JP2022506956A - 脂質ナノ粒子製剤 - Google Patents
脂質ナノ粒子製剤 Download PDFInfo
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Abstract
Description
(a)1つ以上の核酸分子;
(b)コレステロール;
(c)DSPC;
(d)PEG-C-DMA;及び
(e)式:
PEG-C-DMA:約1.5;
カチオン性脂質:約50.0;
コレステロール:約38.5;及び
DSPC:約10.0。
(a)1つ以上の核酸分子;
(b)コレステロール;
(c)DSPC;
(d)PEG-C-DMA;及び
(e)式:
PEG-C-DMA:1.5;
カチオン性脂質:50.0;
コレステロール:38.5;及び
DSPC:10.0。
本明細書で使用される場合、以下の用語は特に明記しない限り以下に帰する意味を有する。
一実施形態では、1つ以上の核酸分子は、siRNAを含む。
本発明の核酸-脂質粒子のsiRNA成分は、目的の標的遺伝子の発現をサイレンシングすることができる。siRNA二重鎖の各鎖は、通常、約15~約60ヌクレオチド長、好ましくは、約15~約30ヌクレオチド長である。特定の実施形態では、siRNAは、少なくとも1つの修飾ヌクレオチドを含む。修飾siRNAは、一般に、対応する非修飾siRNA配列よりも免疫刺激性が低く、かつ目的の標的遺伝子に対するRNAi活性を保持している。いくつかの実施形態では、修飾siRNAは、少なくとも1つの2’OMeプリンヌクレオチドまたは2’OMeピリミジンヌクレオチド、例えば、2’OMe-グアノシンヌクレオチド、2’OMe-ウリジンヌクレオチド、2’OMe-アデノシンヌクレオチド、及び/または2’OMe-シトシンヌクレオチドを含有する。好ましい実施形態では、ウリジン及び/またはグアノシンヌクレオチドのうちの1つ以上は、修飾されている。修飾ヌクレオチドは、siRNAの一方の鎖(すなわち、センスもしくはアンチセンス)または両方の鎖に存在し得る。siRNA配列は、オーバーハング(例えば、Elbashir et al.,Genes Dev.,15:188(2001)またはNykanen et al.,Cell,107:309(2001)に記載されている3’もしくは5’オーバーハング)を有していてもよく、またはオーバーハングを欠いていてもよい(すなわち、平滑末端を有する)。
好適なsiRNA配列は、当該技術分野で公知の任意の手段を使用して同定することができる。通常、Elbashir et al.,Nature,411:494-498(2001)及びElbashir et al.,EMBO J.,20:6877-6888(2001)に記載されている方法を、Reynolds et al.,Nature Biotech.,22(3):326-330(2004)に記載の合理的設計規則と組み合わせる。
siRNAは、例えば、1つ以上の単離された低分子干渉RNA(siRNA)二重鎖として、より長い二本鎖RNA(dsRNA)として、またはDNAプラスミド中の転写カセットから転写されたsiRNAもしくはdsRNAとして、を含むいくつかの形態で提供され得る。siRNA配列は、オーバーハング(例えば、Elbashir et al.,Genes Dev.,15:188(2001)またはNykanen et al.,Cell,107:309(2001)に記載されている3’もしくは5’オーバーハング)を有していてもよく、またはオーバーハングを(すなわち、平滑末端を有するように)欠いていてもよい。
特定の態様では、siRNA分子は、2本の鎖と、二本鎖領域に少なくとも1つの修飾ヌクレオチドとを有する二重鎖を含み、ここで、各鎖は、約15~約60ヌクレオチド長である。有利なことに、修飾siRNAは、対応する非修飾siRNA配列よりも免疫刺激性が低いが、標的配列の発現をサイレンシングする能力を保持している。好ましい実施形態では、siRNA分子に導入される化学修飾の程度は、siRNAの免疫刺激特性の低減または抑制と、RNAi活性の保持との間のバランスをとる。非限定的な例として、目的遺伝子を標的とするsiRNA分子は、標的遺伝子発現をサイレンシングするその能力を保持しながらsiRNAによって生じる免疫応答を排除するように、siRNA二重鎖内の選択的なウリジン及び/またはグアノシンヌクレオチドにおいて最小限に修飾され得る(例えば、約30%未満、約25%未満、約20%未満、約15%未満、約10%未満、または約5%未満修飾される)。
特定の実施形態では、本明細書に記載の核酸-脂質粒子の核酸成分(例えば、siRNA)を使用して、目的遺伝子の翻訳(すなわち、発現)を下方制御またはサイレンシングすることができる。目的遺伝子には、ウイルスの感染及び生存に関連する遺伝子、代謝性疾患及び障害(例えば、肝疾患及び肝障害)に関連する遺伝子、腫瘍形成及び細胞形質転換(例えば、がん)に関連する遺伝子、血管新生遺伝子、炎症応答及び自己免疫応答に関連するものなどの免疫調節遺伝子、リガンド受容体遺伝子、ならびに神経変性障害に関連する遺伝子が含まれるが、これらに限定されない。特定の実施形態では、目的遺伝子は、肝細胞で発現される。
標的化ゲノム編集は、ニッチ技術から多くの生物学研究者が使用する方法へと進化した。この進化は、クラスター化され規則的に間隔が空いた短い回文構造の繰り返し(CRISPR)技術の出現により大いに促進された(例えば、Supplementary Information(2014)を含むSander et al.,Nature Biotechnology,32(4),347-355、国際公開第WO2016/197132号及び同第2016/197133号を参照されたい)。したがって、本明細書で提供されるのは、HBVなどの疾患を治療するためにCRISPR技術と組み合わせて使用することができる改善物(例えば、脂質ナノ粒子及びその製剤)である。CRISPRを使用するための標的に関して、CRISPR技術で利用されるガイドRNA(gRNA)を、特異的に同定された配列、例えば、標的遺伝子(例えばHBVゲノムの標的遺伝子)を標的とするように設計することができる。そのような標的配列の例は、国際公開第WO2016/197132号に示されている。さらに、国際公開第WO2013/151665号(例えば、表6を参照されたい。この文書は、表6及び付随する配列表を特に含めて、具体的に参照により組み込まれる)は、mRNA発現コンストラクトに関連して特許請求された約35,000のmRNA配列を記載している。本発明の特定の実施形態は、これらの配列のいずれかの発現を標的とするためにCRISPR技術を利用する。本発明の特定の実施形態はまた、本明細書で論じられる標的遺伝子の発現を標的とするためにCRISPR技術を利用することができる。
siRNAと同様に、非対称干渉RNA(aiRNA)は、RNA誘導サイレンシング複合体(RISC)を動員し、アンチセンス鎖の5’末端に対するヌクレオチド10と11の間で標的配列の配列特異的切断を媒介することによって、哺乳動物細胞における種々の遺伝子の効果的なサイレンシングをもたらすことができる(Sun et al.,Nat.Biotech.,26:1379-1382(2008))。通常、aiRNA分子は、センス鎖及びアンチセンス鎖を有する短いRNA二重鎖を含み、この二重鎖は、アンチセンス鎖の3’末端及び5’末端にオーバーハングを含有する。aiRNAは一般に、センス鎖が、相補的アンチセンス鎖と比較して両末端で短いため、非対称である。いくつかの態様では、aiRNA分子は、siRNA分子に使用されるものと類似の条件下で、設計、合成、及びアニーリングすることができる。非限定的な例として、aiRNA配列は、siRNA配列を選択するための前述の方法を使用して、選択及び作製することができる。
一般に、マイクロRNA(miRNA)は、遺伝子発現を制御する約21~23ヌクレオチドの長の一本鎖RNA分子である。miRNAは遺伝子によってコードされ、その遺伝子のDNAからmiRNAが転写されるが、miRNAはタンパク質に翻訳されず(非コードRNA)、代わりに、各一次転写物(pri-miRNA)が、pre-miRNAと称される短いステムループ構造にプロセシングされ、最終的に機能的な成熟miRNAにプロセシングされる。成熟miRNA分子は、1つ以上のメッセンジャーRNA(mRNA)分子に部分的に相補的であるかまたは完全に相補的であるかのいずれかであり、それらの主要な機能は、遺伝子発現を下方制御することである。miRNA分子の同定は、例えば、Lagos-Quintana et al.,Science,294:853-858、Lau et al.,Science,294:858-862、及びLee et al.,Science,294:862-864に記載されている。
一実施形態では、核酸は、目的の標的遺伝子または配列を対象とするアンチセンスオリゴヌクレオチドである。「アンチセンスオリゴヌクレオチド」または「アンチセンス」という用語は、標的とするポリヌクレオチド配列に相補的なオリゴヌクレオチドを含む。アンチセンスヌクレオチドは、選択された配列に相補的であるDNAまたはRNAの一本鎖である。アンチセンスRNAオリゴヌクレオチドは、相補的RNA鎖の翻訳を、そのRNAに結合することによって阻止する。アンチセンスDNAオリゴヌクレオチドを使用して、特定の相補的(コードまたは非コード)RNAを標的とすることができる。結合が生じると、このDNA/RNAハイブリッドは、酵素RNase Hによって分解され得る。特定の実施形態では、アンチセンスオリゴヌクレオチドは、約10~約60個のヌクレオチド、より好ましくは約15~約30個のヌクレオチドを含む。この用語はまた、所望の標的遺伝子に厳密に相補的ではない可能性のあるアンチセンスオリゴヌクレオチドを包含する。したがって、本発明は、非標的特異的活性がアンチセンスに見られる場合、または標的配列との1つ以上のミスマッチを含有するアンチセンス配列が特定の使用に最も好ましい場合に、利用可能である。
本発明の別の実施形態によれば、核酸-脂質粒子はリボザイムと会合している。リボザイムは、エンドヌクレアーゼ活性を有する特定の触媒ドメインを有するRNA-タンパク質複合体である(Kim et al.,Proc.Natl.Acad.Sci.USA.,84:8788-92(1987)、及びForster et al.,Cell,49:211-20(1987)を参照されたい)。例えば、多くのリボザイムは、高度な特異性でリン酸エステル転移反応を促進させ、多くの場合、オリゴヌクレオチド基質内のいくつかのリン酸エステルのうちの1つのみを切断する(Cech et al.,Cell,27:487-96(1981)、Michel et al.,J.Mol.Biol.,216:585-610(1990)、Reinhold-Hurek et al.,Nature,357:173-6(1992)を参照されたい)。この特異性は、基質が、化学反応の前にリボザイムの内部ガイド配列(「IGS」)に特異的な塩基対相互作用を介して結合するという要件に起因している。
本発明の脂質粒子に会合する核酸は、ヒトなどの哺乳動物であり得る対象に投与されたときに免疫応答を誘導することができる免疫刺激性オリゴヌクレオチド(ISS;一本鎖または二本鎖)を含む、免疫刺激性であり得る。ISSには、例えば、ヘアピン二次構造をもたらす特定の回文構造(Yamamoto et al.,J.Immunol.,148:4072-6(1992)を参照されたい)、またはCpGモチーフ、及び他の公知のISSの特徴(例えば、多重Gドメイン。PCT公開第WO96/11266号を参照されたく、この開示は、すべての目的のためにその全体が本明細書に参照により組み込まれる)が含まれる。
本発明の特定の実施形態は、生体細胞(例えば、人体内の細胞)内で1つ以上のmRNA分子を発現させるために使用することができる組成物及び方法を提供する。このmRNA分子は、生体細胞内で発現する1つ以上のポリペプチドをコードする。いくつかの実施形態では、このポリペプチドは、罹患生物(例えば、ヒトなどの哺乳動物)内で発現し、このポリペプチドの発現は、疾患の1つ以上の症状を改善する。本発明の組成物及び方法は、人体内の機能的ポリペプチドの欠如またはレベルの低減によって引き起こされるヒトの疾患の治療に特に有用である。したがって、特定の実施形態では、LNPは、1つ以上のmRNA分子(例えば、mRNA分子のカクテル)などの1つ以上の核酸分子を含み得る。
本発明の実施において使用されるmRNAは、1つ、2つ、または2つより多いヌクレオシド修飾を含み得る。いくつかの実施形態では、修飾mRNAは、対応する非修飾mRNAと比較して、mRNAが導入される細胞において分解の低減を示す。
さらなる実施形態では、修飾核酸は、いくつかの実施形態において有益であり得る、他の任意成分を含み得る。これらの任意成分には、非翻訳領域、コザック配列、イントロンヌクレオチド配列、内部リボソーム侵入部位(IRES)、キャップ、及びポリAテールが含まれるが、これらに限定されない。例えば、5’非翻訳領域(UTR)及び/または3’UTRを提供することができ、これらのいずれかまたは両方は独立して1つ以上の異なるヌクレオシド修飾を含み得る。このような実施形態では、ヌクレオシド修飾はまた、翻訳可能領域にも存在し得る。コザック配列を含有する核酸も提供される。
遺伝子の非翻訳領域(UTR)は、転写されるが翻訳はされない。5’UTRは、転写開始部位から始まり開始コドンまで続くが、開始コドンは含まない。一方、3’UTRは終止コドンの直後から始まり、転写終結シグナルまで続く。核酸分子の安定性及び翻訳に関してUTRが果たす調節的役割についてのエビデンスが増えつつある。分子の安定性を増加させるために、UTRの調節機能を本発明で使用されるmRNAに組み込むことができる。特定の機能を組み込んで、望ましくない器官部位に誤って誘導された場合に、転写物の下方制御を確実に制御することもできる。
mRNAの5’キャップ構造は、核外輸送に関与し、mRNAの安定性を増加させ、mRNAキャップ結合タンパク質(CBP)に結合し、これは、CBPとポリ(A)結合タンパク質との会合を通じて細胞内のmRNAの安定性及び翻訳能力に関与して、成熟環状mRNA種を形成する。キャップはさらに、mRNAスプライシングの際に5’近位イントロンの除去を補助する。
内部リボソーム侵入部位(IRES)を含有するmRNAもまた、本発明の実施に有用である。IRESは、唯一のリボソーム結合部位として機能する場合もあれば、mRNAの複数のリボソーム結合部位の1つとして機能する場合もある。複数の機能的なリボソーム結合部位を含有するmRNAは、リボソームによって独立して翻訳されるいくつかのペプチドまたはポリペプチドをコードし得る(「マルチシストロン性mRNA」)。mRNAがIRESとともに提供される場合、さらに任意選択で、第2の翻訳可能領域が提供される。本発明に従って使用できるIRES配列の例には、ピコルナウイルス(例えば、FMDV)、ペストウイルス(pest virus)(CFFV)、ポリオウイルス(PV)、脳心筋炎ウイルス(ECMV)、口蹄疫ウイルス(FMDV)、C型肝炎ウイルス(HCV)、ブタコレラウイルス(CSFV)、ネズミ白血病ウイルス(MLV)、サル免疫不全ウイルス(S1V)またはコオロギ麻痺ウイルス(CrPV)由来のものが含まれるが、これらに限定されない。
RNAプロセシング中に、安定性を増加させるために、アデニンヌクレオチドの長鎖(ポリAテール)がmRNA分子などのポリヌクレオチドに付加され得る。転写直後に、転写物の3’末端が切断され、3’ヒドロキシルが遊離し得る。次に、ポリAポリメラーゼがRNAにアデニンヌクレオチドの鎖を付加する。ポリアデニル化と呼ばれるこのプロセスでは、100~250残基長であり得るポリAテールが付加される。
RNAの単離、RNAの合成、核酸のハイブリダイズ、cDNAライブラリーの作成及びスクリーニング、ならびにPCRの実施のための方法は、PCR法(米国特許第4,683,195号及び同第4,683,202号、PCR Protocols:A Guide to Methods and Applications(Innis et al.,eds,1990)を参照されたい)と同様に、当該技術分野において周知である(例えば、Gubler and Hoffman,Gene,25:263-269(1983)、Sambrook et al.,Molecular Cloning,A Laboratory Manual(2nd ed.1989)を参照されたい)。発現ライブラリーもまた、当業者に周知である。本発明における一般的な使用方法を開示するさらなる基本的な文書には、Kriegler,Gene Transfer and Expression:A Laboratory Manual(1990)、及びCurrent Protocols in Molecular Biology(Ausubel et al.,eds.,1994)が含まれる。これらの参照文献の開示は、すべての目的のためにその全体が本明細書に参照により組み込まれる。
本明細書に記載の核酸-脂質粒子のmRNA成分を使用して、目的ポリペプチドを発現させることができる。ヒトにおける特定の疾患は、機能性タンパク質の、そのタンパク質が通常存在しかつ活性である細胞タイプにおける欠如または障害によって引き起こされる。機能性タンパク質は、例えば、コード化遺伝子の転写不活性に起因して、またはタンパク質を完全にもしくは部分的に非機能的にする突然変異がコード化遺伝子に存在していることに起因して、完全にまたは部分的に欠如する可能性がある。タンパク質の完全または部分的な不活性化によって引き起こされるヒトの疾患の例には、X連鎖重症複合免疫不全症(X-SCID)及び副腎白質ジストロフィー(X-ALD)が含まれる。X-SCIDは、免疫系内のB細胞及びT細胞の発生及び成熟に関与するいくつかのインターロイキンの受容体の成分である、共通ガンマ鎖タンパク質をコードする遺伝子の1つ以上の突然変異によって引き起こされる。X-ALDは、ABCD1と呼ばれるペルオキシソーム膜輸送体タンパク質遺伝子の1つ以上の突然変異によって引き起こされる。X-ALDに罹患している個体は、全身の組織に極めて高レベルの長鎖脂肪酸を有し、これが、精神障害または死に至るおそれのある様々な症状を引き起こす。
特定の実施形態では、核酸は、1つ以上の自己増幅RNA分子である。自己増幅RNA(sa-RNA)はまた、自己複製RNA、複製可能RNA、レプリコン、またはRepRNAと称されることもある。自己増幅mRNAと称されるRepRNAは、プラス鎖ウイルスに由来する場合、少なくとも1つの構造遺伝子を欠くウイルスゲノムから生成され、RepRNAは、感染性の子孫ウイルスを生成することなく、翻訳及び複製(したがって「自己増幅」)することができる。特定の実施形態では、RepRNA技術を使用して、所望の目的抗原をコードする遺伝子カセットを挿入することができる。例えば、アルファウイルスゲノムは2つのオープンリーディングフレーム(ORF)に分割されており、第1のORFはRNA依存性RNAポリメラーゼ(レプリカーゼ)のタンパク質をコードし、第2のORFは構造タンパク質をコードする。sa-RNAワクチンコンストラクトでは、ウイルス構造タンパク質をコードするORFを任意の選択した抗原に置き換えることができるが、一方、ウイルスレプリカーゼは依然としてワクチンの不可欠な部分であり、免疫化後のRNAの細胞内増幅を促進する。
当業者は、核酸-脂質粒子が膜融合性となる速度に応じて、PEG-C-DMAの濃度を変化させることができることを理解するであろう。例えば、核酸-脂質粒子が膜融合性となる速度は、例えばPEGの分子量を変化させることによって、変化させることができる。特定の実施形態では、PEG-C-DMAは以下の構造を有する:
特定の実施形態では、本発明は、連続混合方法、例えば、第1のリザーバに核酸を含む水溶液を供給すること、第2のリザーバに有機脂質溶液を供給すること、及び核酸(例えば、干渉RNAまたはmRNA)を封入するリポソームを実質的に瞬時に生成するように有機脂質溶液が水溶液と混合するように、水溶液を有機脂質溶液と混合することを含むプロセスにより生成されるLNPを提供する。このプロセス及びこのプロセスを実施するための装置は、米国特許出願公開第20040142025号に詳細に記載されており、この開示は、すべての目的のためにその全体が本明細書に参照により組み込まれる。
本発明の脂質粒子(例えば、LNP)は、形成された後、核酸の細胞への導入に有用である。したがって、本発明はまた、核酸(例えば、干渉RNAまたはmRNA)などの核酸を細胞に導入するための方法も提供する。この方法は、まず前述のように粒子を形成し、次に、核酸の細胞への送達が生じるのに十分な一定時間、その粒子を細胞に接触させることにより、in vitroまたはin vivoで実施される。
in vivo療法のための全身送達、例えば、循環などの身体系を介した遠位標的細胞への治療用核酸の送達は、PCT公開第WO05/007196号、同第WO05/121348号、同第WO05/120152号、及び同第WO04/002453号(これらの開示は、すべての目的のためにその全体が本明細書に参照により組み込まれる)に記載されているものなどの核酸-脂質粒子を使用して実現されている。本発明はまた、血清中でヌクレアーゼ分解から核酸を保護し、非免疫原性でありサイズが小さく反復投薬に好適である、完全に封入された脂質粒子を提供する。
in vitro用途の場合、核酸(例えば、干渉RNAまたはmRNA)などの治療剤の送達は、植物起源であるか動物起源であるか、脊椎動物であるか無脊椎動物であるか、及びいずれの組織またはタイプであるかを問わず、培養で増殖させた任意の細胞に対して行うことができる。好ましい実施形態では、細胞は、動物細胞、より好ましくは哺乳動物細胞、最も好ましくはヒト細胞である。
本発明の組成物及び方法は、多種多様な細胞タイプをin vivo及びin vitroで治療するために使用される。好適な細胞には、例えば、造血前駆(幹)細胞、線維芽細胞、ケラチノサイト、肝細胞、内皮細胞、骨格筋及び平滑筋細胞、骨芽細胞、神経細胞、静止リンパ球、最終分化細胞、周期が遅いまたは周期が停止した(noncycling)初代細胞、実質細胞、リンパ系細胞、上皮細胞、骨細胞などが含まれる。一実施形態では、1つ以上の核酸分子(例えば、干渉RNA(例えば、siRNA)またはmRNA)などの核酸は、例えば、肺癌細胞、結腸癌細胞、直腸癌細胞、肛門癌細胞、胆管癌細胞、小腸癌細胞、胃癌(stomach(gastric))細胞、食道癌細胞、胆嚢癌細胞、肝癌細胞、膵癌細胞、虫垂癌細胞、乳癌細胞、卵巣癌細胞、子宮頸癌細胞、前立腺癌細胞、腎癌細胞、中枢神経系の癌細胞、神経膠芽腫腫瘍細胞、皮膚癌細胞、リンパ腫細胞、絨毛癌腫瘍細胞、頭頸部癌細胞、骨原性肉腫腫瘍細胞、及び血液癌細胞などのがん細胞に送達される。
いくつかの実施形態では、本発明の脂質粒子(例えば、LNP)は、約1、2、3、4、5、6、7、8時間またはそれ以上の時点で、対象において検出可能である。他の実施形態では、本発明の脂質粒子(例えば、LNP)は、粒子の投与から約8、12、24、48、60、72、もしくは96時間後、または約6、8、10、12、14、16、18、19、22、24、25、もしくは28日後に対象において検出可能である。粒子の存在は、対象由来の細胞、組織、または他の生体試料から検出することができる。粒子は、例えば、粒子の直接検出により、干渉RNA(例えば、siRNA)もしくはmRNA配列などの治療用核酸の検出により、目的標的配列の検出により(すなわち目的配列の発現における変化を検出することにより)、またはこれらの組み合わせにより、検出することができる。
LNPなどの本発明の脂質粒子は、当該技術分野で公知の任意の方法を使用して検出することができる。例えば、当該技術分野で周知の方法を使用して、脂質粒子の成分に標識を直接または間接的にカップリングさせることができる。必要とされる感度、脂質粒子成分とのコンジュゲーションの容易さ、安定性要件、ならびに利用可能な計測手段及び使い捨て設備(disposal provision)に応じて標識を選択して、多種多様な標識を使用することができる。適切な標識には、蛍光色素(例えば、フルオレセインならびにフルオレセインイソチオシアネート(FITC)及びOregon Green(商標)などの誘導体;ローダミン及びテキサスレッド、テトラローダミンイソチオシアネート(TRITC)などの誘導体、ジゴキシゲニン、ビオチン、フィコエリトリン、AMCA、CyDye(商標)など)などの分光標識;3H、125I、35S、14C、32P、33Pなどの放射標識;西洋ワサビペルオキシダーゼ、アルカリホスファターゼなどの酵素;コロイド状金または着色ガラスまたはポリスチレン、ポリプロピレン、ラテックスなどのプラスチックビーズなどの分光比色標識が含まれるが、これらに限定されない。標識は、当該技術分野で公知の任意の手段を使用して検出することができる。
核酸(例えば、干渉RNAまたはmRNA)は、本明細書において当業者に周知の任意のいくつかの手段により検出及び定量される。核酸の検出は、サザン分析、ノーザン分析、ゲル電気泳動、PCR、放射標識、シンチレーション計数、及びアフィニティークロマトグラフィーなどの周知の方法により行うことができる。分光光度法、X線撮影法、電気泳動、キャピラリー電気泳動、高速液体クロマトグラフィー(HPLC)、薄層クロマトグラフィー(TLC)、及び高拡散(hyperdiffusion)クロマトグラフィーなどのさらなる分析的な生化学的方法もまた、用いることができる。
本発明を、具体的な実施例によってより詳細に説明する。以下の実施例は例示目的のみに提供され、いかなる方法によっても本発明を限定することを意図するものではない。当業者は、本質的に同じ結果をもたらすように変更または修正することができる、様々な重要でないパラメータを容易に認識するであろう。
全体として、LNPを5~8週齢の雌Balb/Cマウスに0.5mg/kgで静脈内注射し、投与後4~6時間で採血した。血液をK2EDTAに採取し、血漿に処理後、分析まで-80℃で凍結保存する。製造業者の指示に従って、StemCell(カタログ番号01630)またはR&D Systems(カタログDEP00)のいずれかのヒトEPO ELISAキットを使用してヒトEPOの発現について血漿を試験することにより、活性をアッセイした。データを以下の表に示す。
Claims (14)
- 前記1つ以上の核酸分子が、siRNAを含む、請求項1に記載の脂質ナノ粒子。
- 前記1つ以上の核酸分子が、mRNAを含む、請求項1に記載の脂質ナノ粒子。
- 約17を超える(総脂質):(核酸)重量比を有する、請求項1~3のいずれか1項に記載の脂質ナノ粒子。
- 約18を超える(総脂質):(核酸)重量比を有する、請求項1~3のいずれか1項に記載の脂質ナノ粒子。
- 約19を超える(総脂質):(核酸)重量比を有する、請求項1~3のいずれか1項に記載の脂質ナノ粒子。
- 約22~約25の(総脂質):(核酸)重量比を有する、請求項1~3のいずれか1項に記載の脂質ナノ粒子。
- 請求項1~7のいずれか1項に記載の脂質ナノ粒子と、薬学的に許容可能な担体とを含む、医薬組成物。
- 皮下投与用に製剤化される、請求項8に記載の医薬組成物。
- 核酸を細胞に送達するための方法であって、
請求項1~7のいずれか1項に記載の脂質ナノ粒子に前記細胞を接触させることを含む、前記方法。 - 機能性タンパク質の欠損を生じさせる遺伝的欠陥を特徴とする疾患を治療するための方法であって、
請求項1~7のいずれか1項に記載の脂質ナノ粒子を前記疾患を有する対象に投与することを含み、ここで、前記核酸分子が、前記機能性タンパク質または前記機能性タンパク質と同じ生物学的活性を有するタンパク質をコードするmRNAである、前記方法。 - ポリペプチドの過剰発現を特徴とする疾患を治療するための方法であって、
請求項1~7のいずれか1項に記載の脂質ナノ粒子を前記疾患を有する対象に投与することを含み、ここで、前記核酸分子が、過剰発現されたポリペプチドの発現を標的とするsiRNAである、前記方法。 - 機能性タンパク質の欠損を生じさせる遺伝的欠陥を特徴とする疾患の治療的または予防的処置のための、請求項1~7のいずれか1項に記載の脂質ナノ粒子。
- ポリペプチドの過剰発現を特徴とする疾患の治療的または予防的処置のための、請求項1~7のいずれか1項に記載の脂質ナノ粒子。
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AU2021252164A1 (en) | 2020-04-09 | 2022-12-15 | Finncure Oy | Mimetic nanoparticles for preventing the spreading and lowering the infection rate of novel coronaviruses |
WO2022099003A1 (en) | 2020-11-06 | 2022-05-12 | Sanofi | Lipid nanoparticles for delivering mrna vaccines |
CN113509542A (zh) * | 2021-04-20 | 2021-10-19 | 嘉晨西海(杭州)生物技术有限公司 | 一种基于mRNA的表达白介素12针对肿瘤的药物及其制备方法 |
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