年齡相關性黃斑病變是已開發國家中成人致盲的主要原因之一，其中脈胳膜新生血管更是造成視力喪失的重要因素。治療的方式繁多，包括雷射光凝法、光動力療法及外科切除等等，但均效果有限。在過去的實驗中，我們發現新生血管抑制劑Vasostatin之基因治療可在動物模式中抑制眼角膜新生血管的發生，並減緩已產生之眼角膜新生血管。本研究在探究以Vasostatin之基因治療抑制脈絡膜新生血管的發生，並減緩已產生之脈絡膜新生血管。觀察動物模式中脈絡膜新生血管的抑制作用，並評估治療前後視網膜的功能。全身性投藥可能帶來影響之生理副作用，因此基因傳送之途徑，包括全身性給予或利用局部投予，作為給藥方式的可行性、有效性及安全性均將探討。聚合物載體具有非病毒載體的安全性與便利性；腺病毒載體具備高效價，宿主範圍廣及高感染率等優點；另外腺相關病毒載體具備分子小及感染時間長等優點，因此我們擇其做為基因傳送的工具之一。光動力療法是近年來對於黃斑部中心窩下新生血管膜的治療方式很重要的發展。尤其在常見的年齡相關性黃斑部病變，已有某些治療成效，本研究改善光動力療法動物模式，評估合併療法的效果。在Vasostatin的蛋白質作用下，內皮細胞表現出抑制管狀形成與抑制細胞遷移作用等抑制新生血管生作用。此特性也表現在Vasostatin的小分子段落—Vasostatin 48。在雷射誘發大鼠脈絡膜新生血管模式下，本研究發現Vasostatin蛋白質局部點眼可抑制脈絡膜新生血管。Vasostatin 48蛋白質局部點眼也有同樣的抑制功能，不論是在脈絡膜新生血管或是角膜新生血管模式。我們以視網膜眼電圖驗証Vsostatin基因運用在大鼠模式下脈絡膜新生血管治療的安全性，並嘗試以視網膜眼電圖反映視覺功能的治療效果。運用聚合物攜帶Vasostatin基因以肌肉注射傳遞，可確實被肌肉細胞表現出基因功能，進而抑制脈絡膜新生血管。以局部結膜下注射投予腺病毒為載體進行Vasostatin基因治療，可抑制大鼠模式下的脈絡膜新生血管，沒有明顯的全身性影響，並且不會造成視網膜毒性。以冷光基因追蹤以局部結膜下注射投予腺病毒為載體，眼部基因表現至少112天，不論是大小鼠。以冷光基因追蹤以局部結膜下注射投予腺相關病毒為載體，小鼠眼部基因表現至少365天，特別是腺相關病毒第五型甚至長達730天。腺相關病毒第八型卻會表現出肝臟部位的感染。年齡相關性黃斑病變的治療中，合併療法日漸重要，我們建立光動力療法治療老鼠脈絡膜新生血管之動物模式，並嘗試以非傳統模式建立一套更便利的光動力治療條件，在光動力療法與合併Vasostatin蛋白質治療老鼠之脈絡膜新生血管也可見其初步效果。研究結果將允許我們檢視Vasostatin作為治療年齡相關性黃斑病變或其他視網膜或眼部疾病之方式，而動物實驗之結果亦可作為將來臨床運用之基礎。

Age-related macular degeneration (AMD) is the leading cause for visual impairment and blindness in the elder population of developed countries. The primary underlying cause for significant visual loss is the choroidal neovascularization (CNV). Current treatment strategies for AMD include laser photocoagulation, photodynamic therapy (PDT) and excision of neovascular membranes, but have met with limited success. In our previous studies, we demonstrated that gene delivery of angiogenesis inhibitor vasostatin (VS) attenuated the corneal neovascularization in animals. The primary objective of this study was to investigate gene delivery of vasostatin (VS) attenuated the choroidal neovascularization in animals. Retinal and visual function will be evaluated. However, systematic expression of angiogenesis inhibitor may bring adverse effects to physiological processes. The feasibility, efficiency and safety of gene delivery with systemic and local routes were evaluated. Intramuscular polymer-based gene delivery had no side effect such as virus vector and revealed the safety. Recombinant adenovirus (Ad) was used gene delivery system because of its high titer, wide host range, and transduction efficiency. Adeno-associated virus (AAV) represents highly efficient that can facilirate long-term transduction. We propose to improve the efficacy and safety of VS gene delivery, and to search for the effective delivery route and other adjuvant therapy in conjunction with VS for treatment of CNV. Recently, PDT with veteporfin is an established treatment for subfoveal CNV secondary to AMD. We tried to compare the effect and safety of standard and reduced-dose light application PDT in an animal mocel of CNV. The 180-residue VS and its 48-residue (VS48) inhibited the migration and tube formation in cultured endothelial cells. Topical VS application suppresses the progression of laser-induced CNV via angiogenesis ihhibition, as well as in VS48. VS-48 inhibited the growthof vessels in arota rings. Electroretinograms (ERG) analysis revealed that topical VS-48 application for 21 days had no effect on rat retinal functions. Topical VS-48 treatment significantly reversed the CNV-induced alterations in ERG. Transfection of pCMV3-VS into muscle cells resulted in increased production and release of exogenous VS, which specifically inhibited the proliferation of endothelial cells. Rats treated with intrmuscular injection with PVP-VS also showed a significant reduction in the CNV lesions for at least 42 days. Subconjunctival injection with Ad vector revealed no retinal toxicity in ERG. Ad-luciferase via subconjunctival injections showed ocular expression for as long as 112 days by using bioluminescence image analysis in rodent. AAV-luciferase via subconjunctival injections showed ocular expression for as long as 365 days by using bioluminescence image analysis in mice, and AAV serotype 5-luciferase even showed expression lasting for 2 years. Suppression of laser photocoagulation–induced CNV by Ad-VS was documented in rat model. Combination therapies are important as treatment options. We demonstrated that PDT could effectively attenuate CNV in a rat model, and reduced doses, worked just as well as the standard dose. In the preliminary study of PDT combined topical VS application, treatment led to CNV attenuation more than alone with PDT. The above experiments would enable us to demonstrate that the vasostatin delivery might be a promising strategy for the treatment of AMD and other retinal or ocular disorders. Furthermore, the results from animal studies might be extrapolated for future clinical application.

誌謝 ---------------------------------------------------1
中文摘要---------------------------------------------5
ABSTRACT --------------------------- -------------7
INTRODUCTION----------------------------------9
CHAPTER 1. Inhibition of Choroidal Neovascularization by Topical Application of Angiogenesis Inhibitor Vasostatin ---------15
1-1. INTRODUCTION---------------------------16
1-2. MATERIALS AND METHODS------------17
1-3. RESULTS ------------------------------------23
1-4. DISCUSSION--------------------------------26
1-5. FIGURES AND LEGENDS --------------29
CHAPTER 2. Topical Application of Recombinant Calreticulin Peptide, Vasostain48, Alleviates Choroidal Neovascularization in Rats --------------------37
2-1. INTRODUCTION -----------------------------38
2-2. MATERIALS AND METHODS -------------39
2-3. RESULTS --------------------------------------46
2-4. DISCUSSION ---------------------------------50
2-5. TABLE AND LEGENDS --------------------54
2-6. FIGURES AND LEGENDS ----------------55
CHAPTER 3. Supression of Choroids Neovascularization by Intramuscular Polymer-Based Gene Delivery of Vasostatin ---------------------63
3-1. INTRODUCTION -----------------------------64
3-2. MATERIALS AND METHODS ------------- 65
3-3. RESULTS ---------------------------------------72
3-4. DISCUSSION ----------------------------------74
3-5. FIGURES AND LEGENDS -----------------77
CHAPTER 4. Subconjunctival Injection of Recombinant Adenovirus-Vasostatin Attenuates The Development of Choroidal Neovascularization in Rats ------------------------------------------------------------82
4-1. INTRODUCTION -----------------------------83
4-2. MATERIALS AND METHODS -------------85
4-3. RESULTS --------------------------------------92
4-4. DISCUSSION ----------------------------------95
4-5. FIGURES AND LEGENDS -----------------98
CHAPTER 5. Expression of Subonjunctival AAV-Gene Delivery in Mice Model ---------------------------106
5-1. INTRODUCTION ----------------------------107
5-2. MATERIALS AND METHODS -------------108
5-3. RESULTS --------------------------------------112
5-4. DISCUSSION ------------------------------ --117
5-5. FIGURES AND LEGENDS ----------------121
CHAPTER 6. Comparison of Multiple Reduced-dose and Standard Light Application in Photodynamic Therapy in an Animal Model of Choroidal Neovasculrization ----------------------------------131
6-1. INTRODUCTION -----------------------------132
6-2. MATERIALS AND METHODS -------------133
6-3. RESULTS --------------------------------------137
6-4. DISCUSSION ---------------------------------140
6-5. FIGURES AND LEGENDS ----------------143
CONCLUSIONS------------------------------------149
FUTURE PERSPECTIVES ----------------------154
REFERENCES -------------------------------------155
PUBLICATIONS ------------------------------------163
CONFERENCE PRESENTATIONS------------165
PUBLICATION MANUSCRIPTS-----------------168

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