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US 9,790,552 B2Granted
Detection of organ rejection
AssigneeThe Brigham and Women's Hospital, Inc.
InventorMark W. Feinberg
Life of this patent
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Abstract
The present invention features methods and compositions for the non-invasive detection of organ rejection using a microRNA score.
Claims12
A method for identifying a subject as having, or having a propensity to develop, organ rejection, the method comprising:
- (i) transplanting an allogeneic organ into a subject in need thereof,
- (ii) measuring the expression of at least 20 miRNAs selected from the group consisting of:
- mmu-miR-134,
- (SEQ ID NO:
- 1)
- UGUGACUGGUUGACCAGAGGGG,
- mmu-miR-144,
- (SEQ ID NO:
- 2)
- UACAGUAUAGAUGAUGUACUAG,
- mmu-miR-466,
- (SEQ ID NO:
- 3)
- AUACAUACACGCACACAUAAGAC,
- mmu-miR-7,
- (SEQ ID NO:
- 4)
- UGGAAGACUAGUGAUUUUGUUG,
- mmu-miR-346,
- (SEQ ID NO:
- 5)
- UGUCUGCCCGAGUGCCUGCCUCU,
- mmu-miR-468,
- (SEQ ID NO:
- 6)
- UAUGACUGAUGUGCGUGUGUCU,
- mmu-miR-188,
- (SEQ ID NO:
- 7)
- CAUCCCUUGCAUGGUGGAGGGU,
- mmu-miR-298,
- (SEQ ID NO:
- 8)
- GGCAGAGGAGGGCUGUUCUUCC,
- mmu-miR-467,
- (SEQ ID NO:
- 9)
- AUAUACAUACACACACCUACAC,
- mmu-miR-292-5p,
- (SEQ ID NO:
- 10)
- ACUCAAACUGGGGGCUCUUUUG,
- mmu-miR-186,
- (SEQ ID NO:
- 11)
- CAAAGAAUUCUCCUUUUGGGCUU,
- mmu-miR-486,
- (SEQ ID NO:
- 12)
- UCCUGUACUGAGCUGCCCCGAG,
- mmu-miR-451,
- (SEQ ID NO:
- 13)
- AAACCGUUACCAUUACUGAGUU,
- mmu-miR-18,
- (SEQ ID NO:
- 14)
- UAAGGUGCAUCUAGUGCAGAUA,
- mmu-miR-25,
- (SEQ ID NO:
- 15)
- CAUUGCACUUGUCUCGGUCUGA,
- mmu-miR-223
- (SEQ ID NO:
- 16)
- UGUCAGUUUGUCAAAUACCCC,
- mmu-miR-320,
- (SEQ ID NO:
- 17)
- AAAAGCUGGGUUGAGAGGGCGAA,
- mmu-miR-148b,
- (SEQ ID NO:
- 18)
- UCAGUGCAUCACAGAACUUUGU,
- mmu-miR-21,
- (SEQ ID NO:
- 19)
- UAGCUUAUCAGACUGAUGUUGA,
- mmu-miR-124a,
- (SEQ ID NO:
- 20)
- UAAGGCACGCGGUGAAUGCC,
- mmu-miR-19a,
- (SEQ ID NO:
- 21)
- UGUGCAAAUCUAUGCAAAACUGA,
- mmu-miR-301
- (SEQ ID NO:
- 22)
- CAGUGCAAUAGUAUUGUCAAAGC,
- mmu-miR-31,
- (SEQ ID NO:
- 23)
- AGGCAAGAUGCUGGCAUAGCUG,
- mmu-miR-20,
- (SEQ ID NO:
- 24)
- UAAAGUGCUUAUAGUGCAGGUAG,
- mmu-miR-29c,
- (SEQ ID NO:
- 25)
- UAGCACCAUUUGAAAUCGGU,
- mmu-miR-148a,
- (SEQ ID NO:
- 26)
- UCAGUGCACUACAGAACUUUGU,
- mmu-miR-17-5p,
- (SEQ ID NO:
- 27)
- CAAAGUGCUUACAGUGCAGGUAGU,
- mmu-miR-185,
- (SEQ ID NO:
- 28)
- UGGAGAGAAAGGCAGUUC,
- mmu-miR-106a,
- (SEQ ID NO:
- 29)
- CAAAGUGCUAACAGUGCAGGUA,
- mmu-miR-106b,
- (SEQ ID NO:
- 30)
- UAAAGUGCUGACAGUGCAGAU,
- mmu-miR-375,
- (SEQ ID NO:
- 31)
- UUUGUUCGUUCGGCUCGCGUGA,
- mmu-miR-216,
- (SEQ ID NO:
- 32)
- UAAUCUCAGCUGGCAACUGUG,
- mmu-miR-217,
- (SEQ ID NO:
- 33)
- UACUGCAUCAGGAACUGACUGGAU,
- mmu-miR-200a,
- (SEQ ID NO:
- 34)
- UAACACUGUCUGGUAACGAUGU,
- mmu-miR-200b,
- (SEQ ID NO:
- 35)
- UAAUACUGCCUGGUAAUGAUGAC,
- mmu-miR-429,
- (SEQ ID NO:
- 36)
- UAAUACUGUCUGGUAAUGCCGU,
- mmu-miR-200c,
- (SEQ ID NO:
- 37)
- UAAUACUGCCGGGUAAUGAUGG,
- mmu-miR-141
- (SEQ ID NO:
- 38)
- UAACACUGUCUGGUAAAGAUGG,
- mmu-miR-148a,
- (SEQ ID NO:
- 39)
- UCAGUGCACUACAGAACUUUGU,
- mmu-miR-152,
- (SEQ ID NO:
- 40)
- UCAGUGCAUGACAGAACUUGGG,
- mmu-miR-182,
- (SEQ ID NO:
- 41)
- UUUGGCAAUGGUAGAACUCACA,
- mmu-miR-99a,
- (SEQ ID NO:
- 42)
- ACCCGUAGAUCCGAUCUUGU,
- mmu-miR-130a,
- (SEQ ID NO:
- 43)
- CAGUGC AAUGUU AAAAGGGC AU,
- mmu-miR-127,
- (SEQ ID NO:
- 44)
- UCGGAUCCGUCUGAGCUUGGC,
- mmu-miR-100,
- (SEQ ID NO:
- 45)
- AACCCGUAGAUCCGAACUUGUG,
- mmu-miR-199a,
- (SEQ ED NO:
- 46)
- CCCAGUGUUCAGACU ACCUGUUC,
- mmu-miR-199b,
- (SEQ ED NO:
- 47)
- CCCAGUGUUU AGACU ACCUGUUC,
- mmu-miR-125a,
- (SEQ ED NO:
- 48)
- UCCCUGAGACCCUUUAACCUGUG,
- mmu-miR-22,
- (SEQ ID NO:
- 49)
- AAGCUGCCAGUUGAAGAACUGU,
- mmu-miR-434-3p,
- (SEQ ID NO:
- 50)
- UUUGAACCAUCACUCGACUCC,
- mmu-miR-34a,
- (SEQ ID NO:
- 51)
- UGGCAGUGUCUUAGCUGGUUGUU,
- mmu-miR-181c,
- (SEQ ID NO:
- 52)
- AACAUUCAACCUGUCGGUGAGU,
- mmu-miR-139,
- (SEQ ID NO:
- 53)
- UCUACAGUGCACGUGUCU,
- mmu-miR-130a,
- (SEQ ID NO:
- 54)
- CAGUGCAAUGUUAAAAGGGCAU,
- mmu-miR-322,
- (SEQ ID NO:
- 55)
- CAGCAGCAAUUCAUGUUUUGGA,
- mmu-miR-181a,
- (SEQ ID NO:
- 56)
- AACAUUCAACGCUGUCGGUGAGU,
- mmu-miR-125a,
- (SEQ ID NO:
- 57)
- UCCCUGAGACCCUUUAACCUGUG,
- mmu-miR-200b,
- (SEQ ID NO:
- 58)
- UAAUACUGCCUGGUAAUGAUGAC,
- mmu-miR-145,
- (SEQ ID NO:
- 59)
- GUCCAGUUUUCCCAGGAAUCCCUU,
- mmu-miR-127,
- (SEQ ID NO:
- 60)
- UCGGAUCCGUCUGAGCUUGGC,
- mmu-miR-199a,
- (SEQ ID NO:
- 61)
- CCCAGUGUUCAGACUACCUGUUC,
- mmu-miR-425,
- (SEQ ID NO:
- 62)
- AUCGGGAAUGUCGUGUCCGCC,
- mmu-miR-99b,
- (SEQ ID NO:
- 63)
- CACCCGU AGAACCGACCUUGCG,
- mmu-let-7e,
- (SEQ ID NO:
- 64)
- UGAGGUAGGAGGUUGUAUAGU,
- mmu-miR-195,
- (SEQ ID NO:
- 65)
- UAGCAGCACAGAAAUAUUGGC,
- mmu-miR-152,
- (SEQ ID NO:
- 66)
- UCAGUGCAUGACAGAACUUGGG,
- mmu-miR-125b,
- (SEQ ID NO:
- 67)
- UCCCUGAGACCCUAACUUGUGA,
- mmu-miR-187,
- (SEQ ID NO:
- 68)
- UCGUGUCUUGUGUUGCAGCCGG,
- mmu-miR-324-3p,
- (SEQ ID NO:
- 69)
- CCACUGCCCCAGGUGCUGCUGG,
- mmu-miR-150,
- (SEQ ID NO:
- 70)
- UCUCCCAACCCUUGUACCAGUG,
- mmu-miR-28,
- (SEQ ID NO:
- 71)
- AAGGAGCUCACAGUCUAUUGAG,
- and
- mmu-miR-143
- (SEQ ID NO:
- 72)
- UGAGAUGAAGCACUGUAGCUCA,
- in a biological sample from the subject, and
- (ii) calculating altered expression of the at least 20 miRNAs relative to a reference, thereby identifying a subject as having, or having a propensity to develop, organ rejection.
290 more elements
A method for hybridizing one or more microRNAs in a sample, the method comprising:
- (i) amplifying at least one miRNA obtained from a biological sample and selected from the group consisting of:
- mmu-miR-134,
- (SEQ ID NO:
- 1)
- UGUGACUGGUUGACCAGAGGGG,
- mmu-miR-144,
- (SEQ ID NO:
- 2)
- UACAGUAUAGAUGAUGUACUAG,
- mmu-miR-466,
- (SEQ ID NO:
- 3)
- AUACAUACACGCACACAUAAGAC,
- mmu-miR-7,
- (SEQ ID NO:
- 4)
- UGGAAGACUAGUGAUUUUGUUG,
- mmu-miR-346,
- (SEQ ID NO:
- 5)
- UGUCUGCCCGAGUGCCUGCCUCU,
- mmu-miR-468,
- (SEQ ID NO:
- 6)
- UAUGACUGAUGUGCGUGUGUCU,
- mmu-miR-188,
- (SEQ ID NO:
- 7)
- CAUCCCUUGCAUGGUGGAGGGU,
- mmu-miR-298,
- (SEQ ID NO:
- 8)
- GGCAGAGGAGGGCUGUUCUUCC,
- mmu-miR-467,
- (SEQ ID NO:
- 9)
- AUAUACAUACACACACCUACAC,
- mmu-miR-292-5p,
- (SEQ ID NO:
- 10)
- ACUCAAACUGGGGGCUCUUUUG,
- mmu-miR-186,
- (SEQ ID NO:
- 11)
- CAAAGAAUUCUCCUUUUGGGCUU,
- mmu-miR-486,
- (SEQ ID NO:
- 12)
- UCCUGUACUGAGCUGCCCCGAG,
- mmu-miR-451,
- (SEQ ID NO:
- 13)
- AAACCGUUACCAUUACUGAGUU,
- mmu-miR-18,
- (SEQ ID NO:
- 14)
- UAAGGUGCAUCUAGUGCAGAUA,
- mmu-miR-25,
- (SEQ ID NO:
- 15)
- CAUUGCACUUGUCUCGGUCUGA,
- mmu-miR-223
- (SEQ ID NO:
- 16)
- UGUCAGUUUGUCAAAUACCCC,
- mmu-miR-320,
- (SEQ ID NO:
- 17)
- AAAAGCUGGGUUGAGAGGGCGAA,
- mmu-miR-148b,
- (SEQ ID NO:
- 18)
- UCAGUGCAUCACAGAACUUUGU,
- mmu-miR-21,
- (SEQ ID NO:
- 19)
- UAGCUUAUCAGACUGAUGUUGA,
- mmu-miR-124a,
- (SEQ ID NO:
- 20)
- UAAGGCACGCGGUGAAUGCC,
- mmu-miR-19a,
- (SEQ ID NO:
- 21)
- UGUGCAAAUCUAUGCAAAACUGA,
- mmu-miR-301
- (SEQ ID NO:
- 22)
- CAGUGCAAUAGUAUUGUCAAAGC,
- mmu-miR-31,
- (SEQ ID NO:
- 23)
- AGGCAAGAUGCUGGCAUAGCUG,
- mmu-miR-20,
- (SEQ ID NO:
- 24)
- UAAAGUGCUUAUAGUGCAGGUAG,
- mmu-miR-29c,
- (SEQ ID NO:
- 25)
- UAGCACCAUUUGAAAUCGGU,
- mmu-miR-148a,
- (SEQ ID NO:
- 26)
- UCAGUGCACUACAGAACUUUGU,
- mmu-miR-17-5p,
- (SEQ ID NO:
- 27)
- CAAAGUGCUUACAGUGCAGGUAGU,
- mmu-miR-185,
- (SEQ ID NO:
- 28)
- UGGAGAGAAAGGCAGUUC,
- mmu-miR-106a,
- (SEQ ID NO:
- 29)
- CAAAGUGCUAACAGUGCAGGUA,
- mmu-miR-106b,
- (SEQ ID NO:
- 30)
- UAAAGUGCUGACAGUGCAGAU,
- mmu-miR-375,
- (SEQ ID NO:
- 31)
- UUUGUUCGUUCGGCUCGCGUGA,
- mmu-miR-216,
- (SEQ ID NO:
- 32)
- UAAUCUCAGCUGGCAACUGUG,
- mmu-miR-217,
- (SEQ ID NO:
- 33)
- UACUGCAUCAGGAACUGACUGGAU,
- mmu-miR-200a,
- (SEQ ID NO:
- 34)
- UAACACUGUCUGGUAACGAUGU,
- mmu-miR-200b,
- (SEQ ID NO:
- 35)
- UAAUACUGCCUGGUAAUGAUGAC,
- mmu-miR-429,
- (SEQ ID NO:
- 36)
- UAAUACUGUCUGGUAAUGCCGU,
- mmu-miR-200c,
- (SEQ ID NO:
- 37)
- UAAUACUGCCGGGUAAUGAUGG,
- mmu-miR-141
- (SEQ ID NO:
- 38)
- UAACACUGUCUGGUAAAGAUGG,
- mmu-miR-148a,
- (SEQ ID NO:
- 39)
- UCAGUGCACUACAGAACUUUGU,
- mmu-miR-152,
- (SEQ ID NO:
- 40)
- UCAGUGCAUGACAGAACUUGGG,
- mmu-miR-182,
- (SEQ ID NO:
- 41)
- UUUGGCAAUGGUAGAACUCACA,
- mmu-miR-99a,
- (SEQ ID NO:
- 42)
- ACCCGUAGAUCCGAUCUUGU,
- mmu-miR-130a,
- (SEQ ID NO:
- 43)
- CAGUGC AAUGUU AAAAGGGC AU,
- mmu-miR-127,
- (SEQ ID NO:
- 44)
- UCGGAUCCGUCUGAGCUUGGC,
- mmu-miR-100,
- (SEQ ID NO:
- 45)
- AACCCGUAGAUCCGAACUUGUG,
- mmu-miR-199a,
- (SEQ ED NO:
- 46)
- CCCAGUGUUCAGACU ACCUGUUC,
- mmu-miR-199b,
- (SEQ ED NO:
- 47)
- CCCAGUGUUU AGACU ACCUGUUC,
- mmu-miR-125a,
- (SEQ ED NO:
- 48)
- UCCCUGAGACCCUUUAACCUGUG,
- mmu-miR-22,
- (SEQ ID NO:
- 49)
- AAGCUGCCAGUUGAAGAACUGU,
- mmu-miR-434-3p,
- (SEQ ID NO:
- 50)
- UUUGAACCAUCACUCGACUCC,
- mmu-miR-34a,
- (SEQ ID NO:
- 51)
- UGGCAGUGUCUUAGCUGGUUGUU,
- mmu-miR-181c,
- (SEQ ID NO:
- 52)
- AACAUUCAACCUGUCGGUGAGU,
- mmu-miR-139,
- (SEQ ID NO:
- 53)
- UCUACAGUGCACGUGUCU,
- mmu-miR-130a,
- (SEQ ID NO:
- 54)
- CAGUGCAAUGUUAAAAGGGCAU,
- mmu-miR-322,
- (SEQ ID NO:
- 55)
- CAGCAGCAAUUCAUGUUUUGGA,
- mmu-miR-181a,
- (SEQ ID NO:
- 56)
- AACAUUCAACGCUGUCGGUGAGU,
- mmu-miR-125a,
- (SEQ ID NO:
- 57)
- UCCCUGAGACCCUUUAACCUGUG,
- mmu-miR-200b,
- (SEQ ID NO:
- 58)
- UAAUACUGCCUGGUAAUGAUGAC,
- mmu-miR-145,
- (SEQ ID NO:
- 59)
- GUCCAGUUUUCCCAGGAAUCCCUU,
- mmu-miR-127,
- (SEQ ID NO:
- 60)
- UCGGAUCCGUCUGAGCUUGGC,
- mmu-miR-199a,
- (SEQ ID NO:
- 61)
- CCCAGUGUUCAGACUACCUGUUC,
- mmu-miR-425,
- (SEQ ID NO:
- 62)
- AUCGGGAAUGUCGUGUCCGCC,
- mmu-miR-99b,
- (SEQ ID NO:
- 63)
- CACCCGU AGAACCGACCUUGCG,
- mmu-let-7e,
- (SEQ ID NO:
- 64)
- UGAGGUAGGAGGUUGUAUAGU,
- mmu-miR-195,
- (SEQ ID NO:
- 65)
- UAGCAGCACAGAAAUAUUGGC,
- mmu-miR-152,
- (SEQ ID NO:
- 66)
- UCAGUGCAUGACAGAACUUGGG,
- mmu-miR-125b,
- (SEQ ID NO:
- 67)
- UCCCUGAGACCCUAACUUGUGA,
- mmu-miR-187,
- (SEQ ID NO:
- 68)
- UCGUGUCUUGUGUUGCAGCCGG,
- mmu-miR-324-3p,
- (SEQ ID NO:
- 69)
- CCACUGCCCCAGGUGCUGCUGG,
- mmu-miR-150,
- (SEQ ID NO:
- 70)
- UCUCCCAACCCUUGUACCAGUG,
- mmu-miR-28,
- (SEQ ID NO:
- 71)
- AAGGAGCUCACAGUCUAUUGAG,
- and
- mmu-miR-143
- (SEQ ID NO:
- 72)
- UGAGAUGAAGCACUGUAGCUCA,
- in the presence of one or more fluorescent nucleotides to generate one or more labeled cDNAs, wherein the biological sample is obtained from a subject having a transplanted organ,
- (ii) contacting the one or more labeled cDNAs with one or more complementary oligonucleotides bound to a microarray, and
- (ii) detecting conformational changes in the cDNA by detecting the presence of at least one hybridization product, wherein the at least one hybridization product is detected using a signal from the fluorescent nucleotides.
290 more elements
Dependencies are inferred from the claim text.