JP2023546735A - Ssu72タンパク質またはSsu72タンパク質をコーディングするヌクレオチドを含む肝癌の予防または治療用薬学的組成物 - Google Patents
Ssu72タンパク質またはSsu72タンパク質をコーディングするヌクレオチドを含む肝癌の予防または治療用薬学的組成物 Download PDFInfo
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Abstract
Description
本発明は、Ssu72タンパク質またはSsu72タンパク質をコーディングするヌクレオチドを含む肝癌の予防または治療用薬学的組成物に係り、さらに詳細には、Ssu72タンパク質またはSsu72タンパク質をコーディングするヌクレオチドを含む肝癌の予防、改善及び治療用薬学的組成物に関する。
国際疾病負担(the Global Burden of Disease、GBD)の2019年の報告書によれば、肝硬変症(Cirrhosis)は、年間死亡率(year of life lost)の側面で6位を占め、肝癌は、早期死亡による寿命損失年数(Number of years of life lost)の側面で4位を占めた。肝硬変症と肝癌は、主に慢性ウイルス性肝炎や脂肪肝疾患のように徐々に進行する慢性肝疾患によって発生し、このような慢性肝疾患は、明確な症状がなく、肝線維化症が次第に蓄積されて肝を非可逆的に損傷させるために、「沈黙の殺人者」と呼ばれる。現代社会の生活習慣と西欧化された食習慣とによって代謝症侯群の発生が増加しており、身体の最も重要な代謝器官である肝が慢性的に激しく影響を受けている。肝疾患、特に、非アルコール性肝脂肪疾患(NALFD)は、全世界的に持続的に増加しており、積極的な保健政策にも拘らず、身体活動の減少と高齢化とによって、それを減らしにくい実情である。非アルコール脂肪肝疾患は、肥満有無と関係なく代謝症侯群の発生危険が高く、病理学的機転でインスリン抵抗性、炎症性サイトカイン分泌、異常脂血症、線維素溶解因子が関与する。非アルコール性脂肪肝炎(NASH)、肝細胞癌腫(HCC)、肝線維症のような深刻な肝疾患に進行しうる。最近、肝での炎症と線維化とを緩和させるための研究が続いており、多様な薬剤が開発されているが、いまだにはFDAの正式承認を受けた薬剤はない(Yoo,J.J.et al.,Clin.Mol.Hepatol.25:1-11,2019)。肝癌は、肝移植、肝切除術などの手術的治療と局所治療、経皮的動脈化学塞栓術(TACE)、放射線療法、免疫療法、全身化学療法などの非手術的治療法で治療されているが、肝癌によく伴われる慢性疾患である肝硬変症と慢性肝炎との場合、そのような方式の治療効果が十分ではない実情である。
〔発明が解決しようとする課題〕
しかし、前記先行技術の場合、慢性肝炎、肝硬変症などの副作用と共に治療効率が高くないという問題点がある。
本発明の一観点によれば、配列番号1で示されるアミノ酸配列からなるSsu72ペプチド、前記ペプチドを暗号化するポリヌクレオチドまたは前記ポリヌクレオチドを含む発現ベクターを有効成分として含む肝癌治療用薬学的組成物が提供される。
本発明の一実施例による薬学的組成物は、個体が高脂肪食餌に慣れ、慢性肝毒性化学物質に露出された場合であるとしても、有効成分であるSsu72が脂質沈着及び肝線維症を抑制するために、肝癌、特に、非アルコール性脂肪肝疾患(NAFLD)から由来した肝細胞癌腫(HCC)の治療に使われる。また、本発明の薬剤学的組成物は、遺伝的原因によって誘発された肝細胞癌腫の治療に使われる可能性がある。
〔図1〕本発明の一実施例による肝細胞癌治療用pCMV.HA-Ssu72ベクターの構造を概略的に示す概要図である。
用語の定義:
本明細書で使われる用語「肝癌(liver cnacer)」は、肝で一次的に発生した、すなわち、原発性の悪性腫瘍を意味する。一般人は、他の器官から肝に転移した癌も、よく肝癌と呼ぶが、厳密には、原発性の癌のみを指す。病理学的(組織的)に原発性肝癌には、肝細胞癌腫と胆管上皮癌腫、肝芽細胞腫、血管肉腫など多種があり、そのうち、肝細胞癌腫と胆管上皮癌腫とがほとんどを占める。
本発明の一観点によれば、配列番号1で示されるアミノ酸配列からなるSsu72ペプチド、前記ペプチドを暗号化するポリヌクレオチドまたは前記ポリヌクレオチドを含む発現ベクターを有効成分として含む肝癌治療用薬学的組成物が提供される。
以下、実施例を通じて本発明をさらに詳しく説明する。しかし、本発明は、以下で開示される実施例に限定されるものではなく、互いに異なる多様な形態として具現可能なものであって、以下の実施例は、本発明の開示を完全にし、当業者に発明の範疇を完全に知らせるために提供されるものである。
本発明で使われたあらゆる動物実験は、大韓民国の成均館大学校医科大学(Sungkyunkwan University School of Medicine;SUSM)にある動物実験倫理委員会(The Institutional Animal Care and Use Committee;IACUC)によって承認された、国際実験動物評価管理人認証協会(Association for Assessment and Accreditation of Laboratory Animal Care International;AAALAC International)と実験動物センター(Institute of Laboratory Animal Resources;ILAR)とのガイドライン(guidelines)によって行った。
<2-1:pCMV.HA-Ssu72プラスミドベクターの作製>
本発明者らは、Ssu72を暗号化するポリヌクレオチド(配列番号2)をPCRを通じてクローニングして、Ssu72を発現する治療用非ウイルス性pCMVベクターを作製した後、増幅されたポリヌクレオチドにBam HI及びXba I制限酵素を処理した後、切断されたポリヌクレオチド断片をpCMV.HAベクター(Clonetech、USA)に挿入した後、構築された組換えベクターを「pCMV.HA-Ssu72」と名付けた(図1)。
本発明者らは、Ssu72を発現するAAV8ベクターを作製するために、実施例2-1から製造されたpCMV.HA-Ssu72ベクターから切断されたHA-Ssu72を暗号化するポリヌクレオチドをpAAV.TBG.PI.Cre.rBGベクター(Addgene、USA)からCreモイエティを暗号化するポリヌクレオチドを除去することにより、pAAV.TBG.PI.Cre.rBGベクターを生成し、それをCla I及びSal I制限酵素で切断された後、挿入した。作製されたベクターは、「AAV8.TBG.HA-Ssu72(AAV8 Ssu72)」と名付けた(図2)。
本発明者らは、前記実施例2-2から収得したプラスミドDNAを使用してAAVを作製した。具体的に、AAVを生産するために、293T細胞を前日準備して24時間安定化させ、前記細胞に実施例2-2で作製したプラスミドDNAとAAV生産に必要なプラスミドであるpHelper及びpAAV-RC8(Agilent、USA)とを形質感染(Transfection)させ、3~4日経過後、AAVを収得した。その後、AAVは、適正キット(AAVpro Titration Kit、Takara、Japan)を通じて定量してAAVを生産した。
本発明者らは、肝疾患が発生すれば、肝でのSsu72タンパク質発現レベルに変化があるかを調査した。具体的に、元気なヒト(normal)及び脂肪肝炎(Steatohepatitis)、軽度線維化(Mild fibrosis)、線維化/硬変症(Fibrosis/Cirrhosis)または肝細胞癌(HCC)を病んでいるヒトの肝組織を用いてタンパク質分析を行った。その結果、Ssu72の発現レベルは、元気なヒトの肝で顕著に高く、肝疾患を保有しているヒトの肝では、Ssu72発現が抑制されているということを確認した(図3)。前記結果は、Ssu72の発現低下と肝疾患との相関関係があるということを示唆するものである。
本発明者らは、Ssu72発現抑制によって肝癌感受性の増加有無を確認するために、Ssu72肝特異的欠損マウス(Ssu72Δhep)と比較群である野生型マウス(Ssu72WT)とにDENを処理して肝癌(hepatocellular calcinoma、HCC)を誘導後、4ヶ月及び10ヶ月後、肝を摘出して組織分析を行った。その結果、野生型マウスと比較してSsu72肝特異的欠損マウス(Ssu72Δhep)の肝表面にさらに多くの結節とさらに大きな肝癌とが発生することを確認することができた(図4A)。組織構造分析のためのH&E染色結果、肝癌誘導4ヶ月後からSsu72Δhep肝で腺腫が表われ始め、肝癌誘導10ヶ月後には、Ssu72WTよりもSsu72Δhep肝でさらに深刻な肝癌が観察された。また、DEN処理を通じた肝癌誘導マウスの肝を摘出して体重に比べて、肝の重量比を測定した結果、Ssu72WTとSsu72Δhepマウス肝の重量比は、発癌誘導4ヶ月までは類似している態様を示したが、深刻な肝癌が発生する9ヶ月及び10ヶ月時点には、Ssu72Δhepの肝の重量比が著しく増加することを確認した(図4B)。引き続き、前記実験で肝組織を摘出した後、H&E染色法を通じて肝内部組織分析を行った結果、発癌誘導4ヶ月後には、Ssu72Δhep肝で腺腫が発見される一方、Ssu72WT肝は、いずれも正常表現型を示した。また、肝癌誘発マウスでDEN処理で肝を切除して、肝の重量に比べて、体重比を測定した結果、Ssu72WT及びSsu72Δhepマウスの肝の重量に比べて、体重比は4日まで類似したパターンを示した。9ヶ月及び10ヶ月経過時に、Ssu72Δhepマウスの肝の重量/体重比が有意に増加することを確認した(図4C)。
本発明者らは、本発明のSsu72に欠損による非アルコール性脂肪肝炎の悪化有無を調査した。具体的に、マウス生後2日である時、ストレプトゾトシンを注射し、生後4週から高脂肪食餌(HFD)を給餌して、線維化及び肝癌を誘発するSTAMモデルを製造した。STAMモデルの期間を長くすれば、重症HCCも誘発が可能であるが、犠牲時点を調節して非アルコール性脂肪肝炎(Non-alcoholic steatohepatitis、NASH)及び肝癌の発生過程を同時に観察することができる。本発明者らは、Ssu72WTとSsu72ΔhepとにSTAMモデルを適用した後、生後4ヶ月の時、腺腫及び肝表面の結節を観察した。
本発明者らは、肝損傷後、Ssu72枯渇によって肝脱分化可能性が増加する潜在的なメカニズムを理解するために、DEN処理されたSsu72WT及びSsu72Δhepマウスから分離された肝細胞でRNA-Seqを使用して遺伝子発現分析を行った。ヒートマップ分析によれば、DEN処理Ssu72WTマウスの肝細胞と比較してDEN処理Ssu72Δhepマウスの肝細胞で肝細胞及び胆汁マーカー遺伝子下位集合の発現レベルが非常に下向き調節された一方、前駆遺伝子は、DEN処理Ssu72WTマウスの肝細胞に比べて、DEN処理Ssu72Δhepマウスの肝細胞で劇的に上向き調節された(図6A)。DEN処理Ssu72WTマウスとDEN処理Ssu72Δhepとの肝細胞の肝遺伝子発現の変化をDAVIDを通じて機能別に分類して信頼度が高い項目を互いに比較した。その結果、DEN処理Ssu72Δhepマウスの肝細胞で脂質、コレステロール、レチノールの代謝過程、ミトコンドリア、ペルオキシソーム、酸化的リン酸化など肝細胞固有の生理学的特徴と関連した遺伝子が下向き調節された。これは、肝細胞の本質的な生理的特徴でSsu72の潜在的な役割を示唆し、Ssu72が肝細胞の本質的な機能の保持に必須的であることを立証するものである(図6B)。一方、細胞周期関連遺伝子下位集合は、DEN処理Ssu72Δhepマウスの肝細胞で非正常に上向き調節されて肝損傷に対する反応でSsu72枯渇によって肝細胞が脱分化されて増殖潜在力を回復することを示唆する。
HNF4αは、肝機能保持と関連したマスター転写因子であり、NASH、ASH、肝硬変及び肝癌の発生で非常に下向き調節される。特に、HNF4αの転写活性は、主にリン酸化変形によって調節される。肝損傷でAMPK、MAPK及びPKAのような多様なキナーゼの活性は、HNF4αの過リン酸化を誘導して転写活性を減少させることができる。これにより、本発明者らは、HNF4αとSsu72との関係を確認するために、実験用マウスでDEN処理後、リン酸化程度を調査した。
<8-1:Ssu72発現誘導を通じた治療効果の検証>
本発明者らは、AAV8 Ssu72投与による肝疾患に対するSsu72の効果を検証した。特に、NASH初期には、脂肪肝が代表的な症状なので、食餌調節することが良く、効果がある場合が多い。しかし、脂肪肝を含めた線維化が進行して食餌調節のみでは、重症NASHを治療しにくい。このような重症NASHは、肝癌に発展することができ、B型肝炎ウイルスによる肝癌に対する予防法がないために、重症NASHを治療する方法及び治療剤の開発が至急な実情である。したがって、重症NASHの効果的な治療のためには、肝線維症の治療が重要であり、この基準は、肝癌の予防可能性を判断する指標になる。STAMモデルを適用した正常マウスは、6週齢に脂肪肝が発生し、8週齢にNASH及び初期肝線維化が表われ、12週齢に肝線維化が激しくなる。本発明のAAV8 Ssu72と対照群であるAAV8 GFPとを8週齢のSTAMモデルマウスにしっぽ静脈(3x1010gc/g)を通じて投与し、4週後にマウスを犠牲にさせてH&E染色を通じて組織内の構造的の差を比較した。
本発明者らは、AAV8 Ssu72投与を通じた肝線維化の抑制有無を評価するために、シリウスレッド染色を行った。具体的に、STAMモデルマウスに本発明のAAV8 Ssu72と対照群であるAAV8 GFPとをしっぽ静脈を通じて投与(3x1010gc/g)し、4週後、マウスを犠牲にさせた後、肝で線維化反応を通じて生成されたコラーゲン沈着の位置と量とを決定するために、コラーゲンI/IIIをシリウスレッドで染色した。
本発明者らは、AAV8 GFPまたはAAV8 Ssu72を投与したSTAMモデルマウスの肝及び血液を用いて血清化学分析、体重に比べて、肝の重量、シリウスレッドで染色された組織の面積比に対する分析を行った。肝の重量対体重は、肝損傷、線維化、脂肪肝などによる肝肥大程度を測定する指標であり、ASTとALT数値は、肝で損傷が発生する場合、血液から検出される酵素の濃度であるために、肝損傷の指標になる。
STAMモデルを適用したマウスは、脂肪症とNASH表現型とを伴い、HFD摂食期間が長くなるほど激しい肝細胞癌腫が表われる。しかし、STAMモデルの限界によって長期間観察時に、一部のマウスが死亡するので、本発明者らは、肝癌モデルを確立するために、HCC表現型が発現される最小期間を先に設定した。STAMモデルを適用した正常マウスを12週齢に犠牲にさせ、切除された肝を分析した。当該実験日程を図9Aに概略的に示した。STAMモデル適用12週後、犠牲になったマウスから得た肝組織を固定し、H&E染色で分析した。その結果、腫瘍病変が確認され、正常組織と異なる細胞の分布と形態とが観察された。IHC分析は、病変でHCCマーカーと知られたCD10及びCD34抗体を使用して行われた。CD10は、多様な細胞から発現される細胞表面タンパク質であるが、多様な癌腫、特に、肝細胞癌腫で発現が増加するために、肝細胞に転移した転移癌と肝細胞癌とを区分するマーカーとして使われる(WG McCluggage et al.,Histopathol.39:273-278,2001)。CD34は、HCCの正弦波型血管(sinosoid-like vessel)の内皮細胞から発現され、HCCの指標である(MacSween’s Pathology of the liver,2017 May;22)。STAMモデルが適用されたマウスで正常食餌マウスである対照群に比べて2つのマーカーの発現が有意に増加することを観察した(図9B)。したがって、前記の結果は、STAMモデルを適用した後、12週にHCCが発生することを示唆する。
本発明は、肝癌治療用薬剤学的組成物に関するものである。したがって、本発明は、治療剤、特に、肝細胞癌のような肝癌治療用治療剤の製造に使われる。
Claims (13)
- 配列番号1で示されるアミノ酸配列からなるSsu72ペプチド、前記ペプチドを暗号化するポリヌクレオチドまたは前記ポリヌクレオチドを含む発現ベクターを有効成分として含む、肝癌治療用薬学的組成物。
- 前記ポリヌクレオチドは、配列番号2で示される核酸配列からなる、請求項1に記載の薬学的組成物。
- 前記発現ベクターは、ウイルス性ベクターまたは非ウイルス性ベクターである、請求項1に記載の薬学的組成物。
- 前記ウイルス性ベクターは、アデノ随伴ウイルス(AAV)ベクター、アデノウイルスベクター、アルファウイルスベクター、単純ヘルペスウイルスベクター、ワクシニアウイルスベクター、センダイウイルスベクター、フラビウイルスベクター、ラドボウイルスベクター、レトロウイルスベクター、ヘルペスウィルスベクター、ポックスウイルスベクターまたはレンチウイルスベクターである、請求項3に記載の薬学的組成物。
- 前記非ウイルス性ベクターは、DNAベクター、ナノ粒子、カチオン性ポリマー、エクソソーム、細胞外小胞またはリポソームである、請求項3に記載の薬学的組成物。
- 前記DNAベクターは、プラスミドベクター、コスミドベクター、ファージミドベクターまたは人工ヒト染色体である、請求項5に記載の薬学的組成物。
- 前記肝癌は、原発性肝癌または続発性肝癌である、請求項1に記載の薬学的組成物。
- 前記原発性癌は、肝細胞癌または胆管細胞癌である、請求項7に記載の薬学的組成物。
- 肝癌患者から収得された試料でSsu72発現程度または前記Ssu72の活性を測定する段階と、
Ssu72が正常者または肝癌患者の正常組織に比べて高く発現されるか、前記Ssu72が不活性の形態で発現される場合、前記肝癌がNASH由来の肝細胞癌であると診断する段階と、
を含む、肝癌患者の肝癌類型の判定方法。 - 肝癌患者から収得された試料でSsu72発現程度または前記Ssu72の活性を測定する段階と、
Ssu72が正常者または患者の正常組織に比べて高く発現されるか、前記Ssu72が不活性の形態で発現されると判定された患者にSsu72タンパク質またはそれを暗号化するポリヌクレオチドを投与する段階と、
を含む、肝癌の治療方法。 - 脂肪肝または脂肪肝炎患者から収得された試料でSsu72発現程度または前記Ssu72の活性を測定する段階と、
Ssu72の発現が正常者または患者の正常組織に比べて低いか、前記Ssu72が不活性の形態で発現される場合、NASH由来の肝細胞癌が発生する確率が高いと判定する段階と、
を含む、脂肪肝または脂肪肝炎患者のNASH由来の肝細胞癌の発病可能性の予測方法。 - 配列番号1で示されるアミノ酸配列からなるSsu72ペプチド、前記Ssu72ペプチドを暗号化するポリヌクレオチドまたは前記ポリヌクレオチドを含む発現ベクターを個体に投与する段階を含む、前記個体で肝癌を予防する方法。
- 培養中である肝細胞またはヒトを除いた実験動物に候補物質を処理する段階と、
前記肝細胞または実験動物でSsu72の発現またはSsu72とHNF4αとの相互作用を測定する段階と、
前記肝細胞または実験動物でSsu72の発現またはSsu72とHNF4αとの相互作用を増加させる候補物質を選別する段階と、
を含む、肝癌治療剤の候補物質のスクリーニング方法。
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