CN1469932A - 非侵入的出生前监测 - Google Patents
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Abstract
本发明的具体实施方式涉及怀孕母体血液样品中胎儿或母体RNA的检测,并且涉及将样品进行测试,寻找其中指示胎儿或母亲的状况或特征的胎儿或母亲的分析指标。例如RNA分析可以包括通过分析母亲血液样品而对未出生的胎儿的基因表达模式进行评价。首先利用出生前监测技术仅通过分析母亲血液样品就可检测胎儿表达的基因。在特定的实施方案中,出生前监测技术是基于发现了在怀孕妇女血浆中胎儿来源的RNA的循环。总之,对怀孕妇女的血清或血浆样品的检测方法包括测定样品中胎儿或母亲来源的RNA的存在。
Description
发明背景
本发明涉及利用非侵入技术的出生前检测方法,尤其是怀孕个体的血液样品中胎儿或母亲的RNA的检测,包括通过分析血液样品对未出生胎儿的基因表达模式进行评价。
我们以前描述了对母体血浆和血清中循环胎儿DNA的检测,如Y.M.Dennis Lo等人在Lancet 1997,350:485-7,杂志上的文章“母体血浆和血清中存在胎儿DNA”,我们已经证明了这种技术在非侵入出生前诊断中的用途。Y.M.Dennis Lo等人在新英格兰医学杂志(New England Journalof Medicine 1998,339:1734-8)上的“通过母体血浆的分子分析进行胎儿的RhD状态的出生前诊断”一文。胎儿DNA在母体血浆中的发现为出生前分子诊断打开了新的视野。自从那时以来,许多研究小组证明可以通过母体血浆中的胎儿DNA来测定胎儿遗传性状,如RhD状态和遗传疾病。
现有技术的主要限制是:胎儿DNA测定只能使人知道母体循环中存在胎儿来源的遗传物质和数量,并不能给出关于婴儿基因表达概况的信息,预期基因表达模式可能受影响母体和婴儿的生理和病理过程的影响,常规的非侵入技术不能做到直接监测胎儿基因表达。
发明概要
本发明的实施方案涉及怀孕个体血液样品中母体或胎儿的RNA的检测,也包括将样品进行显示胎儿或母体状况或特性的胎儿或母体分析指标的测试。比如:RNA分析包括通过分析母体血液样品,评价未出生胎儿的基因表达模式。本发明的用处在怀孕的第二个三月和第三个三月开始显示,可以广泛的用于疾病的诊断和监测,包括惊阙前期和提前分娩。
本发明实施方案中的新的出生前监测技术第一次实现了仅通过分析母体血液样品测定胎儿基因的表达。本发明将成为非侵入方法进行出生前测定的新的一代平台技术。
出生前监测技术基于在怀孕妇女血浆中发现循环的胎儿RNA,此前,人们并不知道胎儿RNA也存在于母体血浆中,应用两步的逆转录酶聚合酶链反应(RT-PCR)技术,我们证明胎儿来源的、男性特有的mRNA存在于怀男孩的妇女血浆中。正如在此描述的,胎儿RNA可以被RT-PCR技术测定,但原则上,可以使用任何RNA测定方法。
预期该技术可以在所有怀孕的情况中测定胎儿的生理或病理状况。在特定情况下,在怀孕期间令人满意的或者必要的是进行一次以上的这样的监测,因此潜在客户的数量和多次使用的可能性是巨大的。
按照本发明的一个方面,出生前监测或测定怀孕的人的血样的方法,包括从血样中除去所有的或基本上所有的有核和无核的细胞群以获得剩余的材料,剩余的材料用于测试胎儿或母体的RNA分析指标,以显示母体或胎儿的状况或特征,剩余的材料包括血浆或血清。
按照本发明的另一个方面,测定怀孕妇女母体血清或血浆样品的检测方法包括测定样品中存在的胎儿RNA。扩增胎儿RNA以促进检测样品中存在的胎儿来源的RNA。例如胎儿RNA可能被反转录酶转变为cDNA,然后通过聚合酶链反应来测定。
在一些具体实施方案中,用序列特异性的探针来测定胎儿RNA。RNA的测定包括测定从Y染色体转录来的胎儿的RNA的存在,或者测定从母亲或父亲遗传来的基因或其他DNA序列转录而来的胎儿RNA。可用任何一种物理方法、免疫方法和生化方法测定RNA。
按照本发明的另一个方面,测定怀孕妇女血清或血浆样品的检测方法包括检测样品中胎儿或母体来源的RNA的存在。RNA检测可能包括检测从染色体6中的基因转录来的RNA的存在,此RNA可能从HLA-G基因转录而来。
本发明的另一个方面涉及进行出生前监测或测试的方法。该方法包括提供母体血液样品、将样品分离为细胞占优势的组分(组分1)和非细胞占优势的组分(组分2)。在组分2中可以检测到胎儿来源的RNA的存在。该方法进一步包括了基于所测定RNA的存在、数量、浓度、序列、和生化成分中至少一种作出诊断。
按照本发明的另一个方面,对母体血液样品进行出生前监测或测试的方法包括获得母体血液样品的非细胞组分和对此组分中人类基因表达的RNA分析。
附图简述
附图1是本发明的实施方案中描述的非侵入出生前监测方法的流程图。
附图2按照本发明的实施方案中描述的母体血浆中胎儿来源的Y染色体特异性的锌指蛋白(ZFY)mRNA的检测,和针对HLA-G mRNA的RT-PCR测试。
特定的实施方案的描述
如附图1所示,按照本发明的实施方案,对由怀孕母体获得的血液样品进行出生前监测或测试的方法首先是提供血液样品(步骤10),在步骤14中,所有的或基本上所有的有核细胞和无核细胞群被从血液样品中除去,步骤18中将剩下的材料用于胎儿或母体RNA分析指标的测试,以显示胎儿或母亲的状况或特征。用于RNA分析的剩下的材料可能是细胞物质或非细胞物质。在特定的实施方式中,剩余的材料可能包括血浆或血清。血清可能由母体血液样品凝块而获得。
对母体的血清或血浆样品进行测试以检测样品中胎儿或母体来源的RNA的存在。为了促进样品中的RNA检测,可以将RNA扩增。在一个例子中,胎儿或母体RNA由反转录酶转变为cDNA,然后经PCR扩增后测定。扩增胎儿或母体RNA可能包括使用胎儿或母体的至少一个序列特异性寡核苷酸。
用一个序列特异性探针可能测定胎儿或母体的RNA。在一个实施例中,存在的胎儿RNA的测定包括测定从Y染色体转录来的胎儿RNA,更具体地说,胎儿RNA可能被从ZFY基因转录。样品中的胎儿来源的RNA可以测定胎儿的性别。在另一个实施例中,测定样品中胎儿来源的RNA的存在包括测定从父亲遗传来的基因或其他DNA序列而来的胎儿RNA。在另一个例子中,测定样品中母亲或胎儿来源的RNA的存在包括测定从染色体6中的基因转录来的RNA的存在,此RNA可能从HLA-G基因中转录而来。用一个或多个物理的、免疫和生化的方法可以测定RNA。
在另外的例子中,母亲的或胎儿的RNA的测定和分析用母亲的血液样品的非细胞组分进行。非细胞组分完全是非细胞或非细胞占优势的,通过分离血液样品中所有的或占优势的细胞组分而获得。RNA分析包括基于测定RNA的存在、数量、浓度、序列、生化组成中的一种或多种给出的诊断。在一个特定的实施例中,对在样品中非细胞组分中表达的人类基因进行RNA分析。
应该说明的是:过滤血液样品、除去所有细胞材料、得到血浆或血清(即:血液中无细胞组分占优势),对此样品仍能进行胎儿或母亲的RNA测定和分析。
如下的例子描述本发明的各种特征,并不以任何形式限制本发明的范围。
在该例子中,在知情同意的情况下,怀孕妇女在产科和妇科医学系、威尔士王子医院、香港等参加出生前诊断试验。临床研究伦理委员会批准了此项研究,21个怀孕早期和37个怀孕晚期的妇女参加了试验,怀孕早期的平均的怀孕时间为16周(范围从11-19周),晚期的平均为33周(范围为26-40周)。所有的早期怀孕样品都是在侵入过程之前获得,另一方面,怀孕晚期的样品或者是从在怀孕早期(n=21)做过侵入过程的妇女获得的,或者是从没有进行任何出生前侵入步骤(n=16)的妇女获得的。所有的血浆样品都是30分钟内从EDTA血液样品获得的,参照Y.M.Dennis Lo等人在《手术刀》(1997,350:485-7)中的文章“胎儿DNA在母体血浆和血清中出现”,按照生产者的说明,血浆中的所有的RNA用Trizol LS试剂(Gibco BRL)分离,一般来说,1mL血浆中分离得RNA被溶解在50uL不含RNA酶的水中。
在本研究中,我们选择测定母亲血浆中的胎儿来源的、Y染色体特异性的锌指蛋白mRNA,参照D.C.page等人“人类Y染色体上性别决定区编码锌指蛋白”(《细胞》杂志1987,51:1091-104),M.S.Palmer等人“人类ZFY和ZFX转录物的比较”(美国科学院年报1990,87:1681-5),如图2,只有当怀男孩的妇女胎盘总RNA用于RT-PCR测定时,可以观察到对应于ZFY mRNA的RT-PCR产物(图2,1泳道)。相反,当反转录(RT)被省略,没有出现阳性信号(图2,2泳道),当女性的胎盘总RNA用于RT-PCR检测时,也没有阳性信号(图2,3泳道)。在怀孕晚期的怀男孩的20个妇女中,13个妇女的血浆样品中检测到了ZFY阳性信号(图2,中间泳道,6-10泳道)。在怀孕早期的怀男孩的妇女中,9个当中的2个检测到了阳性信号。阳性反应中的ZFY mRNA特异性的RF-PCR产物在DNA测序中也得到了证实(数据没有示出)。通过比较,20个怀女孩的妇女,无论是12个怀孕早期的,还是8个怀孕晚期的,除一个之外,所有测试都是阴性反应(图2,中间泳道,11-14泳道)唯一一个假阳性的反应推测是由于RNA加工过程的污染,作为提取的RNA质量的对照,我们将所有样品进行RT-PCR测定以检测HLA-GmRNA,参照T.V.F.Hviid等人,“人类前三个月胚胎滋养层HLA-G基因共显性表达和各种剪切形式的HLA-G mRNA”(Hum.Immunol,1998,59:87-98)。HLA-G基因在胎儿(比如滋养层,参照id.)和母体组织中(比如淋巴细胞,参照M.Kirszenbaum等人)都有表达.“人类滋养层的作为选择的HLA-GmRNA的剪切形式和HLA-G转录物在成人淋巴细胞中存在的证据”(美国科学院年报,1994,91:4209-13)。如图2底下的泳道,HLA-G mRNA的RT-PCR产物在所有的血浆样品中都检测到了,表明这些样品中存在可扩增RNA的。
最近证明,一定比例的母体血浆中的胎儿DNA以完整的胎儿细胞的形式在血液中循环,参照I.J.vzn Wijk等人的“怀孕妇女血浆中的编程性死亡的胎儿细胞的测定[技术简介]”(Clin.Chem.2000,46:729-31).所以我们测定到的胎儿RNA是从血浆中的细胞而来的,这在理论上很可能。为了最终验证是否胎儿RNA以无细胞的形式参与母体的循环,母体血浆样品通过0.2um的膜(Nalgene)过滤,从过滤血浆中的提取的RNA用于ZFY RT-PCR测定。在9个怀孕晚期的怀男孩的妇女的过滤过的血浆样品中,6个样品中检测到了阳性的ZFY mRNA信号(数据没有示出),这个结果显示,至少一部分胎儿RNA在母体血浆中是非细胞形式出现的。
我们的数据显示:胎儿RNA可以在母体血浆中测定到,在早期和晚期怀孕的妇女的血浆中测定到胎儿RNA的比率分别为22%和63%。在怀孕早期妇女的血浆中检测到RNA的比率比怀孕晚期的要低,说明血浆中胎儿RNA的浓度在怀孕早期比较低。这一发现和我们以前的发现相似,即母体血浆中的胎儿DNA浓度随着怀孕时间增加而增加。参照Y.M.Dennis Lo等人“母体血浆和血清中胎儿DNA的分析:非侵入的出生前诊断”(Am.J.Hum.Genet 1998,62:768-75)。我们意识到,血浆中所测定到的胎儿RNA的比率低于DNA的比率,很可能是胎儿RNA在母体血液中更容易降解,所以血浆中的胎儿RNA的数量要少于DNA的数量。在怀男孩的妇女血浆样品中测定到了Y染色体的DNA(数据没有示出),这一点也可以支持上述观点。高灵敏度的实时数量RT-PCR测定可以用于改进母体血浆胎儿RNA的测定的灵敏度。
总之,我们的试验第一次表明:母体血浆中可以测定到胎儿RNA,我们的数据为非侵入出生前诊断提供了新的方法。血浆胎儿DNA分析为在母体循环中存在的胎儿遗传物质的和浓度提供了数据。此外,血浆中的胎儿RNA分析可以为胎儿组织的基因表达模式提供有价值的信息。不正常的怀孕,比如惊阙前期就和胎儿组织中不正常的基因表达模式相关。B.K.Rinehart等人“胎盘细胞因子肿瘤坏死因子α,白介素1β和白介素10在惊阙前期表达量增加”(Am.J.Obstet.Gynecol 1999,181:915-20)。所以随着进一步的RNA标记的研制,母体血浆RNA分析使得在许多生理和病理状况下的非侵入的胎儿基因表达实现。很明白的是,在这里用的术语“血浆胎儿RNA分析”包括母体血浆或血清中胎儿RNA分析。
以上描述的仪器和方法的安排仅仅描述了本发明原理的应用,正像权利要求所述的,在不改变本发明的主旨和范围的情况下,可以有许多其他具体实施方案和改变。比如当我们展示了概念的可行性,进一步的研究可能阐明本技术应用的条件范围。此外,可以对此技术进一步的改善,比如在遵循本发明范围的情况下提高本方法的可靠性。本发明的范围不应按照以上描述确定,而应该按照附带的权利要求和等同物的全部的范围来确定。
Claims (27)
1.对怀孕个体的血液样品进行胎儿出生前监测或测试的方法,该方法包括:
从血液样品中除去所有或基本上所有的有核细胞和无核细胞群,得到剩余的材料,并且
将剩余的材料进行测试,以显示胎儿或母体的状况或特征的胎儿或母体RNA分析指标。
2.根据权利要求1所述的方法,其中从血液样品中除去所有的有核细胞和无核细胞群以得到剩余的材料。
3.根据权利要求1所述方法,其中剩余的材料包括非细胞物质,并且RNA分析是对剩余材料中的非细胞物质进行的。
4.根据权利要求1所述方法,其中剩余材料包括细胞物质,并且RNA分析是针对剩余材料中的细胞物质而进行的。
5.根据权利要求1所述方法,剩余材料包括血浆。
6.根据权利要求1所述方法,剩余材料包括血清。
7.对怀孕母体血清或血浆样品进行检测的方法,该方法包括测定样品中胎儿来源的RNA的存在。
8.根据权利要求7所述方法,进一步包括了扩增胎儿RNA,以有助于测定样品中胎儿RNA的存在。
9.根据权利要求8所述方法,其中胎儿RNA被反转录酶反转录为cDNA,然后以聚合酶链式反应进行测定。
10.根据权利要求8(8或9)所述方法,其中至少一个胎儿序列特异性寡聚核苷酸用于扩增胎儿RNA。
11.根据权利要求7(权利要求7-10中任一项)所述方法,其中用序列特异性的探针检测胎儿RNA。
12.根据权利要求7(权利要求7-10中任一项)所述方法,其中测定样品中胎儿来源的RNA的存在包括测定从Y染色体上转录来的胎儿RNA的存在。
13.根据权利要求12所述方法,其中胎儿RNA是从ZFY基因转录而来。
14.根据权利要求12(权利要求12或13)所述方法,进一步包括通过测定样品中胎儿来源的RNA来判定胎儿性别。
15.根据权利要求7(权利要求7-11中任一项)所述方法,其中测定样品中胎儿来源的RNA的存在包括测定由父亲或母亲遗传来的基因或其他DNA序列而来的胎儿RNA的存在。
16.根据权利要求7(权利要求7-11中任一项)所述方法,其中RNA是用任何一种物理方法、免疫方法、和生化方法进行测定的。
17.对怀孕母体的血清或血浆样品进行检测的方法,该方法包括:测定样品中胎儿或母体来源的RNA的存在。
18.根据权利要求17所述方法,进一步包括了扩增胎儿或母体RNA,以有利于检测样品中胎儿或母体来源的RNA的存在。
19.根据权利要求18所述方法,其中胎儿或母体RNA由反转录酶转变为cDNA,然后通过PCR反应测定。
20.根据权利要求18(权利要求18或19)所述方法,至少一个胎儿或母体序列特异性寡聚核苷酸可用于扩增胎儿或母体RNA。
21.根据权利要求17(权利要求17-20中任一项)所述方法,用序列特异性探针测定胎儿或母体RNA。
22.根据权利要求17(权利要求17-21中任一项)所述方法,测定样品中胎儿或母体来源的RNA的存在包括测定从染色体6上基因转录的RNA的存在。
23.根据权利要求22所述方法,RNA是从HLA-G基因转录而来。
24.出生前监测或测试的方法,包括以下步骤:
(i)提供怀孕母亲血液样品;
(ii)将样品分离为细胞占优势的组分(组分1)和非细胞占优势的的组分(组分2);
(iii)测定组分2中胎儿来源的RNA的存在;
(iv)基于所测定RNA的存在、数量、浓度、序列、和生化成分中至少一种,提供一种诊断结果。
25.根据权利要求24所述方法,进一步包括了母体血液样品结块后获得血清,此血清用于步骤(iii)和(iv)。
26.根据权利要求24所述方法,其中步骤(iii)进一步包括了测定组分2中母亲或胎儿来源的RNA的存在。
27.对母亲血液样品进行出生前监测或测试的方法,包括获得母亲血液样品的非细胞组分和对此组分表达的基因进行RNA分析。
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US09/876,005 US6664056B2 (en) | 2000-10-17 | 2001-06-06 | Non-invasive prenatal monitoring |
US09/876,005 | 2001-06-06 |
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US (1) | US6664056B2 (zh) |
CN (1) | CN1219074C (zh) |
AU (1) | AU2001295738A1 (zh) |
HK (1) | HK1058529A1 (zh) |
WO (1) | WO2002033120A2 (zh) |
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HK1058529A1 (en) | 2004-05-21 |
WO2002033120A3 (en) | 2002-12-27 |
WO2002033120B1 (en) | 2003-02-20 |
CN1219074C (zh) | 2005-09-14 |
US20020045176A1 (en) | 2002-04-18 |
WO2002033120A2 (en) | 2002-04-25 |
US6664056B2 (en) | 2003-12-16 |
AU2001295738A1 (en) | 2002-04-29 |
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