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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 林淑華 | |
| dc.contributor.author | Chung-Yang Kao | en |
| dc.contributor.author | 高仲揚 | zh_TW |
| dc.date.accessioned | 2021-06-15T06:57:29Z | - |
| dc.date.available | 2016-03-03 | |
| dc.date.copyright | 2011-03-03 | |
| dc.date.issued | 2011 | |
| dc.date.submitted | 2011-01-30 | |
| dc.identifier.citation | 1. Hoffman R. Hematology : basic principles and practice. 4th ed. Elsevier Churchill Livingstone; 2005.
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Hemker HC, Giesen PL, Ramjee M, et al. The thrombogram: monitoring thrombin generation in platelet-rich plasma. Thromb Haemost 2000; 83: 589-591. 182. Chandler WL, Roshal M. Optimization of plasma fluorogenic thrombin-generation assays. Am J Clin Pathol 2009; 132: 169-179. 183. Tranholm M, Kristensen K, Kristensen AT, et al. Improved hemostasis with | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/48454 | - |
| dc.description.abstract | 第九因子是一種血漿中的凝血因子，參與血液凝塊的生成以維持正常止血功能。第九因子之質或量不足，是造成B型血友病的主要成因。現階段對於血友病病患的照護是靜脈注射血漿來源的第九因子，或是源自基因工程製造的第九因子。另一方面，基因治療和細胞治療的發展為「治癒」血友病帶來一線曙光。為了有效率地治療血友病患，本研究室已成功研發出一種具有增強活化功能的變異型人類第九因子(FIX-Triple)，分別於胺基酸序列86，277，及338三個位置同時帶有丙胺酸點突變。本論文的研究主題乃是利用小鼠模式，探討FIX-Triple在活體內的治療效果，以及治療劑量與血栓風險的關係。
藉由基因工程製造高活性的第九因子，也許能有效地運用於蛋白補充療法，或基因取代療法；然而其高活性的特性，反而可能因此帶來血栓危機，這一部分至今尚未被研究發表。本研究運用三種小鼠模式研究FIX-Triple與血栓危機的關係。藉由輸注FIX-Triple蛋白於血友病小鼠，結果顯示：FIX-Triple不僅達到並維持治療活性的時間，較原型人類第九因子(FIX-WT)來得長久，即使輸注起始活性總值高於FIX-WT十三倍之餘，亦未發現導致血栓的現象。為了進一步探討FIX-Triple長時間存在於小鼠體內的影響，本研究進一步成功產出第九因子基因座的基因替換(knock-in)小鼠，使其內源性地分別表現FIX-WT和FIX-Triple。針對這類基因替換小鼠之研究結果證明：FIX-Triple基因替換小鼠血漿中之第九因子，不僅活性高於FIX-WT十倍(該活性倍數與FIX-Triple純化蛋白具有十三倍的效果相當)，且顯著呈現更佳之止血效果；尤有甚者，FIX-Triple即使在小鼠體內穩定持續表現，毫無導致小鼠處於高凝血狀態之情事。進一步試驗，分別藉由帶有FIX-WT與FIX-Triple基因片段的腺相關病毒載體，感染純品系野生型小鼠(C57BL/6)與血友病小鼠，進行基因治療之實境模擬測試；結果發現，儘管接受基因治療小鼠體內的第九因子活性，遠較正常小鼠活性高出十三倍之多，攜帶FIX-Triple的基因治療小鼠毫無有提高血栓危機之情事。採用氯化鐵配合活體顯微技術進行誘發血栓形成的模擬測試結果，證明攜帶FIX-Triple的基因治療小鼠，其耐受阻塞血管血栓生成的程度，能高達五倍小鼠第九因子的活性；然而，表現FIX-Triple活性，若高於小鼠第九因子的活性九倍，血栓生成的速度則有明顯加快的趨勢。 肝細胞移植技術為肝臟疾病帶來治癒的契機。目前此技術遭遇的瓶頸是低移植效率，因而大幅降低治療效果。理論上，若能讓肝細胞表現具有強化功能的治療蛋白，便有機會彌補低移植效率的缺憾。本論文因此承接上述的研究成果，將自第九因子基因替換小鼠分離出的肝細胞移植到血友病小鼠的肝臟，用以評估FIX-Triple加強細胞治療效率的可行性。試驗結果證明接受分泌FIX-Triple肝細胞移植的小鼠表現出高於FIX-WT的活性約四倍。進一步分析這些接受肝細胞移植手術的小鼠，FIX-Triple除了可以藉由兩次移植手術，使得第九因子活性呈現倍率的增長外，並能有效地改善血友病小鼠凝血功能的缺陷。 本論文的研究結果證明：就蛋白補充療法、基因取代療法與細胞移植治療等策略而言，FIX-Triple確能更有效地發揮其止血功能，特別其活性表現與輸注劑量分別均顯著優於FIX-WT。針對血栓危險性之試驗結果而言，本研究證明FIX-Triple之活性落在治療濃度範圍內確保是安全的，不會有增加血栓形成之危險性。前述研究成果充分支持FIX-Triple將來於臨床治療血友病的應用潛力。 | zh_TW |
| dc.description.abstract | Factor IX (FIX) is a plasma coagulation factor that is essential for blood clot formation and normal hemostasis. Deficiency or dysfunction of FIX causes hemophilia B (HB). The current standard of care for HB patients involves protein replacement therapy using plasma-derived or recombinant FIX; however, gene therapy and/or cell therapy hold promise for a future cure for the disease. For effective hemophilia treatment, our laboratory has generated a gain-of-function human FIX variant, FIX-Triple, which has alanine substitutions at residues 86, 277, and 338. This dissertation uses mouse models to investigate the in vivo therapeutic efficacy and risk of thrombosis of FIX-Triple.
This engineered recombinant FIX with augmented clotting activity may prove useful for replacement therapy, but it has not been studied for risk of thrombosis. Three mouse models were used to evaluate risk of thrombosis associated with FIX-Triple. Protein infusion of FIX-Triple into HB mice was not thrombogenic, even at a dose of 13-fold higher than FIX-WT. Gene knock-in (KI) to generate mice that constitutively produce FIX-WT (wild-type) or FIX-Triple protein revealed that FIX-Triple KI mice with 10-fold higher FIX activity did not show hypercoagulation. Adeno-associated viral (AAV) delivery of the FIX gene into mice was used to mimic gene therapy. HB and inbred C57BL/6 mice injected with different doses of virus particles carrying FIX-WT or FIX-Triple and expressing up to a nearly 13-fold excess of normal mouse FIX activity did not show increased risk of thrombosis compared with untreated wild-type mice in a normal hemostatic state. When challenged with ferric chloride, the mesenteric venules of AAV-treated C57BL/6 mice that gave a nearly 5-fold excess of normal mouse FIX activity were not thrombotic; however, thrombosis became obvious in mice expressing over 9-fold excess of normal mouse FIX activity achieved by AAV delivery of FIX-Triple. Hepatocyte transplantation offers an opportunity to cure genetic liver diseases. Poor cell engraftment may be overcome by transplantation of hepatocytes secreting gain-of-function proteins. Therapeutic efficacy was evaluated using HB mice as a disease model by transplanting hepatocytes isolated from the FIX-KI mice. FIX-Triple KI recipients exhibited 4-fold higher plasma FIX activity than FIX-WT KI recipients. By repeated transplantations, FIX-Triple KI recipients even showed long-term increase in FIX activity to mild hemophilia correlating with improved hemostasis. These studies provide evidence that FIX-Triple is not only hemostatically effective in protein replacement therapy, gene therapy, and cell therapy, but also not thrombogenic at therapeutic levels when examined with the mouse models. These data support the potential for therapeutic use of FIX-Triple for treating HB. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-15T06:57:29Z (GMT). No. of bitstreams: 1 ntu-100-F94424013-1.pdf: 19542536 bytes, checksum: e0c72bd8e59c6f866ba811b93b645156 (MD5) Previous issue date: 2011 | en |
| dc.description.tableofcontents | 口試委員會審定書 i
誌謝 iii 摘要 v Abstract vii Abbreviation x List of Figures xvii List of Appendixes xix Chapter 1 Introduction 1 1.1 Hemophilia B 1 1.1.1 Hemostasis 1 1.1.2 Hemophilia B 3 1.1.3 FIX 6 1.2 HB therapy 9 1.2.1 Protein replacement therapy 9 1.2.2 Gene therapy 12 1.2.3 Cell therapy 19 1.2.4 Recombinant FIX with improved properties for HB therapy 22 1.3 FIX and thrombosis 26 1.3.1 Epidemiology 26 1.3.2 Genetic variants 28 1.3.3 Animal studies 30 1.4 Research motive and strategy 31 Chapter 2 Materials and Methods 32 2.1 Animal models 32 2.1.1 Production of the FIX knock-in (KI) mice 32 2.1.2 Protein replacement therapy and gene therapy 33 2.1.3 Identification of human FIX transcripts and proteins34 2.1.4 Cell therapy 35 2.2 Protein replacement therapy 36 2.2.1 Purification 36 2.2.2 Activation of FIX and titration of FIXa 37 2.2.3 Thrombin generation 38 2.2.4 Protein infusion 39 2.3 Hemostatic function 40 2.3.1 Blood sampling, protein quantification, and clotting activity assays 40 2.3.2 Tail-bleeding assays 41 2.3.3 Thromboelastography (TEG) and TAT complexes 42 2.4 Gene therapy 42 2.4.1 Construction and production of pseudotyped AAV2/8 particle 42 2.4.2 AAV injection 44 2.5 FeCl3-induced thrombosis models 44 2.5.1 Carotid artery 44 2.5.2 Inferior vena cava 45 2.5.3 Mesenteric venule 46 2.6 Cell therapy 47 2.6.1 Isolation of hepatocytes 47 2.6.2 In-vitro culture of hepatocytes 48 2.6.3 Tx procedure 48 2.6.4 FIX activities and antigen levels in mouse plasma 48 2.6.5 Engraftment efficiency by cell labeling 49 2.6.6 Engraftment efficiency by FIX DNA and mRNA quantification 50 2.6.7 Hemostatic function assay and detection of FIX inhibitors 50 2.7 Statistical analysis 51 Chapter 3 Results 52 3.1 FIX-Triple in protein replacement therapy is more therapeutic but not more thrombogenic than FIX-WT. 52 3.1.1 FIX-Triple has specific clotting activity ~13-fold higher than does FIX-WT. 52 3.1.2 FIX-Triple contributes a greater profile of thrombin generation than does FIX-WT. 52 3.1.3 FIX-Triple is not more thrombogenic than FIX-WT in the treatment of HB mice. 54 3.2 Human FIX-KI mice are specifically generated for in vivo study of FIX-Triple. 55 3.2.1 Human FIX-KI targeting vectors are constructed. 55 3.2.2 Gene targeting in mouse ES cells and screening of targeted ES cells are performed. 56 3.2.3 Human FIX-KI mice are successfully generated. 57 3.2.4 Genotyping of human FIX-KI mice is confirmed. 58 3.2.5 Transcriptional gene expression of human FIX-KI mice is quantitatively different between mice with and without neo. 58 3.2.6 The FIX-KI mice have equal protein expression of human FIX either in the liver or circulation. 59 3.3 FIX-Triple contributes a greater hemostatic profile than does FIX-WT in the FIX-KI mice. 60 3.3.1 aPTT values are improved in FIX-Triple KI mice compared to FIX-WT KI mice. 61 3.3.2 FIX-Triple KI mice have 10-fold FIX activity higher than do FIX-WT KI mice. 61 3.3.3 FIX-Triple provides more effective hemostatic protection than does FIX-WT in the FIX-KI mice. 63 3.4 FIX-Triple is not more thrombogenic than FIX-WT in the FIX-KI mice. 64 3.4.1 FIX-Triple KI mice do not show hypercoagulation in ex vivo whole blood thromboelastography. 64 3.4.2 TAT complexes in the circulation are equivalent in the FIX-KI mice. 65 3.4.3 FIX-Triple KI mice are not more thrombophilic than FIX-WT KI mice in FeCl3-induced arterial and venous thrombosis. 66 3.5 FIX-Triple is not more thrombogenic than FIX-WT in gene therapy with therapeutic levels. 67 3.5.1 AAV carrying FIX cDNA is produced for liver-specific gene therapy. 67 3.5.2 Mice expressing up to a 13-fold excess of physiological mouse FIX activity do not show increased risk of thrombosis in a normal hemostatic state. 68 3.5.3 Mice expressing FIX-Triple to 5 times physiological mouse FIX activity are not thrombophilic in intravital imaging of venous thrombosis. 69 3.5.4 Gene therapy in HB mice by FIX-Triple effectively restores normal hemostasis but may increase risk of thrombosis with supraphysiological levels. 70 3.6 FIX-Triple is a potential substitute for FIX-WT in cell therapy. 71 3.6.1 Human FIX-KI mice are useful tools to evaluate the efficacy of FIX-Triple in cell therapy for HB mice. 71 3.6.2 Hepatocytes isolated from the FIX-KI mice are functional. 72 3.6.3 FIX-Triple is more therapeutic than FIX-WT through a single Tx. 73 3.6.4 FIX-Triple can reach 10% of normal FIX activity by repeated Txs. 74 3.6.5 There is no difference in cell engraftment between FIX-WT and FIX-Triple. 74 3.6.6 Hemostatic function of FIX-Triple in cell therapy is effective. 75 3.6.7 FIX-Triple in cell therapy maintains therapeutic levels during long-term observation. 76 Chapter 4 Discussion 78 4.1 FIX-Triple and thrombosis in protein replacement therapy and gene therapy 78 4.1.1 HB mouse model that mimics protein replacement therapy 78 4.1.2 FIX-KI mouse model that mimics the human natural system with a single copy gene 79 4.1.3 FIX-AAV mouse model that mimics the clinical gene therapy with multiple gene copies 80 4.1.4 FIX-Triple is not more thrombogenic than FIX-WT in a normal hemostatic state during AAV-based gene therapy. 82 4.1.5 FIX-Triple contributes 330% to 402% of normal mouse FIX activity that is not thrombogenic in the FeCl3-induced thrombosis model. 82 4.1.6 FeCl3-induced thrombosis may be one of the models suitable to evaluate the thrombogenicity of FIX-Triple. 83 4.1.7 The thrombogenicity of FIX-Triple: from mouse to human 84 4.2 FIX-Triple and therapeutic efficacy in cell therapy 84 4.2.1 FIX-Triple can compensate for poor cell engraftment in the treatment of HB by hepatocyte Tx. 85 4.2.2 FIX-Triple has 5- to 7-fold specific clotting activity higher than does FIX-WT in cell therapy. 85 4.2.3 FIX-Triple is not likely more immunogenic than FIX-WT in cell therapy. 86 4.2.4 A proposed personalized HB therapy using genetically modified hepatocytes secreting FIX-Triple 87 Chapter 5 Conclusion and Perspective 90 Figure 93 Bibliography 130 Appendix 148 | |
| dc.language.iso | en | |
| dc.subject | 細胞治療 | zh_TW |
| dc.subject | 蛋白補充治療 | zh_TW |
| dc.subject | 凝血第九因子 | zh_TW |
| dc.subject | B型血友病 | zh_TW |
| dc.subject | 小鼠模式 | zh_TW |
| dc.subject | 血栓 | zh_TW |
| dc.subject | 基因治療 | zh_TW |
| dc.subject | cell therapy | en |
| dc.subject | mouse model | en |
| dc.subject | thrombosis | en |
| dc.subject | hemophilia B | en |
| dc.subject | gene therapy | en |
| dc.subject | protein replacement therapy | en |
| dc.subject | coagulation factor IX | en |
| dc.title | 利用小鼠模式探討變異型人類凝血第九因子 | zh_TW |
| dc.title | Investigation of a Human Coagulation Factor IX Variant Using Mouse Models | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 99-1 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 沈銘鏡,鄭登貴,吳華林,高照村,陶秘華 | |
| dc.subject.keyword | B型血友病,凝血第九因子,蛋白補充治療,基因治療,細胞治療,血栓,小鼠模式, | zh_TW |
| dc.subject.keyword | hemophilia B,coagulation factor IX,protein replacement therapy,gene therapy,cell therapy,thrombosis,mouse model, | en |
| dc.relation.page | 152 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2011-01-31 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 醫學檢驗暨生物技術學研究所 | zh_TW |
| 顯示於系所單位： | 醫學檢驗暨生物技術學系 | |
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