JP2023002565A - 広範囲の宿主範囲を有するバクテリオファージバリアント、核酸を目的の宿主に形質導入する際のその調製方法及び用途 - Google Patents
広範囲の宿主範囲を有するバクテリオファージバリアント、核酸を目的の宿主に形質導入する際のその調製方法及び用途 Download PDFInfo
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Abstract
Description
[1]Citorik,R.J.,Mimee,M.& Lu,T.K.Sequence-specific antimicrobials using efficiently delivered rna-guided nucleases.Nat Biotechnol(2014)
[2]Bikard,D.等Exploiting crispr-cas nucleases to produce sequence-specific antimicrobials.Nat Biotechnol 32,1146-1150(2014)
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[5]Yosef,I.,Kiro,R.,Molshanski-Mor,S.,Edgar,R.& Qimron,U.Different approaches for using bacteriophages against antibiotic-resistant bacteria.Bacteriophage 4,e28491(2014)
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[12]Goren,M.G.,Yosef,I.& Qimron,U.Programming bacteriophages by swapping their specificity determinants.Trends Microbiol 23,744-746(2015)
[13]Chung,Y.B.& Hinkle,D.C.Bacteriophage T7 DNA packaging.I.Plasmids containing a T7 replication origin and the T7 concatemer junction are packaged into transducing particles during phage infection.J Mol Biol 216,911-926(1990)
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本明細書に記載の参考文献の謝辞は、本開示の主題の特許性に何らかの関連性があることを意味して推論されるものではない。
本発明のさらなる態様は、目的の核酸分子を目的の標的宿主細胞(複数可)に形質導入する方法に関し、方法は、以下のステップを含む。
図面において、
1)アラニン(A)、グリシン(G);
2)アスパラギン酸(D)、グルタミン酸(E);
3)アスパラギン(N)、グルタミン(Q);
4)アルギニン(R)、リジン(K);
5)イソロイシン(I)、ロイシン(L)、メチオニン(M)、バリン(V);
6)フェニルアラニン(F)、チロシン(Y)、トリプトファン(W);
7)セリン(S)、スレオニン(T);及び
8)システイン(C)、メチオニン(M)
本発明のさらなる態様は、以下を含むキットに関する。
より具体的には、このようなバクテリオファージは、(a)少なくとも1つの改変した宿主認識要素、及び任意に(b)目的の少なくとも1つの核酸分子を含むことができる。
試薬、株及びプラスミド
Luria-Bertani(LB)培地(トリプトン10g/L、酵母抽出物5g/L、及びNaCl5g/L)及び寒天は、Acumedia製であった。2YT培地は、Bacto-トリプトン1.6%(w/v)(Acumedia)、Bacto-酵母抽出物(Acumedia)1%(w/v)、及び蒸留水中のNaCl0.5%(w/v)(Acumedia)を含んだ。抗生物質、リゾチーム、L‐アラビノース及びマルトースは、Calbiochemに由来した。制限酵素、ライゲーション酵素、DNA修飾酵素、及びPhusion(登録商標)高忠実度DNAポリメラーゼは、New England Biolabs製であった。本発明で使用する細菌株及びファージは、表1に列挙する。
標準的な分子生物学技術を用いてプラスミドを構築した。DNAセグメントはPCRで増幅した。標準DNA消化及びライゲーションは、製造者の指示に従って行った。本発明で使用するファージ尾遺伝子を表2に列挙し、GeneScriptによって最適化し、合成したコドンであった。本研究で使用したプラスミドを表3に列挙し、構築に使用したオリゴヌクレオチドを表4に挙げ、構築に使用したプライマー及びテンプレートを表5に挙げた。
BW25113ΔtrxA::kanをKeioコレクション(15)から得た。BW25113ΔtrxAΔwaaCをpCP2016)を用いてカナマイシン耐性マーカーを切除することによって構築した。得た株(BW25113ΔtrxA)をドナー株としてKeioコレクションのBW25113ΔwaaC::kanを用いてP1形質導入のアクセプター株として使用した。P1形質導入は、Yosef等,2011(18)に記載のように実施した。
一晩、T7パッケージングプラスミドを内部に有するE.coli BW25113の培養物を適切な抗生物質を含むLB培地5mlに1:50に希釈した。培地を37℃で数時間曝気した。中間対数期に到達したときに、細胞を2回洗浄し、リン酸緩衝生理食塩水(PBS)に再懸濁した。その後、EMS(Sigma-Aldrich)を培地に1%加え、細胞を37℃で1時間曝気した。細胞をPBSで3回洗浄し、適切な抗生物質を補充した50mlのLBに再懸濁し、37℃で16時間曝気した。一晩の培地を使用して、以下に記載のT7ファージのライブラリを調製した。この手順は、本発明のパッケージングプラスミド、例えば、パッケージングプラスミドpIYPE19(その核酸配列はSEQ ID NO:24に記載)を調製するために使用し、パッケージングプラスミドpIYPE19は、尾繊維タンパク質gp11、gp12及びgp17の少なくとも1つ(それぞれSEQ ID NO:34、39、25に記載)、パッケージングシグナル(複数可)(例えば、SEQ ID NO:20、21、22又は23)及び抗生物質耐性遺伝子(SEQ ID NO.44に記載)の少なくとも1つをコードする核酸配列を特異的に変異する配列を含み、適切な抗生物質を含む2YT培地に1:50で希釈した。
遺伝子17の代わりにtrxA-FLPを有するT7ファージを前述(17)の相同組み換えによって構築した。端的には、pGEMIY398F(gp17をコード)及びpCAIY396(遺伝子17の末端に対して隣接する相同配列でtrxA-FLPをコード)を有するBW25113細胞を一晩培養した。その後、trxAをコードするファージをBW25113ΔtrxA/pGEMIY398Fで選択した。FLPリコンビナーゼを使用して、trxA遺伝子をBW25113/pGEMIY398F/pAC-FRTのファージの連続的伝播によって、T7Δ17trxA-FLPファージからtrxA遺伝子を切除した。最後に、T7Δ17ファージを(17)に記載のように単離した。
T7パッケージングシグナル及び尾タンパク質をコードするプラスミドを内部に有するドナー株E.coli BW25113を一晩培養したものをLBで1:5に希釈し、37℃で追加の時間、曝気した。細胞を遠心分離で洗浄し、新鮮なLBで再懸濁した。培養物を約2の感染効率(MOI)で、T7Δ(11-12-17)の約5*108PFUで感染させた。感染させた培養物を溶解が発生するまで、37℃で1.5~2時間曝気した。溶解した後、クロロホルムを添加し、可溶化液を最大速度で2分間遠心分離にかけた。得られた可溶化液は、ファージDNAを粒子の約半分及びプラスミドコーディング遺伝子11、12、及び17を含む粒子の半分を含んでいた。プラスミドの形質導入の特異性を決定するための実験において、2つのプラスミド:T7パッケージングシグナルを有するプラスミド、及びパッケージングシグナルを欠失している尾タンパク質を内部に有する追加のプラスミドの一晩の培養物がE.coli BW25113を有していたことを除いて、可溶化液を前述のように調製した。
抗生物質を補充した無菌LBを、trxA遺伝子(BW25113ΔtrxA又はΔtrxAΔwaaC)(16)を欠失しているレシピエントE.coli株の単一コロニーに接種させた。培養物を37℃で一晩、250rpmで振盪した。次の朝、新鮮な一晩の培養物を、抗生物質を補充した5mlのLBに1/50で希釈し、約0.5のO.Dに達するまで37℃で振盪した。レシピエント培養物を使用するまで氷の上で保管した。
指数関数的培養期のレシピエント細胞を、前述のように調製したT7 TFU可溶化液の連続希釈で、1:1比(v/v)で混合した。培養物を振盪しながら37℃で60分間インキュベートした。次に、培養物を適切な抗生物質を含むLB-寒天プレートに置き、37℃で一晩インキュベートした。TFU/mlを、示した参照株で得られた108形質導入体に正規化した。
総量10mlのレシピエント細胞及びT7 TFU可溶化液による形質導入アッセイを前述のように行った。形質導入体を選択的プレートからプールし、プラスミドを抽出した。精製したプラスミド(100ng)をBW25113に再形質転換し、50μg/mlのカナマイシンを補充したLBプレートに播種した。形質転換体を一晩のインキュベーション(約1*106)の後に回収し、前述のようにEMSで変異誘発させた。T7可溶化液をEMS処理細胞から調製し、レシピエント細胞を形質導入するために使用した。T7可溶化液は、レシピエント細胞のTFUを正規化するために、参照株を形質導入するためにも使用した。
野生型パッケージプラスミドからの許容的T7受容体結合タンパク質の選択
T7ファージの尾タンパク質が、T7ファージによる異なる宿主の認識を示すことを以前に示した(10)。ファージの宿主範囲を拡張する以前の試みは、宿主のファージの増殖を指示する能力に依存した(10)。ユニークな選択圧力下で、これらの尾タンパク質の定向進化によって、これらの宿主に伝播するファージの能力に関わらず、核酸(例えばDNA)を望ましい宿主に挿入するために使用することができることが推測される。
ハイブリッドT7ファージはDNAを新しい宿主に効率的に形質導入する
本明細書の実施例1に示し、実証したように、T7ファージはプラスミドをパッケージし、形質導入するため、本発明の発明者は、異なる尾が異なる宿主の特異性を決定し、上手くこれらの宿主に伝播させるファージの能力に関わらず、望ましい宿主にDNA形質導入することができると仮説を立てた。ここで、プラスミドをパッケージするために使用するT7ファージは、その尾遺伝子(遺伝子11、12、及び17)を欠失していた。結果として、形質導入粒子への成熟は、形質導入されたプラスミドによってトランスに産生される尾遺伝子に依存する。したがって、プラスミド形質導入は、尾遺伝子産物がハイブリッド粒子に構築される場合にのみ、及びこの尾遺伝子産物が形質導入した宿主の受容体を認識する場合にのみ、生じる可能性がある(図3A)。望ましいハイブリッドは、抗生物質耐性を標的宿主に与えるプラスミド形質導入を可能にする。さらに、本発明の発明者の仮説を支持する本発明のプラットフォームを確立するために、前述の表2に記載の15個の異なるファージの尾遺伝子、ならびに抗生物質耐性マーカー及びT7パッケージング配列をコードするプラスミドを設計した(13)。
変異誘発した野生型パッケージプラスミドからの許容的T7受容体結合タンパク質の選択
さらに、適合性のプラスミド(すなわち、適合性の受容体結合タンパク質をコードするプラスミド)を変異したパッケージプラスミドの集団から選択し、尾タンパク質のバリアントをコードすることを次に実証した。本発明の発明者は、コードする改変した尾遺伝子によってより効率的に形質導入されたプラスミドを選択することによって、形質導入効率を改善することができるという仮説を立てた。より具体的には、本発明の発明者は、DNA形質導入の実験において、このような改変した尾をコードするプラスミドが親の尾をコードするプラスミドよりも効率的に形質導入され、その理由は、改変した尾をコードするプラスミドを示す粒子が、親の尾を示す粒子よりも優れてDNAを形質導入するためであると推測した。以下のいくつかの形質導入サイクルに従って、形質導入したプラスミドを回収し、使用して、より多くのハイブリッド粒子を産生し、高い形質導入能力を有する尾タンパク質をコードする変異体プラスミドの単離が可能になる(図4A)。この原理は、本明細書に記載の手順「GOTraP」を発展させることに基づいていた。
望ましい核酸分子の目的のレシピエント標的宿主細胞への形質導入
前述のように、望ましい宿主を認識する適切な尾及び尾タンパク質を選択することで望ましいDNA送達を可能にすると思われる。これらの尾タンパク質をパッケージングシグナルのないプラスミドにクローンする。追加のプラスミド、すなわち、例えば、CRISPR-Cas又は他の抗生物質感作要素、又はパッケージングシグナルをコードする望ましいDNAを含む送達される構築物を同時導入する。これらのファージを有する2つのプラスミドを内部に有する宿主の感染によって、望ましいDNAを望ましい宿主に注入する適合性の尾タンパク質を有するハイブリッドファージにする。
Claims (43)
- a.少なくとも1つの宿主認識要素又はそのバリアント、変異体、タンパク質又はフラグメントをコードする複数の核酸分子を提供し、前記核酸分子は、少なくとも1つのパッケージングシグナル、及び選択可能な要素をコードする少なくとも1つの核酸配列をさらに含み、
b.前記複数の核酸分子を含む第1宿主細胞(複数可)を、前記送達ビヒクルのパッケージング及び/又は伝播を可能にする条件下で、少なくとも1つの不完全な宿主認識要素又はそのタンパク質又はフラグメントをコードする核酸配列(複数可)を有する送達ビヒクルに接触させ、前記第1宿主細胞に伝播し、及び/又はパッケージした得られた送達ビヒクルバリアントを回収し、
c.第2宿主細胞(複数可)をステップ(b)で回収した送達ビヒクルバリアントに接触させ、
d.前記選択可能な要素を含むステップ(c)で得た宿主細胞を選択し、
e.少なくとも1つの宿主認識要素(複数可)又は同要素をコードする核酸配列を、ステップ(d)で選択した宿主細胞(複数可)から単離し、及び/又は特徴付けして、少なくとも1つの前記第2宿主細胞、及び目的の前記標的細胞(複数可)、又は同標的細胞をコードする核酸配列に適合性の少なくとも1つの宿主認識要素を得ることを含む、目的の標的細胞に適合する宿主認識要素(複数可)を調製し、識別し、及び/又は単離する方法。 - 前記方法がステップ(a)で提供された前記複数の核酸分子を変異誘発し、それにより少なくとも1つの変異した宿主認識要素をコードする複数の核酸分子を得ることをさらに含む請求項1に記載の方法。
- ステップ(a)、(b)、(c)、(d)及び(e)の少なくとも1つが少なくとも1回以上繰り返される請求項1及び2の何れか一項に記載の方法。
- 前記送達ビヒクルが少なくとも1つのバクテリオファージである請求項1から3の何れか一項に記載の方法。
- 前記バクテリオファージが少なくとも1つのT7様ウイルスである請求項4に記載の方法。
- 前記第2宿主細胞及び目的の前記標的細胞の少なくとも1つが原核生物及び真核生物宿主細胞の何れか1つである請求項1から5の何れか一項に記載の方法。
- 前記原核生物細胞が、Escherichia coli(E.coli)、シュードモナス菌種、ブドウ球菌種、連鎖球菌種、サルモネラ菌種、赤痢菌種、クロストリジウム種、腸球菌種、クレブシエラ菌種、アシネトバクター菌種、エルシニア菌種及びエンテロバクター菌種、又は変異体、バリアント単離体又はその組み合わせの少なくとも1つの細菌細胞である請求項6に記載の方法。
- 前記第2宿主細胞が目的の前記標的細胞(複数可)と同一又は類似する請求項1から7の何れか一項に記載の方法。
- 前記宿主認識要素が前記バクテリオファージの尾領域に存在する少なくとも1つのタンパク質を含む請求項3から8の何れか一項に記載の方法。
- 前記バクテリオファージの尾領域に存在する前記少なくとも1つのタンパク質が尾タンパク質及び繊維タンパク質の少なくとも1つである請求項9に記載の方法。
- 前記選択可能な要素が抗生物質耐性遺伝子であり、前記選択ステップ(d)が前記抗生物質の存在下で前記宿主細胞を増殖させることを含む請求項1から10の何れか一項に記載の方法。
- a.少なくとも1つの宿主認識要素又はそのバリアント、変異体、タンパク質又はフラグメントをコードする複数の核酸分子を提供し、前記核酸分子は、少なくとも1つのパッケージングシグナル、及び選択可能な要素をコードする少なくとも1つの核酸配列をさらに含み、
b.前記複数の核酸分子を含む第1宿主細胞(複数可)を、前記送達ビヒクルのパッケージング及び/又は伝播を可能にする条件下で、少なくとも1つの不完全な宿主認識要素又はそのタンパク質又はフラグメントをコードする核酸配列(複数可)を有する少なくとも1つの送達ビヒクルに接触させ、前記第1宿主細胞にパッケージし、及び/又は伝播した得られた送達ビヒクルバリアントを回収し、
c.第2宿主細胞をステップ(b)で回収した送達ビヒクルバリアントに接触させ、
d.前記選択可能な要素を含むステップ(c)で得た宿主細胞(複数可)を選択し、
e.少なくとも1つの宿主認識要素又は同要素をコードする核酸配列を、ステップ(d)で選択した宿主細胞(複数可)から単離し、及び/又は特徴付けして、前記第2宿主細胞、又は同宿主細胞をコードする核酸配列に適合性の少なくとも1つの前記宿主認識要素を得て、
f.ステップ(e)で得た前記適合性の宿主認識要素をコードする少なくとも1つの配列を含む少なくとも1つの核酸配列を第3宿主細胞に導入し、前記第3宿主細胞(複数可)を少なくとも1つの不完全な宿主認識要素又はそのタンパク質又はフラグメントをコードする核酸配列(複数可)を有する送達ビヒクルに接触させ、それにより目的の核酸分子を目的の標的細胞に送達することができる少なくとも1つの前記適合性の宿主認識要素を含む送達ビヒクルバリアントを得るステップを含む核酸送達ビヒクルの調製方法。 - 前記方法がステップ(a)で提供された前記複数の核酸分子を変異誘発し、それにより少なくとも1つの変異した宿主認識要素をコードする複数の核酸分子を得ることをさらに含む請求項12に記載の方法。
- ステップ(a)、(b)、(c)、(d)及び(e)の少なくとも1つが少なくとも1回以上繰り返される請求項12及び13の何れか一項に記載の方法。
- 前記送達ビヒクルが少なくとも1つのバクテリオファージである、請求項12から14の何れか一項に記載の方法。
- 前記第2宿主細胞及び目的の前記標的細胞の少なくとも1つが原核生物及び真核生物宿主細胞である請求項12から15の何れか一項に記載の方法。
- 前記第2宿主細胞が目的の前記標的細胞(複数可)と同一又は類似する請求項12から16の何れか一項に記載の方法。
- 前記宿主認識要素が前記バクテリオファージの尾領域に存在する少なくとも1つのタンパク質を含む請求項12から17の何れか一項に記載の方法。
- 前記第3宿主細胞(複数可)が少なくとも1つのパッケージングシグナルに操作可能に結合してもよい少なくとも1つの目的の核酸分子をさらに含み、ステップ(f)で得た前記送達ビヒクルがそこにパッケージされた目的の前記核酸分子をさらに含む請求項12に記載の方法。
- a.少なくとも1つのパッケージングシグナルに操作可能に結合してもよい目的の核酸分子の少なくとも1つを提供し、
b.少なくとも1つの宿主認識要素(複数可)又はそのバリアント、変異体、タンパク質又はフラグメントをコードする核酸配列(複数可)を提供し、前記認識要素は目的の前記標的細胞に適合することができ、
c.(a)の核酸分子、(b)の核酸配列、又は(a)の核酸分子を含む核酸配列、及び(b)の核酸配列を宿主細胞(複数可)に導入して、目的の核酸分子を含む宿主細胞(複数可)及び適合性の宿主認識要素をコードする核酸配列を含む宿主細胞(複数可)を得て、
d.ステップ(c)で得た前記宿主細胞(複数可)を、少なくとも1つの不完全な宿主認識要素(複数可)又はそのタンパク質又はフラグメントをコードする核酸配列(複数可)を有する送達ビヒクルに接触させ、
e.(d)の感染した宿主細胞から、そこにパッケージした目的の前記核酸分子を含む送達ビヒクル(複数可)を回収し、前記送達ビヒクル(複数可)は、目的の前記標的細胞に適合性の前記宿主認識要素(複数可)を含み、
f.対象、組織、臓器、表面、前記標的細胞(複数可)を含む物質及び物品の少なくとも1つの目的の標的細胞(複数可)を、有効量のステップ(e)で得た前記送達ビヒクル(複数可)の少なくとも1つに接触させ、それにより目的の前記核酸分子を目的の前記標的宿主細胞に形質導入することを含む目的の核酸分子を目的の標的宿主細胞に形質導入する方法。 - ステップ(b)で提供される少なくとも1つの適合性の宿主認識要素(複数可)をコードする前記核酸配列(複数可)が、
a.少なくとも1つの宿主認識要素又はそのバリアント、変異体、タンパク質又はフラグメントをコードする複数の核酸分子を提供し、前記核酸分子は、少なくとも1つのパッケージングシグナル、及び選択可能な要素をコードする少なくとも1つの核酸配列をさらに含み、
b.前記複数の核酸分子を含む第1宿主細胞(複数可)を、前記送達ビヒクルのパッケージング及び/又は伝播を可能にする条件下で、少なくとも1つの不完全な宿主認識要素又はそのタンパク質又はフラグメントをコードする核酸配列(複数可)を有する送達ビヒクルに接触させ、前記第1宿主細胞にパッケージし、及び/又は伝播した得られた送達ビヒクルバリアントを回収し、
c.第2宿主細胞(複数可)をステップ(b)で回収した送達ビヒクルバリアント(複数可)に接触させ、
d.前記選択可能な要素を含むステップ(c)で得た宿主細胞(複数可)を選択し、
e.宿主認識要素(複数可)又は同要素をコードする核酸配列を、ステップ(d)で選択した宿主細胞から単離し、及び/又は特徴付けして、前記目的の標的細胞又は前記標的細胞をコードする核酸配列に適合性の宿主認識要素を得るステップを含む方法によって得た請求項20に記載の方法。 - 前記適合性の宿主認識要素(複数可)が請求項2から11の何れか一項に規定される方法によって調製する請求項21に記載の方法。
- 目的の前記核酸配列が、
a.少なくとも1つのcas遺伝子及び少なくとも1つのクラスター化され、通常はクラスター化して規則的な配置の短い回文配列リピート(CRISPR)アレイを含む少なくとも1つの感作成分であり、前記CRISPRの少なくとも1つのスペーサーは、目的の標的宿主細胞の病原性又は望ましくない遺伝子の内部に含まれるプロトスペーサーを標的にし、前記病原性又は望ましくない遺伝子を特異的に不活性にし、前記CRISPR標的の少なくとも1つのスペーサーは、選択的成分の内部に含まれるプロトスペーサーを標的にし、前記選択的成分を特異的に不活性にし、
b.少なくとも1つのプロトスペーサーを含む少なくとも1つの核酸配列の何れか1つを含む請求項20から22の何れか一項に記載の方法。 - 目的の前記標的宿主細胞(複数可)を含む細胞集団を操作する請求項21から23の何れか一項に記載の方法。
- a.少なくとも1つの宿主認識要素又はそのバリアント、変異体、タンパク質又はフラグメントをコードする複数の核酸分子であって、前記核酸分子は、少なくとも1つのパッケージングシグナル、少なくとも1つの核酸配列及び選択可能な要素をコードする配列をさらに含み、
b.少なくとも1つの不完全な宿主認識要素(複数可)又はそのタンパク質又はフラグメントをコードする核酸配列(複数可)を有する少なくとも1つの送達ビヒクル、
c.前記選択可能な要素を有する細胞を選択するための少なくとも1つの化合物を含むキット。 - 前記送達ビヒクルが少なくとも1つのバクテリオファージである、請求項25に記載のキット。
- 前記宿主認識要素が前記バクテリオファージの尾領域に存在する少なくとも1つのタンパク質を含む、請求項25から26の何れか一項に記載のキット。
- 核酸送達ビヒクルの宿主範囲を拡張する又は調整する方法において使用する請求項25から27の何れか一項に記載のキット。
- 前記送達ビヒクルが請求項12から19の何れか一項に規定される方法によって調製される請求項28に記載のキット。
- a.少なくとも1つの改変した宿主認識要素(複数可)又はそのバリアント、変異体、タンパク質又はフラグメントであって、前記改変した認識要素は目的の前記標的細胞に適合することができ、任意に
b.目的の少なくとも1つの核酸分子を含む改変バクテリオファージ。 - 目的の前記標的細胞(複数可)が原核生物及び真核生物宿主細胞(複数可)の何れか1つである、請求項30に記載の改変バクテリオファージ。
- バクテリオファージが少なくとも1つのT7様ウイルスである請求項30から31の何れか一項に記載の改変バクテリオファージ。
- 前記宿主認識要素が前記バクテリオファージの尾領域に存在する少なくとも1つのタンパク質を含む請求項30から32の何れか一項に記載の改変バクテリオファージ。
- 前記バクテリオファージが広い又は改変した宿主範囲を有し、請求項12から19の何れか一項に記載の方法によって調製した請求項30に記載の改変バクテリオファージ。
- 目的の前記核酸配列が、
a.少なくとも1つのcas遺伝子及び少なくともCRISPRアレイを含む少なくとも1つの感作成分であり、前記CRISPRの少なくとも1つのスペーサーは、目的の標的細胞の病原性又は望ましくない遺伝子の内部に含まれるプロトスペーサーを標的にし、前記病原性又は望ましくない遺伝子を特異的に不活性にし、前記CRISPR標的の少なくとも1つのスペーサーは、選択的成分の内部に含まれるプロトスペーサーを標的にし、前記選択的成分を特異的に不活性にし、
b.少なくとも1つのプロトスペーサーを含む少なくとも1つの核酸配列の何れか1つを含む請求項30から34の何れか一項に記載の改変バクテリオファージ。 - 対象、組織、臓器、表面、前記標的細胞(複数可)を含む物質及び物品の少なくとも1つの細胞集団を、有効量の少なくとも1つの送達ビヒクル又はキット、系又は前記送達ビヒクルを含む組成物に接触させるステップを含み、前記送達ビヒクルは、
a.前記標的細胞(複数可)又はそのバリアント、変異体、タンパク質又はフラグメントに適合性の少なくとも1つの宿主認識要素、及び
b.目的の前記核酸分子の少なくとも1つを含む前記細胞集団の内部に含まれる標的細胞(複数可)に目的の少なくとも1つの核酸配列を形質導入することによって細胞集団を操作する方法。 - 前記送達ビヒクルが請求項12から19の何れか一項に規定される方法によって調製される請求項36に記載の方法。
- 前記細胞集団が原核生物細胞及び真核生物細胞の少なくとも1つの集団である請求項36から37の何れか一項に記載の方法。
- 前記バクテリオファージが
a.少なくとも1つの改変した宿主認識要素、及び任意に
b.目的の少なくとも1つの核酸分子を含む少なくとも1つの改変バクテリオファージ又は改変バクテリオファージのカクテルもしくは混合物を含む組成物。 - 前記改変バクテリオファージが請求項30から35の何れか一項に規定される請求項39に記載の組成物。
- 前記対象に治療有効量の少なくとも1つの送達ビヒクル又はキット、系又は前記送達ビヒクルを含む組成物を投与するステップを含み、前記送達ビヒクルは、
a.前記病因細胞(複数可)そのバリアント、変異体、タンパク質又はフラグメントに適合性の少なくとも1つの宿主認識要素、及び
b.目的の少なくとも1つの核酸分子を含む少なくとも1つの改変バクテリオファージ又は改変バクテリオファージのカクテルもしくは混合物を含む病因細胞(複数可)によって生じた、又は関連する対象の病的障害の発症を治療、予防、改善、抑制又は遅延する方法。 - 前記送達ビヒクルに含まれる少なくとも1つの適合性の宿主認識要素(複数可)が、
a.少なくとも1つの宿主認識要素又はそのバリアント、変異体、タンパク質又はフラグメントをコードする複数の核酸分子を提供し、前記核酸分子は、少なくとも1つのパッケージングシグナル、及び選択可能な要素をコードする少なくとも1つの核酸配列をさらに含み、
b.前記複数の核酸分子を含む第1宿主細胞(複数可)を、前記送達ビヒクルのパッケージング及び/又は伝播を可能にする条件下で、少なくとも1つの不完全な宿主認識要素(複数可)又はそのタンパク質又はフラグメントをコードする核酸配列(複数可)を有する送達ビヒクルに接触させ、前記第1宿主細胞にパッケージし、及び/又は伝播した得られた送達ビヒクルバリアントを回収し、
c.第2宿主細胞(複数可)をステップ(b)で回収した送達ビヒクルバリアント(複数可)に接触させ、前記第2宿主細胞は、前記対象の試料から得た前記病因細胞であり、
d.前記選択可能な要素を含むステップ(c)で得た宿主細胞(複数可)を選択し、
e.宿主認識要素(複数可)又は同要素をコードする核酸配列を、ステップ(d)で選択した宿主細胞(複数可)から単離し、及び/又は特徴付けして、前記病因細胞(複数可)又は前記病因細胞をコードする核酸配列に適合性の宿主認識要素を得るステップを含む方法によって得る請求項41に記載の方法。 - 目的の前記核酸配列が、
a.少なくとも1つのcas遺伝子及び少なくともCRISPRアレイを含む少なくとも1つの感作成分であり、前記CRISPRの少なくとも1つのスペーサーは、前記病因細胞の病原性又は望ましくない遺伝子の内部に含まれるプロトスペーサーを標的にし、前記病原性又は望ましくない遺伝子を特異的に不活性にし、前記CRISPRの少なくとも1つのスペーサーは、選択的成分の内部に含まれるプロトスペーサーを標的にし、前記選択的成分を特異的に不活性にし、
b.少なくとも1つのプロトスペーサーを含む少なくとも1つの核酸配列の何れか1つを含む請求項41及び42の何れか一項に記載の方法。
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US20220370526A1 (en) * | 2019-11-06 | 2022-11-24 | Locus Biosciences, Inc. | Phage compositions comprising crispr-cas systems and methods of use thereof |
CN118234858A (zh) | 2021-08-02 | 2024-06-21 | 特罗比克斯生物有限公司 | 用于调节细胞药物代谢的系统、其方法和组合物 |
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US11419908B2 (en) | 2022-08-23 |
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