PT2529032T - Métodos e composições para diagnóstico pré-natal não invasivo de aneuploidias fetais - Google Patents

Métodos e composições para diagnóstico pré-natal não invasivo de aneuploidias fetais Download PDF

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PT2529032T
PT2529032T PT117094656T PT11709465T PT2529032T PT 2529032 T PT2529032 T PT 2529032T PT 117094656 T PT117094656 T PT 117094656T PT 11709465 T PT11709465 T PT 11709465T PT 2529032 T PT2529032 T PT 2529032T
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seq
dna
sample
methylation
regions
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C Patsalis Philippos
A Papageorgiou Elisavet
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Nipd Genetics Ltd
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    • 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
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    • 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
    • C12Q1/6804—Nucleic acid analysis using immunogens
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    • 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
    • C12Q1/6806—Preparing nucleic acids for analysis, e.g. for polymerase chain reaction [PCR] assay
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    • 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
    • C12Q1/6809—Methods for determination or identification of nucleic acids involving differential detection
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    • 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
    • C12Q1/6844—Nucleic acid amplification reactions
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/154—Methylation markers

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Claims (15)

  1. REIVINDICAÇÕES
    1. Método para o diagnóstico pré-natal de uma trissomia 21 utilizando uma amostra de sangue materno, compreendendo o método: a) enriquecimento do ADN metilado numa amostra de sangue materno contendo uma mistura de ADN fetal e materno por metilação por imunoprecipitação de ADN (MeDIP) para obter uma amostra enriquecida para ADN metilado; b) determinar o nível de metilação das regiões de ADN cromossómico mostrado em SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 42, SEQ ID NO: 43 e SEQ ID NO: 44; c) comparação do valor de metilação das regii^s do passo (b) com um valor padronizado de metilação de referência para as referidas regiões, em que o valor padronizado de metilação de referência é (i) um valor para uma amostra de ADN de uma mulher que é portadora dum feto sem trissomia 21; ou (ii) um valor para uma amostra de ADN de uma mulher portadora de um feto com trissomia 21; d) diagnosticar uma trissomia 21 com base na referida comparação, em que a trissomia 21 é diagnosticada se o valor de metilação da amostra for (i) superior ao valor de metilação de referência padronizado de uma mulher portadora de um feto sem trissomia 21; ou ii) comparável ao valor normalizado de metilação de referência de uma mulher que é portadora dum feto com trissomia 21.
  2. 2. Método de acordo com a reivindicação 1, em que a amostra de sangue materno é uma amostra de sangue periférico materno ou uma porção fracionada de sangue periférico materno.
  3. 3. Método de acordo com a reivindicação 1 ou 2, em que o ADN metilado enriquecido é amplificado antes da realização da análise da proporção de metilação do ADN.
  4. 4. Método de acordo com a reivindicação 3, em que o ADN metilado é amplificado por ligação mediada por reação em cadeia da polimerase (LM-PCR) e em que os níveis das duas ou mais regiões são opcionalmente determinados numa amostra total de ADN de sangue materno não tratado como controlo de eficiência de LM-PCR.
  5. 5. Método de acordo com qualquer uma das reivindicações anteriores, em que os níveis das regiões da amostra enriquecida para ADN metilado são determinados por reação em cadeia da polimerase em tempo real (QPCR em tempo real).
  6. 6. Método de acordo com qualquer uma das reivindicações anteriores, em que o método compreende ainda a determinação da metilação de, pelo menos, uma das regiões de ADN cromossómico escolhido de entre as listas apresentadas no Apêndice A.
  7. 7. Método de acordo com qualquer uma das reivindicações anteriores, em que os níveis de metilação são determinados para, pelo menos, oito ou dez regiões metiladas diferencialmente (DMR).
  8. 8. Método de acordo com qualquer uma das reivindicações anteriores, em que o método compreende ainda a determinação da metilação de uma ou mais regiões de ADN cromossómico selecionado do grupo que consiste em SEQ ID NO: 33, SEQ ID NO: 34 e SEQ ID NO: 35.
  9. 9. Composição compreendendo um par/conjunto de iniciadores oligonucleotídicos que amplificam seletivamente a SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO : 42, SEQ ID NO: 43 e SEQ ID NO: 44 .
  10. 10. Composição de acordo com a reivindicação 9, em que o par/conjunto de iniciadores oligonucleotídicos são selecionados de: CTGTTGCATGAGAGCAGAGG (SEQ ID NO: 7) e CGTCCCCCTCGCTACTATCT (SEQ ID NO: 8); TGCAGGATATTTGGCAAGGT (SEQ ID NO: 9) e CTGTGCCGGTAGAAATGGTT (SEQ ID NO: 10); TGAATCAGTTCACCGACAGC (SEQ ID NO: 11) e GAAACAACCTGGCCATTCTC (SEQ ID NO: 12); CCGTTATATGGATGCCTTGG (SEQ ID NO: 13) e AAACTGTTGGGCTGAACTGC (SEQ ID NO: 14); CCAGGCAAGATGGCTTATGT (SEQ ID NO: 15) e ACCATGCTCAGCCAATTTTT (SEQ ID NO: 16); GACCCAGACGATACCTGGAA (SEQ ID NO: 17) e GCTGAACAAAACTCGGCTTC (SEQ ID NO: 18); CCACATCCTGGCCATCTACT (SEQ ID NO: 19) e T T CCACAGACAGCAGAGACG (SEQ ID NO: 20); TGAGCTCACAGGTCTGGAAA (SEQ ID NO: 21) e CCCCACAGGGTTCTGGTAAT (SEQ ID NO: 22); E ATTCTCCACAGGGCAATGAG (SEQ ID NO: 23) e TTATGTGGCCTTTCCTCCTG (SEQ ID NO: 24).
  11. 11. Composição de acordo com a reivindicação 10, que compreende ainda um ou mais pares/conjuntos de iniciadores oligonucleotídicos selecionados de: GCTGGACCAGAAAGTGTTAGAG (SEQ ID NO: 1) e GTGTGCTGCTTTGCAATGTG (SEQ ID NO: 2); GGTCGAGTTTTTGGTGGTGT (SEQ ID NO: 3) e CCACCGTCACTGTTCCTAGA (SEQ ID NO: 4); E CCTCGTGCTCGTGTCTGTAT (SEQ ID NO: 5) e GAGGAAACAGCTTGGCTCTG (SEQ ID NO: 6).
  12. 12. Composição compreendendo sondas de ácido nucleico que detetam seletivamente a SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 42, SEQ ID NO: 43 e SEQ ID NO: 44.
  13. 13. Kit compreendendo a composição de qualquer uma das reivindicações 9 a 11 e um anticorpo que imunoprecipita p ADN metilado.
  14. 14. Kit compreendendo a composição da reivindicação 12 e um anticorpo que imunoprecipita o ADN metilado.
  15. 15. Kit de acordo com a reivindicação 13 ou 14, que compreende ainda ligantes oligonucleotídicos ou outros iniciadores oligonucleotídicos para realizar a ligação mediada por reação em cadeia da polimerase (LM-PCR).
PT117094656T 2010-01-26 2011-01-26 Métodos e composições para diagnóstico pré-natal não invasivo de aneuploidias fetais PT2529032T (pt)

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US (1) US9249462B2 (pt)
EP (1) EP2529032B1 (pt)
JP (1) JP2013517789A (pt)
KR (1) KR20120107512A (pt)
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AU (1) AU2011210255B2 (pt)
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JP2013517789A (ja) 2013-05-20
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KR20120107512A (ko) 2012-10-02
EA023565B1 (ru) 2016-06-30
WO2011092592A3 (en) 2011-11-03
ES2623156T3 (es) 2017-07-10
AU2011210255A1 (en) 2012-07-26
EP2529032A2 (en) 2012-12-05
CY1118864T1 (el) 2018-01-10
EP2529032B1 (en) 2017-01-25
CA2786174A1 (en) 2011-08-04
EA201290716A1 (ru) 2013-06-28
CN102892899A (zh) 2013-01-23
US9249462B2 (en) 2016-02-02
AU2011210255B2 (en) 2014-11-20
SG182322A1 (en) 2012-08-30
DK2529032T3 (en) 2017-05-01
NZ601079A (en) 2014-08-29
US20120282613A1 (en) 2012-11-08

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