JP2020507059A - ヘモグロビンβ及び鎌状赤血球ヘモグロビンβのための質量分析スタンダードならびにその使用 - Google Patents
ヘモグロビンβ及び鎌状赤血球ヘモグロビンβのための質量分析スタンダードならびにその使用 Download PDFInfo
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Abstract
Description
Claims (14)
- 遺伝子改変された溶血血液サンプルにおける鎌状赤血球突然変異の補正のレベルを評価する方法であって、
(a)トリプシンと共に前記サンプルをインキュベーションしてヘモグロビンの断片を得て、そこで、前記ヘモグロビン断片がHBBペプチド及びHBSペプチドを含むことと;
(b)液体クロマトグラフィーによって、前記トリプシン処理されたサンプル中の他の構成要素から前記HBBペプチド及びHBSペプチドをクロマトグラフィー分離することと;
(c)前記クロマトグラフィー分離されたHBBペプチド及びHBSペプチドを質量分析によって分析して前記溶血血液サンプルにおけるHBB/HBS比を決定し、そこで、前記HBB/HBS比が、ステップ(c)の質量分析の結果を、配列番号1(VHLTPEEKS)を含む合成HBBペプチド対配列番号2(VHLTPVEKS)を含む合成HBSペプチドの既知の比のトリプシン消化物についての質量分析の結果から生成されたスタンダードカーブと比較することによって決定されることと、
を含む、前記方法。 - 前記スタンダードカーブが、
(a)一連のスタンダード溶液を調製し、そこで、一連のスタンダード溶液のメンバーが、配列番号1(VHLTPEEKS)を含む前記合成HBBペプチド及び配列番号2(VHLTPVEKS)を含む前記合成HBSペプチドの異なる既知の比を含有していることと;
(b)ステップ(a)の前記スタンダード溶液をトリプシンと共にインキュベーションすることと;
(c)液体クロマトグラフィーによって、前記インキュベーションされたスタンダード溶液中の他の構成要素から前記合成HBBペプチド及び合成HBSペプチドをクロマトグラフィー分離することと;
(d)各々のスタンダード溶液について前記クロマトグラフィー分離された合成HBBペプチド及び合成HBSペプチドを質量分析によって分析することと;
(e)各々のスタンダード溶液について前記合成HBBペプチド及び合成HBSペプチドの質量分析のピーク体積を決定することと;
(f)スタンダードカーブを生成することと、
によって生成される、請求項1に記載の方法。 - 前記一連のスタンダード溶液が、100:0の合成HBB/合成HBS比を含有する第1の溶液、90:10の合成HBB/合成HBS比を含有する第2の溶液、80:20の合成HBB/合成HBS比を含有する第3の溶液、70:30の合成HBB/合成HBS比を含有する第4の溶液、60:40の合成HBB/合成HBS比を含有する第5の溶液、50:50の合成HBB/合成HBS比を含有する第6の溶液、40:60の合成HBB/合成HBS比を含有する第7の溶液、30:70の合成HBB/合成HBS比を含有する第8の溶液、20:80の合成HBB/合成HBS比を含有する第9の溶液、10:90の合成HBB/合成HBS比を含有する第10の溶液、及び0:100の合成HBB/合成HBS比を含有する第11の溶液を含む、請求項2に記載の方法。
- 前記溶血血液サンプルが、遺伝子改変を含む被験体からの血漿サンプルから得られる、請求項1〜3のいずれか一項に記載の方法。
- 前記溶血血液サンプルが、遺伝子改変を含む被験体からの赤血球の集団から得られる、請求項1〜4のいずれか一項に記載の方法。
- 前記赤血球が、遺伝子改変された造血幹細胞または誘導された多能性幹細胞から分化し、前記細胞が、ヘモグロビンをコードするゲノム配列中の鎌状赤血球突然変異を補正するように治療された、請求項1〜3のいずれか一項に記載の方法。
- ヘモグロビンをコードするゲノム配列中で補正された鎌状赤血球突然変異を有する複数の遺伝子改変された造血幹細胞を含む造血幹細胞の集団が、被験体における鎌状赤血球疾患の1つまたは複数の症状を低減するのに有効かどうかを決定する方法であって、
(a)前記造血幹細胞の集団の第1の亜集団を赤血球へと分化させることと;
(b)前記造血幹細胞の集団の第2の亜集団を保存しておくことと;
(c)前記赤血球から溶血血液サンプルを得ることと;
(d)トリプシンと共に前記溶血血液サンプルをインキュベーションすることと;
(e)液体クロマトグラフィーによって、前記トリプシン処理されたサンプル中の他の構成要素からHBBペプチド及びHBSペプチドをクロマトグラフィー分離することと;
(f)前記クロマトグラフィー分離されたHBBペプチド及びHBSペプチドを質量分析によって分析することと;
(g)前記溶血血液サンプルにおける前記HBB/HBS比を決定し、そこで、約30%以上のHBB/HBS比が、造血幹細胞の保存しておいた亜集団は前記被験体における鎌状赤血球疾患の1つまたは複数の症状の低減に有効であろうことを決定することと、
を含む、前記方法。 - 前記HBB/HBS比が、ステップ(g)の前記結果を、配列番号1(VHLTPEEKS)を含む合成HBBペプチド対配列番号2(VHLTPVEKS)を含む合成HBSペプチドの既知の比のトリプシン消化物についての前記質量分析の結果から生成されたスタンダードカーブと比較することによって決定される、請求項7に記載の方法。
- 前記スタンダードカーブが、
(a)一連のスタンダード溶液を調製し、そこで、一連のスタンダード溶液のメンバーが、配列番号1(VHLTPEEKS)を含む前記合成HBBペプチド及び配列番号2(VHLTPVEKS)を含む前記合成HBSペプチドの異なる既知の比を含有していることと;
(b)ステップ(a)の前記スタンダード溶液をトリプシンと共にインキュベーションすることと;
(c)液体クロマトグラフィーによって、前記インキュベーションされた溶液中の他の構成要素から前記合成HBBペプチド及び合成HBSペプチドをクロマトグラフィー分離することと;
(d)各々のスタンダード溶液について前記クロマトグラフィー分離された合成HBBペプチド及び合成HBSペプチドを質量分析によって分析することと;
(e)各々のスタンダード溶液について前記合成HBBペプチド及び合成HBSペプチドの質量分析のピーク体積を決定することと;
(f)スタンダードカーブを生成することと、
によって生成される、請求項8に記載の方法。 - 前記一連の溶液が、100:0の合成HBB/合成HBS比を含有する第1の溶液、90:10の合成HBB/合成HBS比を含有する第2の溶液、80:20の合成HBB/合成HBS比を含有する第3の溶液、70:30の合成HBB/合成HBS比を含有する第4の溶液、60:40の合成HBB/合成HBS比を含有する第5の溶液、50:50の合成HBB/合成HBS比を含有する第6の溶液、40:60の合成HBB/合成HBS比を含有する第7の溶液、30:70の合成HBB/合成HBS比を含有する第8の溶液、20:80の合成HBB/合成HBS比を含有する第9の溶液、10:90の合成HBB/合成HBS比を含有する第10の溶液、及び0:100の合成HBB/合成HBS比を含有する第11の溶液を含む、請求項9に記載の方法。
- 前記細胞の第2の亜集団が、鎌状赤血球疾患を有する被験体の中へ移植される、請求項7〜10のいずれか一項に記載の方法。
- 前記被験体における鎌状赤血球疾患の前記症状が低減または消失される、請求項11に記載の方法。
- 前記遺伝子改変が相同組み換え修復を含む、請求項7〜12のいずれか一項に記載の方法。
- a)精製されたHBBペプチドを含む組成物であって、前記ペプチドが配列番号1を含み、前記組成物が全長ヘモグロビンβ(HBB)ポリペプチド配列を含まない、前記組成物と;
b)精製されたHBSペプチドを含む組成物であって、前記ペプチドが配列番号2を含み、前記組成物が全長鎌状赤血球ヘモグロビンβ(HBS)ポリペプチド配列を含まず、前記HBBペプチド及び前記HBSペプチドのうちの1つまたは複数がマーカーを含む、前記組成物と、
を含む、キット。
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