JPWO2020092259A5 - - Google Patents
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- JPWO2020092259A5 JPWO2020092259A5 JP2021548520A JP2021548520A JPWO2020092259A5 JP WO2020092259 A5 JPWO2020092259 A5 JP WO2020092259A5 JP 2021548520 A JP2021548520 A JP 2021548520A JP 2021548520 A JP2021548520 A JP 2021548520A JP WO2020092259 A5 JPWO2020092259 A5 JP WO2020092259A5
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Description
本発明の好まれる実施形態が、本明細書に示され記載されてきたが、当業者には、斯かる実施形態が単なる一例として提供されていることが明らかであろう。本発明が、本明細書内に提供される具体例によって限定されることは意図されない。本発明が、上述の明細書を参照しつつ記載されてきたが、本明細書における実施形態の記載および図解は、限定的な意義で解釈されることを意味するものではない。そこで、当業者であれば、本発明から逸脱することなく、多数の変形形態、変化および置換が思い浮かぶ。さらに、本発明のあらゆる態様が、種々の条件および変数に依存する本明細書に示される特異的な描写、構成または相対的比率に限定されないことを理解されたい。本明細書に記載されている本発明の実施形態の様々な代替を、本発明の実施に用いることができることを理解されたい。したがって、本発明が、いかなる斯かる代替、改変、変形形態または均等物も網羅することが企図される。次の特許請求の範囲が、本発明の範囲を定義し、斯かる特許請求の範囲内の方法および構造ならびにそれらの均等物が、それによって網羅されることが意図される。
一実施形態において、例えば、以下の項目が提供される。
（項目１）
被験体の骨髄の病状をモニタリングするための方法であって、
前記病状を有する前記被験体から生体試料を得るステップと、
第１の複数の遺伝子に対応する、前記骨髄に常在するまたはこれに起源をもつ複数の細胞に由来する第１の複数の無細胞ｍＲＮＡ（ｃｆ－ｍＲＮＡ）のｃｆ－ｍＲＮＡレベルを検出するステップと
を含む、方法。
（項目２）
前記生体試料が、血液試料を含む、項目１に記載の方法。
（項目３）
前記血液試料が、血清試料、血漿試料またはバフィーコート試料を含む、項目２に記載の方法。
（項目４）
前記病状が、多発性骨髄腫（ＭＭ）、白血病、骨髄増殖性新生物、骨髄異形成症候群、リンパ腫、血小板血症、骨髄線維症、真性赤血球増加症または貧血を含む、項目１から３のいずれか一項に記載の方法。
（項目５）
前記病状が、ＭＭを含む、項目４に記載の方法。
（項目６）
前記病状が、ＭＭを含む場合、前記第１の複数の遺伝子が、ＩＧＨＧ１、ＩＧＨＡ１、ＩＧＫＣ、ＩＧＨＶ１、ＩＧＨＶ２、ＩＧＨＶ３、ＩＧＨＶ４、ＩＧＨＶ５、ＩＧＨＶ６、ＩＧＨＶ７、ＩＧＨＶ８、ＩＧＨＶ９、ＩＧＨＶ１０、ＩＧＨＶ１１、ＩＧＨＶ１２、ＩＧＨＶ１３、ＩＧＨＶ１４、ＩＧＨＶ１５、ＩＧＨＶ１６、ＩＧＨＶ１７、ＩＧＨＶ１８、ＩＧＨＶ１９、ＩＧＨＶ２０、ＩＧＨＶ２１、ＩＧＨＶ２２、ＩＧＨＶ２３、ＩＧＨＶ２４、ＩＧＨＶ２５、ＩＧＨＶ２６、ＩＧＨＶ２７、ＩＧＨＶ２８、ＩＧＨＶ２９、ＩＧＨＶ３０、ＩＧＨＶ３１、ＩＧＨＶ３２、ＩＧＨＶ３３、ＩＧＨＶ３４、ＩＧＨＶ３５、ＩＧＨＶ３６、ＩＧＨＶ３７、ＩＧＨＶ３８、ＩＧＨＶ３９、ＩＧＨＶ４０、ＩＧＨＶ４１、ＩＧＨＶ４２、ＩＧＨＶ４３、ＩＧＨＶ４４、ＩＧＨＶ４５、ＩＧＨＶ４６、ＩＧＨＶ４７、ＩＧＨＶ４８、ＩＧＨＶ４９、ＩＧＨＶ５０、ＩＧＨＶ５１、ＩＧＨＶ５２、ＩＧＨＶ５３、ＩＧＨＶ５４、ＩＧＨＶ５５、ＩＧＨＶ５６、ＩＧＨＶ５７、ＩＧＨＶ５８、ＩＧＨＶ５９、ＩＧＨＶ６０、ＩＧＨＶ６１、ＩＧＨＶ６２、ＩＧＨＶ６３、ＩＧＨＶ６４、ＩＧＨＶ６５、ＩＧＨＶ６６、ＩＧＨＶ６７、ＩＧＨＶ６８、ＩＧＨＶ６９、ＩＧＫＶ２、ＩＧＫＶ３、ＩＧＫＶ４、ＩＧＫＶ５、ＩＧＫＶ６、ＩＧＫＶ７、ＩＧＫＶ８、ＩＧＫＶ９、ＩＧＫＶ１０、ＩＧＫＶ１１、ＩＧＫＶ１２、ＩＧＫＶ１３、ＩＧＫＶ１４、ＩＧＫＶ１５、ＩＧＫＶ１６、ＩＧＫＶ１７、ＩＧＫＶ１８、ＩＧＫＶ１９、ＩＧＫＶ２０、ＩＧＫＶ２１、ＩＧＫＶ２２、ＩＧＫＶ２３、ＩＧＫＶ２４、ＩＧＬ１、ＩＧＬＶ１－４０、またはこれらの組合せを含む、項目５に記載の方法。
（項目７）
前記病状が、急性骨髄性白血病（ＡＭＬ）を含む、項目４に記載の方法。
（項目８）
前記検出するステップが、ｃｆ－ｍＲＮＡをｃＤＮＡに変換するステップをさらに含む、項目１から７のいずれか一項に記載の方法。
（項目９）
配列決定、アレイハイブリダイゼーションまたは核酸増幅のうち１つまたは複数を行うことにより、前記ｃＤＮＡを測定するステップをさらに含む、項目８に記載の方法。
（項目１０）
処置を提供するステップをさらに含む、項目１から９のいずれか一項に記載の方法。
（項目１１）
前記処置が、イオン化照射、メルファラン媒介性骨髄アブレーション、ブスルファン媒介性骨髄アブレーション、トレオスルファン媒介性アブレーション、化学療法媒介性アブレーション、同種異系移植、自家移植、増殖因子による刺激、自家もしくは異種ＣＡＲ－Ｔ細胞療法、またはこれらのいずれかの組合せを含む、項目１０に記載の方法。
（項目１２）
前記増殖因子による刺激が、エリスロポエチン（ＥＰＯ）による刺激を含む、項目１１に記載の方法。
（項目１３）
前記増殖因子による刺激が、顆粒球コロニー刺激因子（Ｇ－ＣＳＦ）による刺激を含む、項目１１に記載の方法。
（項目１４）
被験体の臓器の処置状況をモニタリングするための方法であって、
前記処置状況を有する前記被験体から血漿試料を得るステップと、
第２の複数の遺伝子に対応する、前記被験体の臓器に由来する第２の複数の無細胞ｍＲＮＡ（ｃｆ－ｍＲＮＡ）のｃｆ－ｍＲＮＡレベルを検出するステップと
を含む、方法。
（項目１５）
前記臓器が、骨髄である、項目１４に記載の方法。
（項目１６）
前記生体試料が、血液試料を含む、項目１５に記載の方法。
（項目１７）
前記血液試料が、血清、血漿試料またはバフィーコート試料を含む、項目１６に記載の方法。
（項目１８）
前記処置状況が、骨髄アブレーション、骨髄再構成、骨髄移植、増殖因子による刺激、免疫療法、免疫調節、ユビキチンリガーゼ活性のモジュレーション、コルチコステロイド、放射線療法、または自家もしくは異種ＣＡＲ－Ｔ細胞療法を含む、項目１５から１７のいずれか一項に記載の方法。
（項目１９）
前記ユビキチンリガーゼ活性の前記モジュレーションが、ユビキチンリガーゼ阻害剤の投与を含む、項目１８に記載の方法。
（項目２０）
前記骨髄アブレーションが、物理的アブレーション、化学的アブレーション、またはこれらの組合せを含む、項目１８に記載の方法。
（項目２１）
前記物理的アブレーションが、イオン化照射を含む、項目１９に記載の方法。
（項目２２）
前記化学的アブレーションが、メルファラン媒介性骨髄アブレーション、ブスルファン媒介性骨髄アブレーション、トレオスルファン媒介性アブレーション、化学療法媒介性アブレーション、またはこれらの組合せを含む、項目１９に記載の方法。
（項目２３）
前記骨髄移植が、同種異系移植を含む、項目１８に記載の方法。
（項目２４）
前記骨髄移植が、自家移植を含む、項目１８に記載の方法。
（項目２５）
前記増殖因子による刺激が、エリスロポエチン（ＥＰＯ）による刺激を含む、項目１８に記載の方法。
（項目２６）
前記増殖因子による刺激が、顆粒球コロニー刺激因子（Ｇ－ＣＳＦ）による刺激を含む、項目１８に記載の方法。
（項目２７）
前記処置が、骨髄アブレーションを含む場合、前記第２の複数の遺伝子に対応する前記第２の複数のｃｆ－ｍＲＮＡのレベルが減少し、前記第２の複数の遺伝子が、赤血球特異的遺伝子を含む、項目１８に記載の方法。
（項目２８）
前記処置が、骨髄再構成を含む場合、前記第２の複数の遺伝子に対応する前記第２の複数のｃｆ－ｍＲＮＡのレベルが、骨髄アブレーションの際の斯かるｃｆ－ｍＲＮＡレベルと比較して増加し、前記第２の複数の遺伝子が、赤血球特異的遺伝子を含む、項目１８に記載の方法。
（項目２９）
前記赤血球特異的遺伝子が、ＧＡＴＡ１、ＳＬＣ４Ａ１、ＴＦ、ＡＶＰ、ＲＵＮＤＣ３Ａ、ＳＯＸ６、ＴＳＰＯ２、ＨＢＺ、ＴＭＣＣ２、ＳＥＬＥＮＢＰ１、ＡＬＡＳ２、ＥＰＢ４２、ＧＹＰＡ、Ｃ１７ｏｒｆ９９、ＨＢＡ２、ＲＨＣＥ、ＨＢＧ２、ＴＲＩＭ１０、ＨＢＡ１、ＨＢＭ、ＨＢＧ１、ＵＣＡ１、ＧＹＰＢ、ＣＴＤ－３１５４Ｎ５．２およびＡＣ１０４３８９．１からなる群由来の１つまたは複数の遺伝子を含む、項目２６または２７のいずれかに記載の方法。
（項目３０）
前記処置が、骨髄再構成を含む場合、前記第２の複数の遺伝子に対応する前記第２の複数のｃｆ－ｍＲＮＡのレベルが増加し、前記第２の複数の遺伝子が、巨核球特異的遺伝子を含む、項目１８に記載の方法。
（項目３１）
前記巨核球特異的遺伝子が、ＩＴＧＡ２Ｂ、ＲＡＢ２７Ｂ、ＧＵＣＹ１Ｂ３、ＧＰ６、ＨＧＤ、ＰＦ４、ＣＬＥＣ１Ｂ、ＣＭＴＭ５、ＧＰ９、ＳＥＬＰ、ＤＮＭ３、ＬＹ６Ｇ６Ｆ、ＬＹ６Ｇ６Ｄ、ＸＸｂａｃ－ＢＰＧ３２１３．１９およびＲＰ１１－８７９Ｆ１４．２からなる群由来の１つまたは複数の遺伝子を含む、項目３０に記載の方法。
（項目３２）
前記処置が、骨髄アブレーションを含む場合、前記第２の複数の遺伝子に対応する前記第２の複数のｃｆ－ｍＲＮＡのレベルが減少し、前記第２の複数の遺伝子が、好中球特異的遺伝子を含む、項目１８に記載の方法。
（項目３３）
前記処置が、骨髄移植を含む場合、前記第２の複数の遺伝子に対応する前記第２の複数のｃｆ－ｍＲＮＡのレベルが、骨髄アブレーションの際の斯かるｃｆ－ｍＲＮＡレベルと比較して増加し、前記第２の複数の遺伝子が、好中球特異的遺伝子を含む、項目３２に記載の方法。
（項目３４）
前記処置が、骨髄再構成を含む場合、前記第２の複数の遺伝子に対応する前記第２の複数のｃｆ－ｍＲＮＡのレベルが、骨髄再構成の際の斯かるｃｆ－ｍＲＮＡレベルと比較して増加し、前記第２の複数の遺伝子が、好中球特異的遺伝子を含む、項目１８に記載の方法。
（項目３５）
前記好中球特異的遺伝子が、前駆体好中球特異的遺伝子を含む、項目２０から３４のいずれかに記載の方法。
（項目３６）
前記前駆体好中球特異的遺伝子が、ＣＴＳＧ、ＥＬＡＮＥ、ＡＺＵ１、ＰＲＴＮ３、ＭＭＰ８、ＲＮＡＳＥ、ＰＧＬＹＲＰ１、またはこれらの組合せを含む、項目３５に記載の方法。
（項目３７）
前駆体好中球特異的遺伝子に対応する前記検出されたｃｆ－ｍＲＮＡが、前記血液試料において、複数の好中球細胞よりも早く現れる、項目３５または項目３６に記載の方法。
（項目３８）
前記処置が、同種異系移植を含む場合、前記第２の複数の遺伝子に対応する前記第２の複数のｃｆ－ｍＲＮＡのレベルが検出され、前記第２の複数の遺伝子が、ドナー細胞由来の前駆体好中球特異的遺伝子を含む、項目１８に記載の方法。
（項目３９）
前記処置が、Ｇ－ＣＳＦによる刺激を含む場合、前記第２の複数の遺伝子に対応する前記第２の複数のｃｆ－ｍＲＮＡのレベルが検出され、前記第２の複数の遺伝子が、好中球特異的遺伝子を含む、項目３８に記載の方法。
（項目４０）
前記好中球特異的遺伝子が、ＰＧＬＹＲＰ１、ＬＴＦ、ＡＴＰ２Ｃ２、ＶＮＮ３、ＣＲＩＳＰ３、ＣＴＳＧ、ＯＬＦＭ４、ＫＲＴ２３、ＭＭＰ８、ＡＲＧ１、ＥＰＸ、ＰＩ３、ＣＲＩＳＰ２、ＳＴＥＡＰ４、ＬＣＮ２、ＰＲＧ３、ＫＣＮＪ１５、ＡＬＰＬ、ＦＣＧＲ３８、Ｓ１００Ａ１２、ＰＲＯＫ２、ＣＸＣＲ１、ＣＡＭＰ、ＲＮＡＳＥ３、ＣＥＡＣＡＭ３、ＡＺＵ１、ＡＢＣＡ１３、ＣＸＣＲ２、ＣＴＤ－３０８８Ｇ３．８、ＰＲＴＮ３、ＥＬＡＩＮＥ、ＣＤ１７７、ＬＩＮＣ００６７１、ＯＲＭ２、ＯＲＭ１、ＨＰおよびＲＰ１１－６７８Ｇ１４．４からなる群由来の１つまたは複数の遺伝子を含む、項目３０から３９のいずれかに記載の方法。
（項目４１）
被験体の骨髄の健康状況をモニタリングするための方法であって、
前記健康状況を有する前記被験体から生体試料を得るステップと、
第３の複数の遺伝子に対応する、前記被験体の骨髄およびその由来細胞に由来する第３の複数の無細胞ｍＲＮＡ（ｃｆ－ｍＲＮＡ）のｃｆ－ｍＲＮＡレベルを検出するステップとを含む、方法。
（項目４２）
前記第３の複数の遺伝子が、骨髄およびその由来細胞に由来する遺伝子のおおよそ少なくとも４５％、５５％、６５％または７５％を構成する、項目４１に記載の方法。
（項目４３）
前記第３の複数の遺伝子が、表７由来の１つまたは複数の遺伝子を含む、項目４１に記載の方法。
（項目４４）
前駆体好中球特異的遺伝子に対応する前記第３の複数のｃｆ－ｍＲＮＡのレベルが、成熟好中球特異的遺伝子に対応するｃｆ－ｍＲＮＡレベルと比較して増加する、項目４１に記載の方法。
（項目４５）
前記生体試料が、血液試料を含む、項目４１に記載の方法。
（項目４６）
前記血液試料が、血清試料、血漿試料またはバフィーコート試料を含む、項目４５に記載の方法。
（項目４７）
前記検出するステップが、ｃｆ－ｍＲＮＡをｃＤＮＡに変換するステップをさらに含む、項目４１に記載の方法。
（項目４８）
配列決定、アレイハイブリダイゼーションまたは核酸増幅のうち１つまたは複数を行うことにより、前記ｃＤＮＡを測定するステップをさらに含む、項目４７に記載の方法。
（項目４９）
活性薬剤をアッセイする方法であって、
第１の時点で被験体の第１の無細胞発現プロファイルを評価するステップと、
前記被験体に活性薬剤を投与するステップと、
第２の時点で前記被験体の第２の無細胞発現プロファイルを評価するステップと
を含む、方法。
（項目５０）
前記第１の無細胞発現プロファイルまたは前記第２の無細胞発現プロファイルのいずれかが、骨髄特異的である、項目４９に記載の方法。
（項目５１）
前記第１の無細胞発現プロファイルを前記第２の無細胞発現プロファイルと比較するステップをさらに含む、項目４９に記載の方法。
（項目５２）
前記第１の発現プロファイルおよび前記第２の発現プロファイルの間の差が、治療の効果を指し示す、項目４９に記載の方法。
（項目５３）
前記活性薬剤が、疾患を処置するための医薬化合物を含む、項目４９から５２のいずれかに記載の方法。
（項目５４）
第３の時点で前記被験体の第３の無細胞発現プロファイルを評価するステップをさらに含む、項目４９から５３のいずれかに記載の方法。
（項目５５）
評価するステップが、配列決定、アレイハイブリダイゼーションまたは核酸増幅のうち１つまたは複数を含む、項目４９から５４のいずれかに記載の方法。
（項目５６）
追加的な時点で前記被験体の追加的な無細胞発現プロファイルを評価するステップをさらに含む、項目４９から５５のいずれかに記載の方法。
（項目５７）
前記第２の時点が、前記第１の時点から１～４週間後である、項目４９から５６のいずれか一項に記載の方法。
（項目５８）
１２～２４ヶ月間の期間にわたり前記追加的な無細胞発現時点を評価するステップをさらに含む、項目４９から５７のいずれか一項に記載の方法。
（項目５９）
前記期間が、約１８ヶ月間である、項目５８に記載の方法。
（項目６０）
１つまたは複数の無細胞発現プロファイルを追跡および／または検出して、治療および／または薬物の発見および／または開発のために１つまたは複数の目的の標的を測定するステップをさらに含む、項目４９から５９のいずれか一項に記載の方法。
（項目６１）
治療および／または薬物の発見および開発におけるリード最適化および／または臨床開発のために薬力学を測定するステップをさらに含む、項目４９から６０のいずれか一項に記載の方法。
（項目６２）
遺伝子発現のプロファイルを作成して、治療および／または薬物の発見および／または開発のために特異的標的の関与に関連する１つまたは複数の薬力学的効果を特徴付けるステップをさらに含む、項目４９から６１のいずれか一項に記載の方法。
（項目６３）
治療および／または薬物の発見および開発のために薬力学標的関与の変化を検出するステップをさらに含む、項目４９から６２のいずれか一項に記載の方法。
While preferred embodiments of the invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. It is not intended that the invention be limited by the specific examples provided within this specification. Although the invention has been described with reference to the foregoing specification, the description and illustrations of the embodiments herein are not meant to be construed in a limiting sense. Thus, numerous variations, changes and substitutions will occur to those skilled in the art without departing from the invention. Furthermore, it is to be understood that all aspects of the invention are not limited to the specific depictions, configurations or relative proportions shown herein which depend on various conditions and variables. It should be understood that various alternatives to the embodiments of the invention described herein may be used in practicing the invention. It is therefore intended that the invention cover any such alternatives, modifications, variations or equivalents. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of such claims and their equivalents be covered thereby.
In one embodiment, for example, the following items are provided.
(Item 1)
A method for monitoring bone marrow pathology in a subject, comprising:
obtaining a biological sample from said subject with said medical condition;
detecting cf-mRNA levels of a first plurality of cell-free mRNAs (cf-mRNA) from a plurality of cells resident in or originating from said bone marrow corresponding to a first plurality of genes (cf-mRNA); When
A method, including
(Item 2)
The method of item 1, wherein the biological sample comprises a blood sample.
(Item 3)
3. The method of item 2, wherein said blood sample comprises a serum sample, plasma sample or buffy coat sample.
(Item 4)
Any of items 1 to 3, wherein said condition comprises multiple myeloma (MM), leukemia, myeloproliferative neoplasm, myelodysplastic syndrome, lymphoma, thrombocythemia, myelofibrosis, polycythemia vera or anemia or the method described in paragraph 1.
(Item 5)
5. The method of item 4, wherein the medical condition comprises MM.
(Item 6)
when the condition comprises MM, the first plurality of genes is ＩＧＨＶ１４、ＩＧＨＶ１５、ＩＧＨＶ１６、ＩＧＨＶ１７、ＩＧＨＶ１８、ＩＧＨＶ１９、ＩＧＨＶ２０、ＩＧＨＶ２１、ＩＧＨＶ２２、ＩＧＨＶ２３、ＩＧＨＶ２４、ＩＧＨＶ２５、ＩＧＨＶ２６、ＩＧＨＶ２７、ＩＧＨＶ２８、ＩＧＨＶ２９、ＩＧＨＶ３０、ＩＧＨＶ３１、ＩＧＨＶ３２、ＩＧＨＶ３３、ＩＧＨＶ３４、ＩＧＨＶ３５、ＩＧＨＶ３６、ＩＧＨＶ３７、ＩＧＨＶ３８、 ＩＧＨＶ３９、ＩＧＨＶ４０、ＩＧＨＶ４１、ＩＧＨＶ４２、ＩＧＨＶ４３、ＩＧＨＶ４４、ＩＧＨＶ４５、ＩＧＨＶ４６、ＩＧＨＶ４７、ＩＧＨＶ４８、ＩＧＨＶ４９、ＩＧＨＶ５０、ＩＧＨＶ５１、ＩＧＨＶ５２、ＩＧＨＶ５３、ＩＧＨＶ５４、ＩＧＨＶ５５、ＩＧＨＶ５６、ＩＧＨＶ５７、ＩＧＨＶ５８、ＩＧＨＶ５９、ＩＧＨＶ６０、ＩＧＨＶ６１、ＩＧＨＶ６２、ＩＧＨＶ６３、 IGHV64, IGHV65, IGHV66, IGHV67, IGHV68, IGHV69, IGKV2, IGKV3, IGKV4, IGKV5, IGKV6, IGKV7, IGKV8, IGKV9, IGKV10, IGKV11, IGKV12, IGKV13, IGKV14, IGKV15, IGKV16, IGKV0, IGKV16, IGKV0, IGKV17, IGKV9, IGKV17, 6. The method of item 5, comprising IGKV21, IGKV22, IGKV23, IGKV24, IGL1, IGLV1-40, or combinations thereof.
(Item 7)
5. The method of item 4, wherein the condition comprises acute myelogenous leukemia (AML).
(Item 8)
8. The method of any one of items 1-7, wherein said detecting step further comprises converting cf-mRNA to cDNA.
(Item 9)
9. The method of item 8, further comprising measuring said cDNA by performing one or more of sequencing, array hybridization or nucleic acid amplification.
(Item 10)
10. The method of any one of items 1-9, further comprising the step of providing treatment.
(Item 11)
said treatment is ionizing irradiation, melphalan-mediated bone marrow ablation, busulfan-mediated bone marrow ablation, treosulfan-mediated ablation, chemotherapy-mediated ablation, allograft, autograft, growth factor stimulation, autologous or xenogeneic CAR - A method according to item 10, comprising T cell therapy, or any combination thereof.
(Item 12)
12. The method of item 11, wherein said growth factor stimulation comprises stimulation with erythropoietin (EPO).
(Item 13)
12. The method of item 11, wherein said growth factor stimulation comprises stimulation with granulocyte colony stimulating factor (G-CSF).
(Item 14)
A method for monitoring treatment status of an organ in a subject, comprising:
obtaining a plasma sample from said subject having said treatment status;
detecting cf-mRNA levels of a second plurality of cell-free mRNAs (cf-mRNAs) from an organ of said subject corresponding to a second plurality of genes;
A method, including
(Item 15)
15. The method of item 14, wherein the organ is bone marrow.
(Item 16)
16. The method of item 15, wherein the biological sample comprises a blood sample.
(Item 17)
17. The method of item 16, wherein said blood sample comprises a serum, plasma sample or buffy coat sample.
(Item 18)
Said treatment context comprises bone marrow ablation, bone marrow reconstitution, bone marrow transplantation, growth factor stimulation, immunotherapy, immunomodulation, modulation of ubiquitin ligase activity, corticosteroids, radiation therapy, or autologous or xenogeneic CAR-T cell therapy. , items 15 to 17.
(Item 19)
19. The method of item 18, wherein said modulation of said ubiquitin ligase activity comprises administration of a ubiquitin ligase inhibitor.
(Item 20)
19. The method of item 18, wherein said bone marrow ablation comprises physical ablation, chemical ablation, or a combination thereof.
(Item 21)
20. The method of item 19, wherein said physical ablation comprises ionizing radiation.
(Item 22)
20. The method of item 19, wherein said chemical ablation comprises melphalan-mediated bone marrow ablation, busulfan-mediated bone marrow ablation, treosulfan-mediated ablation, chemotherapy-mediated ablation, or a combination thereof.
(Item 23)
19. The method of item 18, wherein said bone marrow transplantation comprises allogeneic transplantation.
(Item 24)
19. The method of item 18, wherein said bone marrow transplantation comprises autologous transplantation.
(Item 25)
19. The method of item 18, wherein said growth factor stimulation comprises stimulation with erythropoietin (EPO).
(Item 26)
19. The method of item 18, wherein said growth factor stimulation comprises stimulation with granulocyte colony stimulating factor (G-CSF).
(Item 27)
if said treatment comprises bone marrow ablation, the levels of said second plurality of cf-mRNAs corresponding to said second plurality of genes are decreased, said second plurality of genes comprising an erythrocyte specific gene; , item 18.
(Item 28)
if said treatment comprises bone marrow reconstitution, levels of said second plurality of cf-mRNAs corresponding to said second plurality of genes are increased compared to said cf-mRNA levels upon bone marrow ablation and wherein said second plurality of genes comprises an erythrocyte specific gene.
(Item 29)
The erythrocyte-specific gene is GATA1, SLC4A1, TF, AVP, RUNDC3A, SOX6, TSPO2, HBZ, TMCC2, SELENBP1, ALAS2, EPB42, GYPA, C17orf99, HBA2, RHCE, HBG2, TRIM10, HBA1, HBM, HBG1, UCA1 , GYPB, CTD-3154N5.2 and AC104389.1.
(Item 30)
if said treatment comprises bone marrow reconstitution, increased levels of said second plurality of cf-mRNAs corresponding to said second plurality of genes, wherein said second plurality of genes is a megakaryocyte-specific gene 19. The method of item 18, comprising
(Item 31)
The megakaryocyte-specific gene is from the group consisting of ITGA2B, RAB27B, GUCY1B3, GP6, HGD, PF4, CLEC1B, CMTM5, GP9, SELP, DNM3, LY6G6F, LY6G6D, XXbac-BPG3213.19 and RP11-879F14.2 31. The method of item 30, comprising one or more genes.
(Item 32)
if said treatment comprises bone marrow ablation, the levels of said second plurality of cf-mRNAs corresponding to said second plurality of genes are reduced, and said second plurality of genes is a neutrophil-specific gene 19. The method of item 18, comprising
(Item 33)
if said treatment comprises bone marrow transplantation, the levels of said second plurality of cf-mRNAs corresponding to said second plurality of genes are increased compared to said cf-mRNA levels upon bone marrow ablation; 33. The method of item 32, wherein said second plurality of genes comprises a neutrophil-specific gene.
(Item 34)
if said treatment comprises bone marrow reconstitution, the levels of said second plurality of cf-mRNAs corresponding to said second plurality of genes are compared to said cf-mRNA levels upon bone marrow reconstitution 19. The method of item 18, wherein the second plurality of genes comprises a neutrophil-specific gene.
(Item 35)
35. The method of any of items 20-34, wherein said neutrophil-specific gene comprises a progenitor neutrophil-specific gene.
(Item 36)
36. The method of item 35, wherein said progenitor neutrophil-specific gene comprises CTSG, ELANE, AZU1, PRTN3, MMP8, RNASE, PGLYRP1, or a combination thereof.
(Item 37)
37. The method of item 35 or item 36, wherein said detected cf-mRNA corresponding to a precursor neutrophil-specific gene appears earlier than a plurality of neutrophil cells in said blood sample.
(Item 38)
wherein said treatment comprises allogeneic transplantation, wherein levels of said second plurality of cf-mRNAs corresponding to said second plurality of genes are detected, said second plurality of genes are derived from donor cells; 19. The method of item 18, comprising a progenitor neutrophil-specific gene.
(Item 39)
wherein said treatment comprises stimulation with G-CSF, wherein levels of said second plurality of cf-mRNAs corresponding to said second plurality of genes are detected and said second plurality of genes are associated with neutrophils; 39. A method according to item 38, comprising a specific gene.
(Item 40)
the neutrophil-specific gene is PGLYRP1, LTF, ATP2C2, VNN3, CRISP3, CTSG, OLFM4, KRT23, MMP8, ARG1, EPX, PI3, CRISP2, STEAP4, LCN2, PRG3, KCNJ15, ALPL, FCGR38, S100A12, PROK2 , CXCR1, CAMP, RNASE3, CEACAM3, AZU1, ABCA13, CXCR2, CTD-3088G3.8, PRTN3, ELAINE, CD177, LINC00671, ORM2, ORM1, HP and RP11-678G14.4. 40. The method of any of items 30-39, comprising the gene.
(Item 41)
A method for monitoring bone marrow health status of a subject, comprising:
obtaining a biological sample from said subject with said health status;
detecting cf-mRNA levels of a third plurality of cell-free mRNAs (cf-mRNAs) from the subject's bone marrow and cells derived therefrom corresponding to a third plurality of genes.
(Item 42)
42. The method of item 41, wherein said third plurality of genes constitutes approximately at least 45%, 55%, 65% or 75% of the genes derived from bone marrow and its derived cells.
(Item 43)
42. The method of item 41, wherein said third plurality of genes comprises one or more genes from Table 7.
(Item 44)
42. The method of claim 41, wherein levels of said third plurality of cf-mRNAs corresponding to precursor neutrophil-specific genes are increased compared to cf-mRNA levels corresponding to mature neutrophil-specific genes. Method.
(Item 45)
42. The method of item 41, wherein the biological sample comprises a blood sample.
(Item 46)
46. The method of item 45, wherein said blood sample comprises a serum sample, plasma sample or buffy coat sample.
(Item 47)
42. The method of item 41, wherein said detecting step further comprises converting cf-mRNA to cDNA.
(Item 48)
48. The method of item 47, further comprising measuring said cDNA by performing one or more of sequencing, array hybridization or nucleic acid amplification.
(Item 49)
A method of assaying an active agent comprising:
assessing a first cell-free expression profile of the subject at a first time point;
administering an active agent to said subject;
evaluating a second cell-free expression profile of said subject at a second time point;
A method, including
(Item 50)
50. The method of item 49, wherein either said first cell-free expression profile or said second cell-free expression profile is myeloid specific.
(Item 51)
50. The method of item 49, further comprising comparing said first cell-free expression profile to said second cell-free expression profile.
(Item 52)
50. The method of item 49, wherein a difference between said first expression profile and said second expression profile is indicative of an effect of treatment.
(Item 53)
53. The method of any of items 49-52, wherein the active agent comprises a pharmaceutical compound for treating disease.
(Item 54)
54. The method of any of items 49-53, further comprising evaluating a third cell-free expression profile of said subject at a third time point.
(Item 55)
55. The method of any of items 49-54, wherein the evaluating step comprises one or more of sequencing, array hybridization or nucleic acid amplification.
(Item 56)
56. The method of any of items 49-55, further comprising assessing additional cell-free expression profiles of said subject at additional time points.
(Item 57)
57. The method of any one of items 49-56, wherein said second time point is 1-4 weeks after said first time point.
(Item 58)
58. The method of any one of items 49-57, further comprising evaluating said additional cell-free expression time points over a period of 12-24 months.
(Item 59)
59. The method of item 58, wherein said period of time is about 18 months.
(Item 60)
Item 49, further comprising tracking and/or detecting one or more cell-free expression profiles to measure one or more targets of interest for therapeutic and/or drug discovery and/or development. 60. The method of any one of paragraphs 1 to 59.
(Item 61)
61. The method of any one of items 49-60, further comprising measuring pharmacodynamics for lead optimization and/or clinical development in therapeutic and/or drug discovery and development.
(Item 62)
from item 49, further comprising profiling gene expression to characterize one or more pharmacodynamic effects associated with specific target engagement for therapeutic and/or drug discovery and/or development 62. The method of any one of clauses 61.
(Item 63)
63. The method of any one of items 49-62, further comprising detecting changes in pharmacodynamic target engagement for therapeutic and/or drug discovery and development.
Claims (59)
前記病状を有する前記被験体から得られた生体試料において、第１の複数の遺伝子に対応する、前記骨髄に常在するまたはこれに起源をもつ複数の細胞に由来する第１の複数の無細胞ｍＲＮＡ（ｃｆ－ｍＲＮＡ）のｃｆ－ｍＲＮＡレベルを検出するステップ
を含む、方法。 A method of analyzing cell-free mRNA (cf-mRNA) levels as an indicator for monitoring bone marrow pathology in a subject , comprising:
a first plurality of acellular cells derived from a plurality of cells residing in or originating from said bone marrow corresponding to a first plurality of genes in a biological sample obtained from said subject having said disease state; Detecting cf -mRNA level of mRNA (cf-mRNA)
A method , including
前記処置状況を有する前記被験体から得られた血漿試料において、第２の複数の遺伝子に対応する、前記被験体の臓器に由来する第２の複数の無細胞ｍＲＮＡ（ｃｆ－ｍＲＮＡ）のｃｆ－ｍＲＮＡレベルを検出するステップ
を含む、方法。 A method for analyzing cell-free mRNA (cf-mRNA) levels as an index for monitoring treatment status of an organ of a subject , comprising:
cf- of a second plurality of cell-free mRNAs (cf-mRNAs) from an organ of said subject corresponding to a second plurality of genes in a plasma sample obtained from said subject having said treatment status Detecting mRNA levels
A method , including
前記健康状況を有する前記被験体から得られた生体試料において、第３の複数の遺伝子に対応する、前記被験体の骨髄およびその由来細胞に由来する第３の複数の無細胞ｍＲＮＡ（ｃｆ－ｍＲＮＡ）のｃｆ－ｍＲＮＡレベルを検出するステップ
を含む、方法。 A method of analyzing cell-free mRNA (cf-mRNA) levels as an indicator for monitoring bone marrow health of a subject , comprising:
a third plurality of cell-free mRNAs (cf-mRNAs) derived from bone marrow and cells derived therefrom of said subject corresponding to a third plurality of genes in a biological sample obtained from said subject having said health status; ) detecting the cf -mRNA level of
A method , including
第１の時点で被験体の第１の無細胞発現プロファイルを評価するステップと、
前記被験体に前記活性薬剤を投与するステップと、
第２の時点で前記被験体の第２の無細胞発現プロファイルを評価するステップと
を含む、組成物。 A composition for use in a method of assaying an active agent, said composition comprising an active agent, said method comprising:
assessing a first cell-free expression profile of the subject at a first time point;
administering the active agent to the subject ;
and assessing a second cell-free expression profile of said subject at a second time point.
59. The composition of any one of claims 45-58 , wherein the method further comprises detecting changes in pharmacodynamic target engagement for therapeutic and/or drug discovery and development.
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| PCT/US2019/058380 WO2020092259A1 (en) | 2018-10-29 | 2019-10-28 | Characterization of bone marrow using cell-free messenger-rna |
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| WO2022221283A1 (en) * | 2021-04-13 | 2022-10-20 | Chan Zuckerberg Biohub, Inc. | Profiling cell types in circulating nucleic acid liquid biopsy |
| WO2023017099A1 (en) | 2021-08-10 | 2023-02-16 | Certara Usa, Inc. | Methods and apparatus utilising liquid biopsy to identify and monitor pharmacodynamic markers of disease |
| CA3239735A1 (en) * | 2021-11-30 | 2023-06-08 | Wanzin YAZAR | Generative adversarial network for urine biomarkers |
| WO2023147445A2 (en) * | 2022-01-27 | 2023-08-03 | Oregon Health & Science University | Cell-free rna biomarkers for the detection of cancer or predisposition to cancer |
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| ES2655642T3 (en) * | 2011-05-16 | 2018-02-21 | Ulrike Nuber | Novel cancer therapies and methods |
| SG11201505515XA (en) * | 2012-01-27 | 2015-09-29 | Univ Leland Stanford Junior | Methods for profiling and quantitating cell-free rna |
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