JP6909212B2 - 肝臓特異的コンストラクト、第viii因子発現カセット、およびその使用の方法 - Google Patents
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Description
本出願は、2015年10月28日に出願された米国仮特許出願第62/247,469号;2016年3月14日に出願された米国仮特許出願第62/307,897号;2016年4月22日に出願された米国仮特許出願第62/326,229号;2016年3月30日に出願された米国仮特許出願第62/315,438号;および2016年6月27日に出願された米国仮特許出願第62/355,106号(それらの開示はその全体を参照することにより本明細書に援用される)の利益を主張する。
血友病Aまたは血友病Bに罹患する患者のための遺伝子療法(機能的なFVIIIタンパク質またはF.IXタンパク質をコードするプラスミドおよび他のベクター(例えばAAV)の導入を包含する)が記載されている(例えば米国特許第6,936,243号;同第7,238,346号および6,200,560;Shi et al.(2007)J Thromb Haemost.(2):352−61;Lee et al.(2004)Pharm.Res.7:1229−1232;Graham et al.(2008)Genet Vaccines Ther.3:6−9;Manno et al.(2003)Blood 101(8):2963−72;Manno et al.(2006)Nature Medicine 12(3):342−7;Nathwani et al.(2011)Mol Ther 19(5):876−85;Nathwani et al.(2011);N Engl J Med.365(25):2357−65およびMcIntosh et al.(2013)Blood 121(17):3335−44を参照)。しかしながら、これらのプロトコルにおいて、阻害性の抗第VIII因子または抗第IX因子(抗FVIIIまたは抗F.IX)抗体および送達ベヒクルに対する抗体の形成は、血友病のためのFVIIIおよびF.IXの補充に基づく治療の主要な合併症である。例えばScott & Lozier(2012)Br J Haematol.156(3):295−302を参照されたい。
しかしながら、1つまたは複数の導入遺伝子(血友病において欠如する1つまたは複数のタンパク質をコードする導入遺伝子が含まれる)の発現を肝細胞中で高レベルで駆動する、肝臓に特異的なポリヌクレオチド(発現コンストラクトおよび転写モジュール)についての必要性が依然として存在する。
特定の実施形態では、例えば、以下が提供される:
(項目1)
インスレーター配列を含む少なくとも1つのスペーサー配列、肝臓特異的エンハンサー配列、プロモーター配列および導入遺伝子を含む、ポリヌクレオチド発現コンストラクト。
(項目2)
イントロン配列をさらに含む項目1に記載のポリヌクレオチド発現コンストラクトであって、前記エンハンサー配列が野生型セルピン1エンハンサーもしくは変異セルピン1エンハンサーを含む;および/または、前記プロモーター配列が野生型トランスサイレチン(TTR)プロモーターもしくは変異TTRプロモーターを含む;および/または、前記イントロン配列が野生型マウス微小ウイルス(MVM)イントロン配列もしくは変異MVMイントロン配列を含む、前記コンストラクト。
(項目3)
前記インスレーター配列が、配列番号:28、29および/または30のうちの任意の1つである、項目1または項目2のいずれか一項に記載のポリヌクレオチド発現カセット。
(項目4)
前記肝臓特異的エンハンサー配列、前記プロモーター配列、前記イントロン配列および前記導入遺伝子に隣接する、2つのスペーサー配列を含む、項目1〜3のいずれか一項に記載のポリヌクレオチド発現カセット。
(項目5)
前記インスレーター配列が、配列番号:28、29、30および/または38である、項目4に記載のポリヌクレオチド発現カセット。
(項目6)
前記導入遺伝子が血友病またはリソソーム蓄積症において欠如または欠損するタンパク質をコードする、項目1〜5のいずれか一項に記載のポリヌクレオチド発現カセット。
(項目7)
前記導入遺伝子が1つまたは複数のヌクレアーゼをさらにコードする、項目6に記載のポリヌクレオチド発現カセット。
(項目8)
肝臓特異的エンハンサー配列、プロモーター配列、配列番号:15、16または17のうちの任意の1つ中で示されるようなイントロン配列、および導入遺伝子を含む、ポリヌクレオチド発現コンストラクト。
(項目9)
前記エンハンサー配列が野生型セルピン1エンハンサーまたは変異セルピン1エンハンサーを含む;および/または、前記プロモーター配列が野生型トランスサイレチン(TTR)プロモーターもしくは変異TTRプロモーターを含む、項目8に記載のポリヌクレオチド発現コンストラクト。
(項目10)
インスレーター配列を含む少なくとも1つのスペーサー配列および/またはポリアデニル化シグナルをさらに含む、項目8または項目9のいずれか一項に記載のポリヌクレオチド発現カセット。
(項目11)
前記導入遺伝子が血友病またはリソソーム蓄積症において欠如または欠損するタンパク質をコードする、項目8〜10のいずれか一項に記載のポリヌクレオチド発現カセット。
(項目12)
前記導入遺伝子が1つまたは複数のヌクレアーゼをさらにコードする、項目8〜11のいずれか一項に記載のポリヌクレオチド発現カセット。
(項目13)
配列番号:1〜13のうちの任意のものの位置1、5、14、32および/または39で突然変異を有する肝臓特異的エンハンサー配列、プロモーター配列、および導入遺伝子を含む、ポリヌクレオチド発現コンストラクト。
(項目14)
イントロン配列をさらに含む項目13に記載のポリヌクレオチド発現コンストラクトであって、前記プロモーター配列が野生型トランスサイレチン(TTR)プロモーターもしくは変異TTRプロモーターを含む、および/または、前記イントロン配列が野生型マウス微小ウイルス(MVM)イントロン配列もしくは変異MVMイントロン配列を含む、前記コンストラクト。
(項目15)
インスレーター配列を含む少なくとも1つのスペーサー配列および/またはポリアデニル化シグナルをさらに含む、項目13または14のいずれか一項に記載のポリヌクレオチド発現カセット。
(項目16)
前記導入遺伝子が血友病またはリソソーム蓄積症において欠如または欠損するタンパク質をコードする、項目13〜14のいずれか一項に記載のポリヌクレオチド発現カセット。
(項目17)
前記導入遺伝子が1つまたは複数のヌクレアーゼをさらにコードする、項目13〜16のいずれか一項に記載のポリヌクレオチド発現カセット。
(項目18)
項目1〜17のいずれか一項に記載のポリヌクレオチド発現コンストラクトを含むAAVベクターであって、前記ポリヌクレオチド発現コンストラクトが前記AAVベクターの5’逆方向末端反復(ITR)と3’ITRとの間にある、前記ベクター。
(項目19)
前記AAVベクターがCRMSBS1(配列番号:34)またはCRMSBS2(配列番号:37)と表記される、項目18に記載のAAVベクター。
(項目20)
項目18または19のいずれか一項に記載のAAVベクターを含む、医薬組成物。
(項目21)
タンパク質を、それを必要とする被験体へ提供する方法であって、項目18もしくは19のいずれか一項に記載のAAVベクターを前記被験体の肝臓へ、または項目20に記載の医薬組成物を前記被験体へ、投与することを含み、前記導入遺伝子が前記タンパク質をコードし、前記タンパク質が前記被験体中で産生される、前記方法。
(項目22)
前記導入遺伝子が肝細胞のゲノムの中へ組み込まれる、項目21に記載の方法。
(項目23)
1つまたは複数のヌクレアーゼを被験体へ投与することをさらに含む、項目21または22のいずれか一項に記載の方法であって、前記ヌクレアーゼが内在性アルブミン遺伝子を切断し、前記導入遺伝子が内在性アルブミン遺伝子の中へ組み込まれる、前記方法。
(項目24)
哺乳動物において治療用タンパク質への寛容を誘導する方法であって、項目21〜23のいずれか一項に記載の方法に従ってタンパク質を産生するように前記哺乳動物における細胞を修飾すること、ならびに前記哺乳動物が治療用タンパク質へ寛容化されるようになるように、1つまたは複数のステロイドおよび/またはB細胞阻害因子により哺乳動物を治療することを含む、前記方法。
(項目25)
項目1〜17のいずれか一項に記載のポリヌクレオチド発現カセット、項目18もしくは項目19のいずれか一項に記載のAAVベクター、および/または項目20に記載の医薬組成物を含む、キット。
本明細書において開示される方法の実践に加えて、組成物の調製および使用は、特別の指示のない限り、当業者の技能の範囲内にあるような、分子生物学、生化学、クロマチンの構造および分析、計算機化学、細胞培養、組換DNAならびに関連する分野における従来の技法を用いる。これらの技法は文献中で完全に説明される。例えば、Sambrook et al.,MOLECULAR CLONING:A LABORATORY MANUAL,Second edition,Cold Spring Harbor Laboratory Press,1989およびThird edition,2001;Ausubel et al.,CURRENT PROTOCOLS IN MOLECULAR BIOLOGY,John Wiley & Sons,New York,1987および定期的な改訂版;シリーズ、METHODS IN ENZYMOLOGY,Academic Press、San Diego;Wolffe、CHROMATIN STRUCTURE AND FUNCTION、Third edition、Academic Press,San Diego,1998;METHODS IN ENZYMOLOGY,Vol.304,「Chromatin」(P.M.Wassarman and A.P.Wolffe,eds.),Academic Press,San Diego,1999;ならびにMETHODS IN MOLECULAR BIOLOGY,Vol.119,「Chromatin Protocols」(P.B.Becker,ed.)Humana Press,Totowa,1999を参照されたい。
「核酸」、「ポリヌクレオチド」および「オリゴヌクレオチド」という用語は、互換的に使用され、直線状または環状の立体配座、および一本鎖または二本鎖の形態のいずれかである、デオキシリボヌクレオチドまたはリボヌクレオチドのポリマーを指す。本開示の目的のために、これらの用語はポリマーの長さに関して限定するものとして解釈するべきではない。これらの用語は、天然ヌクレオチドの既知の類似体に加えて、塩基部分、糖部分および/またはリン酸塩部分中で修飾されたヌクレオチド(例えばホスホロチオエート骨格)を包含することができる。一般に、特定のヌクレオチドの類似体は同じ塩基対を作る特異性を有し、すなわち、Aの類似体はTと塩基対を作るだろう。
肝細胞における導入遺伝子の発現の指令における使用(後続する発現カセット(複数可)の被験体へのインビボの投与(例えば肝臓への送達)が含まれる)のための発現カセット(コンストラクト)が本明細書において記載される。発現コンストラクトはエピソームとして維持され、導入遺伝子の発現を染色体外で駆動し得るかまたは、あるいは、発現コンストラクトは、例えばヌクレアーゼ媒介性標的化組み込みによって肝細胞のゲノムの中へ組み込まれ得る。
CRMSBS1(配列番号:35):
5’GGGGGAGGCTGCTGGTGAATATTAACCAAGATCAGCCCAGTTACCGGAGGAGCAAACAGGGGCTAAGTTCAC
CRMSBS2(配列番号:36):5’
GGGGGAGGCTGCTGGTGAATATTAACCAAGATCACCCCAGTTACCGGAGGAGCAAACAGGGACTAAGTTCAC
hF8 cDNA、イントロンなし(プロモーターモジュール、ポリAおよびIns、CRMSBS2イントロンなし、を含む、完全な配列)(配列番号:34):
5’
本明細書において記載されるコンストラクトは、任意の導入遺伝子の肝臓への送達のために使用され得る。例示的な導入遺伝子(対象となる遺伝子および/または外来性配列とも称される)には、任意のポリペプチドコーディング配列(例えばcDNA)、プロモーター配列、エンハンサー配列、エピトープタグ、マーカー遺伝子、切断酵素認識部位、および様々なタイプの発現コンストラクトも含まれるがこれらに限定されない。マーカー遺伝子には、抗生物質耐性(例えばアンピシリン耐性、ネオマイシン耐性、G418耐性、ピューロマイシン耐性)を媒介するタンパク質をコードする配列、着色タンパク質または蛍光タンパク質または発光タンパク質(例えば緑色蛍光タンパク質、増強緑色蛍光タンパク質、赤色蛍光タンパク質、ルシフェラーゼ)をコードする配列、ならびに細胞増殖および/または遺伝子増幅の促進を媒介するタンパク質(例えばジヒドロ葉酸還元酵素)が含まれるがこれらに限定されない。エピトープタグには、例えば、FLAG、His、myc、Tap、HAまたは任意の検出可能なアミノ酸配列のうちの1つまたは複数のコピーが含まれる。
上で指摘されるように、発現カセットはエピソームとして維持され得るか、または細胞のゲノムの中へ組み込まれ得る。組み込みはランダムであり得る。好ましくは、導入遺伝子コンストラクト(複数可)の組み込みは、1つまたは複数のヌクレアーゼ(例えばジンクフィンガーヌクレアーゼ(「ZFN」)、TALEN、TtAgo、CRISPR/Casヌクレアーゼ系、およびホーミングエンドヌクレアーゼ)による標的遺伝子の切断に後続して標的化され、コンストラクトは、相同性指向修復(HDR)によってまたは非相同末端結合(NHEJ)駆動性プロセスの間の末端捕捉によってのいずれかで組み込まれる。例えば米国特許第9,255,250号;同第9,200,266号;同第9,045,763号;同第9,005,973号;同第9,150,847号;同第8,956,828号;同第8,945,868号;同第8,703,489号;同第8,586,526号;同第6,534,261号;同第6,599,692号;同第6,503,717号;同第6,689,558号;同第7,067,317号;同第7,262,054号;同第7,888,121号;同第7,972,854号;同第7,914,796号;同第7,951,925号;同第8,110,379号;同第8,409,861号;米国特許公報第20030232410号;同第20050208489号;同第20050026157号;同第20050064474号;同第20060063231号;同第20080159996号;同第201000218264号;同第20120017290号;同第20110265198号;同第20130137104号;同第20130122591号;同第20130177983号;第20130196373号および第20150056705号(それらの開示はその全体をすべての目的のために参照することにより本明細書に援用される)を参照されたい。
本明細書において記載されるコンストラクト(および/またはヌクレアーゼ)は、任意の好適な手段によってインビボでまたはエクスビボで任意の細胞タイプの中へ、好ましくは肝臓へ送達され得る(肝臓への送達)。同様に、標的化組み込みのためにヌクレアーゼと組み合わせて使用される場合に、ヌクレアーゼは、ポリヌクレオチドおよび/もしくはタンパク質の形態(例えば非ウイルスベクター(複数可)、ウイルスベクター(複数可)を使用して)において、ならびに/またはRNAの形態(例えばmRNAとして)において、送達され得る。
本明細書において開示される方法および組成物は、疾患において欠如もしくは欠損する産物を発現するか、またはそうでなければ疾患を治療もしくは防止する、導入遺伝子の供与による任意の疾患についての治療法の提供のためのものである。細胞はインビボで修飾され得るか、またはエクスビボで修飾され、続いて被験体へ投与され得る。したがって、方法および組成物はかかる遺伝性疾患の治療および/または予防を提供する。
DNAコンストラクト
ヒト第VIII因子cDNAを保有する例示的なコンストラクトの開発のために行われた全体構造およびアプローチを、図1中で描写する。コンストラクトは、肝臓特異的エンハンサー、肝臓特異的プロモーター、随意のイントロン、インスレーター配列および導入遺伝子(例えばコドン至適化ヒト第VIII因子Bドメイン欠失導入遺伝子)、合成ポリアデニル化配列、スペーサーおよび5’/3’逆方向末端反復を含む。すべてのコンストラクトをルーチンの分子生物学クローニング法を使用してアセンブルした。
qRT−PCR(ヒト第VIII因子mRNAのレベルのための):製造者の指示によって、FastPrepおよびLysing Matrix D(MP Biomedicals、Santa Ana CA)を使用して、マウス組織を溶解した。製造者の指示(Qiagen、Carlsbad CA)によって、AllPrep DNA/RNAキットを使用して、RNA/DNAをマウス組織から単離した。次いで抽出されたRNAを使用し、Quantitect cDNA合成キット(Qiagen、Carlsbad CA)を使用してcDNAを作製した。次いでIDT(Coralville IA)からの標識プライマー/プローブアッセイを使用するBiorad CFX 96上でSsoAdvanced Universal Probes Supermix(Biorad、Hercules CA)を使用して、定量的PCRを実行した。マウスGAPDHアッセイはMm.PT.39a.1であった。ヒト第VIII因子mRNAの特異的な検出のために、プライマー/プローブアッセイはカスタムであり、フォワードプライマー(GGAGATGAAGAAGGAGGACTTTG)(配列番号:18)、プローブ(ACATCTACGACGAGGACGAGAACCA)(配列番号:19)およびリバースプライマー(TCCACAGCAGCAATGAAGTAG)(配列番号:20)であった。定量的qRT−PCR(絶対的でない)をGAPDHへ正規化して各々のサンプルについて使用し、最終データ解析を、1.0に設定した1つのマウスサンプルと比べて報告した。テンプレートなしの対照および逆転写酵素なしの対照をすべてのサンプルと共に実行し、それは検出可能なシグナルを産生しなかった。
野生型マウス:8〜10週齢のC57BL/6マウスをインビボの研究のために使用した。本研究は、動物の人道的なケアおよび使用のために動物福祉法を遵守した。試験品(コンストラクトを含有するAAVウイルス)を投薬の前に室温で融解し、すべての動物に単一の200μLの静脈内(IV)注射を与えた。以下の表1は、図8中のインビボで研究されるコンストラクトの試験のための研究デザインを示す(図4、6および7中でマップが示される)。表2は、図15中で略述されるコンストラクトの試験のための研究デザインを示す。用量は1マウスあたり1.8E+11vgであり、それはおよそ7E+12vg/kgであった。すべての動物に、0および14日目で200μLのシクロホスファミドのフォローアップの腹腔内注射を与えた。表1および2中で略述されるように、非終了時および終了時の血液収集を行った。
実施例1および2において記載されるコンストラクトを、アルブミン遺伝子座の中への発現コンストラクトの標的化組み込みのために、アルブミン特異的ヌクレアーゼと組み合わせて使用した場合の発現についても評価した。特に、コンストラクトをアルブミン特異的ジンクフィンガーヌクレアーゼ共にHepG2細胞へ投与した。例えば米国特許第9,150,847号;同第9,255,250号ならびに米国特許公報第20130177983号;同第20150159172号;同第20150056705号および同第20150166618号を参照されたい。
Claims (15)
- 1つまたは2つの、配列番号:28、29、30および38から選択されるインスレーター配列、
野生型セルピン1エンハンサー配列もしくは変異セルピン1エンハンサー配列、
野生型トランスサイレチン(TTR)プロモーター配列もしくは変異TTRプロモーター配列、および
導入遺伝子
を含む、ポリヌクレオチド発現コンストラクト。 - さらに、ポリアデニル化配列を含む、請求項1に記載のポリヌクレオチド発現コンストラクト。
- イントロン配列をさらに含む請求項1または請求項2に記載のポリヌクレオチド発現コンストラクトであって、前記イントロン配列が野生型マウス微小ウイルス(MVM)イントロン配列もしくは変異MVMイントロン配列を含む、前記コンストラクト。
- 前記イントロン配列が、配列番号:15、16、17、および、配列番号:37のヌクレオチド340〜432から選択される、請求項3に記載のポリヌクレオチド発現コンストラクト。
- 前記エンハンサー配列が、配列番号:1〜13のうちの任意のものの位置1、5、14、32および39のいずれかで突然変異を有する、請求項1〜4のいずれか一項に記載のポリヌクレオチド発現コンストラクト。
- 配列番号:28を含む第1のインスレーター配列および配列番号:30を含む第2のインスレーター配列を含む、請求項1〜5のいずれか一項に記載のポリヌクレオチド発現コンストラクト。
- 前記2つのインスレーター配列が、前記エンハンサー配列、前記プロモーター配列、前記イントロン配列および前記導入遺伝子、および、前記ポリアデニル化配列に隣接する、請求項1〜6のいずれか一項に記載のポリヌクレオチド発現コンストラクト。
- 前記導入遺伝子が血友病またはリソソーム蓄積症に罹患する被検体において機能が欠如または欠損するタンパク質をコードする、請求項1〜7のいずれか一項に記載のポリヌクレオチド発現コンストラクト。
- 前記導入遺伝子が、ZFN、TALEN、TtAgoおよびCRISPR/Cas系から選択される1つまたは複数のヌクレアーゼをさらにコードする、請求項1〜8のいずれか一項に記載のポリヌクレオチド発現コンストラクト。
- 請求項1または請求項2に記載のポリヌクレオチド発現コンストラクトであって、5’から3’に、以下:
配列番号:28を含む第1のインスレーター配列、
配列番号:36を含むエンハンサー配列、
TTR最小プロモーター配列、
配列番号:37のヌクレオチド340〜432を含むイントロン配列、
ヒト第VIII因子をコードする導入遺伝子、
ポリアデニル化シグナル配列、および、
配列番号:30を含む第2のインスレーター配列
を含む、ポリヌクレオチド発現コンストラクト。 - 配列番号:37を含むポリヌクレオチド発現コンストラクト。
- 配列番号:34を含むポリヌクレオチド発現コンストラクト。
- 請求項1〜12のいずれか一項に記載のポリヌクレオチド発現コンストラクトを含むAAVベクターであって、前記ポリヌクレオチド発現コンストラクトが前記AAVベクターの5’逆方向末端反復(ITR)と3’ITRとの間にある、前記ベクター。
- 前記ベクターがAAV6カプシドを含む、請求項13に記載のAAVベクター。
- 請求項13または14に記載のAAVベクターを含む、医薬組成物。
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JP2021176305A (ja) * | 2015-10-28 | 2021-11-11 | サンガモ セラピューティクス, インコーポレイテッド | 肝臓特異的コンストラクト、第viii因子発現カセット、およびその使用の方法 |
JP7324249B2 (ja) | 2015-10-28 | 2023-08-09 | サンガモ セラピューティクス, インコーポレイテッド | 肝臓特異的コンストラクト、第viii因子発現カセット、およびその使用の方法 |
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