JP2021526819A - Bag3遺伝子治療の最適化 - Google Patents
Bag3遺伝子治療の最適化 Download PDFInfo
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Abstract
【選択図】 図1
Description
[0010]ある特定の実施形態では、心疾患を有する患者を診断及び処置する方法は、対照BAG3核酸配列と比較して患者試料中の少なくとも1つのBcl2関連アサノジーン3(BAG3)遺伝的バリアントを同定するステップであって、ある特定のバリアントの検出が、BAG3レベルの増加が前記患者に治療的であるかどうかを予測するステップ、及びかかるバリアントを有するとして同定された患者に、薬剤の治療有効量を投与するステップであって、前記薬剤がBAG3分子、そのタンパク質又はペプチドの標的細胞又は組織における発現又は量を正常対照と比較して調節するステップを含む。ほとんどアフリカ系の個体においてのみ見出されるBAG3における遺伝的バリアントは、疾患の原因ではなかったが、BAG3の機能の調節を通じて非虚血性又は虚血性拡張型心筋症を有する患者の転帰に悪影響を与えた。
[0027]他に定義する場合を除いて、本明細書で使用するすべての技術的及び科学的用語は、本発明が関連する当業者によって一般に理解されるものと同じ意味を有する。本明細書に記載のものと類似の又は同等の任意の方法及び材料は、本発明の検査のための実施において使用され得るが、ある特定の材料及び方法が本明細書に記載される。本発明の記載及び特許請求において、以下の用語が使用される。
[0073]40を超える遺伝子における遺伝的バリアントは、DCMと関連付けられている。かかる遺伝子の1つは、心臓、骨格筋において及び多数のがんにおいて主に発現されている進化的に保存されたタンパク質、BAG3(Bcl関連アサノジーン3)をコードしている。BAG3は、多面的な(pleotropic)効果を心臓に有する:それは、アポトーシスを阻害し、オートファジーを促進し、興奮収縮連関を調節し、筋節の完全性を維持し17、18、主なDCM遺伝子座として出現した19。いくつかの観察は、BAG3変異がアフリカ系アメリカ人において蔓延している可能性を示唆している:1)BAG3遺伝的バリアントは、隔離集団において最も蔓延している20;及び2)Genome Aggregation Database(gnomAD)は、ヨーロッパ系の個体におけるBAG3バリアントの対立遺伝子頻度と比較した場合に、アフリカ系個体において一般に見出されるBAG3バリアントの対立遺伝子頻度との間に著しい差異を示している21。いかなる特定の理論にも束縛されることを望むものではないが、BAG3バリアントがアフリカ系アメリカ人におけるIDCの有病率の増加の原因である可能性があることが仮定された。実施例セクションにおいて詳細に記載されるとおり、まれな例外を除いてアフリカ系の個体において見出される機能性BAG3バリアントの群がIDCを有する患者における転帰不良と関連しており、治療的介入のための正確な標的を提供する可能性があることが初めて見出された。
[0154]本明細書で具現化される組成物は、創薬及び標的の検証の領域においても適用され得る。本発明は、Bcl−2関連アサノジーン−3(BAG3)ポリヌクレオチドと疾患状態、表現型又は状態との間に存在する関係を明らかにする創薬の努力における本明細書において具現化される核酸配列及びペプチドの使用を包含する。方法は、患者試料中において、対照BAG3核酸配列と比較して少なくとも1つのBcl2関連アサノジーン3(BAG3)遺伝的バリアントを同定すること;及び、BAG3遺伝的多様性を有するとして同定された患者に薬剤の治療有効量を投与することを含み、ここで薬剤は、正常対照と比較して、BCL2関連アサノジーン3(BAG3)分子、そのタンパク質又はペプチドの標的細胞又は組織における発現又は量を調節する。ある特定の実施形態では、遺伝的バリアントは、単一ヌクレオチドバリアント(SNV)インフレーム挿入、欠失、置換又はこれらの組合せである。ある特定の実施形態では、SNVは:p.Pro63Ala(10:121429369C/G;rs133031999);p.His83Gln(10:151331972;rs151331972);Pro380Ser(10:121436204C/T;rs144692954);Ala479Val(10:121436502C/T、rs34656239)又はこれらの組合せを含む。ある特定の実施形態では、インフレーム挿入は、アミノ酸をコードしている。ある特定の実施形態では、インフレーム挿入は、非極性アミノ酸をコードしている。ある特定の実施形態では、インフレーム挿入は、160位にアラニンをコードしている。
[0194]診断、治療、キット
[0195]本明細書の組成物及び本発明の化合物は、診断、治療及び予防のために、並びに研究試薬として並びにキットの構成成分として利用され得る。
[0211]本明細書において具現化される方法によって同定される薬剤は、製剤化され得る、及び本発明の組成物は、1つ又は複数の追加的活性成分、医薬組成物又は他の化合物と併せて投与され得る。本発明の治療剤は、ヒトを含む哺乳動物などの動物に投与され得る。
[0238]患者:ゲノムDNAを、3つの米国臨床試験に登録したDCMを有し、そのDNAが預けられた509名のアフリカ系アメリカ人から得た:Genetic Risk Assessment of African Americans with Heart Failure(GRAHF)治験からの患者342名、(コホートA);22〜25、Intervention in Myocarditis and Acute Cardiomyopathy Trial−2からの患者109名(IMAC−2;コホートB);26及びGenetic Risk Assessment of Cardiac Events(GRACE)研究からの患者58名(コホートC)27、28。DNAは、University of Colorado(コホートD)又はUniversity of Pittsburgh(コホートE)で心臓移植を受けたアフリカ系の対象の左心室(LV)心筋からも得た。移植のために使用され得なかった非不全ヒト心臓組織を非不全対照として使用した29。DNA又は組織を前述の研究リポジトリに寄付したすべての患者からインフォームドコンセントを得て、手順は、参加施設それぞれのIRBによって承認された。
[0247]研究対象:DCMを有する合計509名のアフリカ系アメリカ人由来のゲノムDNAは、3つの独立した研究から得た:GRAHF(コホートA)からの患者342名;23、24GRACE(コホートB)からの患者109名;27、28及びIMAC−2(コホートC)からの患者58名26。急性心筋炎、周産期心筋症又はDCMについての任意の潜在的に改善可能な原因を有する場合、患者は分析から除外された26。GRAHF及びIMAC−2の患者は、死亡又はHF入院加療の心配のないエンドポイントまで経過観察した。GRACEの対象は、心臓移植又は死亡のエンドポイントまで経過観察した。
[0249]GRAHFコホートのサンガー配列決定は、18個のバリアント(表1)を明らかにし、その内8個は、同義であった。4個のSNVは、この研究についての選定基準に合致した:p.Pro63Ala(10:121429369C/G;rs133031999);p.His83Gln(10:151331972;rs151331972);Pro380Ser(10:121436204C/T;rs144692954);及びAla479Val(10:121436502C/T、rs34656239)。160位でタンパク質にアラニンを付加する3ヌクレオチドインフレーム挿入(p.Ala160dup;10:121429647A/AGCG)も同定した。サンガーの結果は、標的化配列決定によって確認した。p.Pro63Alaバリアントを保有するすべての個体は、p.Pro380Serバリアントも保有し、gnomAD中のこれら2つのSNVについての対応する対立遺伝子頻度は、ほとんど同一であり、2つのSNVがシスで連結している証拠を提供している。このことは、サンガー配列決定によって確認した。4個の同定されたBAG3バリアントを有する及び有さないアフリカ系のHF患者の特徴を表1に示す。連結されたSNVは、p.Pro63Ala+Pro380Serと称される。図1に見られるとおり、BAG3バリアントに影響を与える残基(His83、Ala160、Pro380及びAla479)は、哺乳動物にわたって高度に保存されている。
[0258]BAG3は、タンパク質品質管理、アポトーシス及び興奮/収縮連関を含む重要な細胞機能を制御する17。BAG3のレベルは、ヒト末期HFにおいて、及びLV機能障害の動物モデルにおいて低減している。BAG3不全の機能的重要性は、興奮収縮連関を損なうsiRNAによるBAG3のノックダウンによって実証され、BAG3ハプロ不全を有するマウスは、顕著なLV機能障害、オートファジーの減少及びアポトーシスの増加を10週齢までに示す32、35。本研究では、DCMを有するヨーロッパ系の個体においては認識できるレベルで見られなかった(0.00%)、2つの一般的な(>1%)非同義SNV、一般的な二重ヘテロ接合体バリアント及び3ヌクレオチドインフレーム挿入をDCMを有するアフリカの家系の対象において同定した。本研究の結果は、重要なBAG3機能の減少及びアフリカ系アメリカ人の排他性の両方が示されている以前の研究と異なる。
1. BenjaminEJ, Blaha MJ, Chiuve SE, et al. Heart Disease andStroke Statistics-2017 Update: A Report From the American Heart Association.Circulation. 2017;135(10):e146-e603.
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当業者は、単に日常的実験を使用して、本明細書に記載される本発明の具体的な実施形態への多数の等価物を認識及び確認できる。かかる等価物は、以下の特許請求の範囲によって包含されることが意図される。
[0001]本出願は、2018年6月8日出願の米国特許仮出願第62/682,404号に対する優先権を主張する。前述の出願の内容全体は、すべての文章、表、配列表及び図を含んで参照により本明細書に組み込まれる。
[0002]本発明は、National Institutes of Healthによって承認された助成金番号RO1 HL123093及びHL091799−01の政府の支援の下で実施された。政府は、本発明に一定の権利を有する。
Claims (33)
- 心疾患を有する患者を診断及び処置する方法であって、
対照BAG3核酸配列と比較して患者試料中の少なくとも1つのBcl2関連アサノジーン3(BAG3)遺伝的バリアントを同定するステップであって、ある特定の遺伝的バリアントの検出が、BAG3レベルの増加が前記患者に治療的であるかどうかを予測するステップ、及び
かかる遺伝的バリアントを有するとして同定された患者に薬剤の治療有効量を投与するステップであって、前記薬剤がBAG3分子、そのタンパク質又はペプチドの標的細胞又は組織における発現又は量を正常対照と比較して調節するステップを含む、方法。 - 前記バリアントの検出が、BAG3の機能の調節を通じて、非虚血性又は虚血性拡張型心筋症を有する患者の転帰に悪影響を与える、請求項1に記載の方法。
- 前記遺伝的バリアントが、ヌクレオチドバリアント(NV)インフレーム挿入、インフレーム欠失、短縮化、置換又はこれらの組合せである、請求項2に記載の方法。
- 前記インフレーム挿入がアミノ酸をコードしている、請求項3に記載の方法。
- 前記インフレーム挿入が非極性アミノ酸をコードしている、請求項3に記載の方法。
- 前記インフレーム挿入が160位にアラニンを付加する3ヌクレオチド挿入を含む(p.Ala160dup、10:121429647A/AGCG;rs139438727)、請求項3に記載の方法。
- 前記遺伝的バリアントが、単一ヌクレオチドバリアント(SNV)インフレーム挿入、インフレーム欠失、短縮化、置換又はこれらの組合せである、請求項2に記載の方法。
- 前記SNVが:p.Pro63Ala(10:121429369C/G;rs133031999);p.His83Gln(10:151331972;rs151331972);Pro380Ser(10:121436204C/T;rs144692954);Ala479Val(10:121436502C/T、rs34656239)又はこれらの組合せを含む、請求項4に記載の方法。
- 前記薬剤がBAG3タンパク質又はその活性断片を発現する発現ベクター、オリゴヌクレオチド又はこれらの組合せを含む、請求項1に記載の方法。
- 前記発現ベクターが、ウイルスベクター、心臓作用性ベクター、プラスミド、又は酵母ベクターを含む、請求項9に記載の方法。
- 心臓作用性ベクターがアデノウイルスベクター、アデノ随伴ウイルスベクター(AAV)、コクサッキーウイルスベクター、サイトメガロウイルスベクター、エプスタイン・バーウイルスベクター、パルボウイルスベクター又は肝炎ウイルスベクターを含む、請求項10に記載の方法。
- 前記発現ベクターが、心臓作用性偽型ウイルスベクターである、請求項11に記載の方法。
- 前記薬剤がタンパク質又はそのペプチド、ペプチド模倣物、小分子、有機又は無機化合物、合成又は天然化合物を含む、請求項1に記載の方法。
- 前記心疾患が心不全である、請求項1に記載の方法。
- 患者が対照BAG3核酸配列と比較して少なくとも1つのBcl2関連アサノジーン3(BAG3)ヌクレオチドバリアント(NV)インフレーム挿入を有し、前記患者に薬剤の治療有効量を投与するステップであって、前記薬剤が標的細胞又は組織においてBAG3分子、そのタンパク質又はペプチドの発現又は量を調節するステップを含む、心疾患を有する患者を処置する方法。
- 前記インフレーム挿入が、アミノ酸をコードしている、請求項15に記載の方法。
- 前記インフレーム挿入が、非極性アミノ酸をコードしている、請求項15に記載の方法。
- 前記インフレーム挿入が、160位にアラニンを付加する3ヌクレオチド挿入を含む(p.Ala160dup、10:121429647A/AGCG;rs139438727)、請求項15に記載の方法。
- 対照BAG3核酸配列と比較してBcl2関連アサノジーン3(BAG3)ヌクレオチドバリアント(NV)インフレーム挿入の存在について患者試料をスクリーニングするステップであって、BAG3ヌクレオチドバリアント(NV)インフレーム挿入の検出が悪い予後を有するとして心臓疾患患者を同定するステップを含む、悪い予後を有する心臓疾患患者を同定する方法。
- 対照BAG3核酸配列と比較してBcl2関連アサノジーン3(BAG3)ヌクレオチドバリアント(NV)インフレーム挿入の存在について患者試料をスクリーニングするステップであって、前記BAG3ヌクレオチドバリアント(NV)インフレーム挿入の検出が心臓疾患のリスクがあるとして前記患者を同定するステップを含む、心臓疾患のリスクがある患者を同定する方法。
- 前記インフレーム挿入がアミノ酸をコードしている、請求項19又は20に記載の方法。
- 前記インフレーム挿入が非極性アミノ酸をコードしている、請求項19又は20に記載の方法。
- 前記インフレーム挿入が、160位にアラニンを付加する3ヌクレオチド挿入を含む(p.Ala160dup、10:121429647A/AGCG;rs139438727)、請求項19又は20に記載の方法。
- Bcl2関連アサノジーン3(BAG3)遺伝的バリアントの存在について患者試料をスクリーニングするステップであって、前記BAG3遺伝的バリアントがp.Ala160dup(10:121429647A/AGCG;rs139438727);p.Pro63Ala(10:121429369C/G;rs133031999);p.His83Gln(10:151331972;rs151331972);Pro380Ser(10:121436204C/T;rs144692954);Ala479Val(10:121436502C/T、rs34656239)又はこれらの組合せを含むステップを含む、心臓疾患のリスクがある患者を同定する方法。
- 生物学的試料中のBCL2関連アサノジーン3(BAG3)バリアントを同定するための検出可能な標識にコンジュゲートされた1つ又は複数のプローブを含む、キット。
- 前記BAG3バリアントが:p.Ala160dup(10:121429647A/AGCG;rs139438727);p.Pro63Ala(10:121429369C/G;rs133031999);p.His83Gln(10:151331972;rs151331972);Pro380Ser(10:121436204C/T;rs144692954);又はAla479Val(10:121436502C/T、rs34656239)の1つ又は複数を含む、請求項25に記載のキット。
- ある特定のバリアントの検出が、対象が処置から利益を得るかどうかを予測する、請求項25に記載のキット。
- BCL2関連アサノジーン3(BAG3)分子の発現又は量を調節する少なくとも1つの薬剤の治療有効量を含む医薬組成物を対象に投与するステップであって、前記対象が対照BAG3核酸配列と比較して少なくとも1つのBAG3遺伝的バリアントを有し、前記BAG3遺伝的バリアントがインフレーム挿入であり、前記薬剤がBCL2関連アサノジーン3(BAG3)分子をコードしている発現ベクターを含むステップを含む、心不全のリスクがある、又はそれを罹患している対象を処置する方法。
- 前記インフレーム挿入がアミノ酸をコードしている、請求項28に記載の方法。
- 前記インフレーム挿入が非極性アミノ酸をコードしている、請求項28に記載の方法。
- 前記インフレーム挿入が、160位にアラニンを付加する3ヌクレオチド挿入を含む(p.Ala160dup、10:121429647A/AGCG;rs139438727)、請求項28に記載の方法。
- BAG3レベルにおける増加が対象に治療的であるかどうかを予測するバリアントを生物学的試料において同定するステップ、及びかかるバリアントを有するとして同定された患者に薬剤の治療有効量を投与するステップであって、前記薬剤がBAG3分子、そのタンパク質又はペプチドの標的細胞又は組織における発現又は量を正常対照と比較して調節するステップをさらに含む、請求項28に記載の方法。
- 前記遺伝的バリアントが疾患の原因ではないが、BAG3の機能の調節を通じて非虚血性又は虚血性拡張型心筋症を有する患者の転帰に悪影響を与える、請求項1〜8のいずれか一項に記載の方法。
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CA3103167A1 (en) | 2019-12-12 |
KR20210030342A (ko) | 2021-03-17 |
EP3802576A4 (en) | 2022-06-15 |
US20210254159A1 (en) | 2021-08-19 |
MX2020013334A (es) | 2021-05-27 |
BR112020025071A2 (pt) | 2021-03-23 |
SG11202012223UA (en) | 2021-01-28 |
AU2019281008A1 (en) | 2021-01-28 |
EP3802576A1 (en) | 2021-04-14 |
WO2019237002A1 (en) | 2019-12-12 |
CN113015742A (zh) | 2021-06-22 |
IL279281A (en) | 2021-01-31 |
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