JP6285436B2 - 雌性不妊症のための治療標的および診断マーカーとしての無細胞dna - Google Patents
雌性不妊症のための治療標的および診断マーカーとしての無細胞dna Download PDFInfo
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- JP6285436B2 JP6285436B2 JP2015524896A JP2015524896A JP6285436B2 JP 6285436 B2 JP6285436 B2 JP 6285436B2 JP 2015524896 A JP2015524896 A JP 2015524896A JP 2015524896 A JP2015524896 A JP 2015524896A JP 6285436 B2 JP6285436 B2 JP 6285436B2
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Description
(i)前記雌由来の体液サンプル中の無細胞DNAのレベルを決定することと、
(ii)前記レベルを所定の閾値と比較することと
を含み、前記所定の閾値を上回る無細胞DNAのレベルが不妊症を示す、方法である。
精液サンプル
50歳未満の受胎性男性および不妊男性由来の精液サンプルを、3〜6日間の禁欲後の自慰行為によって収集した。精子の計数ならびに運動性、活力および形態の分析を、World Health Organizationのガイドラインに従って実施した。合計161人の男性をこの研究に含めた:73人の受胎性男性および88人の不妊男性。
血漿中の無細胞DNA(cfDNA)量は、37歳未満の94人の受胎性(AMH>2ng/ml)および96人の不妊女性において測定された。ゲノム研究を実施して、特に不妊女性において、このcfDNAの起源を検証した。
ほとんどの患者を、組換えFSH(Gonal F(登録商標)(Merck laboratory)もしくはPuregon(登録商標)(Schering Plough laboratory))またはHMG(Menopur(登録商標):Ferring laboratory)を用いた長期アゴニストプロトコルまたはアンタゴニストプロトコルを使用して、ARTについて刺激した。ホルモンおよび超音波検査制御の後、卵巣を組換えまたは尿HCGで誘発し、その36時間後に、周知の技術に従って卵母細胞回収を行った。2つまたは3つの支配的な卵胞液を単離し、貯蔵前に遠心分離した。次いで、cfDNA含量を、血漿/血清中と同じ方法を使用して評価した。
血漿cfDNAを、製造業者の推奨に従って、High Pure PCR鋳型調製キット(Roche)を使用して単離した。溶出緩衝液を、ddH2Oを使用することによって20%溶液に希釈し、70℃で予め温めた。サンプルを、16,000gで5分間遠心分離し、400μlの血漿を、細胞残骸を回避して、2mlのEppendorfチューブに移した。400μlの結合緩衝液および40μlの再構成されたプロテイナーゼKを、このサンプルに混合した。短時間のボルテックス後、チューブを、70℃で10分間インキュベートした。インキュベーション後、200μlの100%イソプロパノールをこのサンプルに混合し、これを結果として、High Pure PCR鋳型調製キット中に提供されている高純度フィルター収集チューブの上部リザーバーに移した。カラムを、室温で8,000gで1分間遠心分離した。フロースルーおよび収集チューブを廃棄し、フィルターを新たな収集チューブに合わせた。このローディング工程を、全サンプルがフィルター上にロードされるまで反復した。500μlのインヒビター除去緩衝液を上部リザーバーに添加し、室温で8,000gで1分間遠心分離した。フロースルーおよび収集チューブを廃棄し、フィルターを新たな収集チューブと合わせた。これらのチューブを、上部リザーバーに500μlの洗浄緩衝液を添加することによって2回洗浄し、室温で1分間遠心分離した。カラムを、最大速(およそ13,000g)で10秒間遠心分離することによって乾燥させ、新たな1.5mlのEppendorfチューブに移し、インキュベータ中で70℃で5分間温めた。100μlの予め温めた20%溶出緩衝液を、注意深くフィルターに添加した。このチューブおよびフィルターを、70℃のインキュベータ中に配置し、低速(およそ400rpm)で5分間振盪した。DNAサンプルを、8,000gで5分間遠心分離することによってこれらのカラムから溶出させ、引き続いて、使用の前に4℃で貯蔵したか、または長期貯蔵のために−70℃で凍結させた。
JmJC2遺伝子座およびDXS1285遺伝子座を増幅するために使用したマスターミックスは、200mMの各dNTP、1×Taqポリメラーゼ緩衝液、2μMの各プライマーセット、1.5mMのMgCl2および0.5UのBiotaq(商標)DNAポリメラーゼ(Bioline)を、15μlの反応容量中に含んでいた。JmJC2(Y染色体のマーカー)およびDXS1285(X染色体のマーカー)を増幅するために使用したプライマーの配列は、60℃のアニーリングで、それぞれ
5’−GAGTATGCGACCAGT−3’(配列番号1)、
5’−TGGCACACCATGGGA−3’(配列番号2)および
5’−CGTGCTTAGGCTTAATCCC−3’(配列番号3)、
5’−GAACTGACTGTAGAGAAGG−3’(配列番号4)である。
血液サンプルを、EDTA含有バキュテナーチューブ中に収集した。それらを、血漿単離のために遠心分離した(3,400rpmで15分間)。cfDNA定量の前に、血漿および卵胞液サンプルを、3,400rpmで20分間遠心分離した。サンプルは、赤血球なしで透明でなければならない。実際、cfDNA定量は、着色サンプル中では変化し得る。標準DNA溶液を、166μl中で20ng/ml、50ng/ml、100ng/mlおよび500ng/mlに希釈し、標準曲線を描いた。166μlの1N HCLO4(過塩素酸)および664μlのジフェニルアミンを、各166μlの血漿または卵胞液の上清サンプルに添加した。サンプルを、37℃で20時間インキュベートし、引き続いて、15,000gで10分間遠心分離した。300μlの上清を、96ウェルプレートに移し、600nmで分光光度計(Tecan、Genios)で測定した。
患者を、書面によるインフォームドコンセントを得た後に登録した。
両側t検定を使用して、受胎性個体と不妊個体との間のcfDNAレベルにおける差異を評価した。相関係数を、Spearman相関両側検定を使用して計算した。統計的差異を、P<0.05の場合に有意とみなした。
この第1の予備研究の目的は、増加したcfDNAにDNA断片化が関与し得るという事実を前提として、雄性不妊症と高レベルのcfDNAとの間の関連の概念を検証することであった。
男性と同様、より高いレベルのcfDNAが、それぞれの受胎性コントロールと比較して、不妊女性由来の血液血漿サンプルにおいて検出された。しかし、受胎性個体と不妊個体との間の差異は、男性においてよりも女性において、より大きかった。
血液血漿中のcfDNA濃度を、卵胞液中のcfDNA濃度と比較した。統計的に有意な正の相関が、血液血漿cfDNA濃度と卵胞液との間で見出された(r=0.43、p=6.4e−3)(図2)。予備研究では、妊娠女性は、非妊娠女性よりも、卵胞液および血清中の少ないcfDNAを有した(データ示さず)。
今日まで、4年間より長い間不妊であったおよび/または原因不明で数回のIVF/ICSIの失敗の履歴を有した10人の患者を、次のサイクルの2日目に開始し、GnRHアゴニストまたはアンタゴニストと共に組換えまたは尿FSHを使用する卵巣誘導治療の直前に、以前のサイクルの黄体期後期中の7日間にわたって治療した。全ての患者は、分割された胚を得、患者1人当たり、3日目の1つまたは数個の胚を移植した。
その遊離DNAレベルに従った、DNaseによる、IVF/ICSIの前の不妊カップルの女性の短い予防的治療は、症例のうち50%よりも多くにおいて、妊娠を導いた。全ての治療された女性は、4年よりも長い原因不明不妊症、または着床なしの発生の初期段階における多くの胚移植を示した。
本発明は、以下の態様を包含し得る。
[1]
雌性不妊症の治療において使用するための、DNase。
[2]
受胎性雌における無細胞DNAのレベルよりも統計的に高い無細胞DNAのレベルと関連した雌性不妊症の治療において使用するための、上記[1]に記載のDNase。
[3]
前記雌が子宮内膜症を有さない、雌性不妊症の治療において使用するための、上記[1]または上記[2]に記載のDNase。
[4]
前記DNaseが組換えDNaseである、雌性不妊症の治療において使用するための、上記[1]〜[3]のいずれかに記載のDNase。
[5]
前記DNaseがDNase Iである、雌性不妊症の治療において使用するための、上記[1]〜[4]のいずれかに記載のDNase。
[6]
前記DNaseが静脈内経路または筋肉内経路によって投与される、雌性不妊症の治療において使用するための、上記[1]〜[5]のいずれかに記載のDNase。
[7]
前記DNaseが、黄体期後期の間に不妊性雌に投与される、雌性不妊症の治療において使用するための、上記[1]〜[6]のいずれかに記載のDNase。
[8]
ヒト雌性不妊症の治療において使用するための、上記[1]〜[7]のいずれかに記載のDNase。
[9]
少なくとも2500UIのDNase Iが、少なくとも4日間、不妊女性に毎日投与される、ヒト雌性不妊症の治療において使用するための、上記[1]〜[8]のいずれかに記載のDNase。
[10]
2500UIのDNase Iが、黄体期後期の7日間、不妊女性に1日2回投与される、ヒト雌性不妊症の治療において使用するための、上記[1]〜[9]のいずれかに記載のDNase。
[11]
哺乳動物の雌において不妊症をin vitroで診断する方法であって、
(i)前記雌由来の体液サンプル中の無細胞DNAのレベルを決定することと、
(ii)前記レベルを所定の閾値と比較することと
を含み、前記所定の閾値を上回る無細胞DNAのレベルが不妊症を示す、方法。
[12]
前記雌が子宮内膜症を有さない、上記[11]に記載の方法。
[13]
前記体液サンプルが、血漿、血清、血液または卵胞液のサンプルである、上記[11]または上記[12]に記載の方法。
[14]
前記雌がヒトである、上記[11]〜[13]のいずれかに記載の方法。
[15]
前記体液サンプルが血漿サンプルであり、前記所定の閾値が、50ng/μl〜100ng/μlに含まれる、上記[14]に記載の方法。
[16]
上記[11]〜[15]のいずれかに記載の方法を実施するためのキットであって、生物学的サンプル中の無細胞DNAのレベルの測定に特異的な反応体、および生物学的サンプル中の少なくとも1つの他の生理学的パラメータの測定に特異的な反応体を含み、前記生理学的パラメータが、抗ミュラー管ホルモン(AMH)のレベル、テロメラーゼ活性およびホモシステイン濃度からなる群から選択される、キット。
[17]
少なくとも1種のDNA挿入剤およびAMHを特異的に認識する抗体を含む、上記[16]に記載のキット。
Claims (16)
- 雌性不妊症の治療剤であって、DNaseを含む、治療剤。
- 前記雌性不妊症が、受胎性雌における無細胞DNAのレベルよりも統計的に高い無細胞DNAのレベルと関連する、請求項1に記載の治療剤。
- 前記雌性不妊症が、子宮内膜症と関連しない、請求項1または請求項2に記載の治療剤。
- 前記DNaseが組換えDNaseである、請求項1〜3のいずれかに記載の治療剤。
- 前記DNaseがDNase Iである、請求項1〜4のいずれかに記載の治療剤。
- 前記DNaseが静脈内経路または筋肉内経路によって投与される、請求項1〜5のいずれかに記載の治療剤。
- 前記DNaseが、黄体期後期の間に不妊性雌に投与される、請求項1〜6のいずれかに記載の治療剤。
- 前記雌性不妊症が、ヒト雌性不妊症である、請求項1〜7のいずれかに記載の治療剤。
- 少なくとも2500UIのDNase Iが、少なくとも4日間、不妊女性に毎日投与される、請求項8に記載の治療剤。
- 2500UIのDNase Iが、黄体期後期の7日間、不妊女性に1日2回投与される、請求項9に記載の治療剤。
- 子宮内膜症を有さない哺乳動物の雌において不妊症のin vitroでの診断を補助する方法であって、
(i)前記雌由来の体液サンプル中の無細胞DNAのレベルを決定することと、
(ii)前記レベルを所定の閾値と比較することと
を含み、前記所定の閾値を上回る無細胞DNAのレベルが不妊症を示す、方法。 - 前記体液サンプルが、血漿、血清、血液または卵胞液のサンプルである、請求項11に記載の方法。
- 前記雌がヒトである、請求項11または請求項12に記載の方法。
- 前記体液サンプルが血漿サンプルであり、前記所定の閾値が、50ng/μl〜100ng/μlに含まれる、請求項13に記載の方法。
- 請求項11〜14のいずれかに記載の方法を実施するためのキットであって、生物学的サンプル中の無細胞DNAのレベルを測定するための反応体、および生物学的サンプル中の少なくとも1つの他の生理学的パラメータを測定するための反応体を含み、前記生理学的パラメータが、抗ミュラー管ホルモン(AMH)のレベル、テロメラーゼ活性およびホモシステイン濃度からなる群から選択される、キット。
- 少なくとも1種のDNA挿入剤およびAMHを認識する抗体を含む、請求項15に記載のキット。
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US11939634B2 (en) | 2010-05-18 | 2024-03-26 | Natera, Inc. | Methods for simultaneous amplification of target loci |
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EP2086642B1 (en) * | 2006-10-18 | 2014-06-25 | Periness Ltd. | Dnase for the treatment of male sub-fertility |
EP1944611A1 (en) * | 2007-01-11 | 2008-07-16 | Université de la Méditerranée | Biomarker for the medicine and the biology of the reproduction |
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IL236924B (en) | 2018-05-31 |
KR20150036776A (ko) | 2015-04-07 |
US20150246103A1 (en) | 2015-09-03 |
HK1210592A1 (zh) | 2016-04-29 |
EA201590115A1 (ru) | 2015-07-30 |
EP2879696A1 (en) | 2015-06-10 |
WO2014020564A1 (en) | 2014-02-06 |
EA028855B1 (ru) | 2018-01-31 |
MX359291B (es) | 2018-09-24 |
PL2879696T3 (pl) | 2016-12-30 |
CN104519906B (zh) | 2016-10-05 |
DK2879696T3 (en) | 2016-09-12 |
JP2015526079A (ja) | 2015-09-10 |
HUE030690T2 (en) | 2017-05-29 |
EA201590115A8 (ru) | 2016-04-29 |
CA2880261C (en) | 2021-02-02 |
PT2879696T (pt) | 2016-09-09 |
CA2880261A1 (en) | 2014-02-06 |
SI2879696T1 (sl) | 2016-10-28 |
US9950040B2 (en) | 2018-04-24 |
HRP20161108T1 (hr) | 2016-11-04 |
LT2879696T (lt) | 2016-09-26 |
RS55087B1 (sr) | 2016-12-30 |
KR102082735B1 (ko) | 2020-02-28 |
CN104519906A (zh) | 2015-04-15 |
NZ704039A (en) | 2018-04-27 |
MX2015001538A (es) | 2015-05-11 |
AU2013298144B2 (en) | 2018-03-08 |
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