JP5425537B2 - 筋重量を増加させるためのフォリスタチンの使用方法 - Google Patents
筋重量を増加させるためのフォリスタチンの使用方法 Download PDFInfo
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- JP5425537B2 JP5425537B2 JP2009147316A JP2009147316A JP5425537B2 JP 5425537 B2 JP5425537 B2 JP 5425537B2 JP 2009147316 A JP2009147316 A JP 2009147316A JP 2009147316 A JP2009147316 A JP 2009147316A JP 5425537 B2 JP5425537 B2 JP 5425537B2
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Description
本発明は、一般的に増殖分化因子(GDF)受容体に関し、より詳しくはGDF-8(ミオスタチン)受容体、細胞においてミオスタチンシグナル伝達に影響を及ぼす組成物、および細胞におけるミオスタチンシグナル伝達を調節するためにそのような組成物を用いる方法に関する。
アメリカにおいて、体重を減らそうと考えている人が消費する時間、労力、およびお金の量は驚異的である。これらの人の多くにとって、目標は単に外見を良くすることではなく、より重要なことは、過体重であることに関連した避けて通れない医学的問題を回避することである。
本発明は、プロミオスタチンポリペプチドの実質的に精製されたペプチド部分を提供する。これまで増殖分化因子-8(GDF-8)と呼ばれていたプロミオスタチンは、アミノ末端プロドメインとC末端成熟ミオスタチンペプチド(米国特許第5,827,733号を参照のこと)とを含む。ミオスタチン活性は、プロミオスタチンからの切断後の成熟ミオスタチンペプチドによって示される。このように、プロミオスタチンは、蛋白質分解によって切断されて活性ミオスタチンを生じる前駆体ポリペプチドである。本明細書に開示するように、ミオスタチンプロドメインは、ミオスタチン活性、GDF-11活性またはその双方を阻害することができる。
(1)BLASTPおよびBLAST3は、蛋白質配列データベースに対してアミノ酸問い合わせ配列を比較する;
(2)BLASTNは、ヌクレオチド配列データベースに対してヌクレオチド問い合わせ配列を比較する;
(3)BLASTXは、蛋白質配列データベースに対する問い合わせヌクレオチド配列(双方の鎖)の6個のフレーム概念的翻訳産物を比較する;
(4)TBLASTNは、全ての6個のリーディングフレーム(双方の鎖)において翻訳されたヌクレオチド配列データベースに対して問い合わせ蛋白質配列を比較する;および
(5)TBLASTXは、ヌクレオチド配列データベースの6個のフレーム翻訳に対するヌクレオチド問い合わせ配列の6個のフレーム翻訳を比較する。
ミオスタチンは用量依存的に作用する
本実施例は、筋増殖の阻害におけるミオスタチンの活性がインビボでミオスタチン発現レベルに依存することを示す。
ミオスタチンの作用はノックアウトマウスの年齢と共に減少する
本実施例は、野生型マウスとホモ接合ミオスタチンノックアウトマウスのあいだの体重の差の減少が、変異体マウスの筋重量の減少に関連していることを証明する。
ミオスタチンは用量依存的に脂肪の蓄積に影響を及ぼす
本実施例は、ミオスタチンノックアウトマウスが脂肪を蓄積させることができないこと、および脂肪蓄積の減少がインビボでのミオスタチン発現レベルに関連していることを証明する。
代謝に及ぼすミオスタチンの影響
本実施例は、血清インスリンとグルコースレベルが代謝活性と共にミオスタチン発現レベルによって影響を受けることを証明する。
ミオスタチンは遺伝的肥満マウスにおける脂肪蓄積に影響を及ぼす
本実施例は、ミオスタチン発現の欠如が、肥満の遺伝子モデルであるマウスにおいて脂肪の蓄積を抑制することを証明する。
組換えミオスタチンの精製
本実施例は、組換えミオスタチンを調製および単離する方法を提供する。
ミオスタチンはアクチビン受容体と特異的に相互作用する
本実施例は、ミオスタチンが培養細胞上で発現されたアクチビンII型受容体に特異的に結合すること、およびこの特異的結合がミオスタチンプロドメインによって阻害されることを証明する。
ミオスタチンレベルの増加は体重減少を誘導する
本実施例は、ミオスタチンレベルの上昇がインビボでの実質的な体重減少につながりうることを証明する。
アクチビン受容体に対するミオスタチン結合の特徴付け
本実施例は、アクチビン受容体に対するミオスタチンの結合と、インビボでミオスタチンによって生じた生物作用との関係の特徴を調べる方法を記述する。
肥満およびII型糖尿病の遺伝子モデルにおけるミオスタチンの作用の特徴付け
本実施例は、肥満またはII型糖尿病の治療におけるミオスタチンの作用を決定する方法を記述する。
ミオスタチン活性に影響を及ぼしうるドミナントネガティブポリペプチドを発現するトランスジェニックマウスの特徴付け
本実施例は、ミオスタチン発現またはミオスタチンシグナル伝達を阻害しうるドミナントネガティブポリペプチドを発現することによって生後にミオスタチンの作用の特徴を調べる方法を記述する。
生後にミオスタチン活性を調節することを用いて、筋繊維数(過形成)および筋繊維の大きさ(肥大)に及ぼすミオスタチンの作用を調べることができる。ミオスタチン遺伝子が動物の一生の間で一定期間欠失している条件付ミオスタチンノックアウトマウスをこれらの試験に用いることができる。creレコンビナーゼと組み合わせたtet調節物質は、そのようなマウスを作製するためのシステムを提供する。この系において、creの発現は、ドキシサイクリンの投与によって誘導される。
ミオスタチン導入遺伝子を含むトランスジェニックマウスも同様に調べて、ミオスタチンの発現時に生じた作用を、ミオスタチン発現CHO細胞を含むヌードマウスにおいて認められた作用と比較することができる。上記と同様に、ミオスタチンは、条件(tet)および組織特異的調節エレメントの制御下に置くことができ、ヌードマウスにおいて認められたものと類似の消耗性症候群が起こるか否かを決定するために、トランスジェニックマウスにおけるミオスタチンの発現を調べることができる。ミオスタチン導入遺伝子は、例えば、導入遺伝子が内因性のミオスタチン遺伝子と区別できるように、SV40に由来するプロセシングシグナルを含みうる。
骨格筋において特異的に発現されるTGF-βシグナル伝達経路の成分を含みうる、ミオスタチンシグナル伝達経路のいずれかのドミナントネガティブ型を含むトランスジェニックマウスを作製することができる。本明細書において開示するように、アクチビンII型受容体によって誘導される経路を通してシグナル伝達を媒介するSmad蛋白質は、ミオスタチンシグナル伝達に関係しうる。
カヘキシアの誘導に及ぼすミオスタチン作用の特徴付け
本実施例は、カヘキシアの発症および進行におけるミオスタチンシグナル伝達の役割を調べる方法について記述する。
増殖分化因子-8(GDF-8)およびGDF-11受容体の同定と特徴付け
本実施例は、GDF-8(ミオスタチン)とGDF-11の細胞表面受容体を同定して特徴を調べる方法を記述する。
GDF-11ノックアウトマウスの作製と特徴付け
いくつかの局面におけるGDF-11ノックアウトマウスの表現型は、アクチビンIIB型受容体(Act RIIB)を含むTGF-βスーパーファミリーのいくつかのメンバーの受容体の欠失を有するマウスの表現型に類似する。GDF-11の生物機能を決定するために、GDF-11遺伝子を胚性幹細胞において相同的ターゲティングによって破壊した。
ミオスタチンプロペプチド、フォリスタチンまたはドミナントネガティブACT RIIBを発現するトランスジェニックマウスの作製
ミオスタチンの精製
ミオスタチン発現構築物の増幅コピーを有するチャイニーズハムスター卵巣(CHO)細胞株に、前駆体蛋白質のプロセシングを改善するために、フリンプロテアーゼPACEの発現構築物(Monique Davies氏の好意による提供)をトランスフェクトした。条件培地(セルトレンズ社の調製、ミドルタウン、メリーランド州)を、ヒドロキシアパタイト(200 mM燐酸ナトリウム、pH 7.2によって溶出)、レンチルレクチンセファロース(50 mMトリス、pH 7.4、500 mM NaCl、500 mMメチルマンノースによって溶出)、DEAEアガロース(50 mMトリス、pH 7.4、50 mM NaCl中でカラムの中を通過した材料を集める)、およびヘパリンセファロース(50 mMトリス、pH 7.4、200 mM NaClによって溶出)に連続的に通過させた。ヘパリンカラムからの溶出液を逆相C4 HPLCカラムに結合させて、0.1%トリフルオロ酢酸中でアセトニトリル勾配によって溶出した。成熟C-末端蛋白質に対する抗体は既に記述されている(参照として本明細書に組み入れられる、米国特許第5,827,733号を参照のこと)。プロペプチドに対する抗体を作製するために、アミノ酸122〜261位に及ぶヒトミオスタチン蛋白質の一部をRSETベクター(インビトロジェン社、サンジエゴ、カリフォルニア州)を用いて細菌に発現させ、ニッケルキレートクロマトグラフィーによって精製して、ウサギに注射した。免疫は、スプリングバレー研究所(ウッドバイン、メリーランド州)が行った。
クロラミンT法(Frolik, C.A., Wakefield, L.M., Smith, D.M., and Sporn, M.B.(1984)、J. Biol. Chem. 259、10995〜11000)を用いて、精製ミオスタチンに放射性ヨウ素を標識した。6または12ウェルプレートにおいて増殖させたCOS-7細胞に、リポフェクタミン(ギブコ社、ロックビル、メリーランド州)を用いて、pCMV5またはpCMV5/受容体構築物1〜2μgをトランスフェクトした。クロスリンク実験は、記述のようにトランスフェクションの2日後に行った(Franzen, P.、ten Dijke, P.、Ichijo, H.、Yamashita, H.、Schultz, P.、Heldin、C.H.、およびMiyazono, K.(1993)、Cell 75:681〜692)。定量的受容体結合アッセイ法を行うために、細胞単層を、1 mg/ml BSAを含むPBSによって2回洗浄して、様々な濃度の非標識ミオスタチン、プロペプチド、またはフォリスタチンの存在下または非存在下で、4℃で標識ミオスタチンと共にインキュベートした。次に、細胞を同じ緩衝液によって3回洗浄して、0.5 N NaOH中で溶解し、γカウンターにおいて計数した、特異的結合は、Act RIIBをトランスフェクトした細胞と、ベクターをトランスフェクトした細胞との結合ミオスタチンの差として計算した。特異的結合を計算するこの方法は、プロペプチドを加えても同様に非特異的結合が濃度依存的に減少することから、プロペプチドの影響を評価するために特に重要であった。
アミノ酸1〜174位に及ぶマウスAct RIIBの切断型、アミノ酸1〜267位に及ぶマウスミオスタチンプロペプチド、およびヒトフォリスタチン短縮型をコードするDNAを、ミオシン軽鎖プロモーターおよび1/3エンハンサー(McPherron, A.C.とLee, S.J.、(1993)、J. Biol. Chem. 268:3444〜3449)を含むMDAF2ベクターにクローニングした。ミオシン軽鎖調節配列とSV40プロセシング部位とを含む精製導入遺伝子をマイクロインジェクションのために用いた。マイクロインジェクションおよび胚の移入は全て、ジョンホプキンス大学メディカルスクールのトランスジェニックコア施設(John Hopkins of Medicine Trandgenic Core Facility)が行った。ハイブリッドSJL/C57BL/6バックグラウンドのトランスジェニック創始動物を野生型C57BL/6マウスと交配させて、研究は全てF1子孫を用いて行った。筋重量の分析に関して、個々の筋肉をほぼ全ての動物の両側から切除して、左右の筋重量の平均値を用いた。線維数と大きさの分析は記述通りに行った(McPherron, A.C.、Lawler, A.M.、およびLee, S.J.(1997)、Nature 387:83〜90)。RNA単離およびノザン分析は記述通りに行った(McPherron, A.C.、およびLee, S.J(1993)、J. Biol.Chem. 268:3444〜3449)。
Claims (16)
- アクチビンIIB型受容体(ActRIIB)の細胞外ドメインからなるActRIIBポリペプチドの治療上の有効量を含む、哺乳動物の筋重量の増加に使用するための薬学的組成物。
- ActRIIBポリペプチドがGDF-8活性を調節する、請求項1記載の薬学的組成物。
- 組成物が、経口投与または非経口投与のために調製される、請求項1記載の薬学的組成物。
- 哺乳動物が、筋疾患および神経筋疾患から選択される疾患または障害に罹患している、請求項1記載の薬学的組成物。
- 疾患または障害が筋疾患である、請求項4記載の薬学的組成物。
- 筋疾患が、筋ジストロフィー、筋萎縮、および筋消耗性疾患の少なくとも1つから選択される、請求項5記載の薬学的組成物。
- 筋疾患が筋ジストロフィーである、請求項5記載の薬学的組成物。
- 筋ジストロフィーがDuchenne筋ジストロフィーである、請求項7記載の薬学的組成物。
- 筋疾患が筋萎縮である、請求項5記載の薬学的組成物。
- 筋疾患が筋消耗性疾患である、請求項5記載の薬学的組成物。
- 筋消耗性疾患がカヘキシアである、請求項10記載の薬学的組成物。
- 筋消耗性疾患が食欲不振である、請求項10記載の薬学的組成物。
- 疾患または障害が神経筋疾患である、請求項4記載の薬学的組成物。
- 神経筋疾患が筋萎縮性側索硬化症(ALS)である、請求項13記載の薬学的組成物。
- 哺乳動物がヒトである、請求項1記載の薬学的組成物。
- ActRIIBポリペプチドが、増殖分化因子-8(GDF-8)に結合し、GDF-8活性を阻害する、請求項1記載の薬学的組成物。
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