JP6812346B2 - mRNAを効率よく生体内に送達できるポリイオンコンプレックス並びにこれを用いた関節症の治療薬および治療法 - Google Patents
mRNAを効率よく生体内に送達できるポリイオンコンプレックス並びにこれを用いた関節症の治療薬および治療法 Download PDFInfo
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Description
(1)カチオン性ポリマーとmRNAとを含んでなる、ポリイオンコンプレックスであって、
カチオン性ポリマーが、カチオン性非天然アミノ酸をモノマー単位として含む重合体であり、カチオン性非天然アミノ酸が、側鎖として、−(NH−(CH2)2)p−NH2で表される基{ここで、pは2、3または4である}を有するアミノ酸である、ポリイオンコンプレックス。
(2)カチオン性ポリマーが、ポリエチレングリコールとのブロック共重合体である、上記(1)に記載のポリイオンコンプレックス。
(3)カチオン性ポリマーが、下記一般式(I):
R1は、ポリエチレングリコールであり、ポリエチレングリコールと隣り合うアミノ酸とはリンカーを介して結合してもよく、
R2は、メチレンまたはエチレンであり、
R3は、−(NH−(CH2)2)p−NH2で表される基であり、pは、2、3または4であり、
R4は、水素、保護基、疎水基、または重合性基であり、
Xは、カチオン性天然アミノ酸であり、
nは、2〜5000のいずれかの整数であり、
n1は、0〜5000のいずれかの整数であり、
n3は、0〜5000のいずれかの整数であり、
n−n1−n3は、0以上の整数であり、式中の各繰り返し単位は記載の都合上特定の順で示されているが、各繰り返し単位は順不同に存在することができ、各繰り返し単位はランダムに存在してもよく、また、各繰り返し単位は同一であっても異なっていてもよい}で表される、上記(1)または(2)に記載のポリイオンコンプレックス。
(4)上記(1)〜(3)のいずれかに記載のポリイオンコンプレックスを含んでなる、関節症を処置するための医薬組成物であって、
mRNAが、Runx1のmRNAである、医薬組成物。
(5)pが、3または4である、上記(4)に記載の医薬組成物。
(6)pが、4である、上記(5)に記載の医薬組成物。
(7)2日に1回または3日に1回投与することを特徴とする、上記(4)〜(6)のいずれかに記載の医薬組成物。
(8)7日に1回投与することを特徴とする、上記(5)または(6)に記載の医薬組成物。
(9)関節症が、変形性関節症またはリウマチ性関節炎である、上記(4)〜(8)のいずれかに記載の医薬組成物。
(10)上記(3)に記載のポリイオンコンプレックスであって、pが3または4であるポリイオンコンプレックスを含む、mRNAの細胞内への送達剤。
(11)pが4である、上記(10)に記載の送達剤。
R1は、ポリエチレングリコールであり、ポリエチレングリコールと隣り合うアミノ酸とはリンカーを介して結合してもよく、
R2は、メチレンまたはエチレンであり、
R3は、−(NH−(CH2)2)p−NH2で表される基であり、pは、2、3または4であり、
R4は、水素、保護基、疎水基、または重合性基であり、
Xは、カチオン性アミノ酸であり、
nは、2〜5000のいずれかの整数であり、
n1は、0〜5000のいずれかの整数であり、
n3は、0〜5000のいずれかの整数であり、
n−n1−n3は、0以上の整数であり、式中の各繰り返し単位は記載の都合上特定の順で示されているが、各繰り返し単位は順不同に存在することができ、各繰り返し単位はランダムに存在してもよく、また、各繰り返し単位は同一であっても異なっていてもよい}で表されるものとすることができる。
まず、mRNAを含有するポリイオンコンプレックスを作製した。
本実施例では、ポリアスパラギン酸の側鎖に−(NH−(CH2)2)p−NH2で表される基{ここで、pは2、3または4である}を導入することにより、表題の重合体を得た。具体的には、一方の末端がメトキシ基であり、他方の末端がアミノプロピル基である、数平均分子量23,000のポリエチレングリコール(MeO−PEG−NH2)(日本油脂から購入した)を塩化メチレンに溶解した。β−ベンジル−L−アスパルテート−N−カルボン酸無水物(BLA−NCA)(中央化製品社から購入した)をN,N−ジメチルホルムアミド(DMF)と上記塩化メチレン溶液の混合液に添加して溶解させ、反応溶液を得た。次いで、反応溶液を40℃で2日間反応させて、ポリエチレングリコール−ポリ(β−ベンジル−L−アスパルテート)ブロック共重合体(MeO−PEG−PBLA)を得た。1H−NMRによる解析から、PBLA部分の数平均分子量は約14,000であり、重合度は約66であった。
まず、ヒトRUNX1発現ベクターを調製した。pUC57ベクター内に、XhoIおよびBalI/SmaI制限酵素切断部位で挟んだ3×FLAGタグ付きヒトRUNX1(GenBank登録番号:NM_001754.4;配列番号1)のオープンリーディングフレーム(以下、RUNX1−FLという)をクローン化した。得られたRUNX1−FLをpSP17ベクターに導入した。mMESSAGE mMACHINE T7 Ultra Kit (Ambion, Carlsbad, CA, USA)を用いて直鎖状化したpSP17ベクターからT7プロモーター駆動性にヒトRUNX1−FLの転写を行い、その後、poly(A) tail kit (Ambion)を用いて転写物にポリAを付加した。転写されたmRNAをRNeasy Mini Kit (Qiagen, Hilden, Germany)を用いて精製した。同様の方法で、EGFPのmRNAを調製した。Luc2は、pGL4.13 (Promega, Madison, WI, USA)のタンパク質転写領域を用い、同様の方法でmRNAを調製した。
1−1で得られたそれぞれの共重合体溶液と各種mRNA溶液とを別々に10mM Hepes緩衝液(pH7.3)中で混合して、ポリイオンコンプレックスを得た。mRNAの濃度は、225μg/mLとし、共重合体中のアミノ酸残基のアミノ基(N)と核酸中のリン酸基(P)との混合比(N/P)は、8となるようにした。共重合体溶液とmRNA溶液とは1:2の量比で混合されたので、mRNAの濃度は150μg/mLとなった。
ICRマウス(8週齢)の正常なひざ関節に麻酔下で3μgのLuc2を含むように調製された20μLのポリイオンコンプレックス型ミセルを投与した。1.5mgのD−ルシフェリンを含む100μLの溶液を前記マウスに静脈内投与し、IVIS(商標)Imaging System (Xenogen, Alameda, CA, US)を用いて、様々な時点(ミセル投与後24時間、48時間、または96時間)でルシフェラーゼの関節内での発現を確認した。
現在までのところ、mRNAの生体内への送達とその持続的発現が困難であることから、生体における疾患の治療には高い障壁が存在した。実施例2により、本発明のポリイオンコンプレックスを用いると、生体内でmRNAを長期間持続的に高発現させることができた。そこで、本実施例では、本発明のポリイオンコンプレックスを用いて疾患の治療を試みた。
Claims (8)
- カチオン性ポリマーとmRNAとを含んでなる、ポリイオンコンプレックスであって、
カチオン性ポリマーが、カチオン性非天然アミノ酸をモノマー単位として含む重合体であり、カチオン性非天然アミノ酸が、側鎖として、−(NH−(CH2)2)p−NH2で表される基{ここで、pは2、3または4である}を有するアミノ酸である、ポリイオンコンプレックスを含む、変形性関節症またはリウマチ性関節炎を処置することに用いるための医薬組成物であって、
mRNAが、Runt関連転写因子1(Runx1)、コア結合因子ベータ(Cbfbeta)、性決定ボックス9(Sox9)、およびプロテオグリカン4からなる群から選択される関節形成を促進する因子をコードするものである、医薬組成物。 - カチオン性ポリマーが、ポリエチレングリコールとのブロック共重合体である、請求項1に記載の医薬組成物。
- カチオン性ポリマーが、下記一般式(I):
R1は、ポリエチレングリコールであり、ポリエチレングリコールと隣り合うアミノ酸とはリンカーを介して結合してもよく、
R2は、メチレンまたはエチレンであり、
R3は、−(NH−(CH2)2)p−NH2で表される基であり、pは、2、3または4であり、
R4は、水素、保護基、疎水基、または重合性基であり、
Xは、カチオン性天然アミノ酸であり、
nは、2〜5000のいずれかの整数であり、
n1は、0〜5000のいずれかの整数であり、
n3は、0〜5000のいずれかの整数であり、
n−n1−n3は、0以上の整数であり、式中の各繰り返し単位は記載の都合上特定の順で示されているが、各繰り返し単位は順不同に存在することができ、各繰り返し単位はランダムに存在してもよく、また、各繰り返し単位は同一であっても異なっていてもよい}で表される、請求項1または2に記載の医薬組成物。 - mRNAが、Runx1をコードするものである、請求項1〜3のいずれか一項に記載の医薬組成物。
- pが、3または4である、請求項4に記載の医薬組成物。
- pが、4である、請求項5に記載の医薬組成物。
- 2日に1回または3日に1回投与することを特徴とする、請求項1〜6のいずれか一項に記載の医薬組成物。
- 7日に1回投与することを特徴とする、請求項1〜6のいずれか一項に記載の医薬組成物。
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PCT/JP2016/072322 WO2017022665A1 (ja) | 2015-07-31 | 2016-07-29 | mRNAを効率よく生体内に送達できるポリイオンコンプレックス並びにこれを用いた関節症の治療薬および治療法 |
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