JP7382437B2 - 眼疾患を治療するための脱メチル化 - Google Patents
眼疾患を治療するための脱メチル化 Download PDFInfo
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Description
本出願は、2018年6月11日および2018年8月9日にそれぞれ出願された米国仮出願第62/683,292号および同第62/716,554号の優先利益権を主張し、これらの出願は参照により本明細書に組み込まれる。
本出願には、ASCIIフォーマットで電子的に提出された配列表が含まれ、参照によりその全体が本明細書に組み込まれる。2019年5月20日に作成された該ASCIIコピーの名称は、24978-0488_SL.txtであり、サイズは、17,271バイトである。
両側性の乾式加齢性黄斑変性症(AMD)を有する75歳の女性が眼科クリニックを受診する。患者は、それ以外は健康である。患者は、脱メチル化療法と対照とを比較する実験的研究に同意する。ベースラインでは、両眼は、視力、自家蛍光により測定された地図状萎縮のサイズ、光干渉断層撮影、および網膜電図での暗所視応答の臨床評価により証明されるように、類似のレベルのAMDを示す。患者を、左眼に硝子体内注射により投与される、無菌の等張性のpH緩衝溶液として処方された100uLのデシタビン(20μM)で治療する(能動的治療)。患者は、100ulの同じ無菌の等張性のpH緩衝溶液を受けるが、右眼には硝子体内注射によるデシタビンを投与しない(対照治療)。能動的治療および対照治療の施術の直後に、ELOVL2発現およびメチル化レベルのベースライン測定のために硝子体内液の試料を各眼から取り出す。ELOVL2は、両眼で同程度に高メチル化されていることが観察される。ELOVL2発現のレベルも類似しており、両眼で低レベルの発現が観察される。能動的治療および対照治療の両方が、それぞれ左眼および右眼で継続され、3ヶ月間隔週で投与される。能動的治療および対照治療の両方は、投与期間にわたって等しく十分に許容される。最後の投与の直後に、ELOVL2遺伝子発現およびメチル化の測定のために硝子体内液の試料を両眼から採取する。ベースラインで実行した地図状萎縮の同じ臨床評価を各眼に対して繰り返す。デシタビンで治療された眼と対照との間を比較すると、著しい差が観察される。デシタビンで治療された眼では、ELOVL2メチル化はベースラインと比較してほぼ30%低減し、ELOVL2遺伝子発現もほぼ30%増加する。また、暗所視応答は、ベースラインよりも約30%増加する。さらに、ベースラインと比較して、眼底自家蛍光により測定される場合の地図状萎縮の成長の進行はない。非常に対照的に、他のパラメータのいずれにおいても、対照の眼に観察可能な変化はない。遺伝子のメチル化および遺伝子の発現および暗所視応答の値は、ベースライン値で観察された値と同じようなままである。患者は6ヶ月でフォローアップ訪問のためにクリニックに戻る。臨床評価は、デシタビンで治療された眼の暗所視応答の改善が持続していることを明らかにし、ベースラインよりも約20%~30%の改善を示す。対照の眼における暗所視応答は、ベースライン値と同じようなままである。
地図状萎縮を伴う乾式加齢性黄斑変性症(AMD)を有する65歳の男性が眼科クリニックを受診する。暗所視応答により評価される患者の視力は低下している。過去2年間の患者の地図状萎縮の領域は、眼底自家蛍光により測定されるように着実な進行を示している。患者は、それ以外は健康である。患者を、硝子体内注射により投与される、無菌の等張性のpH緩衝溶液として処方された100uLのデシタビン(15μM)で治療する。デシタビン投与直後に取り出された硝子体内試料は、ELOVL2プロモーターの高メチル化および低レベルのELOVL2発現を明らかにする。デシタビン治療は、12ヶ月間にわたって5週間ごとに同じ用量を投与して継続する。投与は十分に許容され、副作用は観察されない。最後のデシタビン投与後、硝子体液の試料を採取し、ELOVL2遺伝子のメチル化およびELOVL2遺伝子の発現について試験する。研究は、ELOVL2メチル化が(ベースラインから)ほぼ60%減少し、ELOVL2遺伝子発現が(ベースライン値よりも)約50%増加することを明らかにする。患者の暗所視応答は著しく改善され、ベースラインよりも約30%増加する。眼底自家蛍光により測定される場合、地図状萎縮の成長はない。
地図状萎縮を伴う乾式加齢性黄斑変性症(AMD)を有する70歳の男性が眼科クリニックを受診する。暗所視応答により評価される患者の視力は着実に低下している。患者の地図状萎縮の領域は、眼底自家蛍光により測定されるように着実な進行を示している。患者は、それ以外は健康で、ELOVL2遺伝子療法を使用した治療に同意する。遺伝子療法手順の1週間前に、患者は経口プレドニゾン(0.5mg/kg)を開始した。ELOVL2コード配列を有する組換えアデノ随伴ウイルスベクターが作成され、良好な医療行為ガイドラインの下でパッケージ化される。これを、0.3mlのアリコートに1.5×1011ゲノムの力価で緩衝生理食塩水に懸濁する。経口プレドニゾンで1週間後、全身麻酔下で標準的な硝子体網膜技法を使用して皮質硝子体を除去するために標準的な硝子体切除術が実行される。次に、ちょうど黄斑の外に特殊用途の網膜下カニューレを使用して網膜下腔に注射合計で1.5×1011ゲノムの力価を含有する0.3mlの緩衝生理食塩水を患者に投与する。空気流体交換を実行し、傷を標準的な方法で縫合する。患者に経口プレドニゾン(0.5mg/kg)を継続し、ゆっくりと漸減して術後4週間で終了する。硝子体試料から採取された細胞の分析は、低レベルのELOVL2発現を明らかにする。遺伝子療法手順後の6ヶ月および1年のフォローアップでは、眼底自家蛍光により測定される場合の地図状萎縮の領域に著しい進行はなく、暗所視応答により評価した視力は約20%~約30%改善されている。
以前の研究では、ELOVL2プロモーターのメチル化とヒトの年齢との間に非常に著しい相関関係があることが明らかになっている¥[3、29、30]。現在の研究では、ELOVL2のメチル化および発現がヒト線維芽細胞およびマウスの網膜モデルの加齢表現型に役割を担うかどうかを調査した。
細胞培養および処理。
WI-38およびIMR-90ヒト線維芽細胞を、10%ウシ胎児血清(Omega)および1%ペニシリン/ストレプトマイシン(Gibco)を補充したEMEM(ATCC)で培養し、5%CO2および37°Cの加湿インキュベーターで保存した。コンフルエンスを試料ごとに3つの視野(10倍)を含むImageJ撮像ソフトウェアを介して計算した。コンフルエンス状態になると、細胞を分割し、1:3の比率で播種した。集団倍増(PD)を細胞数により計算した。製造元の指示に従ってMISSION shRNA(Sigma)を使用して、ノックダウンレンチウイルスを生成した。5-アザ-2’-デオキシシチジンをTSZ Chem(CAS#2353-33-5)から購入し、2μMの濃度で細胞培養培地に溶解した。細胞を48時間処理した。次に、培地を通常の細胞培養培地と交換し、細胞をさらに5日間培養した。
製造元の指示に従って老化β-ガラクトシダーゼ染色キット(Cell Signaling Technology)を使用して、培養細胞におけるSA-β-gal活性を決定した。その後、細胞をDAPIで染色し、陽性に染色された細胞の割合を、3つの視野(10倍)を含む撮像ソフトウェア(Keyence)で計算した。
製造元の指示に従ってTRIzol(Ambion)を使用して、DNAおよびRNAをヒト線維芽細胞およびマウス組織から単離した。RNAをiScript cDNA合成キット(Bio-Rad)でcDNAに変換した。qPCRを、SsoAdvanced Universal SYBR Green Supermix(Bio-Rad)を使用して実行した。
様々な発達段階のWTマウスの網膜からTRIzol(Ambion)で単離された10μgの総タンパク質をSDS-PAGEにかけた。ウエスタンブロッティングを、広く受け入れられているプロトコルを使用して実行した(研究で使用した抗体については表2を参照されたい)。ELOVL2タンパク質の発現レベルをH3に正規化した。
CRISPR-Cas9試薬を本質的には前述のように生成した[34]。T7プロモーターをPCR増幅によりクローン化されたCas9コード配列に添加した。次に、T7-Cas9生成物をゲル精製し、mMESSAGE mMACHINE T7 ULTRAキット(Life Technologies)を使用してインビトロ転写(IVT)のテンプレートとして使用した。T7プロモーターおよびsgRNA配列を長いオリゴヌクレオチド(Ultramer,IDT)として合成し、PCRにより増幅した。T7-sgRNA PCR生成物をゲル精製し、MEGAshortscript T7キット(Life Technologies)を使用してIVTのテンプレートとして使用した。C217Wバリアントをコードする修復テンプレートを一本鎖オリゴヌクレオチド(Ultramer,IDT)として合成し、精製せずに使用した。潜在的なオフターゲットを、Cas-OFFinder35を使用して特定し、不一致が最も少ない標的を選択した(http://www.rgenome.net/cas-offinder/)。ファウンダーマウスおよびすべてのF1マウスをオフターゲットのために配列決定した。
すべての動物の手順をUniversity of California,San Diegoの施設内動物管理委員会の承認を得て実施した。C57BL/6Nマウス接合子にCRISPR-Cas9構築物を注射した。オリゴを前核段階で接合子の細胞質に注射した。マウスを従来の動物施設の静的ラックに収容し、Teklad Global2020X食餌を自由に与えた。5-Aza-dc注射研究では、マウスをケタミン/キシラジン(それぞれ、100mg/kgおよび10mg/kg)の腹腔内注射により麻酔し、プロパラカイン(0.5%、Bausch&Lomb)の鎮痛点眼薬を与えた。動物に2ヶ月間にわたって隔週で、片方の眼には1μLのPBSを、反対側の眼にはPBSに溶解した1μLの2μM 5-Aza-dcを眼内注射した。
マウスを犠牲にした直後に網膜を収集し、4%パラホルムアルデヒドで1時間固定し、4℃でPBSに保存した。免疫染色に関して、網膜を切片化し、スライドに乗せ、5%BSA、0.1%トリトン-XPBSブロッキング溶液で1時間インキュベートした。一次抗体(研究で使用した抗体については表2を参照されたい)を5%BSA PBSに1:50で添加し、4℃で16時間インキュベートした。PBSで3回洗浄した後、二次抗体を5%BSA PBSで1:1000、室温で30分間添加した。次に、試料をPBSで3回洗浄し、DAPIを用いて室温で5分間染色し、乗せて、画像化した(Keyence BZ-X700)。
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Claims (8)
- 超長鎖脂肪酸様2遺伝子(ELOVL2)タンパク質又はポリペプチドをコードするウイルスベクターを含む、加齢性黄斑変性症(AMD)を治療又は予防するための医薬組成物。
- 前記組成物が、硝子体内、網膜下、結膜下、テノン嚢下、又は後強膜近傍経路による眼への投与のために処方されている、請求項1に記載の医薬組成物。
- 前記ウイルスベクターが、アデノウイルスベクター、アデノ随伴ウイルスベクター、レンチウイルスベクター、ワクシニアウイルスベクター、およびレトロウイルスベクターから選択される、請求項1又は2に記載の医薬組成物。
- 前記組成物が、ヒトへの投与に好適な1又は複数の賦形剤を更に含む、請求項1~3のいずれか一項に記載の医薬組成物。
- 前記加齢性黄斑変性症(AMD)が、乾式AMDである、請求項1~4のいずれか一項に記載の医薬組成物。
- 前記ウイルスベクターが、ELOVL2タンパク質又はポリペプチドをコードする配列の転写および翻訳に必要な要素を含み、前記必要な要素が、網膜細胞において発現する構成的若しくは誘導的プロモーター、及び/又はエンハンサー、を含む、請求項1に記載の医薬組成物。
- 前記網膜細胞が、網膜色素上皮(RPE)および/または光受容体を含む、請求項6に記載の医薬組成物。
- RPEにおいて発現するプロモーターがVMD2プロモーターである、請求項7に記載の医薬組成物。
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