2019-01-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/653973摘要：運動（或稱共濟）失調（ataxia）是小腦或相關連結神經路徑病變所引發的動作失調，屬於多病因的動作疾患（movement disorder）。患者常有步伐及姿態不穩、肢體平衡感差、隨意運動協調障礙、言語障礙、肌張力降低等症狀，患者常漸漸失能造成呼吸的停止與衰弱的併發症，最後導致死亡。目前僅能針對症狀嘗試控制惡化程度，仍無有效治療藥物。運動失調是由神經系統各個部位的很多病因所引發，可概分為遺傳型與散發型，病灶可能在小腦本身，或橋腦的神經元、脊髓小腦路徑（spinocerebellar tracts）等。世界各地隨著地域及人種的不同，盛行率也不盡相同。由於動作失調症迄今仍無有效藥物，家屬與病患從發病到漸漸失能到死亡的過程中，承受相當大的身體與心理的痛苦，動作失調症仍是未被滿足的醫藥需求，急需開發新藥物。迄今累積越來越多研究證據發現d-amino acid oxidase (DAO)抑制劑，可以抑制腦中d-絲胺酸(d-serine)的分解並提升其濃度，同時透過其 co-agonist 的功效增進NMDA受體功能與減少毒性，有機會改善動作失調的相關症狀。在過往的研究也指出使用d-環絲氨酸(d-cycloserine，一種 NMDA受體 partial agonist)後，可以在體內分解成d-絲胺酸，可以改善動作失調症患者的一些臨床症狀，但是d-cycloserine可能會產生許多嚴重的副作用並且無法長期使用。我們團隊針對DAO抑制劑，以repurposing方式找到市售專利過期藥物(RS-D7pro)並開發出 RS-D7，作為更有效且安全性高的DAO抑制劑，可以抑制腦中d-絲胺酸的分解，提高腦中的d-絲胺酸的濃度。同時也有研究顯示補充d-絲胺酸可有效緩解小鼠的運動失調症狀。考量NMDA系統在大腦及認知功能的重要性，針對NMDA受體的研發是世界各國積極努力的目標之一，近期日本Takeda Pharmaceuticals也正積極開發NMDA modulators 用於治療動作失調症等病症。我們團隊的RS-D7若能在小鼠及ataxia病人身上發揮預期療效，將滿足 unmet medical need 並成為ataxia first-in-class藥物，大大造福病人、家屬及社會國家。<br> Abstract: Neurodegenerative disorders, an umbrella term for a range of conditions which primarily affect the neurons in the brain, are debilitating and largely untreatable conditions that are strongly linked with age. Neurodegenerative disorders are usually incurable and debilitating conditions that result in progressive degeneration and / or death of nerve cells. These disorders cause problems with not only motor movement (such as in ataxia) but also mental functioning (such as AD and dementia). While large investments have been made in other diseases such as cancer and heart disease, to date neurodegenerative disorders have not received the same level of funding, despite having a large negative impact on healthy life years and our aging society. Unfortunately, existing treatments for neurodegenerative disorders are usually limited, and only treat the symptoms, rather than addressing the cause. There is a clear unmet medical need in the development of new therapeutic agents for many neurodegenerative disorders, such as ataxia, multiple system atrophy (MSA), AD, MCI, and essential tremor (ET). In the past decade, compelling animal and clinical studies support the importance of NMDAR in the modulation of functional decline during aging process and suggest potential pharmacological agents to ameliorate some symptoms in neurodegenerative disorders. For example, a recent study indicated that peripheral D-amino acid oxidase (DAO) levels may increase with age-related cognitive decline and Takeda Pharmaceuticals launched a phase 2 study of TAK-831 (a DAO inhibitor) in the treatment of Friedreich’s ataxia in the United States in 2018. Following the same line of thought, our research team has discovered RS-D7, a novel DAO inhibitor with high safety profile and developed RS-D7 derivatives as novel NMDAR modulators for several years. RS-D7 is also a non-active metabolite of a currently market drug, RS-D7pro, with non-CNS indications as a strong binder of DAOI. Taking advantage of RS-D7 and RS-D7pro, we have conducted animal studies and small-sample, proof-of concept clinical studies to investigate the effect of RS-D7 and RS-D7pro on AD and MSA-cerebellar type (MSA-C) ataxia, respectively.N-methyl-D-aspartic Acid (NMDA) 受體D-胺基酸氧化&#37238D-胺基酸氧化&#37238抑制劑臨床前試驗RS-D7神經退化疾患N-methyl-D-aspartic Acid (NMDA) receptorD-amino acid oxidase (DAO)DAO inhibitor (DAOI)preclinical trialRS-D7neurodegenerative disorders