complementary to the sequence to be detected; (ii) an antibody reagent capable of binding to hybrids formed between any of the particular polynucleotide sequences to be detected in the sample and the primary probe, but incapable of binding substantially to single stranded nucleic acids;
(iii) an amplification probe adapted to permit enhanced detectable labelling of a selected nucleic acid target, such probe comprising at least two regions of nucleic acid sequences: a first region including a sequence complementary to a sequence of said selected nucleic acid target, and a second region including a plurality of discreetly labelable sequence units;
(iv) a labelling probe covalently attached to a detectable chemical label, such probe comprising sequences complementary to sequences on the amplification probe.
26. The reagent system as claimed in Claim 2Scapable to converting double stranded nucleic acids in a test sample into single stranded form.
27. A diagnostic kit for detecting a particular polynucleotide sequence within a sample comprising:
(i) a primary nucleic acid probe comprising at least one single stranded base sequence that is substantially complementary to the sequence to be detected; (ii) an antibody reagent capable of binding to hybrids formed between any of the particular polynucleotide sequences to be detected in the sample and the primary probe, but incapable of binding substantially to single stranded nucleic acids;
(iii) an amplification probe adapted to permit enhanced detectable labelling of a selected nucleic acid target, such probe comprising at least two regions of nucleic acid sequences: a first region including a sequence complementary to a sequence on a selected primary probe which also contains a sequence complementary to a sequence of said selected nucleic acid target, and a second region including a plurality of discretely labelable sequence units;
(iv) a labelling probe covalently attached to a detectable chemical label, such probe comprising sequences complementary to sequences on the amplification probe.
28. The diagnostic kit of Claim 27 which additionally comprises a denaturation agent capable to converting double stranded nucleic acids in a test sample into single stranded form.
29. A diagnostic kit for the detection of Escheri c ia coli in a test sample comprising the diagnostic kit as claimed in Claim 27.
30. A diagnostic kit for the detection of Salmonella typhi in a test sample comprising the diagnostic kit as claimed in Claim 27.
31. A diagnostic kit for the detection of Lis teria monocytogenes in a test sample comprising the diagnostic kit as claimed in Claim 27.
Priority Applications (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8502671A JPH10508741A (en) | 1994-06-28 | 1995-06-27 | Amplification method for increasing sensitivity of nucleic acid-probe target hybrid detection |
| AT95922381T ATE188744T1 (en) | 1994-06-28 | 1995-06-27 | METHOD FOR INCREASING THE DETECTION SENSITIVITY OF NUCLEIC ACID HYBRIDS (TARGET/SAMPLE) |
| DE69514521T DE69514521D1 (en) | 1994-06-28 | 1995-06-27 | METHOD FOR INCREASING THE DETECTION SENSITIVITY OF NUCLEIC ACID HYBRIDS (TARGET / SAMPLE) |
| AU27099/95A AU2709995A (en) | 1994-06-28 | 1995-06-27 | Method of amplification for increasing the sensitivity of detecting nucleic acid-probe target hybrids |
| EP95922381A EP0770142B1 (en) | 1994-06-28 | 1995-06-27 | Method for increasing the sensitivity of detecting nucleic acid-probe target hybrids |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA2,126,952 | 1994-06-28 | ||
| CA2126952A CA2126952C (en) | 1994-06-28 | 1994-06-28 | Probe, kit, and method of amplification for increasing the sensitivity of nucleic acid hybridization assays |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| WO1996000795A2 WO1996000795A2 (en) | 1996-01-11 |
| WO1996000795A3 WO1996000795A3 (en) | 1996-02-22 |
| WO1996000795B1 true WO1996000795B1 (en) | 1996-05-02 |
Family
ID=4153909
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/CA1995/000369 WO1996000795A2 (en) | 1994-06-28 | 1995-06-27 | Method of amplification for increasing the sensitivity of detecting nucleic acid-probe target hybrids |
Country Status (8)
| Country | Link |
|---|---|
| US (1) | US5627030A (en) |
| EP (1) | EP0770142B1 (en) |
| JP (1) | JPH10508741A (en) |
| AT (1) | ATE188744T1 (en) |
| AU (1) | AU2709995A (en) |
| CA (1) | CA2126952C (en) |
| DE (1) | DE69514521D1 (en) |
| WO (1) | WO1996000795A2 (en) |
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| US7135312B2 (en) | 1993-04-15 | 2006-11-14 | University Of Rochester | Circular DNA vectors for synthesis of RNA and DNA |
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| WO1999024612A2 (en) * | 1997-11-06 | 1999-05-20 | Mosaic Technologies | Multiple sequential polynucleotide displacement reactions for signal amplification and processing |
| EP1038022B1 (en) * | 1997-12-12 | 2005-07-20 | Digene Corporation | Assessment of human papilloma virus-related disease |
| US6287772B1 (en) * | 1998-04-29 | 2001-09-11 | Boston Probes, Inc. | Methods, kits and compositions for detecting and quantitating target sequences |
| US6503747B2 (en) | 1998-07-14 | 2003-01-07 | University Of Hawaii | Serotype-specific probes for Listeria monocytogenes |
| JP2002525078A (en) | 1998-09-15 | 2002-08-13 | イェール ユニバーシティ | Artificial long terminal repeat |
| US6238927B1 (en) | 1998-10-05 | 2001-05-29 | Mosaic Technologies, Incorporated | Reverse displacement assay for detection of nucleic acid sequences |
| KR20010102992A (en) * | 1999-01-29 | 2001-11-17 | 추후보정 | Non-invasive method for detecting target rna |
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| US20030198966A1 (en) * | 2002-04-19 | 2003-10-23 | Stojanovic Milan N. | Displacement assay for detection of small molecules |
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| US7470516B2 (en) * | 2003-04-14 | 2008-12-30 | The Trustees Of Columbia University In The City Of New York | Cross reactive arrays of three-way junction sensors for steroid determination |
| US20040203007A1 (en) * | 2003-04-14 | 2004-10-14 | Stojanovic Milan N. | Cross reactive arrays of three-way junction sensors for steroid determination |
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| TWI417389B (en) * | 2008-10-27 | 2013-12-01 | Qiagen Gaithersburg Inc | Fast results hybrid capture assay on an automated platform |
| AU2009334505B2 (en) | 2008-12-31 | 2013-05-09 | Abbott Point Of Care Inc. | Method and device for immunoassay using nucleotide conjugates |
| EP2385979B1 (en) * | 2009-01-28 | 2017-08-16 | QIAGEN Gaithersburg, Inc. | Sequence-specific large volume sample preparation method and assay |
| JP5738278B2 (en) | 2009-05-01 | 2015-06-24 | キアジェン ゲイサーズバーグ インコーポレイテッド | Non-target amplification method for detecting RNA splicing morphology in a sample |
| AU2010291990B2 (en) | 2009-09-14 | 2016-05-05 | Qiagen Gaithersburg, Inc. | Compositions and methods for recovery of nucleic acids or proteins from tissue samples fixed in cytology media |
| CA2787924A1 (en) * | 2010-01-29 | 2011-08-04 | Qiagen Gaithersburg, Inc. | Methods and compositions for sequence-specific purification and multiplex analysis of nucleic acids |
| EP2529031B1 (en) | 2010-01-29 | 2014-07-09 | QIAGEN Gaithersburg, Inc. | Method of determining and confirming the presence of hpv in a sample |
| ES2606012T3 (en) * | 2010-02-26 | 2017-03-17 | Ventana Medical Systems, Inc. | In situ hybridization with PolyTag probes |
| CA2799200A1 (en) | 2010-05-19 | 2011-11-24 | Qiagen Gaithersburg, Inc. | Methods and compositions for sequence-specific purification and multiplex analysis of nucleic acids |
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| US9885092B2 (en) | 2011-02-24 | 2018-02-06 | Qiagen Gaithersburg Inc. | Materials and methods for detection of HPV nucleic acids |
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| EP2971104A2 (en) | 2013-03-15 | 2016-01-20 | Abbott Molecular Inc. | Method for amplification and assay of rna fusion gene variants, method of distinguishing same and related primers, probes, and kits |
| WO2016014240A2 (en) | 2014-07-24 | 2016-01-28 | Abbott Molecular Inc. | Compositions and methods for the detection and analysis of mycobacterium tuberculosis |
| US10526664B2 (en) | 2015-07-14 | 2020-01-07 | Abbott Molecular Inc. | Compositions and methods for identifying drug resistant tuberculosis |
| CN114480585B (en) * | 2020-10-28 | 2024-02-23 | 清华大学 | Nucleic acid probe composition, pretreatment liquid, nucleic acid detection kit and detection method |
| CN113025690B (en) * | 2021-05-27 | 2021-08-10 | 广东品博易视生物科技有限公司 | Nucleic acid probe group and application thereof |
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-
1994
- 1994-06-28 CA CA2126952A patent/CA2126952C/en not_active Expired - Fee Related
- 1994-07-15 US US08/275,849 patent/US5627030A/en not_active Expired - Lifetime
-
1995
- 1995-06-27 EP EP95922381A patent/EP0770142B1/en not_active Expired - Lifetime
- 1995-06-27 WO PCT/CA1995/000369 patent/WO1996000795A2/en active IP Right Grant
- 1995-06-27 JP JP8502671A patent/JPH10508741A/en not_active Ceased
- 1995-06-27 AU AU27099/95A patent/AU2709995A/en not_active Abandoned
- 1995-06-27 DE DE69514521T patent/DE69514521D1/en not_active Expired - Lifetime
- 1995-06-27 AT AT95922381T patent/ATE188744T1/en not_active IP Right Cessation
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