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研究生:陳彥廷
研究生(外文):Yen-Ting Chen
論文名稱:以磁性奈米包膜材料作為核酸載體建構 A 型血友病動物模式之新式基因療法
論文名稱(外文):A novel gene therapy in hemophilia A mouse model by using lipid-coated Fe3O4 nanoparticles
指導教授:陳全木陳全木引用關係
口試委員:陳小玲張國友范洪春
口試日期:2018-01-26
學位類別:碩士
校院名稱:國立中興大學
系所名稱:生命科學系所
學門:生命科學學門
學類:生物學類
論文種類:學術論文
論文出版年:2018
畢業學年度:106
語文別:中文
論文頁數:90
中文關鍵詞:基因治療A 型血友病DPPC-Fe3O4B 區域刪除之第八凝血因子尾靜脈注射
外文關鍵詞:gene therapyhemophilia ADPPC-Fe3O4B-domain deleted FVIIItail-vein injection
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A 型血友病 (hemophilia A) 為出血性疾病的一種,主要病因是第八凝血因子缺失或功能喪失,係由於基因突變所導致的隱性 X 染色體性聯遺傳性疾病。根據世界血友病聯盟 (WFH) 的統計,在 2015 年,A 型血友病總人數高達十五萬人,而現行的 A 型血友病治療仍具相當高的風險及會造成昂貴的治療花費,且一週需進行多次的注射才能維持正常凝血功能,因此大約 60 % 的病患並未獲得妥善的醫療照顧。雙棕櫚酸磷脂醯膽鹼-氧化鐵 (DPPC-Fe3O4) 為一具高度生物相容性的新式材料,其安全性較高,不會造成生物體肝臟損傷,亦不會產生中和性抗體,可以被用來攜帶 DNA,甚至能利用磁導引的方式將藥物帶入特定組織中,在生醫領域上,被認為具有作為外來基因載體開發之潛力。因此本實驗目的係利用 DPPC-Fe3O4 作為非病毒性基因治療之載體,開發 A 型血友病新式治療模式。實驗分為兩大部分:(1) A 型血友病新式治療之系統建立;(2) DPPC-Fe3O4 基因治療之動物實驗評估。首先,實驗證明環型質體相較於線型質體,與 DPPC-Fe3O4 結合之結合效率較高、粒徑大小較小、分子量分佈指數較穩定,較適合用於DPPC-Fe3O4 之結合。接著,我們利用尾靜脈注射將 10 μg B 區域刪除之第八凝血因子質體及 DPPC-Fe3O4 打入 A 型血友病小鼠 (B6;129S-F8tm1Kaz/J) 進行基因治療,並以 C57BL/6 小鼠作為控制組,未治療之 A 型血友病小鼠作為負控制組。結果顯示,治療組之部份凝血活酶時間 (aPTT) 與未治療組別相較,顯著改善其凝血功能不全病徵 (P<0.05);大約有 75 % 的DPPC-Fe3O4 及質體會進入到細胞核中表現,並且會隨著時間增加,逐漸被細胞所代謝;而經由 DPPC-Fe3O4 基因治療後,血液生化數值及肝臟組織病理切片皆未發現異常,證明此基因治療不會造成肝臟損傷。注射 10 μg B 區域刪除之第八凝血因子質體及 DPPC-Fe3O4 可以有效改善 A 型血友病小鼠之病徵,並維持其正常凝血功能至兩週。本研究提供 A 型血友病小鼠基因治療上一新式非病毒性載體,大幅延長 A 型血友病治療之療效,證明 DPPC-Fe3O4 具有開發於遺傳性疾病基因治療載體之潛力。
Hemophilia A is a bleeding disorder caused by missing or defective coagulation factor VIII (FVIII), a clotting protein. It’s an X-linked recessive genetic disease mainly due to gene mutation. There are about 150,000 hemophilia A patients around the world in 2015, but approximately sixty percent of hemophilia A patients don’t have appropriate medical therapy, due to the high risk and expensive treatments at present, and also patients needed multiple injection in one week to maintain normal FVIII concentration. Dipalmitoylphosphatidylcholine (DPPC) formulated with iron oxide nanoparticles is high biocompatibility material which can binding with DNA. DPPC-Fe3O4 won’t cause any liver injury and neutralizing antibody when entered organism, and may use magnet to guide medicines to the target organ, is considered as a potential foreign gene carrier in biomedical therapy. The aim of this research is to establish a non-viral gene therapy approach to cure hemophilia A by using DPPC-Fe3O4. There are two parts in this study: (1) Establishment of new hemophilia A gene therapy system; (2) Evaluation of DPPC-Fe3O4 gene therapy in animal models. At first, we found out that circular form plasmid is the optimal form binding with DPPC-Fe3O4 when compared with linear form plasmid. In animal experiment, B6;129S-F8tm1Kaz/J knockout mice were used as the animal model which mimics severe hemophilia A patients. The biocompatible material- DPPC-Fe3O4 was used as a DNA carrier to bring human B-domain deleted FVIII plasmid (10 μg/mice) into hemophilia A mice by tail vein injection. C57BL/6 mice were used as a normal control and untreated hemophilia A mice as a negative control. Activated partial thromboplastin time results revealed that the blood clotting activity significantly improved in the treatment groups when compared with untreated group (P<0.05). Furthermore, approximately 75% of DPPC-Fe3O4 and the FVIII-eGFP plasmids entered the hepatocyte nucleus and will be metabolized over time. Moreover, this therapy did not cause any liver injury from the blood biochemical values and the histology examination in the safety test. In this research, injecting 10 μg/mice of FVIII-eGFP plasmids showed a promising therapeutic effects on hemophilia A mice, and maintained the therapeutic levels for two weeks. In short, we have successfully improved the bleeding disorder in hemophilia A knockout mice, and prolonged the therapeutic levels in current therapy, which provides a potential novel gene therapy approach in the clinical use of hemophilia A patients.
中文摘要 i
Abstract ii
目錄 iii
表次 vi
圖次 vii
壹、緒論 1
貳、文獻探討 2
一、凝血機制 2
(一)、凝血因子 2
二、血友病 (hemophilia) 6
(一)、A型血友病 6
(二)、B型血友病 7
(三)、von Willebrand 氏症 7
(四)、後天性血友病 8
三、第八凝血因子 14
(一)、生理生化特性 14
四、臨床上的治療方法 19
(一)、血漿製劑 19
(二)、基因工程蛋白 19
(三)、預防性治療 20
五、基因治療 25
(一)、病毒性基因治療 25
(二)、非病毒性基因治療 26
六、奈米材料在基因治療的應用 27
(一)、雙棕櫚酸磷脂醯膽鹼 (dipalmitoylphosphatidylcholine;DPPC) 27
(二)、氧化鐵 (iron oxide, Fe3O4) 奈米粒子 27
(三)、雙棕櫚酸磷脂醯膽鹼-氧化鐵 28
七、靜脈注射 30
(一)、眼窩注射 30
(二)、尾靜脈注射 30
八、研究動機 31
參、材料方法 32
一、不同肝臟專一性表現型啟動子之構築及分析 32
(一)、不同肝臟專一性表現型啟動子之構築 32
(二)、不同肝臟專一性表現型啟動子於不同細胞株中之雙冷光素酶 活性分析 34
二、mAlb-ΔB FVIII 質體 DNA 35
(一)、mAlb-ΔB FVIII 質體 DNA 構築 35
(二)、mAlb-ΔB FVIII 質體 DNA 之定序 35
(三)、mAlb-ΔB FVIII 質體 DNA 之大量萃取 36
三、DPPC-Fe3O4 材料製作及特性分析 37
(一)、DPPC-Fe3O4 之製備 37
(二)、DPPC-Fe3O4 特性分析 37
四、細胞實驗 38
(一)、細胞株培養 39
(二)、細胞繼代 39
(三)、細胞轉染 39
(四)、細胞樣品之取得 40
(五)、逆轉錄聚合酶連鎖反應 (RT-PCR) 40
五、動物實驗 42
(一)、實驗動物品系來源及飼養 42
(二)、藥品配置 42
(三)、尾靜脈注射 42
(四)、犧牲前預備及流程 43
(五)、部份凝血活酶時間 (activated partial thromboplastin time ; aPTT) 43
(六)、第八凝血因子活性分析 44
(七)、血液生化數值 44
(八)、組織切片 45
(九)、剪尾測試 46
六、動物及細胞樣本共同之分析 47
(一)、流式細胞儀前處理 47
七、統計方法 47
肆、結果 48
第一部份:A 型血友病新式治療之系統建立 48
一、B 區域刪除之第八凝血因子質體之確認 48
(一)、雙冷光素酶活性分析 48
(二)、B 區域刪除之第八凝血因子序列確認 49
二、DPPC-Fe3O4 材料之特性分析 52
(一)、DPPC-Fe3O4 與不同型態質體結合前後之型態探討 52
(二)、DPPC-Fe3O4與不同型態質體結合前後之粒徑大小分析 52
(三)、DPPC-Fe3O4 與不同型態質體結合後之電泳阻滯分析 52
(四)、DPPC-Fe3O4 與環型質體結合前後之介面電位分析 53
(五)、DPPC-Fe3O4 與環型質體結合前後之奈米粒徑探討 53
三、外來基因於細胞表現之分析 57
(一)、外來基因於細胞內基因表現之分析 57
(二)、外來基因於細胞內蛋白表現之分析 57
第二部份:DPPC-Fe3O4 基因治療之動物實驗評估 61
一、A 型血友病小鼠凝血功能評估 61
(一)、血友病鼠血液中第八凝血因子活性之分析 61
(二)、以剪尾試驗進行血友病鼠表現型之確認 61
二、以 DPPC-Fe3O4 進行血友病鼠基因治療之可行性評估 64
(一)、以部份凝血活酶時間評估基因治療之功效 64
(二)、以普魯士藍染色分析DPPC-Fe3O4 於肝臟組織中之分佈情形 64
(三)、以血液生化數值測定是否產生副作用 65
(四)、以蘇木素-伊紅染色進行組織病理切片之分析 65
(五)、基因治療之長期追蹤 65
三、以 ICR 小鼠作為 DPPC-Fe3O4 基因治療之改善評估 75
(一)、注射不同劑量質體以探討基因治療改善之評估 75
伍、討論 77
一、第八凝血因子序列差異之比對分析 77
二、DPPC-Fe3O4 特性之分析 77
三、以尾靜脈注射進行外來基因表現之比較 78
四、血友病小鼠基因治療之比較 78
陸、結論 80
柒、附錄 81
捌、文獻資料 84
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