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論文中文名稱:以中樞神經為標的之基因治療於球狀細胞腦白質退化症之應用 [以論文名稱查詢館藏系統]
論文英文名稱:CNS-targeted Gene Therapy in Globoid Cell Leukodystrophy [以論文名稱查詢館藏系統]
院校名稱:臺北科技大學
學院名稱:工程學院
系所名稱:工程科技研究所
畢業學年度:101
出版年度:102
中文姓名:林達雄
英文姓名:Dar-Shong Lin
研究生學號:99679017
學位類別:博士
語文別:英文
口試日期:2013-05-30
論文頁數:52
指導教授中文名:劉宣良
口試委員中文名:黃志宏;林忻怡;李勝祥;劉信孚
中文關鍵詞:溶酶體储積性疾病球狀細胞腦白質退化症基因治療神經髓鞘
英文關鍵詞:lysosomal storage diseaseGloboid cell leukodystrophygene therapy
論文中文摘要:溶酶體储積性疾病為溶酶體酵素缺乏,導致受質無法代謝,儲積於臟器或(及)神經系統引發疾病。球狀細胞大腦白質失養症 (globoid-cell leukodystrophy; GLD),為隱性遺傳之先天性溶酶體储積性神經去髓鞘疾病,其乳糖腦苷脂酶 (galactosylcerebrosidase: GALC) 基因突變,造成神經系統白質部位神經髓鞘脫失。約90% 的GLD 患者為嬰兒期致死型,在6 個月大前發病,出現躁動不安、抽搐、錐體症候、眼神經萎縮、心智生長遲緩,於2 歲前便死亡,至今尚無有效的治療。目前有一自然突變的 twitcher 小鼠,在臨床與病理上,類似此嬰兒期致死型,可作為疾病治療模型。本研究藉由GLD的疾病模型twitcher小鼠,研發適當的基因治療傳輸策略,以達到將治療基因全面性散佈至中樞神經系統的目的。我們先前應用AAV-GALC載體來治療新生twitcher 小鼠,經單獨腦內注射AAV或者合併幹細胞移植治療的小鼠,腦部 GALC 酵素活性高達正常值的2~3倍,並且其壽命顯著延長,但所增加的壽命與增加的酵素活性並不成比例。分析其可能原因包括小腦、腦幹、與脊髓未能得到充分治療。此一研究中,我們進一步結合大腦與小腦的基因治療,藉由軸突運輸,將轉殖基因與蛋白,送至腦內其他未注射的部位,達成的轉殖基因與蛋白於中樞神經全面性散佈的成效。經治療的小鼠,其體內的毒性累積物質psychosine顯著的下降,腦內的發炎反應減經、神經髓鞘與小腦的Purkinje cells 保存良好、且壽命延長;而且轉殖基因與蛋白全面性的散佈於中樞神經系統。這項研究確立了中樞神經全面性治療的良好策略,除了適用於GLD的治療,還可以應用於中樞神經退化性疾病及小腦退化性疾病的基因治療。
論文英文摘要:Globoid cell leukodystrophy (GLD) is a devastating lysosomal storage disease caused by deficiency of the enzyme galactocerebrosidase (GALC). Currently, there is no definite cure for the GLD. Several attempts with CNS-directed gene therapy in twitcher mice (a murine model of GLD) demonstrated restricted expression of GALC activity in CNS and failure of therapeutic efficacy in cerebellum and spinal cord, resulting in various degrees of correction of biochemical, pathological and clinical phenotype. More recently, twitcher mice receiving a combination of hematopoietic and viral vector gene transfer therapies were not protected from neurodegneration and axonopathy in both cerebellum and spinal cord. This evidence indicates the requirement of sufficient and widespread GALC expression in CNS and rescue of cerebellum and spinal cord in the therapeutic intervention of murine model of GLD. In this study, we have optimized intracranial delivery of AAV2/5-GALC to the neocortex, hippocampus and cerebellum, instead of the thalamus as was previously conducted, of twitcher mice. The CNS-targeted AAV2/5 gene transfer effectively dispersed GALC transgen along the neuraxis of CNS as far as the lumbar spinal cord, and reduced the accumulation of psychosine in the CNS of twitcher mice. Most importantly, the treated twitcher mice were protected from loss of oligodendrocytes and purkinje cells, axonopathy and marked gliosis, and had significantly improved neuromotor function and prolonged lifespan. Collectively, our study addresses that this severe GLD murine model can be rescued by CNS-targeted AAV5 gene transfer and supports the development of AAV-mediated intervention as a potential therapeutic approach for GLD.
論文目次:中文摘要........i
英文摘要........iii
銘謝............v
目錄............vii
圖目錄..........ix

第一章: Introduction....................1
1.1: Background of GLD...............1
1.2: Review of therapy in GLD........2
1.3: Therapeutic strategy............4
第二章: Material and Method............6
2.1: Animal procedures..............6
2.2: Body weight assessment and survivability.......6
2.3: Recombinant AAV2/5 vector...................7
2.4: Tissue harvesting, processing, GALC activity and psychosine..................8
2.5: Histochemical localization of GALC activity..............9
2.6: Immunohistochemistry.................10
2.7: Analysis of vector genome.............10
2.8: Behavioral phenotyping..............11
2.9: Statistical analyses................11
第三章: Results.............................13
3.1: GALC distribution...................13
3.2: GALC level and psychosine accumulation......................16
3.3: Reduced inflammatory markers in the brain.............19
3.4: CNS myelination histolopathology........22
3.5: Calbindin-positive cells in the Purkinje cell layer.....................25
3.6: Axonal degeneration in twitcher mice.....................27
3.7: Rescue of neuromuscular function, improve survival, and maintenance of body weight..............27
第四章: Discussion....................31
4.1: The scope of this study.......31
4.2: Axonal Transport of vector...........31
4.3: Benefit of neonatal treatment..........33
4.4: Protection from the loss of Purkinje cells........................35
4.5: Prevention of loss of oligodendroctes and axonopathy by cross-correction.....36
4.6: Insufficient rescue of spinal cord and optimal strategies in future..................38
4.7: Efficacy of CNS-targeted gene therapy.......................39
4.8: Limitations of this study.................40
4.9: Conclusion.........41
References................43
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