2016-08-012024-05-17https://scholars.lib.ntu.edu.tw/handle/123456789/683496摘要：芳族L-氨基酸脫羧酶（AADC)缺乏症是一種少見的自體隱性遺傳性神經疾病。臨床上在早 期即表現出肌肉張力低下，oculogyric危機，肌張力不全，和神經功能紊亂。AADC缺乏症在 台灣的發病率相對較高，此歸因於始祖突變IVS6 + 4A> T的效果。患者同基因型組合IVS6 + 4A> T突變或異基因型組合突變（IVS6 + 4A> T加上其他突變）經常有嚴重臨床症狀，並對 藥物治療反應差。迄今為止藥物治療對AADC缺乏患者效果並不佳，儘管基因治療正在進行 中，這需要腦外科手術和使用病毒，同時基因治療的長遠效果仍未知。過去我們在國科會計 劃支持下進行了不少AADC缺乏的研究，但那畢竟是在動物實驗或是使用細胞transfection的 結果。因此利用一些新的方法使用人類細胞去探討AADC缺乏的致病機轉和治療，是可行的 一些方法。我們推測，利用AADC缺乏症患者白血球衍生的誘導性多功能幹細胞（Induced pluripotent stem cells ； iPSC)是一個很好的工具，可用來剖析其致病的分子和細胞機制，特別是在AADC缺 乏所導致的神經細胞凋亡和失調的晝夜節律基因的問題。這樣的疾病特異性的iPSC也可用於 測試潛在的新治療，包括反義療法。因此在這項研究中，我們計劃與中研院生醫所謝老師合 作利用IVS6 + 4A> T突變AADC缺乏白血球產生疾病特異性的iPSC，並利用這些細胞探討 神經細胞凋亡和失調的致病機制。在這項研究中的知識將被利用來測試有潛力的藥物。此外， 我們也將使用該體外細胞疾病模型測試以IVS6 + 4A> T突變為標的剪接突變反義治療 (antisense therapy)的功效。我們希望我們的研究能夠真的釐清AADC缺乏的致病分子機制與 找到新的治療。<br> Abstract: Aromatic L-amino acid decarboxylase (AADC) deficiency is an uncommon neurological disease. AADC is an enzyme responsible for the synthesis of two important neurotransmitters in the brain -dopamine and serotonin. Patients with AADC deficiency, an autosomal recessive disorder, exhibit hypotonia, vegetative symptoms, oculogyric crises, dystonia, and autonomic dysfunction since the early childhood. The incidence of AADC deficiency is relatively high in Taiwan and is attributed to the effect of a founder mutation IVS6+4A>T in the population. Patients with homozygous IVS6+4A>T mutation or compound heterozygous mutation (IVS6+4A>T plus the other severe mutation) often have relentless clinical courses and show partial or poor response to drug treatments, such as vitamin B6, dopamineagonists, or monoamine oxidase (MAO) inhibitors. The majority of these patients die of choking andrespiratory infection around the age of 5-6 years due to lack of effective treatment. In the past few years,under the grand support from National Science Council, we established the animal models and found increased cell death, decreased differentiation, and impaired circadian rhythm in AADC knockdown or IVS6+4A>T plasmid transfected cells. However, all results arise from animal and cell study. Therefore, further studies using human cells are another important choice.In this study, we plan to collaborate with Prof Hsieh in IBMS of Academia Sinica to generate disease-specific iPSCs from patients with AADC deficiency (IVS6+4A>T mutation) and use these cells for the elucidation of pathogenic molecular mechanisms that lead to enhanced neuronal apoptosis and circadian dysregulation, two important features we found in our patients with AADC deficiency. The knowledge we obtain in this study will be exploited to select and test novel and promising drugs that may reduce these cellular phenotypes. Moreover, we will also use this in vitro disease model for testing the efficacy of antisense therapy that is designed to target the pathogenic splicing mutation (IVS6+4A>T mutation) in the majority of patients with AADC deficiency in Taiwan.