JP7411154B2 - コドン最適化TIF1γポリヌクレオチドを含む組換えベクターおよびその用途 - Google Patents
コドン最適化TIF1γポリヌクレオチドを含む組換えベクターおよびその用途 Download PDFInfo
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- JP7411154B2 JP7411154B2 JP2022540858A JP2022540858A JP7411154B2 JP 7411154 B2 JP7411154 B2 JP 7411154B2 JP 2022540858 A JP2022540858 A JP 2022540858A JP 2022540858 A JP2022540858 A JP 2022540858A JP 7411154 B2 JP7411154 B2 JP 7411154B2
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Description
本発明のTIF1γ遺伝子のN末端部位をコドン最適化したポリヌクレオチドを用いてTIF1γ組換えタンパク質を生産する場合、同量の遺伝子を用いて組換えタンパク質の生産量を増加させることができるだけでなく、これによって、線維化疾患の治療効果もまた増加することを確認したので、本発明の最適化されたTIF1γポリヌクレオチドを用いて線維化治療など多様な分野に適用可能であることが期待される。
TIF1γ組換えタンパク質の発現を最大化するために、TIF1γのコドン最適化(codon optimization)を実施した。コドン最適化による組換えタンパク質生産量の差異を確認するために、TIF1γのヌクレオチド配列(Sequence ID:NM_015906)の全体を特にヒト細胞で発現頻度の高い遺伝子コドンで最適化させた3種類の配列を準備した。そして、それぞれのTIF1γ遺伝子をpVAX1(ThermoFisher)に挿入して、293T細胞株で発現させた。対照群としては、TIF1γの元の配列を用いた。また、CMV-emGFPベクターを共に形質注入(transfection)して、形質注入効率を比較した。そして、発現したTIF1γ組換えタンパク質は、ウェスタンブロッティングで確認した。ウェスタンブロッティングのために、回収された細胞をprotein lysis buffer(50mM Tris-HCl、150mM NaCl、0.5% deoxycholate、1% NP40およびProtease inhibitor cocktail(Roche))が含まれた0.1% sodium dodecyl sulfateに溶解させ、タンパク質抽出物25~30μgを5分間95℃で加熱させた後、SDS-pageを実施した。そして、SDS-pageが完了した後、サイズによって分離したタンパク質をBioRad transfer unit(BioRad)を用いてpolyvinylidene fluoride membranes(Millipore)に移動させた。
そして、5% skim milkを用いてブロッキングさせた後、TIF1γ抗体(ThermoFisher Scientific)を用いて反応させ、anti-GAPDH antibody(Abcam)は、内部対照群として用いた。抗体を用いて反応させたメンブレンは、洗浄して、結合されていない抗体を除去した後、HRP複合2次抗体(horseradish peroxidase-conjugated secondary antibodies)を用いて反応させ、Enhanced chemiluminescence(ThermoFisher)を用いてバンドを確認した。その結果は、図1に示した。
コドン最適化によって生産されたTIF1γ組換えタンパク質の肝線維化疾患の治療効果を確認するために、実施例1と同じ方法で製造したベクターをヒト肝星状細胞株であるLX2に形質注入した。そして、形質注入された細胞に5ng/mLの濃度でTGFβを7日間毎日処理した。そして、細胞を回収して、タンパク質発現量をウェスタンブロッティングで確認した。ウェスタンブロッティングは、実施例1と同じ方法で実施し、1次抗体としては、α-SMA(Abcam)またはCol1A(Abcam)抗体を用いた。その結果は、図3に示した。
コドン最適化によって生産されたTIF1γ組換えタンパク質の肺線維化疾患の治療効果を確認するために、一次にブレオマイシン(bleomycin)を処理して、肺線維化動物モデルを製造した。より詳しくは、5~8週齢のC57BL/6Nマウスにブレオマイシンを2mg/kgの濃度で気管内注射(endotracheal administration)で注入し、9日後、実施例1と同じ方法で製造したベクターを18μg/マウスで尾静脈を通じて注射した。ベクターのプロモーター配列としては、CMVプロモーターまたは配列番号5のhuman TGF beta promoter(hTGF)を用いた。そして、21日後、マウスを安楽死させ、肺組織を採取した。採取した右側の肺組織は、10%ホルマリン溶液を用いて固定させた後、パラフィンを用いて包埋させ、4μmの厚さに切って組織切片を製作した。そして、製作した組織切片のパラフィンを除去した後、ヘマトキシリンおよびエオシン(hematoxylin and eosin)を用いて免疫染色を実施した後、顕微鏡を用いて観察した。その結果は、図4に示した。そして、採取した左側の肺組織は、masson trichrome(MT)stain kit(Abcam)を用いて染色した。その結果は、図5に示した。
Claims (8)
- TIF1γ(transcriptional intermediary factor 1 gamma)遺伝子のN末端部位をコードする部分のコドンを最適化したポリヌクレオチドであって、
前記ポリヌクレオチドは、配列番号2の塩基配列を含むことを特徴とする、ポリヌクレオチド。 - 前記ポリヌクレオチドが、配列番号1の塩基配列を含むことを特徴とする、請求項1に記載のポリヌクレオチド。
- 前記ポリヌクレオチドが、配列番号2および3の塩基配列を含むことを特徴とする、請求項1に記載のポリヌクレオチド。
- 請求項1から3のいずれか一項に記載のポリヌクレオチドを有効成分として含む、線維化疾患の予防または治療用薬学的組成物。
- 前記線維化疾患は、肝線維症、腎線維症、肺線維症、膵臓線維症、全身性強皮症、黄斑変性、心臓線維症、膵臓と肺の嚢胞性線維症、注射線維症、心内膜心筋線維症、全身性特発性線維症、特発性肺線維症、縦隔線維症、骨髄線維症、後腹膜線維症、進行性塊状線維症、腎性全身性線維症、結節性上皮下線維症、乳房線維症、リンパ節線維症、瘢痕、皮膚硬化症、皮膚線維症、膀胱線維症、筋線維症、動脈線維症、慢性閉塞性肺疾患、甲状腺線維症、関節線維症、肋膜線維症、外科手術の結果としての線維症、増殖性線維症、パイプ軸線維症および後線維素性線維症よりなる群から選ばれるいずれか一つ以上であることを特徴とする請求項4に記載の薬学的組成物。
- 請求項1から3のいずれか一項に記載のポリヌクレオチドを含む、組換えベクター。
- 請求項6に記載の組換えベクターを有効成分として含む、線維化疾患の予防または治療用薬学的組成物。
- 前記線維化疾患は、肝線維症、腎線維症、肺線維症、膵臓線維症、全身性強皮症、黄斑変性、心臓線維症、膵臓と肺の嚢胞性線維症、注射線維症、心内膜心筋線維症、全身性特発性線維症、特発性肺線維症、縦隔線維症、骨髄線維症、後腹膜線維症、進行性塊状線維症、腎性全身性線維症、結節性上皮下線維症、乳房線維症、リンパ節線維症、瘢痕、皮膚硬化症、皮膚線維症、膀胱線維症、筋線維症、動脈線維症、慢性閉塞性肺疾患、甲状腺線維症、関節線維症、肋膜線維症、外科手術の結果としての線維症、増殖性線維症、パイプ軸線維症および後線維素性線維症よりなる群から選ばれるいずれか一つ以上であることを特徴とする請求項7に記載の薬学的組成物。
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US20200011855A1 (en) | 2016-07-25 | 2020-01-09 | Seoul National University Hospital | COMPOSITION FOR PREVENTING OR TREATING LIVER FIBROSIS OR CIRRHOSIS, COMPRISING EXPRESSION OR ACTIVITY ENHANCER OF TIF1y AS ACTIVE INGREDIENT |
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WO2013151667A1 (en) * | 2012-04-02 | 2013-10-10 | modeRNA Therapeutics | Modified polynucleotides |
AU2016271635B2 (en) * | 2015-05-29 | 2021-11-04 | The Trustees Of The University Of Pennsylvania | Compositions and methods for degradation of misfolded proteins |
KR101957632B1 (ko) | 2017-06-30 | 2019-03-12 | 한국생명공학연구원 | 섬유화증 예방, 개선 또는 치료용 조성물 |
KR102114880B1 (ko) * | 2020-01-15 | 2020-05-26 | 서울대학교병원 | 코돈 최적화된 TIF1γ 폴리뉴클레오티드를 포함하는 재조합 벡터 및 이의 용도 |
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Publication number | Priority date | Publication date | Assignee | Title |
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US20150218242A1 (en) | 2012-07-31 | 2015-08-06 | Inserm (Institut National De La Sante Et De La Recherche Medicale) | TIF1-Gamma for Treating and Diagnosing Inflammatory Diseases |
US20200011855A1 (en) | 2016-07-25 | 2020-01-09 | Seoul National University Hospital | COMPOSITION FOR PREVENTING OR TREATING LIVER FIBROSIS OR CIRRHOSIS, COMPRISING EXPRESSION OR ACTIVITY ENHANCER OF TIF1y AS ACTIVE INGREDIENT |
Non-Patent Citations (2)
Title |
---|
Journal of biological chemistry,Vol.288/No.45,2013年11月08日,P.32357-32369 |
Nature communications,2019年,Vol.10/Article number 4273,P.1-17 |
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US20230203112A1 (en) | 2023-06-29 |
WO2021145704A1 (ko) | 2021-07-22 |
EP4092044A1 (en) | 2022-11-23 |
KR102114880B1 (ko) | 2020-05-26 |
JP2023509067A (ja) | 2023-03-06 |
EP4092044A4 (en) | 2023-07-19 |
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