JP7246359B2 - 組織選択的導入遺伝子発現 - Google Patents
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Description
本願は、2017年4月3日に出願された米国仮出願第62/480,998号の利益を主張する。この出願はその全体が本明細書に参考として援用される。
本出願は、ASCII形式で電子的に提出された配列表を含み、この配列表は、参照によりその全体が本明細書に組み込まれる。2018年3月29日に作成された前記ASCIIのコピーは、46482-704_601_SL.txtという名称であり、サイズが78,248バイトである。
遺伝子療法は、ヒト疾患をどのように対処および処置するかに関するその莫大な可能性が、長期にわたり認識されている。薬物または外科手術に依存するのではなく、患者、特に、根底にある遺伝学的要因を有するものは、根底にある原因を直接的に標的とすることによって、処置することができる。さらに、根底にある遺伝学的原因を標的とすることによって、遺伝子療法は、患者を効果的に治癒するか、またはより長期間にわたる持続的な処置を提供する可能性を有する。しかしながら、それにもかかわらず、遺伝子療法の臨床適用は、依然として、いくつかの側面で改善を必要とする。懸念となっている1つの領域は、標的外作用である。標的外作用に対処するための有望なアプローチは、遺伝子療法の遺伝子発現を、目的の細胞型もしくは組織、または標的細胞型もしくは組織に標的化することである。そのため、遺伝子療法または遺伝子発現を、目的の組織または細胞型に標的化するための、エレメントおよびそれを使用する方法を特定する必要性が存在する。
遺伝子療法およびその遺伝子/導入遺伝子の発現を、in vivoにおいて所望される組織および/または細胞型に標的化することに対して、相当な必要性が存在する。標的化することによって、標的外作用を減少させ、標的組織および/または細胞型における治療有効性を増加させ、有効性を達成するために必要とされる有効用量を低下させることにより患者の安全性および寛容性を増加させることができる。
本明細書において言及されるすべての刊行物、特許、および特許出願は、それぞれ個別の刊行物、特許、または特許出願が、具体的かつ個別に参照により援用されると示されるのと同程度に、参照により本明細書に援用される。
本開示は、中枢神経系(CNS)と関連する疾患または状態、たとえば、ドラベ症候群、アルツハイマー病、てんかん、および/またはけいれんを処置するための組成物、および遺伝子療法においてそのような組成物を使用する方法を企図する。
制御エレメントは、目的とされる特定の組織または細胞型において、遺伝子の発現に影響を及ぼす(たとえば、発現を増加もしくは減少させる)ことができる、かつ/または遺伝子(たとえば、レポーター遺伝子、たとえば、eGFP、導入遺伝子、もしくは治療用遺伝子)の選択的な発現をもたらす、核酸配列または遺伝子エレメントである。一部の事例では、制御エレメントは、導入遺伝子、イントロン、プロモーター、エンハンサー、UTR、インシュレーター、リプレッサー、末端逆位反復(ITR)配列、長い末端反復配列(LTR)、安定性エレメント、翻訳後応答エレメント、もしくはポリA配列、またはこれらの組合せであり得る。一部の事例では、制御エレメントは、プロモーターもしくはエンハンサー、またはそれらの組合せである。一部の事例では、制御エレメントは、ヒト配列に由来する。
「発現カセット」および「核酸カセット」という用語は、ポリヌクレオチド分子または核酸配列を指して、互換可能に使用される。一部の事例では、発現カセットは、導入遺伝子に作動可能に連結された、本明細書に開示される1つまたは複数の制御エレメントを含む。一部の事例では、発現カセットは、1つまたは複数の制御エレメントを含む。一部の事例では、発現カセットは、本明細書に開示される1つまたは複数の細胞型選択的制御エレメントを含む。一部の事例では、発現カセットは、本明細書に開示される1つまたは複数のPV細胞選択的制御エレメントを含む。一部の事例では、発現カセットは、プロモーターをさらに含む。一部の事例では、発現カセットは、配列番号1~32のうちの1つもしくは複数の配列、および/またはそれらの任意の組合せを含む。一部の事例では、発現カセットは、配列番号1~32、(ii)配列番号1~32のうちのいずれか1つに対して少なくとも80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、もしくは99%の配列同一性を有する核酸配列、(iii)(i)もしくは(ii)のうちのいずれかの配列の機能性断片、または(iv)(i)、(ii)、および/もしくは(iii)のうちのいずれかの配列の組合せのうちの1つまたは複数を含む。一部の事例では、配列同一性は、BLASTによって測定される。一部の事例では、制御エレメントは、発現カセットにおいて、導入遺伝子の上流に位置する。一部の事例では、制御エレメントは、発現カセットにおいて、導入遺伝子の下流に位置する。一部の事例では、発現カセットは、プロモーター、たとえば、hSyn1プロモーター、CBAプロモーター、CMVプロモーター、EF1αプロモーター、ポリAシグナル(たとえば、SV40ポリAシグナル)、または転写後制御エレメント、たとえば、ウッドチャック肝炎ウイルス転写後制御エレメント(WPRE)をさらに含む。
GABA作動性ニューロンは、CNSにおける主要な抑制性神経伝達物質であるガンマアミノ酪酸(GABA)を産生する。GABAは、神経系全体の神経興奮性を低減させるのに重要である。GABAは、特定の膜貫通受容体に結合し、膜の分極を負に変化させるイオンチャネルの開口をもたらすことによって、抑制性シナプスとして作用する。これは、一般に、細胞の過分極をもたらし、活動電位をトリガーするのに必要なシグナルを増加させる。GABA作動性ニューロンにおける欠陥は、興奮性シグナル伝達と抑制性シグナル伝達との間の不均衡をもたらし得、ドラベ症候群、てんかん、神経変性、タウオパチー、およびアルツハイマー病を含む、多数の神経学的疾患に関係付けられている。関係している他の神経学的状態または疾患としては、精神障害(たとえば、統合失調症、強迫性障害、依存症、うつ、不安症、精神病)、自閉症スペクトラム障害(たとえば、脆弱X染色体症候群、レット症候群)、てんかん(たとえば、慢性外傷性脳症、全般性てんかん熱性けいれんプラス(GEFS+)、てんかん性脳症、側頭葉てんかん、焦点性てんかん、結節性硬化症)、および/または神経変性(たとえば、アルツハイマー病、パーキンソン病)が挙げられる。一部の事例では、神経学的状態または疾患は、任意のけいれんおよび/またはてんかんに関連する状態または疾患であり、PVニューロンが関係している。
推定上のPV選択的制御エレメントの特定
PV細胞に対して選択的な推定上の制御エレメントを特定およびスクリーニングするために、親和性精製を使用して、たとえば、抗GFP抗体または抗Myc抗体およびプロテインGコーティング磁気ビーズを使用して、R26-CAG-LSL-Sun1-sfGFP-MycノックインマウスからPV細胞を採取することができる。PV細胞は、抗PV抗体で被覆したビーズまたは親和性精製マトリクスを使用して濃縮することができる。核を次いでPV細胞から単離する。核RNAは、核から精製され、cDNAに変換され、そしてNugen Ovation RNA-seq System V2(Nugen 7102)で増幅し、その後、Illumina HISEQ(登録商標) 2500を使用してシーケンシングすることができる。ゲノムDNAは、核から精製され、断片化され、そしてメチルC-seqライブラリーを作成するために使用することができ、このライブラリーは、Illumina HISEQ(登録商標) 2000を使用してシーケンシングすることができる。ATAC-seqライブラリーを作成するために、ビーズに結合した核を、Tn5トランスポザーゼ(Illumina FC-121-1030)を使用して転位させる。9~12サイクルのPCR増幅の後、ライブラリーを、Illumina HISEQ(登録商標) 2500を使用してシーケンシングする。ChIP-seqライブラリーを作成するために、小球菌ヌクレアーゼを使用してPV細胞の核をモノヌクレオソームに消化し、その後、クロマチンの塩抽出、ならびにネイティブChIPおよびライブラリーの構築を行い、これを、Illumina HISEQ(登録商標) 2500を使用してシーケンシングすることができる。これらのライブラリーをシーケンシングした後、配列をマッピングして、PV細胞における、CGリッチ領域での低メチル化、ヒストン修飾、転写因子結合部位、ならびに高度に発現した転写因子に関連するパターンにおける、相関およびパターンを特定する。上記の複数のアッセイおよび/またはライブラリーから得られるオーバーラップする特徴および相関は、推定上のPV選択的制御エレメントである候補配列を特定するための収束的証拠を提供する。推定上のPV選択的制御エレメントは、以下の実施例5において記載される共局在アッセイを使用して、さらに試験することができる。推定上のPV選択的制御エレメントはまた、B6 PV-Creマウス(Jackson Laboratory)において試験することができ、このマウスは、以下の実施例2において記載されるように、パルブアルブミンの発現においてCreリコンビナーゼを発現するB6 PV-Creノックインマウスである。制御エレメントのPV選択性を検証した後、少なくとも1つ、2つ、3つ、4つ、5つ、または5つより多くの非PV細胞よりもPV細胞に対して選択的に発現を標的化するために、制御エレメントを導入遺伝子に作動可能に連結させることができる。
PV-CreマウスにおけるPVニューロンに対する選択性
PVニューロンに対する選択性は、蛍光イメージングを使用して判定することができる。(i)対照プロモーター(EF1a)、または(ii)上記の実施例1で特定されたPV選択的RE、または(iii)配列番号1~32から選択されるPV選択的REに作動可能に連結しているeGFPを含むAAV9ベクター、およびCre依存性tdTomatoを含むAAV9ベクターを、B6 PV-Creマウス(Jackson Labs)に共注射する。PV-Creは、内因性Pvalbの発現を妨害することなく、パルブアルブミン発現ニューロン(脳における介在ニューロン、および後根神経節における固有受容性の求心性感覚ニューロンなど)においてCreリコンビナーゼを発現する、ノックインマウスである。
ドラベマウスモデルにおけるてんかん発作の低減
B6(Cg)-Scn1atm1.1Dsf/Jマウスを、Dravet syndrome European Federationから、Jackson Laboratoriesを介して入手した。これらのマウスは、ドラベ症候群に関連する変異を、SCN1Aのエキソン24に含む(1783位でのAからV)。このマウスはまた、floxedエキソン24と野生型配列とを含む。遺伝子操作されていない場合、このマウス株は、SCN1AのWT対立遺伝子の2つのコピーを発現する。しかし、Creリコンビナーゼを発現するAAVが送達されると、AAVによって標的化されるいかなる細胞も、変異体対立遺伝子の1つのコピーを発現するように切り替わる。変異体SCN1Aサブユニットが発現すると、マウスは10日以内に自発てんかん発作を発症する。
マウスモデルにおけるアルツハイマー病の処置
PsychoGenicsで飼育されたメスAPP/PS1マウスおよびWTマウスを研究で使用した。APP/PS1マウスは、共にThy1プロモーターの制御下の、Swedish変異(670G-Tおよび671A-C)を有するアミロイドベータ前駆体タンパク質(APP)およびL166P変異を含むPresenilin1(PSEN1)の両方について、ヒト導入遺伝子を含む。これらのマウスは、アミロイド斑および記憶障害を含む、アルツハイマー病の症候を発症する。これらのマウスについてのさらなる記載は、Raddeら、2006年(Radde、Rebeccaら、「Aβ42-driven cerebral amyloidosis in transgenic mice reveals early and robust pathology.」EMBO reports 7.9巻(2006年):940~946頁)で見ることができる。
C57BL/6J(WT)マウスにおけるPVニューロンに対する選択性
本明細書において開示される様々なREの選択性を、免疫組織化学的方法を使用して、PVニューロンにおける選択的遺伝子発現について試験した。C57BL/6J(WT)マウス系統を、PV免疫組織化学的アッセイに使用した。AAV9構築物において、発現カセットは、制御エレメント(配列番号1もしくは配列番号8)またはCAGプロモーターに作動可能に連結しているレポーター導入遺伝子eGFPを含む。
様々なマウス系統におけるドラベ症候群の処置
本明細書において記載される発現カセットを使用する、ドラベ症候群および/またはその症候の処置は、上記のB6(Cg)-Scn1atm1.1Dsf/J、Scn1atm1Kea、およびScn1a-R1470Xマウス系統などの様々なマウス系統において試験することができる。これらのマウス系統は、ドラベ症候群についての確立されたマウスモデルである。Scn1atm1Keaマウス系統およびScn1a-R1470Xマウス系統は、CREリコンビナーゼを必要としない。
マウスにおけるアルツハイマー病の処置
PsychoGenicsで飼育され、アルツハイマー病の確立されたマウスモデルである、メスAPP/PS1マウスおよび野生型(WT)マウスを使用して、1つまたは複数のPV選択的REを含むアルツハイマー病の処置における本明細書において記載される組成物の安全性および有効性を研究することができる。APP/PS1マウスは、実施例4において上記で説明されている。
Claims (29)
- 導入遺伝子に作動可能に連結されたパルブアルブミン(PV)ニューロン選択的制御エレメントを含む、核酸カセットであって、前記PVニューロン選択的制御エレメントが、配列番号1~22のうちのいずれか1つの配列を有するポリヌクレオチドを含み、前記制御エレメントが0.1kb~2.5kbのサイズである、核酸カセット。
- 前記制御エレメントが、配列番号1の配列を含む、請求項1に記載の核酸カセット。
- 前記制御エレメントが、配列番号8の配列を含む、請求項1に記載の核酸カセット。
- 前記導入遺伝子が、イオンチャネルサブユニット、神経伝達物質制御因子、DNA結合ドメイン、または遺伝子編集タンパク質をコードする、請求項1~3のいずれか一項に記載の核酸カセット。
- 前記導入遺伝子が、前記イオンチャネルサブユニットをコードし、前記イオンチャネルサブユニットが、ナトリウムイオンチャネルのアルファサブユニット、ナトリウムイオンチャネルのベータサブユニット、またはカリウムイオンチャネルのサブユニットである、請求項4に記載の核酸カセット。
- 前記導入遺伝子が、配列番号37~43のうちのいずれか1つのアミノ酸配列をコードする、請求項5に記載の核酸カセット。
- 前記イオンチャネルサブユニットが、SCN1A、SCN2A、SCN8A、SCN1B、SCN2B、KV3.1、もしくはKV3.3を含む、請求項5に記載の核酸カセット。
- 前記導入遺伝子が、神経伝達物質制御因子をコードし、前記神経伝達物質制御因子が、STXBP1を含む、請求項4に記載の核酸カセット。
- 前記導入遺伝子が、DNA結合タンパク質をコードし、前記DNA結合タンパク質が、内因性遺伝子の発現をモジュレートする、請求項4に記載の核酸カセット。
- 前記内因性遺伝子が、SCN1A、SCN2A、SCN8A、SCN1B、SCN2B、KV3.1、KV3.2、KV3.3、またはSTXBP1である、請求項9に記載の核酸カセット。
- 前記導入遺伝子が、遺伝子編集タンパク質をコードする、請求項4に記載の核酸カセット。
- 前記遺伝子編集タンパク質が、Casタンパク質である、請求項11に記載の核酸カセット。
- 直鎖状構築物である、請求項1~12のいずれか一項に記載の核酸カセット。
- ベクターである、請求項1~12のいずれか一項に記載の核酸カセット。
- 前記ベクターが、プラスミドである、請求項14に記載の核酸カセット。
- 前記ベクターが、ウイルスベクターである、請求項14に記載の核酸カセット。
- 前記ウイルスベクターが、アデノ随伴ウイルス(AAV)ベクターである、請求項16に記載の核酸カセット。
- 前記AAVベクターが、AAV1、AAV8、AAV9、scAAV1、scAAV8、またはscAAV9である、請求項17に記載の核酸カセット。
- 前記ウイルスベクターが、レンチウイルスベクターである、請求項16に記載の核酸カセット。
- 前記制御エレメントが、GAD2、GAD1、SYN1、NKX2.1、DLX1、DLX5/6、SST、PV、またはVIPの転写開始部位の10kb以内に由来する、600bpを下回る連続的な配列を含む、請求項1~19のいずれか一項に記載の核酸カセット。
- 神経学的状態または障害の処置のための組成物であって、請求項1から20のいずれか一項に記載の核酸カセットを含む、組成物。
- 前記神経学的状態または障害が、てんかん、神経変性、タウオパチー、またはニューロン興奮性低下である、請求項21に記載の組成物。
- 前記神経学的状態または障害が、ドラベ症候群である、請求項21に記載の組成物。
- 前記神経学的状態または障害が、アルツハイマー病である、請求項21に記載の組成物。
- 神経学的状態または障害を処置するための医薬の製造における、請求項1から20のいずれか一項に記載の核酸カセットの使用。
- 前記神経学的状態または障害が、てんかん、神経変性、タウオパチー、またはニューロン興奮性低下である、請求項25に記載の使用。
- 前記神経学的状態または障害が、ドラベ症候群である、請求項25に記載の使用。
- 前記神経学的状態または障害が、アルツハイマー病である、請求項25に記載の使用。
- 請求項1~20のいずれか一項に記載の核酸カセットを含む、PVニューロンにおける前記導入遺伝子の発現を増加させるための組成物。
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