JP2015155459A - 腎線維症処置剤 - Google Patents
腎線維症処置剤 Download PDFInfo
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- JP2015155459A JP2015155459A JP2015100873A JP2015100873A JP2015155459A JP 2015155459 A JP2015155459 A JP 2015155459A JP 2015100873 A JP2015100873 A JP 2015100873A JP 2015100873 A JP2015100873 A JP 2015100873A JP 2015155459 A JP2015155459 A JP 2015155459A
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- kidney
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- retinoid
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Abstract
Description
ビタミンAを含む担体が、ビタミンAを貯蔵する星細胞に薬物を送達すること(特許文献13)や、同担体にHSP47に対するsiRNAを担持させた組成物が肝線維症(特許文献13)、肺線維症(特許文献14)および骨髄線維症(特許文献15)を改善させることは知られていたが、腎線維症、腎の間質組織、メサンギウムとの関係についてはこれまで全く知られていなかった。
(1)レチノイドを腎臓における細胞外マトリックス産生細胞への標的化剤として含む、腎臓における細胞外マトリックス産生細胞への物質送達用担体。
(2)レチノイドがレチノールを含む、上記(1)の担体。
(3)リポソームの形態を有し、レチノイドと、リポソームに含まれる脂質とのモル比が8:1〜1:4である、上記(1)または(2)の担体。
(4)上記(1)〜(3)のいずれかの担体と、腎臓における細胞外マトリックス産生細胞の活性または増殖を制御する薬物とを含む、腎線維症処置用医薬組成物。
(5)腎臓における細胞外マトリックス産生細胞の活性または増殖を制御する薬物が、PAI−1の活性または産生阻害剤、細胞活性抑制剤、増殖阻害剤、アポトーシス誘導剤、および、細胞外マトリックス構成分子または該細胞外マトリックス構成分子の産生もしくは分泌に関与する分子の少なくとも1つを標的とするRNAi分子、リボザイム、アンチセンス核酸、DNA/RNAキメラポリヌクレオチドおよびこれらを発現するベクターからなる群から選択される、上記(4)の医薬組成物。
(7)薬物と担体とを、医療の現場またはその近傍で混合してなる、上記(4)〜(6)のいずれかの医薬組成物。
(8)腎における細胞外マトリックス産生細胞の活性または増殖を制御する薬物、レチノイド、ならびに、必要に応じてレチノイド以外の担体構成物質を、単独でまたは組み合わせて含む1つまたはそれ以上の容器を含む、上記(4)〜(7)のいずれかの医薬組成物の調製キット。
(9)レチノイドを腎臓における細胞外マトリックス産生細胞への標的化剤として配合する工程を含む、腎臓における細胞外マトリックス産生細胞への物質送達用担体の製造方法。
(10)レチノイドを腎臓における細胞外マトリックス産生細胞への標的化剤として、腎臓における細胞外マトリックス産生細胞の活性または増殖を制御する薬物を有効成分としてそれぞれ配合する工程を含む、腎線維症処置用医薬組成物の製造方法。
したがって、本発明の担体により、有効成分を作用部位、さらには標的細胞に効率的に送達できるため、腎線維症、特にこれまで治療が困難であった糖尿病性腎炎などの治癒、進行の抑制または発症の予防が可能となり、ヒト医療および獣医療への貢献は極めて大きい。
また、本発明の担体は、任意の薬剤(例えば、既存の腎線維症治療薬)と組み合わせてその作用効率を高めることができるため、製剤的な応用範囲が広く、効果的な処置剤の製造を簡便に行うことができるという利点もある。
レチノイドのシス−トランスを含む異性体全ては、本発明の範囲内に入る。レチノイドはまた、1または2以上の置換基で置換されることもある。本発明におけるレチノイドは、単離された状態のものはもちろんのこと、これを溶解または保持することができる媒体に溶解または混合した状態のレチノイドをも含む。
本発明における担体は、特定の3次元構造を有してもよい。かかる構造としては、限定されずに、直鎖状または分枝状の線状構造、フィルム状構造、球状構造などが挙げられる。したがって、担体は、限定されずに、ミセル、リポソーム、エマルジョン、微小球、ナノ小球などの任意の3次元形態を有してもよい。
また、本発明における「腎における細胞外マトリックス産生細胞の活性または増殖を制御する薬物」は、腎線維症の発症、進行および/または再発の抑制に直接または間接に関係する腎における細胞外マトリックス産生細胞の物理的、化学的および/または生理的な作用等、例えば、MMP(MMP1、MMP2などを含む)、プラスミノーゲンアクチベーター(PA)などの産生・分泌を直接または間接に促進する何れの薬物であってもよい。かかる薬物としては、限定することなく、例えば、これらの物質の活性化剤や発現増強剤などが挙げられる。本発明の担体は、上記薬物の1種または2種以上を送達することができる。
これらのsiRNA設計は、当業者であれば、標的とする遺伝子のメッセンジャーRNA配列および既知のsiRNAの配列を参照することにより、一般的なテキスト(実験医学別冊 改訂RNAi実験プロトコール 2004年 羊土社、RNAi実験なるほどQ&A 2006年 羊土社)の教示に従って適宜行なうことができる。
本発明における腎線維症は、任意の間質性腎炎、例えば、レンサ球菌腎炎、ブドウ球菌腎炎、肺炎球菌腎炎、水痘、B型肝炎、C型肝炎、HIVなどに伴うウイルス性腎炎、マラリアなどの寄生虫感染による腎炎、真菌性腎炎、マイコプラズマ腎炎などに伴う感染性間質性腎炎、全身性エリテマトーデス(ループス腎炎)、全身性強皮症(膠原病腎)、シェーグレン症候群などの膠原病に伴う間質性腎炎、紫斑病性腎炎、多発性動脈炎、急速進行性糸球体腎炎などの血管の免疫疾患に伴う腎炎、放射線被曝に伴う間質性腎炎、金製剤、NSAIDs、ペニシラミン、ブレオマイシンなどの抗癌剤、抗生物質、パラコートなどによる薬剤性間質性腎炎、昆虫の刺し傷、花粉、ウルシ科の植物などによるアレルギー性腎炎、アミロイドーシス腎炎、糖尿病性腎症、慢性糸球体腎炎、悪性腎硬化症、多発性嚢胞腎症などに伴う腎炎、尿細管間質性腎炎、妊娠中毒症や癌に伴う腎炎、膜性増殖性糸球体腎炎、IgA腎症、混合型クリオグロブリン血症腎炎、グッドパスチャー症候群腎炎、ヴェーゲナー肉芽腫症腎炎、急性間質性腎炎などの特発性間質性腎炎などに起因し得、したがって、これらの間質性腎炎が慢性化したものを含む。本発明における腎線維症は、好ましくは糖尿病性腎炎、薬剤性間質性腎炎および特発性間質性腎炎が慢性化したものを含む。
例えば、経口投与に適した剤形としては、限定することなく、散剤、顆粒剤、錠剤、カプセル剤、液剤、懸濁剤、乳剤、ゲル剤、シロップ剤などが挙げられ、また非経口投与に適した剤形としては、溶液性注射剤、懸濁性注射剤、乳濁性注射剤、用時調製型注射剤などの注射剤が挙げられる。非経口投与用製剤は、水性または非水性の等張性無菌溶液または懸濁液の形態であることができる。
投与経路としては、経口および非経口の両方を包含する種々の経路、例えば、経口、静脈内、筋肉内、皮下、局所、肺内、気道内、気管内、気管支内、経鼻、直腸内、動脈内、門脈内、心室内、骨髄内、リンパ節内、リンパ管内、脳内、髄液腔内、脳室内、経粘膜、経皮、鼻内、腹腔内および子宮内等の経路が含まれる。
投与頻度は、用いる組成物の性状や、上記のような対象の条件によって異なるが、例えば、1日多数回(すなわち1日2、3、4回または5回以上)、1日1回、数日毎(すなわち2、3、4、5、6、7日毎など)、1週間に数回(例えば、1週間に2、3、4回など)、1週間毎、数週間毎(すなわち2、3、4週間毎など)であってもよい。
また、用語「処置」は、疾患の治癒、一時的寛解または予防などを目的とする医学的に許容される全ての種類の予防的および/または治療的介入を包含するものとする。例えば、「処置」の用語は、腎線維症の進行の遅延または停止、病変の退縮または消失、腎線維症発症の予防または再発の防止などを含む、種々の目的の医学的に許容される介入を包含する。
例1 siRNA含有VA結合リポソームの作製
siRNAとして、以下の配列を有するものを用いた。
配列名:Hsp47-C
5'-GGACAGGCCUGUACAACUA-dTdT-3'(センス、配列番号1)
5'-UAGUUGUACAGGCCUGUCC-dTdT-3'(アンチセンス、配列番号2)
(1)腎線維症モデル動物の作製
腎線維症モデルマウスを株式会社ステリック再生医科学研究所に依頼して作製した。具体的には、出生後2日齢のC57BL6J/JcLマウス雄(日本クレア社)にN−アセチル−β−D−グルコサミニダーゼ阻害剤を与え、4週齢まで飼料CE−2(日本クレア社製)および滅菌水を与えて飼育し、満4週齢で離乳後、粗脂肪含量が通常食よりも高いHigh Fat Diet32(日本クレア社)および滅菌水を与え、12週齢まで飼育し、STAMマウスを作製した。本モデルマウスは、糖尿病性腎炎を発症することが知られており(特開2009-178143参照)、糖尿病性腎炎による腎線維症を観察することができる。
上記モデルマウスを、12週3日齢時に10匹ずつ以下の4群に振り分けた。
(第1群)No treatment-STAM マウス、処置前対照群(以下、 NT-STAM (Pre) 群)
(第2群)No treatment-STAM マウス群(以下、 NT-STAM群)
(第3群)5%グルコース投与群(以下、Vehicle群)
(第4群)VA Liposome-siRNA Hsp47C投与群(以下、VL-Hsp47C群)
NT-STAM (Pre)群については、群分け後の治療開始前にマウスを安楽死させ、病態確認を行った。NT-STAM群を除く上記2群に対し、対応する以下の投与液を、12週5日齢時から1日おきに合計10回の尾静脈注射による投与を行った。
(第3群)溶媒対照として、ヌクレアーゼフリー水 0.75ml/kg体重と5%グルコース(大塚製薬株式会社)3.250ml/kg体重とを混合した投与液(5%グルコースまたはVehicle)を用いた。
(第4群)投与液100μlあたり、VAを75nmol、リポソーム構成脂質を75nmol、siRNAを112.5μgとなるよう混合し、5%グルコースで最終調整を行った投与液(VA Liposome-siRNA Hsp47CまたはVL-Hsp47C)を用いた。
各投与液は、投与開始日の体重を基準体重とし、投与日の体重変化率が基準体重の20%以内の場合、4ml/kg体重を尾静脈より投与した。20%を超えた場合は、以降その体重を新たな基準体重として投与量を再設定した。
最終投与終了後2日目(15週4日齢時)にジエチルエーテル麻酔下で心臓より採血し、マウスを安楽死させてから腎臓を摘出した。
摘出した腎臓は、4%パラホルムアルデヒド−リン酸緩衝液にて固定後、パラフィン包埋して薄切標本を作製した。腎線維症に対する治療効果を検討するため、シリウス・レッド染色(コラーゲンを特異的に赤染する線維染色)を行い、オールインワン蛍光顕微鏡BZ−9000(株式会社キーエンス)を用いて、80倍にて撮影した。解析は、腎皮質領域から無作為に20視野を撮影して、BZ−9000付属の解析ソフトを用いて定量化した。
以上の結果から、VL-Hsp47C投与群において線維化の改善傾向が認められた。siRNAが基本的に細胞質内で作用することを考慮すれば、この結果は、レチノイドが腎における細胞外マトリックス産生細胞への標的化剤として機能し、同細胞に効率的に薬物を送達することにより、腎線維症の進行を抑制できることを示すものである。
(1)細胞の分離・回収
肝星細胞に類似した性状を示す腎における細胞外マトリックス産生細胞を、以下のようにして分離・回収した。
まず、事前に以下の5種の溶液の調製を行った。すべての溶液は4℃にて保存した。
・EGTA液:HBSS (Invitrogen 14170)500mlに対し、HEPES1.19gと EGTA0.1gを加え混合した。
・0.02% Collagenase液:HBSS (Invitrogen 24020)500mlに対し、 HEPES1.19g、CaCl2 2H2O 0.235gとCollagenase(Yakult YK-102) 0.1gを加え混合した。
・0.02% Collagenase+0.1% Protease 液:0.02% Collagenase 40mlに対し、Protease(Sigma P6911-1G)40mgを加え混合した。
・Hanks液:HBSS (Invitrogen 24020)500mlに対し、MgSO40.05gを加え混合した。
・10% Nycodenz(R)液(Axis-Shield Prod. No 1114542-1):蒸留水500mlに対し、50g Nycodenz(R)を加え混合溶解した。
1.siRNA含有VA結合liposomeの作製
siRNAとして、以下の配列を有するものを用いた。
配列名:Hsp47-C
5'-GGACAGGCCUGUACAACUA-dTdT-3'(センス、配列番号1)
5'-UAGUUGUACAGGCCUGUCC-dTdT-3'(アンチセンス、配列番号2)
事前に実験用の細胞として、上述の回収方法にてマウス腎臓より回収した細胞外マトリックス産生細胞を、細胞数0.2×105個/ウェルにて6ウェルプレートに播種し、2日間、37℃、10% FBS DMEMにて培養した。
培養2日後、トランスフェクション前に各ウェルの10% FBS DMEMをすべて取り除き、900μlのフレッシュな10% FBS DMEMを加え、15分程度37℃で培養した。
以上の結果は、例2で用いたHSP47遺伝子に対するsiRNAが、腎の細胞外マトリックス産生細胞においてHSP47遺伝子の発現を抑制することを示すものであり、本発明の治療剤に含まれるsiRNAが、腎の細胞外マトリックス産生細胞特異的に取り込まれ、同細胞内で標的遺伝子の発現を抑制することによって、腎線維症の進行の抑制をもたらしたことを示唆するものである。
Claims (10)
- レチノイドを腎臓における細胞外マトリックス産生細胞への標的化剤として含む、腎臓における細胞外マトリックス産生細胞への物質送達用担体。
- レチノイドがレチノールを含む、請求項1に記載の担体。
- リポソームの形態を有し、レチノイドと、リポソームに含まれる脂質とのモル比が8:1〜1:4である、請求項1または2に記載の担体。
- 請求項1〜3のいずれか一項に記載の担体と、腎臓における細胞外マトリックス産生細胞の活性または増殖を制御する薬物とを含む、腎線維症処置用医薬組成物。
- 腎臓における細胞外マトリックス産生細胞の活性または増殖を制御する薬物が、PAI−1の活性または産生阻害剤、細胞活性抑制剤、増殖阻害剤、アポトーシス誘導剤、および、細胞外マトリックス構成分子または該細胞外マトリックス構成分子の産生もしくは分泌に関与する分子の少なくとも1つを標的とするRNAi分子、リボザイム、アンチセンス核酸、DNA/RNAキメラポリヌクレオチドおよびこれらを発現するベクターからなる群から選択される、請求項4に記載の医薬組成物。
- 細胞外マトリックス産生細胞の活性または増殖を制御する薬物が、HSP47の阻害剤である、請求項4に記載の医薬組成物。
- 薬物と担体とを、医療の現場またはその近傍で混合してなる、請求項4〜6のいずれか一項に記載の医薬組成物。
- 腎における細胞外マトリックス産生細胞の活性または増殖を制御する薬物、レチノイド、ならびに、必要に応じてレチノイド以外の担体構成物質を、単独でまたは組み合わせて含む1つまたはそれ以上の容器を含む、請求項4〜7のいずれか一項に記載の医薬組成物の調製キット。
- レチノイドを腎臓における細胞外マトリックス産生細胞への標的化剤として配合する工程を含む、腎臓における細胞外マトリックス産生細胞への物質送達用担体の製造方法。
- レチノイドを腎臓における細胞外マトリックス産生細胞への標的化剤として、腎臓における細胞外マトリックス産生細胞の活性または増殖を制御する薬物を有効成分としてそれぞれ配合する工程を含む、腎線維症処置用医薬組成物の製造方法。
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RU2635460C2 (ru) | 2017-11-13 |
RU2013101969A (ru) | 2014-07-27 |
TWI549691B (zh) | 2016-09-21 |
IN2013CN00342A (ja) | 2015-07-03 |
RU2017136720A3 (ja) | 2019-02-08 |
JP2012020995A (ja) | 2012-02-02 |
AU2011266057A1 (en) | 2013-01-10 |
EP2583691A1 (en) | 2013-04-24 |
EP2583691B1 (en) | 2019-01-16 |
KR20130121813A (ko) | 2013-11-06 |
WO2011158933A1 (ja) | 2011-12-22 |
US20150259683A1 (en) | 2015-09-17 |
US20130136789A1 (en) | 2013-05-30 |
TW201204389A (en) | 2012-02-01 |
RU2017136720A (ru) | 2019-02-08 |
EP2583691A4 (en) | 2016-04-27 |
JP5873589B2 (ja) | 2016-03-01 |
CA2802414C (en) | 2018-01-09 |
ES2712086T3 (es) | 2019-05-09 |
CA2802414A1 (en) | 2011-12-22 |
RU2711531C2 (ru) | 2020-01-17 |
CN102933233A (zh) | 2013-02-13 |
AU2011266057B2 (en) | 2014-12-04 |
KR101967868B1 (ko) | 2019-08-19 |
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