JP5866283B2 - トリヌクレオチド反復疾患を治療するための方法および組成物 - Google Patents
トリヌクレオチド反復疾患を治療するための方法および組成物 Download PDFInfo
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Description
本出願は、2009年7月28日に出願された米国仮出願第61/271,913号、および2009年7月29日に出願された同第61/273,009号の利益を主張し、これらの開示は、参照によりその全体が本明細書に組み込まれる。
該当せず。
本開示は、遺伝子発現の分野にある。
トリヌクレオチド反復伸長疾患は、1990年初期に初めて特徴付けられた(Di Prospero and Fischbeck,(2005)Nature Reviews Genetics vol 6:756−765を参照のこと)。これらの疾患は、3個のヌクレオチドのセットの不安定な反復の局所的伸長を有し、この反復が存在する遺伝子の機能喪失、毒性機能の増加、または両方を引き起こし得る。トリヌクレオチド反復は、非コードおよびコード遺伝子領域を含む、遺伝子のあらゆる部分に位置し得る。コード領域内に位置する反復には、一般的に、トリプレットをコードする反復したグルタミン(CAG)またはトリプレットをコードするアラニン(CGA)のいずれかが含まれる。非コード配列内の長く伸びる反復領域は、遺伝子の異常な発現を引き起こし得る一方で、コード領域内の長く伸びる反復(コドン反復疾患としても知られている)は、ミスフォールディングおよびタンパク質凝集を引き起こし得る。異常なタンパク質に関連する病態生理学的な正確な原因は、多くの場合、知られていない。一般的に、トリヌクレオチド伸長を起こしやすい野生型遺伝子において、これらの領域は、正常な集団において可変数の反復配列を含むが、罹患集団において、反復の数は、場合によっては、反復の数の単純な2倍から、反復の数の対数で1桁まで増加し得る。例えば、脆弱X症候群患者におけるCGG伸長を受けるFMR1遺伝子において、野生型集団は、2〜50の反復を示す一方で、脆弱X症候群に罹患しているこれらの患者は、200〜2000のCGG反復を有し得る(Nadel et al(1995)Journal Biological Chemistry 270(48):28970−28977)。
トリヌクレオチド反復疾患を治療するための方法および組成物を本明細書に開示する。特に、トリヌクレオチド反復疾患を治療するために、トリヌクレオチド反復を含む遺伝子の発現を調節する、例えば、ハンチントン病を治療するためにHD Htt対立遺伝子の発現を調節するための方法および組成物が、本明細書に提供される。また、トリヌクレオチド反復疾患の動物モデルを生成するための方法および組成物も提供される。
ハンチントン病、SBMA、フリードライヒ運動失調症、ならびに脆弱X症候群AおよびE等のトリヌクレオチド反復疾患を治療するための組成物および方法を本明細書に開示する。特に、亜鉛フィンガータンパク質(ZFP TF)を含むHttを調節する転写因子およびこのようなタンパク質を利用する方法が、ハンチントン病を治療で用いるために提供される。例えば、変異Htt対立遺伝子の発現を抑制する、または野生型Htt対立遺伝子の発現を活性化するZFP−TFを提供する。加えて、これらの疾患に関連する遺伝子のゲノム構造を修飾する亜鉛フィンガーヌクレアーゼ(ZFN)を提供する。例えば、変異型のHttの部分を特異的に変化させることができるZFNを提供する。これらには、改変された亜鉛フィンガータンパク質、すなわち、所定の核酸標的配列に結合する天然に存在しないタンパク質を用いる組成物および方法が含まれる。
本明細書に開示される方法の実践、ならびに組成物の調製および使用は、特に指示がない限り、分子生物学、生化学、クロマチン構造および分析、計算化学、細胞培養、組み換えDNA、および関連分野における従来の技術は、当技術分野の技術範囲内である。これらの技術は、文献に十分に説明されている。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および定期的に更新されたもの;METHODS IN ENZYMOLOGY,Academic Press,San Diegoシリーズ;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を参照のこと。
「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、交換可能に使用され、線状または環状構造で、一本鎖または二本鎖形態の、デオキシリボヌクレオチドポリマーまたはリボヌクレオチドポリマーを指す。本開示については、これらの用語をポリマーの長さに関する限定と解釈すべきではない。これらの用語は、天然ヌクレオチドの公知の類似体、ならびに塩基、糖、および/またはリン酸(ホスホロチオエート主鎖)部分内で修飾されるヌクレオチド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、同じ塩基対形成特異性を有し、すなわち、Aの類似体は、Tと塩基対を形成する。
Httを含むが、これに限定されない、トリヌクレオチド反復を含む任意の遺伝子において、標的部位に特異的に結合するDNA結合ドメインを含む組成物が、本明細書に記載されている。GDNFまたはBDNF遺伝子において、標的部位に特異的に結合するDNA結合ドメインを含む組成物も提供される。任意のDNA結合ドメインは、本明細書に開示される組成物および方法で使用することができる。
本明細書に記載されるDNA結合タンパク質(例えば、ZFP)を含む融合タンパク質および異種調節(機能的)ドメイン(またはその機能的断片)も提供される。一般的なドメインには、例えば、転写因子ドメイン(活性化剤、リプレッサー、共活性化剤、コリプレッサー)、サイレンサー、癌遺伝子(例えば、myc、jun、fos、myb、max、mad、rel、ets、bcl、myb、mosファミリーメンバー等)、DNA修復酵素ならびにそれらの関連する因子および修飾因子、クロマチン結合性タンパク質およびそれらの修飾因子(例えば、キナーゼ、アセチラーゼ、およびデアセチラーゼ)、ならびにDNA修飾酵素(例えば、メチルトランスフェラーゼ、トポイソメラーゼ、ヘリカーゼ、リガーゼ、キナーゼ、ホスファターゼ、ポリメラーゼ、エンドヌクレアーゼ)、ならびにそれらの関連する因子および修飾因子が含まれる。DNA結合ドメインならびにヌクレアーゼ開裂ドメインの融合に関する詳細ついて、米国特許出願公開第2005/0064474号、同第2006/0188987号、および同第2007/0218528号明細書を参照されたく、参照によりそれらの全体が本明細書に組み込まれる。
特定の実施形態において、融合タンパク質は、DNA結合結合ドメインおよび切断(ヌクレアーゼ)ドメインを含む。したがって、遺伝子修飾は、ヌクレアーゼ、例えば、改変されたヌクレアーゼを用いて達成することができる。改変されたヌクレアーゼ技術は、天然に存在するDNA結合タンパク質の改変に基づいている。例えば、目的に合わせたDNA結合特異性を有するホーミングエンドヌクレアーゼの改変が、記載されている。Chames et al.(2005)Nucleic Acids Res 33(20):e178、Arnould et al.(2006)J.Mol.Biol.355:443−458。加えて、ZFPの改変も記載されている。例えば、米国特許第6,534,261号、同第6,607,882号、同第6,824,978号、同第6,979,539号、同第6,933,113号、同第7,163,824号、および同第7,013,219号明細書を参照されたい。
タンパク質(例えば、ZFP)、同一物をコードするポリヌクレオチド、ならびに本明細書に記載されるタンパク質および/またはポリヌクレオチドを含む組成物は、任意の好適な手段で、例えば、ZFP TFまたはZFN mRNAを注入することによって、標的細胞に送達され得る。好適な細胞には、真核および原核細胞ならびに/または細胞株が含まれるが、これらに限定されない。このような細胞またはこのような細胞から生成された細胞株の非制限的な例には、COS、CHO(例えば、CHO−S、CHO−K1、CHO−DG44、CHO−DUXB11、CHO−DUKX、CHOK1SV)、VERO、MDCK、WI38、V79、B14AF28−G3、BHK、HaK、NS0、SP2/0−Ag14、HeLa、HEK293(例えば、HEK293−F、HEK293−H、HEK293−T)、およびperC6細胞、ならびにツマジロクサヨトウ(Sf)等の昆虫細胞、またはサッカロミセス、ピチア、およびシゾサッカロミセス等の真菌細胞が挙げられるが、これらに限定されない。ある特定の実施形態において、細胞株は、CHO−K1、MDCK、またはHEK293細胞株である。また、好適な細胞には、例として、胚幹細胞、誘導多能性幹細胞、造血幹細胞、および間充織幹細胞等の幹細胞も含まれる。
トリヌクレオチド反復疾患に関連する遺伝子を調節する、および/またはこれらの疾患に関連する遺伝子におけるトリヌクレオチド反復の経路を取り除くことが望ましい任意の用途のために、開示される組成物および方法を使用することができる。特に、治療および研究用途を含むが、これらに限定されない、Htt対立遺伝子の調節が望ましい任意の用途のために、これらの方法および組成物を使用することができる。
Httを標的化した亜鉛フィンガータンパク質は、米国特許第6,534,261号明細書に記載されるように、基本的に改変された。表1は、例示的なHtt標的ZFPの認識へリックスDNA結合ドメインを示す。
ZFP TFを抑制するHttの活性を試験するために、ZFP TFをヒト細胞にトランスフェクトし、PCRを用いてHttの発現を観察した。
インビボでのHtt特異的ZFP TFを試験するために、ZFPをコードするAAV2ベクターを産生する。次いで、これらのAAV2ベースの構築体を、マウスの脳に送達する。ヒトHtt特異的ZFP TFにおいては、AAVベクターをR6.2マウスまたはBAC HDマウス(C57Bl/6またはFVB/N株)に送達し、ヒト導入遺伝子の抑制を評価する。マウスHtt特異的ZFPにおいては、AAVベクターを野生型マウス(C57Bl/6またはFVB/N)に送達し、内因性マウスHtt発現の抑制を評価する。CAGを伸長した対立遺伝子を優先的に標的化するZFPにおいては、AAVベクターをR6.2マウスまたはヒトHttノックインマウスに送達し、野生型対伸長したHtt対立遺伝子の選択的抑制を検証する。殺処分後、脳組織を、TaqmanリアルタイムRT−PCRによって、Htt発現に対して分析する。
上で同定されるHtt特異的ZFP TFは、脳神経栄養因子に対して特異的なZFP TFで共トランスフェクトされる。使用した脳神経栄養因子に対して特異的なZFP TFは、GDNFあるいはBDNFのいずれかに対して特異的である。
ヒトHttおよびマウスHttを標的化するZFNは、CAG反復に隣接する配列、ならびに最初および最後のコーディングエクソンの配列を標的化するように設計される。ZFNは、Urnov et al.(2005)Nature 435(7042):646−651、Perez et al(2008)Nature Biotechnology 26(7):808−816、および米国特許出願公開第2008/0131962号明細書に記載されるように基本的に設計され、プラスミドまたはアデノウイルスベクターに組み込まれた。
上記のヒトHtt特異的ZFNの対をコードするプラスミドを、K562細胞にトランスフェクトする。K562細胞は、American Type Culture Collectionから入手して、10%規格ウシ胎仔血清(FCS、Cyclone)を補足したF−12培地(Invitrogen)中で推奨されるように、成長させた。細胞を、TrypLE Select(商標)プロテアーゼ(Invitrogen)を用いて、プラスチック容器から引き離した。トランスフェクションのために、100万個のK562細胞を、2μgの亜鉛フィンガーヌクレアーゼプラスミドおよび100μL Amaxa溶液Tと混合した。細胞を、プログラムU−23を用いてAmaxa Nucleofector II(商標)中でトランスフェクトし、1.4mLの温F−12培地+10%FCS中に回収した。
上記の、CAG反復に隣接する配列に対して最大の切断活性を有するHtt特異的ZFNを、標的化組込み戦略に使用して、Httの野生型コピーへの可変長のCAG反復を導入する。50、80、109、および180のCAG反復単位を含むドナーが、構築される。次いで、これらのドナーは、上記のように、Htt特異的ZFNをコードするプラスミドを用いて、K562細胞にトランスフェクトされる。ドナー組込みの検証は、ゲノムDNA単離、PCT増幅(上記のような)、続いて、対象となる領域のシークエンシングによって達成される。
最初または最後のコーディングエクソンに対して最大の切断活性を有するZFNを使用して、異なるレポータータンパク質を用いて、野生型および変異Htt対立遺伝子を標識化する。それぞれのレポーター(AおよびB)に対してドナーDNAは、レポーター遺伝子の標的化組込みが、Httへのインフレーム融合を産生することができるように、リードZFN対の切断部位に基づいて設計される。ドナーDNAは、組込みの最も高い頻度を与えるドナーDNA構築体を選択するために、リードZFN対を用いて、ニューロ2A細胞に共トランスフェクトされる。
Claims (13)
- 前記遺伝子は、野生型または少なくとも1つの長く伸びるトリヌクレオチド反復を含む遺伝子である、請求項1に記載の亜鉛フィンガータンパク質。
- 請求項1または請求項2に記載の少なくとも2つの亜鉛フィンガータンパク質を含む、多量体であって、前記多量体の前記亜鉛フィンガータンパク質は、野生型トリヌクレオチド反復と比較して、長く伸びるトリヌクレオチド反復に優先的に結合する、多量体。
- 前記長く伸びるトリヌクレオチド反復は、ポリグルタミンまたはポリセリンをコードする、請求項1乃至3のいずれかに記載の亜鉛フィンガータンパク質または多量体。
- 前記亜鉛フィンガータンパク質は、前記遺伝子の発現を活性化するか、または抑制する、請求項1乃至4のいずれかに記載の亜鉛フィンガータンパク質または多量体。
- 請求項1乃至5のいずれかに記載の亜鉛フィンガータンパク質または多量体、ならびに、機能ドメインを含む、融合タンパク質。
- 前記機能ドメインが、転写活性化ドメイン、転写抑制ドメイン、開裂ドメインまたは開裂ハーフドメインである、請求項6に記載の融合タンパク質。
- 請求項1乃至7のいずれかに記載の亜鉛フィンガータンパク質、多量体、または融合タンパク質をコードする、ポリヌクレオチド。
- 請求項1乃至8のいずれかに記載の亜鉛フィンガータンパク質、多量体、融合タンパク質、またはポリヌクレオチドを含む、単離された細胞。
- 請求項1乃至8のいずれかに記載の亜鉛フィンガータンパク質、多量体、融合タンパク質、またはポリヌクレオチドを含む、薬学的組成物。
- インビトロで、長く伸びるトリヌクレオチド反復を標的修飾する方法であって、前記融合タンパク質の活性により、前記長く伸びるトリヌクレオチド反復が修飾されるように、請求項6に記載の1つ以上の融合タンパク質または前記1つ以上の融合タンパク質をコードするポリヌクレオチドを、長く伸びるトリヌクレオチド反復を含む遺伝子を有するゲノムを含む細胞にインビトロで投与することを含む、方法。
- 前記細胞は、誘導多能性幹細胞(iPSC)、ヒト胚幹細胞(hES)、間充織幹細胞(MSC)、神経幹細胞、またはこれらの組み合わせからなる群から選択される、請求項11に記載の方法。
- 前記修飾は、トリヌクレオチド反復の数を減少させることを含む、請求項11に記載の方法。
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Families Citing this family (52)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2713560T3 (es) | 2010-10-15 | 2019-05-22 | Fund Centre De Regulacio Genòmica | Péptidos que tienen dominios de dedos de zinc y usos de estos |
US8569254B2 (en) * | 2010-12-10 | 2013-10-29 | National Yang Ming University | Methods for modulating the expression and aggregation of CAG-expanded gene product in cells and methods for identifying agents useful for doing the same |
US20120239681A1 (en) * | 2011-03-14 | 2012-09-20 | Splunk Inc. | Scalable interactive display of distributed data |
GB201122458D0 (en) | 2011-12-30 | 2012-02-08 | Univ Wageningen | Modified cascade ribonucleoproteins and uses thereof |
JP6490426B2 (ja) * | 2012-02-29 | 2019-03-27 | サンガモ セラピューティクス, インコーポレイテッド | ハンチントン病を治療するための方法および組成物 |
GEP20217251B (en) | 2012-05-25 | 2021-04-26 | Charpentier Emmanuelle De Emanuel | Methods and compositions for rna-directed target dna modification and for rna-directed modulation of transcription |
KR102676910B1 (ko) | 2012-12-06 | 2024-06-19 | 시그마-알드리치 컴퍼니., 엘엘씨 | Crispr-기초된 유전체 변형과 조절 |
MX2015007550A (es) | 2012-12-12 | 2017-02-02 | Broad Inst Inc | Suministro, modificación y optimización de sistemas, métodos y composiciones para la manipulación de secuencias y aplicaciones terapéuticas. |
EP2931892B1 (en) | 2012-12-12 | 2018-09-12 | The Broad Institute, Inc. | Methods, models, systems, and apparatus for identifying target sequences for cas enzymes or crispr-cas systems for target sequences and conveying results thereof |
CN111454951A (zh) | 2013-03-14 | 2020-07-28 | 卡里布生物科学公司 | 以核酸为靶的核酸的组合物和方法 |
CN116083487A (zh) | 2013-05-15 | 2023-05-09 | 桑格摩生物治疗股份有限公司 | 用于治疗遗传病状的方法和组合物 |
WO2014204727A1 (en) | 2013-06-17 | 2014-12-24 | The Broad Institute Inc. | Functional genomics using crispr-cas systems, compositions methods, screens and applications thereof |
WO2014204725A1 (en) | 2013-06-17 | 2014-12-24 | The Broad Institute Inc. | Optimized crispr-cas double nickase systems, methods and compositions for sequence manipulation |
DK3011031T3 (da) | 2013-06-17 | 2020-12-21 | Broad Inst Inc | Fremføring og anvendelse af crispr-cas-systemerne, vektorer og sammensætninger til levermålretning og -terapi |
AU2014281031B2 (en) * | 2013-06-17 | 2020-05-21 | Massachusetts Institute Of Technology | Delivery, use and therapeutic applications of the CRISPR-Cas systems and compositions for targeting disorders and diseases using viral components |
DK3011029T3 (da) | 2013-06-17 | 2020-03-16 | Broad Inst Inc | Administration, modificering og optimering af tandem-guidesystemer, fremgangsmåder og sammensætninger til sekvensmanipulering |
BR112015031611A2 (pt) * | 2013-06-17 | 2017-12-12 | Massachusetts Inst Technology | aplicação, manipulação e otimização de sistemas, métodos e composições para direcionamento e modelação de doenças e distúrbios de células pós-mitóticas |
CN104419756B (zh) * | 2013-08-30 | 2018-03-02 | 中国科学院上海生命科学研究院 | 检测哺乳动物基因组三核苷酸重复序列的方法及其应用 |
EP3068905A4 (en) | 2013-11-11 | 2017-07-05 | Sangamo BioSciences, Inc. | Methods and compositions for treating huntington's disease |
WO2015089486A2 (en) | 2013-12-12 | 2015-06-18 | The Broad Institute Inc. | Systems, methods and compositions for sequence manipulation with optimized functional crispr-cas systems |
EP3080257A1 (en) | 2013-12-12 | 2016-10-19 | The Broad Institute Inc. | Compositions and methods of use of crispr-cas systems in nucleotide repeat disorders |
WO2015089465A1 (en) * | 2013-12-12 | 2015-06-18 | The Broad Institute Inc. | Delivery, use and therapeutic applications of the crispr-cas systems and compositions for hbv and viral diseases and disorders |
WO2015089364A1 (en) | 2013-12-12 | 2015-06-18 | The Broad Institute Inc. | Crystal structure of a crispr-cas system, and uses thereof |
EP3079725B1 (en) | 2013-12-12 | 2019-10-16 | The Broad Institute, Inc. | Delivery, use and therapeutic applications of the crispr-cas systems and compositions for genome editing |
WO2015143046A2 (en) | 2014-03-18 | 2015-09-24 | Sangamo Biosciences, Inc. | Methods and compositions for regulation of zinc finger protein expression |
US11110154B2 (en) * | 2014-05-08 | 2021-09-07 | Sangamo Therapeutics, Inc. | Methods and compositions for treating Huntington's Disease |
EP3151846A4 (en) | 2014-06-05 | 2017-12-27 | Sangamo BioSciences, Inc. | Methods and compositions for nuclease design |
WO2016094867A1 (en) | 2014-12-12 | 2016-06-16 | The Broad Institute Inc. | Protected guide rnas (pgrnas) |
US10179918B2 (en) | 2015-05-07 | 2019-01-15 | Sangamo Therapeutics, Inc. | Methods and compositions for increasing transgene activity |
KR20170141217A (ko) * | 2015-05-12 | 2017-12-22 | 상가모 테라퓨틱스, 인코포레이티드 | 유전자 발현의 뉴클레아제-매개된 조절 |
WO2016196012A1 (en) | 2015-05-29 | 2016-12-08 | The Board Of Trustees Of The Leland Stanford Junior University | Nucleoside agents for the reduction of the deleterious activity of extended nucleotide repeat containing genes |
TW202400626A (zh) | 2015-06-18 | 2024-01-01 | 美商博得學院股份有限公司 | 降低脫靶效應的crispr酶突變 |
WO2016205759A1 (en) | 2015-06-18 | 2016-12-22 | The Broad Institute Inc. | Engineering and optimization of systems, methods, enzymes and guide scaffolds of cas9 orthologs and variants for sequence manipulation |
WO2017024111A1 (en) * | 2015-08-04 | 2017-02-09 | The University Of Chicago | Inhibitors of cacna1a/alpha1a subunit internal ribosomal entry site (ires) and methods of treating spinocerebellar ataxia type 6 |
EA037993B1 (ru) * | 2015-09-23 | 2021-06-21 | Сангамо Терапьютикс, Инк. | Репрессоры htt и их применение |
GB2544270A (en) * | 2015-11-05 | 2017-05-17 | Fundació Centre De Regulació Genòmica | Nucleic acids, peptides and methods |
CN110381943A (zh) * | 2016-08-12 | 2019-10-25 | 儿童医院 | 用于治疗与重复不稳定性相关的疾病的方法 |
CA3035534A1 (en) | 2016-09-07 | 2018-03-15 | Sangamo Therapeutics, Inc. | Modulation of liver genes |
IL266862B2 (en) | 2016-12-01 | 2024-01-01 | Sangamo Therapeutics Inc | Tau modulators and methods and preparations for their administration |
WO2018200943A1 (en) | 2017-04-28 | 2018-11-01 | Acuitas Therapeutics, Inc. | Novel carbonyl lipids and lipid nanoparticle formulations for delivery of nucleic acids |
AU2018291041B2 (en) | 2017-06-30 | 2021-08-05 | Inscripta, Inc. | Automated cell processing methods, modules, instruments, and systems |
US10435713B2 (en) | 2017-09-30 | 2019-10-08 | Inscripta, Inc. | Flow through electroporation instrumentation |
WO2019204457A1 (en) | 2018-04-18 | 2019-10-24 | Sangamo Therapeutics, Inc. | Zinc finger protein compositions for modulation of huntingtin (htt) |
JP2021523733A (ja) * | 2018-04-18 | 2021-09-09 | アルティウス インスティテュート フォー バイオメディカル サイエンスィズ | 動物病原体由来ポリペプチドおよびその遺伝子工学的利用 |
CN113474328A (zh) | 2019-01-11 | 2021-10-01 | 爱康泰生治疗公司 | 用于脂质纳米颗粒递送活性剂的脂质 |
CN113301909A (zh) * | 2019-01-15 | 2021-08-24 | 桑格摩生物治疗股份有限公司 | Htt阻遏物及其应用 |
US20200339638A1 (en) | 2019-04-23 | 2020-10-29 | Sangamo Therapeutics, Inc. | Modulators of Chromosome 9 Open Reading Frame 72 Gene Expression and Uses Thereof |
TW202132565A (zh) | 2019-11-01 | 2021-09-01 | 美商聖加莫治療股份有限公司 | Gin重組酶變異體 |
EP4247392A1 (en) * | 2020-06-03 | 2023-09-27 | Takeda Pharmaceuticals U.S.A., Inc. | Methods for the treatment of nucleotide repeat expansion disorders associated with msh3 activity |
GB202010075D0 (en) * | 2020-07-01 | 2020-08-12 | Imp College Innovations Ltd | Therapeutic nucleic acids, peptides and uses |
KR20230051172A (ko) | 2020-07-16 | 2023-04-17 | 아퀴타스 테라퓨틱스 인크. | 지질 나노 입자에 사용하기 위한 양이온성 지질 |
WO2023129940A1 (en) | 2021-12-30 | 2023-07-06 | Regel Therapeutics, Inc. | Compositions for modulating expression of sodium voltage-gated channel alpha subunit 1 and uses thereof |
Family Cites Families (94)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4217344A (en) | 1976-06-23 | 1980-08-12 | L'oreal | Compositions containing aqueous dispersions of lipid spheres |
US4235871A (en) | 1978-02-24 | 1980-11-25 | Papahadjopoulos Demetrios P | Method of encapsulating biologically active materials in lipid vesicles |
US4186183A (en) | 1978-03-29 | 1980-01-29 | The United States Of America As Represented By The Secretary Of The Army | Liposome carriers in chemotherapy of leishmaniasis |
US4261975A (en) | 1979-09-19 | 1981-04-14 | Merck & Co., Inc. | Viral liposome particle |
US4485054A (en) | 1982-10-04 | 1984-11-27 | Lipoderm Pharmaceuticals Limited | Method of encapsulating biologically active materials in multilamellar lipid vesicles (MLV) |
US4501728A (en) | 1983-01-06 | 1985-02-26 | Technology Unlimited, Inc. | Masking of liposomes from RES recognition |
US4897355A (en) | 1985-01-07 | 1990-01-30 | Syntex (U.S.A.) Inc. | N[ω,(ω-1)-dialkyloxy]- and N-[ω,(ω-1)-dialkenyloxy]-alk-1-yl-N,N,N-tetrasubstituted ammonium lipids and uses therefor |
US4946787A (en) | 1985-01-07 | 1990-08-07 | Syntex (U.S.A.) Inc. | N-(ω,(ω-1)-dialkyloxy)- and N-(ω,(ω-1)-dialkenyloxy)-alk-1-yl-N,N,N-tetrasubstituted ammonium lipids and uses therefor |
US5049386A (en) | 1985-01-07 | 1991-09-17 | Syntex (U.S.A.) Inc. | N-ω,(ω-1)-dialkyloxy)- and N-(ω,(ω-1)-dialkenyloxy)Alk-1-YL-N,N,N-tetrasubstituted ammonium lipids and uses therefor |
US4797368A (en) | 1985-03-15 | 1989-01-10 | The United States Of America As Represented By The Department Of Health And Human Services | Adeno-associated virus as eukaryotic expression vector |
US4774085A (en) | 1985-07-09 | 1988-09-27 | 501 Board of Regents, Univ. of Texas | Pharmaceutical administration systems containing a mixture of immunomodulators |
US5422251A (en) | 1986-11-26 | 1995-06-06 | Princeton University | Triple-stranded nucleic acids |
US4837028A (en) | 1986-12-24 | 1989-06-06 | Liposome Technology, Inc. | Liposomes with enhanced circulation time |
US5176996A (en) | 1988-12-20 | 1993-01-05 | Baylor College Of Medicine | Method for making synthetic oligonucleotides which bind specifically to target sites on duplex DNA molecules, by forming a colinear triplex, the synthetic oligonucleotides and methods of use |
US5264618A (en) | 1990-04-19 | 1993-11-23 | Vical, Inc. | Cationic lipids for intracellular delivery of biologically active molecules |
WO1991017424A1 (en) | 1990-05-03 | 1991-11-14 | Vical, Inc. | Intracellular delivery of biologically active substances by means of self-assembling lipid complexes |
US5173414A (en) | 1990-10-30 | 1992-12-22 | Applied Immune Sciences, Inc. | Production of recombinant adeno-associated virus vectors |
US5420032A (en) | 1991-12-23 | 1995-05-30 | Universitge Laval | Homing endonuclease which originates from chlamydomonas eugametos and recognizes and cleaves a 15, 17 or 19 degenerate double stranded nucleotide sequence |
US5436150A (en) | 1992-04-03 | 1995-07-25 | The Johns Hopkins University | Functional domains in flavobacterium okeanokoities (foki) restriction endonuclease |
US5356802A (en) | 1992-04-03 | 1994-10-18 | The Johns Hopkins University | Functional domains in flavobacterium okeanokoites (FokI) restriction endonuclease |
US5487994A (en) | 1992-04-03 | 1996-01-30 | The Johns Hopkins University | Insertion and deletion mutants of FokI restriction endonuclease |
US5792632A (en) | 1992-05-05 | 1998-08-11 | Institut Pasteur | Nucleotide sequence encoding the enzyme I-SceI and the uses thereof |
US5587308A (en) | 1992-06-02 | 1996-12-24 | The United States Of America As Represented By The Department Of Health & Human Services | Modified adeno-associated virus vector capable of expression from a novel promoter |
EP0770129B1 (en) | 1994-01-18 | 2005-11-23 | The Scripps Research Institute | Zinc finger protein derivatives and methods therefor |
US6242568B1 (en) | 1994-01-18 | 2001-06-05 | The Scripps Research Institute | Zinc finger protein derivatives and methods therefor |
US6140466A (en) | 1994-01-18 | 2000-10-31 | The Scripps Research Institute | Zinc finger protein derivatives and methods therefor |
CA2186118C (en) | 1994-03-23 | 2010-10-19 | Richard W. Hanson | Compacted nucleic acids and their delivery to cells |
US5585245A (en) | 1994-04-22 | 1996-12-17 | California Institute Of Technology | Ubiquitin-based split protein sensor |
US6007988A (en) | 1994-08-20 | 1999-12-28 | Medical Research Council | Binding proteins for recognition of DNA |
GB9824544D0 (en) | 1998-11-09 | 1999-01-06 | Medical Res Council | Screening system |
US5789538A (en) | 1995-02-03 | 1998-08-04 | Massachusetts Institute Of Technology | Zinc finger proteins with high affinity new DNA binding specificities |
US5786146A (en) * | 1996-06-03 | 1998-07-28 | The Johns Hopkins University School Of Medicine | Method of detection of methylated nucleic acid using agents which modify unmethylated cytosine and distinguishing modified methylated and non-methylated nucleic acids |
US5928638A (en) | 1996-06-17 | 1999-07-27 | Systemix, Inc. | Methods for gene transfer |
US5925523A (en) | 1996-08-23 | 1999-07-20 | President & Fellows Of Harvard College | Intraction trap assay, reagents and uses thereof |
GB9703369D0 (en) | 1997-02-18 | 1997-04-09 | Lindqvist Bjorn H | Process |
GB2338237B (en) | 1997-02-18 | 2001-02-28 | Actinova Ltd | In vitro peptide or protein expression library |
US6342345B1 (en) | 1997-04-02 | 2002-01-29 | The Board Of Trustees Of The Leland Stanford Junior University | Detection of molecular interactions by reporter subunit complementation |
GB9710809D0 (en) | 1997-05-23 | 1997-07-23 | Medical Res Council | Nucleic acid binding proteins |
GB9710807D0 (en) | 1997-05-23 | 1997-07-23 | Medical Res Council | Nucleic acid binding proteins |
US6410248B1 (en) | 1998-01-30 | 2002-06-25 | Massachusetts Institute Of Technology | General strategy for selecting high-affinity zinc finger proteins for diverse DNA target sites |
AU746454B2 (en) | 1998-03-02 | 2002-05-02 | Massachusetts Institute Of Technology | Poly zinc finger proteins with improved linkers |
US6410245B1 (en) | 1998-04-01 | 2002-06-25 | Affymax, Inc. | Compositions and methods for detecting ligand-dependent nuclear receptor and coactivator interactions |
US6140081A (en) | 1998-10-16 | 2000-10-31 | The Scripps Research Institute | Zinc finger binding domains for GNN |
US6599692B1 (en) | 1999-09-14 | 2003-07-29 | Sangamo Bioscience, Inc. | Functional genomics using zinc finger proteins |
US7013219B2 (en) | 1999-01-12 | 2006-03-14 | Sangamo Biosciences, Inc. | Regulation of endogenous gene expression in cells using zinc finger proteins |
US7070934B2 (en) | 1999-01-12 | 2006-07-04 | Sangamo Biosciences, Inc. | Ligand-controlled regulation of endogenous gene expression |
US6534261B1 (en) | 1999-01-12 | 2003-03-18 | Sangamo Biosciences, Inc. | Regulation of endogenous gene expression in cells using zinc finger proteins |
US6453242B1 (en) | 1999-01-12 | 2002-09-17 | Sangamo Biosciences, Inc. | Selection of sites for targeting by zinc finger proteins and methods of designing zinc finger proteins to bind to preselected sites |
US7030215B2 (en) | 1999-03-24 | 2006-04-18 | Sangamo Biosciences, Inc. | Position dependent recognition of GNN nucleotide triplets by zinc fingers |
US6794136B1 (en) | 2000-11-20 | 2004-09-21 | Sangamo Biosciences, Inc. | Iterative optimization in the design of binding proteins |
IL150069A0 (en) | 1999-12-06 | 2002-12-01 | Sangamo Biosciences Inc | Methods of using randomized libraries of zinc finger proteins for the identification of gene function |
EP1254369B1 (en) | 2000-02-08 | 2010-10-06 | Sangamo BioSciences, Inc. | Cells for drug discovery |
US20020061512A1 (en) | 2000-02-18 | 2002-05-23 | Kim Jin-Soo | Zinc finger domains and methods of identifying same |
US7001768B2 (en) | 2000-04-28 | 2006-02-21 | Sangamo Biosciences, Inc. | Targeted modification of chromatin structure |
GB2365011A (en) | 2000-04-28 | 2002-02-13 | Sangamo Biosciences Inc | Methods for the characterisation of regulatory DNA sequences |
AU2001263155A1 (en) | 2000-05-16 | 2001-11-26 | Massachusetts Institute Of Technology | Methods and compositions for interaction trap assays |
WO2002008286A2 (en) | 2000-07-21 | 2002-01-31 | Syngenta Participations Ag | Zinc finger domain recognition code and uses thereof |
JP2002060786A (ja) | 2000-08-23 | 2002-02-26 | Kao Corp | 硬質表面用殺菌防汚剤 |
US6919204B2 (en) | 2000-09-29 | 2005-07-19 | Sangamo Biosciences, Inc. | Modulation of gene expression using localization domains |
AU2002217929A1 (en) | 2000-11-28 | 2002-06-11 | Sangamo Biosciences, Inc. | Modulation of gene expression using insulator binding proteins |
US7067317B2 (en) | 2000-12-07 | 2006-06-27 | Sangamo Biosciences, Inc. | Regulation of angiogenesis with zinc finger proteins |
GB0108491D0 (en) | 2001-04-04 | 2001-05-23 | Gendaq Ltd | Engineering zinc fingers |
EP1421177A4 (en) | 2001-08-20 | 2006-06-07 | Scripps Research Inst | ZINC FINGER FASTENING DOMAINS FOR CNN |
US7262054B2 (en) | 2002-01-22 | 2007-08-28 | Sangamo Biosciences, Inc. | Zinc finger proteins for DNA binding and gene regulation in plants |
DE60310202T2 (de) | 2002-01-23 | 2007-11-22 | The University Of Utah Research Foundation, Salt Lake City | Zielgerichtete chromosomale mutagenese mit zinkfingernukleasen |
US8206965B2 (en) | 2002-03-15 | 2012-06-26 | Cellectis S.A. | Hybrid and single chain meganucleases and use thereof |
US20030232410A1 (en) | 2002-03-21 | 2003-12-18 | Monika Liljedahl | Methods and compositions for using zinc finger endonucleases to enhance homologous recombination |
US7361635B2 (en) | 2002-08-29 | 2008-04-22 | Sangamo Biosciences, Inc. | Simultaneous modulation of multiple genes |
CA2497913C (en) | 2002-09-05 | 2014-06-03 | California Institute Of Technology | Use of chimeric nucleases to stimulate gene targeting |
AU2004208030B2 (en) | 2003-01-28 | 2009-05-07 | Cellectis | Custom-made meganuclease and use thereof |
JP4120817B2 (ja) | 2003-08-01 | 2008-07-16 | 株式会社ジェイテクト | ブーツ嵌合部の構造 |
US8409861B2 (en) | 2003-08-08 | 2013-04-02 | Sangamo Biosciences, Inc. | Targeted deletion of cellular DNA sequences |
US7888121B2 (en) | 2003-08-08 | 2011-02-15 | Sangamo Biosciences, Inc. | Methods and compositions for targeted cleavage and recombination |
US7972854B2 (en) * | 2004-02-05 | 2011-07-05 | Sangamo Biosciences, Inc. | Methods and compositions for targeted cleavage and recombination |
CA2561714A1 (en) | 2004-04-08 | 2005-10-27 | Sangamo Biosciences, Inc. | Methods and compositions for treating neuropathic and neurodegenerative conditions |
AU2005233550B2 (en) | 2004-04-08 | 2010-11-18 | Sangamo Therapeutics, Inc. | Treatment of neuropathic pain with zinc finger proteins |
US20080131962A1 (en) | 2006-05-25 | 2008-06-05 | Sangamo Biosciences, Inc. | Engineered cleavage half-domains |
CA2579677A1 (en) | 2004-09-16 | 2006-03-30 | Sangamo Biosciences, Inc. | Compositions and methods for protein production |
WO2006121866A2 (en) | 2005-05-05 | 2006-11-16 | The Arizona Board Of Regents On Behalf Of The University Of Arizona | Sequence enabled reassembly (seer) - a novel method for visualizing specific dna sequences |
CA2615532C (en) | 2005-07-26 | 2016-06-28 | Sangamo Biosciences, Inc. | Targeted integration and expression of exogenous nucleic acid sequences |
EP2341135A3 (en) | 2005-10-18 | 2011-10-12 | Precision Biosciences | Rationally-designed meganucleases with altered sequence specificity and DNA-binding affinity |
US20080015164A1 (en) | 2006-05-19 | 2008-01-17 | Sangamo Biosciences, Inc. | Methods and compositions for inactivation of dihydrofolate reductase |
US7951925B2 (en) | 2006-05-25 | 2011-05-31 | Sangamo Biosciences, Inc. | Methods and compositions for gene inactivation |
WO2009006816A1 (fr) | 2007-07-10 | 2009-01-15 | Huawei Technologies Co., Ltd. | Procédé, dispositif et système de contrôle de politique pour une application |
EP2188384B1 (en) | 2007-09-27 | 2015-07-15 | Sangamo BioSciences, Inc. | Rapid in vivo identification of biologically active nucleases |
CN101868241A (zh) | 2007-09-28 | 2010-10-20 | 英特瑞克斯顿股份有限公司 | 表达生物治疗分子的治疗基因开关构建物和生物反应器以及它们的应用 |
EP2205752B1 (en) | 2007-10-25 | 2016-08-10 | Sangamo BioSciences, Inc. | Methods and compositions for targeted integration |
EP2297318B1 (en) | 2008-05-28 | 2018-05-23 | Sangamo Therapeutics, Inc. | Compositions for linking dna-binding domains and cleavage domains |
CA2726768C (en) | 2008-06-10 | 2016-09-06 | Sangamo Biosciences, Inc. | Methods and compositions for generation of bax- and bak-deficient cell lines |
EP2206723A1 (en) | 2009-01-12 | 2010-07-14 | Bonas, Ulla | Modular DNA-binding domains |
EP2393506B1 (en) | 2009-02-04 | 2018-03-28 | Sangamo Therapeutics, Inc. | Methods and compositions for treating neuropathies |
SG177711A1 (en) * | 2009-07-24 | 2012-02-28 | Sigma Aldrich Co Llc | Method for genome editing |
DE102009039095A1 (de) | 2009-08-27 | 2011-03-10 | Siemens Aktiengesellschaft | Verfahren und Vorrichtung zum Erzeugen, Decodieren und Transcodieren eines codierten Videodatenstroms |
US9405700B2 (en) | 2010-11-04 | 2016-08-02 | Sonics, Inc. | Methods and apparatus for virtualization in an integrated circuit |
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US10646543B2 (en) | 2020-05-12 |
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JP2013500045A (ja) | 2013-01-07 |
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EP2461819A4 (en) | 2013-07-31 |
US20160082081A1 (en) | 2016-03-24 |
AU2010281705A1 (en) | 2012-02-09 |
CA2769262C (en) | 2019-04-30 |
US9943565B2 (en) | 2018-04-17 |
EP2461819A2 (en) | 2012-06-13 |
JP6290853B2 (ja) | 2018-03-07 |
EP2727600B1 (en) | 2019-03-27 |
US9234016B2 (en) | 2016-01-12 |
CA2769262A1 (en) | 2011-02-10 |
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US20180200332A1 (en) | 2018-07-19 |
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