JP2015535010A - 部位特異的酵素および使用方法 - Google Patents
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Classifications
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- C—CHEMISTRY; METALLURGY
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- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/14—Hydrolases (3)
- C12N9/16—Hydrolases (3) acting on ester bonds (3.1)
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
Abstract
Description
式中、X1が、天然に存在するか、または天然に存在しないアミノ酸であり、
X2が、天然に存在するか、または天然に存在しないアミノ酸である。
式中、任意の組み合わせで、X1およびX2は、独立して、可変であり、X1=A、N、H、R、またはGであり、X2=I、N、H、K、Y、T、D、S、またはPである。
式中、X1=Sであり、X2=Iである。
式中、X1=Sであり、X2=Nである。
ベクター
配列番号16、配列番号17、配列番号18、または配列番号19のうちの少なくとも1つから選択された連続するポリペプチドの任意の組み合わせ、またはその少なくとも70%、75%、80%、85%、90%、95%、96%、97%、98%、または99%パーセント相同であるその任意のバリアントもしくは類似体を含み、各モノマーは、核酸配列の存在下でDNA標的配列の1つのヌクレオチドに結合し、かつ融合タンパク質は、エフェクタータンパク質/ポリペプチド機能を含むか、またはエフェクタータンパク質もしくはそのバリアントである少なくとも2つのポリペプチド配列をさらに含む。いくつかの実施形態では、本発明は、DNA認識要素である連続するモノマーサブ単位を含む融合タンパク質に関し、融合タンパク質は、以下のポリペプチド配列:配列番号1、配列番号2、配列番号3、配列番号4、配列番号5、配列番号6、配列番号7、配列番号8、配列番号9、配列番号10、配列番号11、配列番号12、配列番号13、配列番号14、配列番号15、配列番号16、配列番号17、配列番号18、または配列番号19のうちの少なくとも1つから選択された連続するポリペプチドの任意の組み合わせ、またはその少なくとも70%、75%、80%、85%、90%、95%、96%、97%、98%、または99%パーセント相同であるその任意のバリアントもしくは類似体を含み、各モノマーは、核酸配列の存在下でDNA標的配列の1つのヌクレオチドに結合し、かつ融合タンパク質は、エフェクター/タンパク質機能を含む少なくとも3つ以上のポリペプチド配列をさらに含む。いくつかの実施形態では、本発明は、DNA認識要素である連続するモノマーサブ単位を含む融合タンパク質に関し、融合タンパク質は、以下のポリペプチド配列:配列番号1、配列番号2、配列番号3、配列番号4、配列番号5、配列番号6、配列番号7、配列番号8、配列番号9、配列番号10、配列番号11、配列番号12、配列番号13、配列番号14、配列番号15、配列番号16、配列番号17、配列番号18、または配列番号19のうちの少なくとも1つから選択された連続するポリペプチドの任意の組み合わせ、またはその少なくとも70%、75%、80%、85%、90%、95%、96%、97%、98%、または99%パーセント相同であるその任意のバリアントもしくは類似体を含み、各モノマーは、核酸配列の存在下でDNA標的配列の1つのヌクレオチドに結合し、かつ融合タンパク質は、エフェクタータンパク質/ポリペプチドを含む少なくとも4つ以上のポリペプチド配列をさらに含む。
少なくとも1つの生物は、1つ以上の幹細胞を含み、1つ以上の幹細胞は、以下の変異のうちの1つ以上:(i)欠失変異、(ii)ノックアウト変異、および/または(iii)異種核酸配列の付加を含み、(i)、(ii)、および/または(iii)のうちの1つ以上の変異は、本明細書に開示される1つ以上のポリペプチド(1つ以上のRTN)、および(b)下位区分(a)の生物の子孫によって生じた部位特異的変異である。
(a)動物または植物の生殖系列系統に由来する少なくとも1つの幹細胞を、(i)目的とする遺伝子を変異させる少なくとも1つのRTN、または(ii)目的とする遺伝子を変異させるRTNをコードする少なくとも1つの発現ベクターを有する幹細胞と接触させ、それにより目的とする遺伝子に少なくとも1つの変異を含む幹細胞を作製することと、
(b)目的とする遺伝子に少なくとも1つの変異を含む幹細胞のインビトロ培養を拡張することと、
(c)工程(b)の培養からの目的とする遺伝子に少なくとも1つの変異を含む少なくとも1つの幹細胞を、第1の生物に移植することと、
(d)第1の生物を、同じ種の第2の生物と交配することと、
(e)目的とする遺伝子に少なくとも1つの変異を含む第1および第2の生物の子孫を選択することと、
(f)目的とする遺伝子に少なくとも1つの変異を含む生物のコロニーを作製するために、子孫を交配することと、を含む。
(a)第1の幹細胞を、(i)目的とする第1の遺伝子を変異させるRTN、または(ii)目的とする第1の遺伝子を変異させるRTNをコードする発現ベクターと接触させ、それにより第1の変異を含む第1の幹細胞を作製することと、
(b)第2の幹細胞を変性剤と接触させ、それにより第2の変異を含む第2の幹細胞を作製することと、
(c)第1および第2の幹細胞の各々のインビトロ培養を拡張することと、
(d)第1および第2の幹細胞を含む幹細胞の混合集団を生物内に移植することと、
(e)生物を、同じ種の別の生物と交配することとを含む。
(a)目的とする遺伝子で核酸配列を切断するRTN、またはRTNをコードする核酸配列と、
(b)説明を含む取り扱い説明書と、任意に、を含む。
本発明のいくつかの実施形態では、キットは、
(a)本発明のいくつかの実施形態では、および任意に、
(b)1つ以上の幹細胞または1つ以上の胚芽用の培養培地を含む。
発明のいくつかの実施形態では、キットは、
(a)目的とする遺伝子で核酸配列を切断するRTN、またはRTNをコードする核酸配列と、任意に、
(b)1つ以上の幹細胞または1つ以上の胚芽用の培養培地と、を含む。
本発明のいくつかの実施形態では、キットは、
(a)目的とする遺伝子で核酸配列を切断するRTN、またはRTNをコードする核酸配列と、
(b)動物または植物の生殖系列系統に由来する1つ以上の幹細胞系と、任意に、
(c)1つ以上の幹細または1つ以上の胚芽用の培養培地と、任意に、
(d)1つ以上の幹細胞を、目的とする遺伝子で核酸配列を切断するRTNまたはRTNをコードする核酸配列でどのように変異させるかの説明書を含む、取り扱い説明書とを含む。
ラルストニアゲノムの配列相同性のクラスター分析および再考察は、既知のTAL配列に相同である配列番号1の配列を明らかにした。
Reyon D,Tsai SQ,Khayter C,Foden JA,Sander JD,Joung JK(参照によりその全体が本明細書に組み込まれる)に記載される方法を用いて検証される。
予め組み立てられたTALE反復をコードするプラスミドアーカイブの構築
FLASHアセンブリのためのTALE反復コードDNA断片の調製
GGATCCGGTCTCTTAAGGCCGTGG−3’)を使用して、テンプレートとして各α単位プラスミドを用いてPCRを20回行う。得られたPCR生成物を5’端上でビオチン化する。次いで、各αPCR生成物は、4bpオーバーハングを生成するために40単位のBsaI−HF制限酵素で消化され、最終生成物が50μlの0.1×EB中で溶出されることを除き、製造者の指示に従いQIAquick PCR精製キット(QIAGEN)を使用して精製された。
自動FLASHアセンブリ
TALE反復アレイコードDNA断片のTALEN発現ベクター内へのサブクローニング
TCTCCTCCAGTTCACTTTTGACTAGTTGGG−3’)を使用して、PCRにより同じコロニーをスクリーニングする。PCR生成物は、QIAxcelキャピラリー電気泳動システム(Qiagen)により分析される。正確に寸法決定されたPCR生成物を含むクローンからのミニプレップDNAは、プライマーoSQT1(5’−AGTAACAGCGGTAGAGGCAG−3’)、oSQT3(5’−
ATTGGGCTACGATGGACTCC−3’)、およびoJS2980(5’−
TTAATTCAATATATTCATGAGGCAC−3’)を用いたDNA配列確認のために送られ、oSQT1は、TALE反復アレイコード配列の5’端でアニールし、
組み立てられたアレイの半分のアミノ末端の配列決定を可能にし、oSQT3は、TALE反復アレイコード配列の3’でアニールし、組み立てられたアレイの半分のカルボキシ末端の配列決定を可能にし、oJS2980は、FokIドメイン(oSQT3の下流)のコード配列内を刺激し、カルボキシ末端の0.5TALE反復ドメインの配列決定および検証を可能にする。
EGFP TALEN活性および毒性アッセイ
EGFPレポーターアッセイは、EGFP−PEST融合タンパク質を構成的に発現する組み込まれた構築物を坦持するクローン性U2OSヒト細胞系において行われる。このクローン性系は、多クローン性U2OS EGFP−PESTレポーター系に由来する。クローン性U2OS EGFP−PEST細胞は、10%のFBS、2mMのGlutaMax(Life Technologies)、ペニシリン/ストレプトマイシン、および400μg/mlのG418で補足されたAdvanced DMEM(Life Technologies)中で培養される。細胞は、製造者の指示に従い、Lonza 4D−Nucleofector System、溶液SE、およびプログラムDN−100を使用して、500ngの各TALENプラスミドDNAおよび50ngのptdTomato−N1プラスミドDNAにより3つ組で遺伝子移入される。1μgのptdTomato−N1プラスミドのみが陰性対照として3つ組で遺伝子移入される。細胞は、BD FACSAriaIIフローサイトメーターを使用して、遺伝子移入2日後および5日後にEGFPおよびtdTomato発現に関してアッセイされる。
内因性ヒト遺伝子のPCR増幅および配列検証
標的遺伝子座を増幅するためのPCR反応は、補足表5に示されるプライマーを使用して行われる。Phusion Hot Start II高忠実度DNAポリメラーゼ(Thermo−Fisher)を用いた標準的なPCR条件は、製造者の指示に従い、35サイクル(98℃、10秒変性;68℃、15秒アニーリング;72℃、30秒伸長)で行われる。標準的な条件下で増幅されない遺伝子座に関しては、以下の修飾うちの1つを使用する:1)1.8Mの最終濃度にするためのベタインの添加、2)1.8Mのベタインを用いてタッチダウンPCR([98℃、10秒;72〜62℃、−1℃/サイクル、15秒;72℃、30秒]10サイクル、[98℃、10秒;62℃、−1℃/サイクル、15秒;72℃、30秒]25サイクル)、ならびに3)3%または5%のDMSOの添加および65℃のアニーリング温度。PCR生成物は、QIAxcelキャピラリー電気泳動システムにより正確な大きさに関して分析される。正確に寸法決定された生成物は、組み込まれなかったヌクレオチドまたはプライマーを除去するためにExoSap−IT(Affymetrix)で処理され、内因性遺伝子配列を確認するためにDNA配列決定に送られる。
内因性ヒト遺伝子のNHEJ媒介変異を定量化するためのT7エンドヌクレアーゼIアッセイ
(%遺伝子修飾=100×(1−(1−切断された画分)1/2)
実施例2
RTN1 EBEs:
実施例3.メチルエステラーゼを用いた核酸ベクターの生成
メチルエステラーゼに対するTAL EBE
#1
キサントモナスコンセンサスEBE
用語:
Eg:Z4はEBE11〜14を保持し、Z5はEBE11〜15を保持し、Z6はEBE11〜16を保持する。遺伝子合成し、pHSG−298(SacI、SbfI)内にクローニングした。
下線付き配列はサブアレイpFUS−XおよびpFUS−Zと重複する。
XTN−bbA:NNNNNNNNNは、TCTAACATCと置き換えられる。
XTN−bbC:NNNNNNNNNは、TCCCACGACと置き換えられる。
XTN−bbG:NNNNNNNNNは、AATAATAACと置き換えられる。
XTN−bbT:NNNNNNNNNは、TCTAATGGGと置き換えられる。
QTTERIVAIGT nn GGTQALEAVLTALPRVCPGMV
34aa QTTERIVAIGT SH GGTQALEAVLTALPRVCPGMVのBacktranseq(SHは非特異的RVDである)
CAGACCACCGAGAGGATCGTGGCCATCGGCACCAGCCACGGCGGCACCCAGGCCCTGGAGGCCGTGCTGACCGCCCTGCCCAGGGTGTGCCCCGGCATGGTG
メチルエステラーゼEBE(XTN骨格中の14EBE):
青字体:メチルエステラーゼEBE。この例において、全ては非特異的RVD SHである。
黒字体:FLASH XTN骨格。
配列は連続である:
Claims (21)
- 配列番号1と少なくとも80%の配列同一性を有する少なくとも1つのアミノ酸配列を含むタンパク質またはポリペプチド。
- 前記ポリペプチドが、配列番号1:LSTEQVVAIASX1X2GGKQALEAVKAQLLVLRAAPYE(配列番号1)と少なくとも少なくとも80%、85%、90%、95%、96%、97%、98%、または99%の配列同一性のアミノ酸配列から選択される少なくとも1つのアミノ酸配列をさらに含み、
式中、X1が、天然に存在するか、または天然に存在しないアミノ酸であり、
X2が、天然に存在するか、または天然に存在しないアミノ酸である、請求項1に記載のポリペプチド。 - 少なくとも75%(または80%、85%、90%、95%、または99%)の配列同一性の配列番号1、配列番号2、配列番号3、配列番号4、配列番号5、配列番号6、配列番号7、配列番号8、配列番号9、配列番号10、配列番号11、配列番号12、配列番号13、配列番号14、配列番号15、配列番号16、配列番号17、配列番号18、および配列番号19のうちの少なくとも1つ、またはこれらのうちのいずれかの組み合わせをさらに含む、請求項1または2に記載のポリペプチド。
- 前記タンパク質が、配列番号2、配列番号3、配列番号4、配列番号5、配列番号6、配列番号7、配列番号8、配列番号9、配列番号10、配列番号11、配列番号12、配列番号13、配列番号14、配列番号15、配列番号16、配列番号17、配列番号18、配列番号19のうちの少なくとも1つ、もしくはこれらのうちのいずれかの組み合わせ、または表1に列記される配列のいずれも含まない、請求項1〜3のいずれかに記載のタンパク質。
- 配列番号1と少なくとも90%の配列同一性を有し、かつ本明細書に記載される少なくとも1つのRVDを含む、請求項1〜4のいずれかに記載のタンパク質。
- 配列番号1と少なくとも95%の配列同一性を有し、かつ本明細書に記載される少なくとも1つのRVDを含む、請求項1〜5のいずれかに記載のタンパク質。
- 配列番号1と少なくとも99%の配列同一性を有し、かつ本明細書に記載される少なくとも1つのRVDを含む、請求項1〜6のいずれかに記載のタンパク質。
- 配列番号1と少なくとも90%の配列同一性を有し、かつ表1に記載される少なくとも1つのアミノ酸配列をさらに含む、請求項1〜7のいずれかに記載のタンパク質。
- 配列番号1と少なくとも95%の配列同一性を有し、かつ表1に記載される少なくとも1つのアミノ酸配列をさらに含む、請求項1〜8のいずれかに記載のタンパク質。
- 配列番号1と少なくとも99%の配列同一性を有し、かつ表1に記載される少なくとも1つのアミノ酸配列をさらに含む、請求項1〜9のいずれかに記載のタンパク質。
- 前記タンパク質が、配列番号1、配列番号2、配列番号3、配列番号4、配列番号5、配列番号6、配列番号7、配列番号8、配列番号9、配列番号10、配列番号11、配列番号12、配列番号13、配列番号14、配列番号15、配列番号16、配列番号17、配列番号18、配列番号19、もしくは表1に列記される任意の配列、またはこれらの任意のバリアントもしくは類似体を含む、請求項1〜10のいずれかに記載のタンパク質。
- 前記タンパク質が、核酸エフェクタードメインを含み、前記核酸エフェクタードメインが、ヌクレアーゼ、ニッカーゼ、転写活性化因子、転写抑制因子、メチルトランスフェラーゼ、デアセチラーゼ、またはこれらの任意の機能断片を含む、請求項2〜11のいずれかに記載のタンパク質。
- 請求項1〜12のいずれか一項に記載のタンパク質をコードする核酸。
- 請求項1〜12のいずれか一項に記載のタンパク質をコードする核酸を含むベクター。
- プラスミドまたはRNA分子である、請求項14に記載のベクター。
- レトロウイルスである、請求項14または15のいずれかに記載のベクター。
- 前記レトロウイルスが、長い末端反復、psiパッケージングシグナル、クローニング部位、および選択可能マーカーをコードする配列を含む、請求項16に記載のレトロウイルス。
- 請求項13〜17のいずれか一項に記載の核酸を含む細胞。
- 請求項14〜17のいずれか一項に記載のベクターを含む細胞。
- キットであって、
請求項1〜12のいずれか一項に記載のタンパク質をコードする核酸を含むベクターを含む、キット。 - 請求項1〜12のいずれか一項に記載のタンパク質をコードする核酸分子を含む細胞。
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AU2013344375B2 (en) | 2017-09-14 |
CN105051204A (zh) | 2015-11-11 |
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AU2019216699A1 (en) | 2019-09-19 |
AU2013344375A1 (en) | 2015-06-11 |
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WO2014078819A2 (en) | 2014-05-22 |
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US10844361B2 (en) | 2020-11-24 |
AU2017221779A1 (en) | 2017-09-28 |
EP2920319B1 (en) | 2020-02-19 |
JP2018099136A (ja) | 2018-06-28 |
CA2891510C (en) | 2022-10-18 |
AU2019216699B2 (en) | 2021-03-04 |
JP6502259B2 (ja) | 2019-04-17 |
CN105051204B (zh) | 2023-07-21 |
HK1215284A1 (zh) | 2016-08-19 |
AU2017221779B2 (en) | 2019-05-16 |
ES2778033T3 (es) | 2020-08-07 |
US20210062170A1 (en) | 2021-03-04 |
US20200199553A1 (en) | 2020-06-25 |
BR112015010911A2 (pt) | 2022-10-25 |
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