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研究生:吳為吉
研究生(外文):WEI-CHI WU
論文名稱:膠質細胞株衍生滋養因子基因治療對視網膜傷害的保護效果
論文名稱(外文):GDNF gene therapy for retinal injuries
指導教授:曹友平曹友平引用關係
指導教授(外文):YEOU-PING TSAO
學位類別:博士
校院名稱:長庚大學
系所名稱:臨床醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2003
畢業學年度:91
語文別:中文
論文頁數:199
中文關鍵詞:基因治療腺相關病毒長期安全性視網膜剝離視網膜缺血再灌流傷害膠質細胞衍生滋養因子神經保護機轉
外文關鍵詞:gene therapyadeno-associated viruslong-term safetyretinal detachmentretinal ischemia-reperfusion injuryglial cell line-derived neurotrophic factorneuroprotectionmechanism
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神經保護 (neuroprotection)是指使用一種藥物到一受損的組織並和細胞中的某些成分起反應後,減低細胞死亡的過程。(根據Osborne in Survey Opathalmology, 1999 的定義),由於視網膜細胞屬於中樞神經的一部份,乃是分化完全的細胞,因此在細胞受傷死亡後即不能複製也不能再生,因此目前治療的重點在於如何保存好受傷後的視網膜細胞?由於現今一些視網膜細胞的置換或移植手術,如視網膜義眼或是視網膜色素上皮細胞移植,仍未得到完全成功,臨床運用也很遙遠,因此保存視網膜細胞的活性更形重要。而近來基因治療的發展可說是一日千里,在200 1年「人類基因體計劃」完成後更是宣告著基因的時代來臨,其重要性猶如當年的登月計劃「阿波羅」計劃,宣示著新世紀嶄新的治療方法的誕生,也由於基因治療有優於傳統治療的優點,因此,如何運用基因治療的方式運用在視網膜傷害的模式中,達到神經保護的效果,將是本論文的重點。本論文首先回顧之前有關眼睛的基因治療的研究,並設計了數個實驗,將討論視網膜傷害的基因治療之可行性,安全性及可能的分子機轉。我們將以腺相關病毒為載體,攜帶神經滋養因子GDNF的基因 (rAAV-GDNF)測試其長期安全性,對視網膜剝離以及視網膜缺血再灌流是否有保護作用,最後,再探討其可能的分子機轉。本論文內容分述如下:
第一章:之前有關眼睛的基因治療的研究回顧。
第二章:為實驗設計一。為了了解腺相關病毒長期表達神經滋養因子對視網膜是否有長期毒性,我們在大鼠的玻璃體內注入rAAV-GDNF,觀察是否能在眼內長期表現 (大於一年),並觀察其視網膜外觀有否異常,並以免疫組織染色分析法測試是否有發炎細胞浸潤,以神經追蹤染料標示視網膜神經節細胞,看是否數目有所減少,最後用視網膜電圖測試實驗眼與控制眼其視力有否不同。結果發現rAAV-GDNF可在視網膜內長期表現 (大於一年),並且受基因轉殖的視網膜其型態與正常眼並無不同,也未發現有發炎細胞浸潤,視網膜神經節細胞也未減少。更重要的,視網膜電圖並未測出基因轉殖的眼睛與控制組的眼睛有何不同。因此,我們的結論是以腺相關病毒為載體在視網膜內長期表達神經滋養因子 (GDNF)對眼睛並無明顯的毒性。
第三章:為實驗設計二。為了解利用基因傳遞的方法評估膠質細胞衍生營養因子 (glial cell line-derived neurotrophic factor, GDNF)對視網膜剝離 (retinal detachment, RD)引發之感光細胞損傷是否能提供的保護效果。我們以視網膜下注射 (subretinal injection)的方法達到基因傳遞的作用,在Lewis大白鼠的右眼注射rAAV-GDNF,而左眼注射表現大腸桿菌LacZ基因之重組腺相關病毒 (recombinant adeno-associated virus expressing Escherichia coli LacZ, rAAV-LacZ)。在基因傳遞後三個星期,利用視網膜下注射高密度玻璃替代品 (high-density vitreous substitute)的方法誘發雙眼之視網膜剝離。視網膜下注射重組腺相關病毒載體後三週,分別使用免疫組織染色 (immunohistochemistry)和酵素連結免疫分析法 (enzyme-linked immunosorbent assay; ELISA)來觀察GDNF在視網膜中合成及累積的情形。感光細胞 (photoreceptors)傷害的情形則依感光細胞之感光細胞外節(outer segment, OS)及外核層 (outer nuclear layer, ONL)保留完好的程度來評估。視網膜剝離後二天使用DNA原位末端標記 (TdT-dUTP terminal nick-end labeling , TUNEL)的方法來研究感光細胞之細胞凋亡情況。Müller cell的活性檢查則是在視網膜剝離二十八天後使用膠質纖維酸性蛋白(glial fibrillary acidic protein, GFAP)之抗體進行免疫組織染色。結果發現使用免疫組織染色的研究已證實可達到基因傳遞之作用,ELISA的結果也證實視網膜中產生高量親神經性因子 (neurotrophic factors)。在視網膜剝離後,所有的眼睛均發生感光細胞之感光細胞外節(outer segment, OS)退化及外核層 (outer nuclear layer, ONL)逐漸變短的現象,然而,注射rAAV-GDNF之眼睛比注射rAAV-LacZ之眼睛在7天 (P=0.012; Wilcoxon signed-ranks test)及28天 (P=0.008; Wilcoxon signed-ranks test)後保留了較長的感光細胞外節 (outer segment, OS)。在感光細胞層的凋亡細胞數目,以GDNF處理過的眼睛比控制組的眼睛少,且數據具有統計學上的意義 (P=0.043; Wilcoxon signed-ranks test)。以GDNF處理過的組別抑制了Müller cell在視網膜下增生,這意指會有較少的疤形成。我們的結論是GDNF是有潛力可以保護感光細胞防止退化的因子發生視網膜剝離後,GDNF可能是藉由防止感光細胞凋亡來達到保護的作用。在某些因複雜因素所導致的視網膜剝離,GDNF基因治療可在現今療法中成為有價值的佐劑。
第四章:為實驗設計三。為了了解是否利用基因傳遞的方法表達膠質細胞衍生營養因子 (glial cell line-derived neurotrophic factor; GDNF)對於視網膜缺血再灌流的傷害也有保護效果。我們將基因攜帶至視網膜細胞,我們在大白鼠 (Sprague-Dawley rates; SD rates)的右眼以玻璃體內注射rAAV-GDNF,而左眼則注射表現rAAV-LacZ作為對照。在注射AAV後的三個星期施行眼睛的缺血傷害的手術。在基因傳遞後三個星期內,視網膜中GDNF合成及累積的情形則分別利用免疫組織染色 (immunohistochemistry)和酵素連結免疫分析法 (enzyme-linked immunosorbent assay, ELISA)來觀察。神經保護效果的評估方法則是施行再灌流後一個星期,計數內層視網膜的厚度及視網膜神經節細胞 (retinal ganglion cell; RGC)的數目。功能性研究使用視網膜電圖 (electroretinogram, ERG)來進行。視網膜神經節細胞凋亡的情形則是在施行再灌流六小時後,使用DNA原位末端標記 (TdT-dUTP terminal nick-end labeling, TUNEL)的方法來評估。結果發現GDNF可在視網膜神經節細胞表達。所有的眼睛在局部性缺血後七天均呈現內層視網膜細胞變薄以及視網膜神經節細胞數目減少的現象,但是有施打rAAV-GDNF的眼睛視網膜內層細胞的厚度以及視網膜神經節細胞數目比施打rAAV-Lac Z的眼睛保存的較為良好(分別是p=0.038及p=0.003; Wilcoxon signed-ranks test)。而且施打rAAV-GDNF的眼睛比施打rAAV-Lac Z的眼睛保留了較明顯的視網膜電圖b波 (p=0.003; Wilcoxon signed-ranks test),在視網膜神經節細胞凋亡程度減少的情形也具有統計學上的意義 (p=0.011; Wilcoxon signed-ranks test)。我們的結論是GDNF保護視網膜免於缺血再灌流後所造成的傷害,其機轉可能是藉由保護視網膜細胞免於凋亡而來。
第五章:為實驗設計四、為了了解上述rAAV-GDNF在眼內長期表現為何對視網膜有神經保護的功效,因此我們將大鼠轉殖rAAV-GDNF後,給予視網膜剝離傷害,在不同的時間點 (傷害後一天、一週、二週) 測試是否與MAPK之神經路徑活化有關,我們發現以rAAV-GDNF轉殖的視網膜在視網膜剝離傷害後有phospho-MAPK(MAPK的活化型)染色的視網膜細胞比對照組多,顯示rAAV-GDNF之基因治療的分子機轉可能有MAPK路徑的活化有關,且此保護作用可能透過中間神經元或Müller細胞達成。
本論文所得之結論如下:rAAV-GDNF載體可長期有效的轉殖視網膜,在視網膜長期表達rAAV-GDNF對視網模式無毒性的,且rAAV-GDNF的基因治療可減輕視網膜剝離以及視網膜缺血再灌流傷害,而上述的神經保護機轉可能與視網膜細胞MAPK路徑的活化有關,之後仍需後續的研究以便更深入了解其治療機轉。
ntroduction
Neuroprotection describes the process whereby an agent interacts with specific cellular components to attenuate the process of death. As retina is a part of the central nervous system and its cells are terminally differentiated, it cannot be regenerated when injured. Therefore, current treatments for retinal diseases largely aim at stopping the disease progressions.
Tremendous progress has been made in the past decade in delineating the molecular bases of ocular diseases, which allows for the development of rational strategies to resolve them. One of the most important break-through is the advent of gene therapy, as it offers many benefits unparalleled by traditional therapies. Although there has not, as yet, a demonstration of cure using gene therapy, proof-of-principle has been established in a number of animal models for ocular diseases.
As attempts to “cure” retinal injuries with retinal stem cell transplantation or retinal prosthesis are largely inconclusive and their clinical value being uncertain, our current study intends to achieve neuroprotection against retinal injuries via gene therapy. We transfected retinal cells with recombinant adeno-associated virus (RAAV) carrying a gene for glial cell-line derived neurotrophic factor (GDNF), in an attempt to achieve neuroprotection. We evaluated this gene therapy’s protective potential against retinal detachment (RD)-induced and retinal ischemia-reperfusion (I/R)-induced injuries. We also examined the long-term effects of this therapy and its possible underlying mechanism.
Experiment 1: Long-term safety of GDNF Gene Therapy
We examined the long-term effects of GDNF gene therapy by comparing 4 criteria between the treated eyes and the control eyes. Sprague-Dawley (SD) rats’ retinal cells were transfected with RAAV carrying GDNF gene via intravitreal injection. The right eyes served as the experimental group while the left served as the control. First, retinal morphology was analyzed via microscopy 1 year after transfection. Second, retinal inflammation was assessed using antibodies against phagocytes. Third, Retinal ganglion cell (RGC) were labeled with neuro-tracer dye to allow for its quantification. Finally, retinal function was evaluated with electroretinogram (ERG).
In this experiment, we found that neither retinal morphology nor RGC counts were significantly affected by GDNF gene therapy. In addition, immunohistochemical staining detects no additional inflammatory cells in the experimental group. Most importantly, ERG studies demonstrated that b-wave was not significantly decreased in the transfected eyes. Hence, we concluded that long-term expression of GDNF poses insignificant toxic effects to retina.
Experiment 2. GDNF Gene Therapy’s Protective Potential against Retinal Detachment (RD)-induced photoreceptor injury
In this study, we examined GDNF gene therapy’s protective potential against injuries induced by RD. RAAV carrying GDNF gene and RAAV carrying E. coli LacZ gene were injected into subretinal space in the right and left eyes of Lewis rats respectively to establish the experimental group and the control. Three weeks following gene delivery, we induced RD through subretinal injection of high-density vitreous substitute. The synthesis and accumulation of GDNF within retina was examined 3 weeks after transfection via immunohistochemical staining and enzyme-linked immunosorbent assay (ELISA) respectively. Subsequently, the lengths of photoreceptors outer segments (OS) and the thickness of retina’s outer nuclear layers (ONL) were used as evaluation criteria for photoreceptor integrity. Photoreceptor apoptosis was studied using TdT-dUTP terminal nick-end labeling (TUNEL) 2 days after RD. Finally, Müller cell activation was observed immunohistochemically with antibodies against glial fibrillary acidic protein (GFAP) 28 days after RD induction.
Immunohistochemical analysis and ELISA both demonstrated successful gene delivery. Although photoreceptor OS degeneration and ONL thinning were noted in both experimental and control groups, it was observed that the experimental group sustained less severe damages both 7 days and 28 days after RD. More over, GDNF gene therapy-treated eyes showed statistically less apoptosis than control eyes in the photoreceptor layer (p=0.043). Lastly, Müller cell activation was less prominent in the experimental group, indicating less scar formation. These results have led us to conclude GDNF gene therapy as a good method to protect photoreceptors from RD-induced degeneration. In addition to preserving OS and ONL integrities, GDNF gene therapy may also exert its protective effect by attenuating photoreceptor apoptosis.
Experiment 3. GDNF Gene Therapy’s Protective Effect against Retinal Ischemia-Reperfusion (I/R)-induced injury
We assessed GDNF gene therapy’s protective potential against retinal I/R-induced injuries. RAAV carrying GDNF gene and RAAV carrying E. coli LacZ gene were injected intravitreally into the right and left eyes of SD rats respectively to establish the experimental and control groups. Subsequently, ischemic injury was induced 3 weeks following gene delivery. The synthesis and accumulation of GDNF within retina were studied 3 weeks after gene delivery via immunohistochemical staining and ELISA. The neuroprotective effects were evaluated1 week after reperfusion, using inner retina thickness and RGC counts as evaluation criteria. Retinal function study was performed with ERG. Finally, TUNEL method was used to assess RGC apoptosis 6 hours after reperfusion.
Immunohistochemical analysis and ELISA both confirmed successful GDNF transfection. We also found that inner retina thickness and RGC counts were both better preserved in rAAV-GDNF-treated eyes than in rAAV-LacZ-treated eyes 7 days after reperfusion (P=0.038 and P=0.003, respectively). In addition, rAAV-GDNF-treated eyes demonstrated larger b-wave amplitudes than rAAV-LacZ-treated eyes 7 days after reperfusion (P=0.003). Finally, rAAV-GDNF-treated eyes demonstrated statistically less RGC apoptosis (P=0.021). We concluded that GDNF gene therapy can effectively protect retina against I/R injury and may exert its protective role through the attenuation of retinal cell apoptosis.
Experiment 4. Mitogen-Activated Protein Kinase (MAPK) Pathway’s Involvement in GDNF’s Neuroprotective Mechanism
In this section, we compared retinas at various time periods after their detachments in eyes that underwent GDNF gene therapy and control eyes. Immunohistochemical study was used to identify phospho-MAPK positive (active form of MAPK) cells in retina at various time periods. Our results indicated that there were significantly more phospho-MAPK positive cells in retinas transfected with RAAV carrying GDNF as compared to the control group (p<0.05). However, as the duration of RD increased, the number of phospho-MAPK-positive cells decreased in both groups. It may be possible that GDNF’s neuroprotective mechanism against RD is related to the activation of MAPK pathway.
Conclusion
Recombinant adeno-associated virus can effectively transfect retinal cells with GDNF gene for over one year without significant toxic effects. GDNF gene therapy can protect retina from injuries induced by retinal detachment and retinal ischemia-reperfusion. The neuroprotective effect of GDNF may be related to MAPK activation. Further studies are needed to elucidate the underlying mechanisms of GDNF gene therapy.
正 文 目 錄
頁次
目錄 ----------------------------------------------------------------------------I
圖目錄 -------------------------------------------------------------------------IV
中文摘要 ----------------------------------------------------------------------VIII
英文摘要 ----------------------------------------------------------------------XIV
第一章 眼睛基因治療研究回顧 ----------------------------------------- 1
第一節 視網膜神經保護與基因治療-------------------------------1
第二節 眼內基因傳遞之目標細胞----------------------------------2
第三節 眼睛基因治療的優點----------------------------------------2
第四節 眼睛基因治療的理想條件----------------------------------4
第五節 基因治療的工具----------------------------------------------4
第六節 基因治療在眼睛各部位的進展----------------------------22
第七節 結論-------------------------------------------------------------48
第八節 參考文獻-------------------------------------------------------49
第二章 腺相關病毒載體轉殖視網膜細胞後之長期安全性--------------------------------------------------------------------78
第一節 前言-------------------------------------------------------------78
第二節 材料與方法----------------------------------------------------79
第三節 結果-------------------------------------------------------------87
第四節 討論------------------------------------------------------------100
第五節 參考文獻------------------------------------------------------102
第三章膠質細胞衍生滋養因子對視網膜剝離的基因治療------------------------------------------------------------------------106
第一節 前言-------------------------------------------------------------106
第二節 材料與方法----------------------------------------------------108
第三節 結果-------------------------------------------------------------115
第四節 討論-------------------------------------------------------------129
第五節 參考文獻-------------------------------------------------------133
第四章使用GDNF基因治療的方法可減弱大鼠視網膜缺血後的傷害-------------------------------------------------------------------------141
第一節 前言-------------------------------------------------------------141
第二節 材料與方法----------------------------------------------------143
第三節 結果-------------------------------------------------------------150
第四節 討論-------------------------------------------------------------165
第五節 參考文獻-------------------------------------------------------168
第五章GDNF基因治療之可能神經保護機轉----------------------------------------------------------------176
第一節 前言-------------------------------------------------------------176
第二節 材料與方法----------------------------------------------------177
第三節 結果-------------------------------------------------------------179
第四節 討論-------------------------------------------------------------182
第五節 參考文獻-------------------------------------------------------185
第六章 綜合討論、未來研究方向與結論-----------------------------------------------------------------------------188
附錄 -------------------------------------------------------------------197
圖目錄
頁次
第一章
圖一、基因傳遞的方法--------------------------------6
圖二、基因治療策略----------------------------------22
第二章
圖一、rAAV-GFP轉殖大鼠的視網膜一年之後,在視網膜的表達--------------------------------------------------88
圖二、大鼠眼內轉殖rAAV-GDNF一年後,GDNF在眼內組織的表達--------------------------------------------------89
圖三、利用ELISA檢測rAAV-GDNF轉殖眼睛一年後眼內GDNF累積量----------------------------------------------91
圖四、rAAV-GDNF轉殖眼睛一年後的型態檢查--------------------------------------------------93
圖五、rAAV-GDNF轉殖眼睛一年後以免疫組織染色檢查吞噬細胞的浸潤--------------------------------------------------95
圖六、rAAV-GDNF轉殖眼睛後以神經追蹤染料測量視網膜神經節細胞的數目-------------------------------------------------97
圖七、rAAV-GDNF轉殖眼睛一年後的視網膜電圖結果
-------------------------------------------------99
第三章
圖一、使用免疫組織染色來偵測rAAV-GDNF轉殖眼的GDNF蛋白合成--------------------------------------------116
圖二、利用ELISA測量rAAV-GDNF注射後GDNF蛋白累積------------------------------------------------118
圖三、以rAAV-GDNF保護感光細胞之光學代表圖------------------------------------------------122
圖四、以rAAV-GDNF保護感光細胞外節之代表性電子顯微鏡圖------------------------------------------------123
圖五、在接受不同治療後,平均的視網膜外節及外核層長度------------------------------------------------124
圖六、利用TUNEL染色在視網膜剝離2天後測得之感光細胞凋亡----------------------------------------------126
圖七、以免疫螢光顯示Müller cells的活性-----------128
第四章
圖一、使用免疫組織染色偵測玻璃體內注射rAAV-GDNF之眼睛合成GNDF的情形-----------------------------------------------151
圖二、以ELISA偵測rAAV-GDNF注射後GDNF累積在視網膜組織中的量------------------------------------------------153
圖三、在缺血再灌流傷害七天後,以視網膜切片顯示GDNF對視網膜的保護效果----------------------------------155
圖四、在缺血再灌流傷害後7天,平均內側視網膜之厚度測量------------------------------------------------156
圖五、在缺血再灌流傷害後7天,視網膜神經節細胞的數目比較----------------------------------------------158
圖六、在缺血再灌流傷害前,及之後1天及7天,視網膜電圖b波的大小比較------------------------------------161
圖七、在缺血再灌流6小時後利用TUNEL染色檢驗視網膜神經節細胞之凋亡------------------------------------163
圖八、缺血再灌流傷害6小時後,每250 mm視網膜之平均有TUNEL染色之視網膜神經節細胞數目------------------------------------------------164
第五章
圖一、視網膜剝離後1天、7天及14天以辨識phospo-MAPK的抗體做免疫組織染色-------------------------------181
第六章
圖一、以雙股DNA腺相關病毒 (dsAAV-GFP)感染視網膜後的表達情形-------------------------------------------189
Chapter 1
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Chapter 4
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