JP2020500526A - タウモジュレーターならびにその送達のための方法および組成物 - Google Patents
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Abstract
Description
本出願は、2016年12月1日に出願された米国仮出願第62/428,871号、2017年1月26日に出願された米国仮出願第62/450,895号、2017年3月2日に出願された米国仮出願第62/466,198号、2017年5月3日に出願された米国仮出願第62/500,807号、および2017年11月10日に出願された米国仮出願第62/584,342号の利益を主張し、それらの開示は、その全体が本明細書において参考として援用される。
本開示は、アルツハイマー病などのタウオパチーの診断および治療の分野に属する。
したがって、脳への広範な送達を示すモダリティを含む、AD、FTD、PSP CBD、および発作を含むタウオパチーを予防および/または処置するための方法に対する必要性が依然として存在している。
基本的事項
定義
タウおよびアルツハイマー病
DNA結合ドメイン
種 PAM
S.pyogenes NGG
S.pyogenes NAG
S.mutans NGG
S.thermophilius NGGNG
S.thermophilius NNAAAW
S.thermophilius NNAGAA
S.thermophilius NNNGATT
C.jejuni NNNNACA
N.meningitides NNNNGATT
P.multocida GNNNCNNA
F.novicida NG
タウ遺伝子モジュレーター
送達
CNS障害のモデル
応用
MAPTリプレッサー
本質的に米国特許第6,534,261号、米国特許出願公開第2015/0056705号、第2011/0082093号、第2013/0253040号、および第2015/0335708号に記載のように遺伝子操作されたおよそ185個のジンクフィンガータンパク質のスクリーニングを実施し、ZFPをそれらのMAPT標的部位に結合させた。マウスMAPTを標的とするジンクフィンガータンパク質52288、52322、52364、52366、52389、57880、57890、および65888(下記の表1〜3を参照)を、さらなる研究のために選択した。65888に関して列挙されているホスフェート接触突然変異体は、以前に記載されている(例えば、米国特許出願第15/685,580号を参照)。表1は、これらZFPのDNA結合ドメインの認識ヘリックスおよびこれらZFPの標的配列を示す。また、1セットのZFPを、マウスおよびヒト遺伝子間で共有されるMAPT配列を標的とするように製作した。それらは表2に示されている。表3は、親ZFP TF、および潜在的な非特異的ホスフェート接触を除去するためにZFP骨格を表示位置で突然変異させた誘導体ZFP TFを示す。ZFPは、標準的SELEX分析により評価したところ、それらの標的部位に結合することが示された。
表1:マウスMAPT特異的リプレッサー設計
マウスニューロンでのタウ抑制
(実施例3)
MAPT抑制の特異性
(実施例4)
CNS限定ZFP−TF発現のためのニューロンプロモーター
(実施例5)
iPS由来ニューロンでのヒトMAPTの抑制
(実施例6)
AAV送達ZFP TFにより駆動されるin vivo MAPT抑制
(実施例7)
ニューロンプロモーターから発現されるAAV送達ZFP TFにより駆動されるin vivo MAPT抑制およびタンパク質ノックダウン
(実施例8)
海馬および接続脳領域の全体にわたるタウ低減の組織学的証拠
(実施例9)
マウス海馬でのZFP−TFのin vivo安全性、タウ低減、および持続発現
(実施例10)
ADのマウスモデルにおけるタウ低減
(実施例11)
霊長類脳におけるin vivoでのタウ低減
Claims (16)
- 微小管結合タンパク質タウ(MAPT)遺伝子の遺伝子モジュレーターであって、
該MAPT遺伝子の少なくとも12個のヌクレオチドの標的部位に結合するDNA結合ドメイン、および
転写制御ドメインまたはヌクレアーゼドメイン
を含む遺伝子モジュレーター。 - 前記DNA結合ドメインが、ジンクフィンガータンパク質(ZFP)、TAL−エフェクタードメインタンパク質(TALE)、または単鎖ガイドRNAを含む、請求項1に記載の遺伝子モジュレーター。
- 前記転写制御ドメインが、抑制ドメインまたは活性化ドメインを含む、請求項1または請求項2に記載の遺伝子モジュレーター。
- 請求項1から3のいずれかに記載の遺伝子モジュレーターをコードするポリヌクレオチド。
- 請求項4に記載のポリヌクレオチドを含む遺伝子送達ビヒクル。
- AAVベクターを含む、請求項5に記載の遺伝子送達ビヒクル。
- 請求項1から3に記載の1つまたは複数の遺伝子モジュレーター、請求項4に記載の1つまたは複数のポリヌクレオチド、および/または請求項5または6に記載の1つまたは複数の遺伝子送達ビヒクルを含む医薬組成物。
- 前記遺伝子モジュレーターが、ヌクレアーゼドメインを含み、該遺伝子モジュレーターが、前記MAPT遺伝子を切断する、請求項7に記載の医薬組成物。
- 切断された前記MAPT遺伝子に組み込まれるドナー分子をさらに含む、請求項8に記載の医薬組成物。
- 請求項1から3に記載の1つまたは複数の遺伝子モジュレーター、請求項4に記載の1つまたは複数のポリヌクレオチド、請求項5または6に記載の1つまたは複数の遺伝子送達ビヒクル、および/または請求項7から9のいずれかに記載の医薬組成物を含む単離細胞。
- 対象のMAPT発現を調節するための、請求項1から3に記載の1つまたは複数の遺伝子モジュレーター、請求項4に記載の1つまたは複数のポリヌクレオチド、請求項5または6に記載の1つまたは複数の遺伝子送達ビヒクル、および/または請求項7から9のいずれかに記載の医薬組成物の使用。
- MAPT発現が抑制される、請求項11に記載の使用。
- 前記対象への投与が、脳室内、髄腔内、頭蓋内、静脈内、後眼窩的、または槽内である、請求項11または12に記載の使用。
- 前記対象中のMAPT発現の抑制が、タウオパチーを処置および/または予防する、請求項11から13のいずれかに記載の使用。
- 前記対象中のタウの量が低減される、請求項11から14のいずれかに記載の使用。
- 請求項1から3に記載の1つまたは複数の遺伝子モジュレーター、請求項4に記載の1つまたは複数のポリヌクレオチド、請求項5または6に記載の1つまたは複数の遺伝子送達ビヒクル、請求項7から9のいずれかに記載の医薬組成物、および/または使用のための指示を含むキット。
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AU2017367722A1 (en) | 2019-05-30 |
IL266862B1 (en) | 2023-09-01 |
AU2017367722A8 (en) | 2019-06-13 |
CN110214184B (zh) | 2024-07-02 |
IL266862B2 (en) | 2024-01-01 |
BR112019010014A2 (pt) | 2019-08-20 |
RU2019120040A3 (ja) | 2021-04-09 |
MX2019006426A (es) | 2019-08-14 |
US11504389B2 (en) | 2022-11-22 |
JP2023078446A (ja) | 2023-06-06 |
WO2018102665A1 (en) | 2018-06-07 |
KR20190085529A (ko) | 2019-07-18 |
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US20180153921A1 (en) | 2018-06-07 |
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