摘要:思覺失調症是一種嚴重的心智疾患影響世界上1%的人口,包括臺灣。患者普遍會受正性、負性、認知功能失調、與情緒障礙等症狀影響,目前針對負性和認知功能失調症狀至今仍無有效的藥物。思覺失調症負性症狀的潛在市場近美金15億,這個疾病的全球市場也將從2012年的63億成長到2022年的80億美金。近期思覺失調症麩胺酸假說獲得愈多的關注,NMDA受體調節藥物也成為許多中樞神經疾患的標的,NMDA受體參與需許多神經功能,同時這類藥物也具有治療思覺失調症的潛力。近幾年我們的跨校研發團隊針對NMDA受體調節藥物研究與開發了具有高安全性的RS-D7系列藥物,並獲得研究計畫獎助、國家新創獎、及多國專利。利用RS-D7及其現有市售老藥RS-D7pro,我們已在動物模式及思覺失調病人上獲得顯著的療效。且從其機制來看,這一線藥物的療效可能也適用於其他神經心理疾患。據此在這個整合型計畫中,我們整合台大神經生物與認知科學中心的跨領域專家與醫師,組成三個基礎研究、三個臨床測試(包含思覺失調症、阿滋海默症與慢性中風)、及一個核心共同儀器。整合電生理、鈣離子影像、臨床前藥物篩選、動物行為測試、腦腸軸及藥動分析、語言處理、神經心理測驗、腦造影掃描等取向從基礎到臨床去探討及釐清RS-D7系列的基礎機制與臨床藥效。團隊將在既有的成果與基礎上,積極與國內外藥廠、創投商談合作,期盼能在計畫結束後設立公司或與國內外藥廠共同研發,完成後續研究及上市以嘉惠更多的病患及家人。
Abstract: Schizophrenia, a severe mental illness, affects 1% of population worldwide, including Taiwan. Common symptoms associated with schizophrenia include positive, negative, cognitive, and mood-related symptoms. To date, there is no drug for the treatment of negative and cognitive symptoms. According to Decision Resources, negative symptoms of schizophrenia will garner $1.5 billion in major-market sales, and the schizophrenia market will grow from $6.3 billion in 2012 to $8.0 billion in 2022. In recent years, the glutamate hypothesis of schizophrenia has attracted more attention. N-methyl-D-aspartic acid receptor (NMDAR) modulator has also been a popular target for many CNS diseases. The dysfunction of NMDAR signaling has been implicated in many fundamental functions in the brain and it is also a potential therapeutic target for the treatment of schizophrenia. Our inter-institutional research team has researched NMDAR modulators and developed RS-D7 and derivatives for several years. RS-D7 series are new chemical entities with good safety profile, which obtained several grant supports, National Innovator Award, and international patents. Importantly, oral administration of RS-D7 improved negative and cognitive symptoms in animal models. Taking advantage of RS-D7 can be converted through a market drug RS-D7pro; our team has further demonstrated RS-D7’s significant therapeutic effects in negative and cognition symptoms improvements (particularly in verbal and cognitive memory) in 14 schizophrenic patients. Given the importance of NMDAR in neuroplasticity, learning and memory, and many fundamental functions, it is reasonable that RS-D7’s potential therapeutic applicability isn’t limited to schizophrenia alone. There are urgent needs to treat unmet medical needs in many individuals with various neuropsychological disorders as well. It is of great interest to evaluate the effect of RS-D7 series on different animal models of neuropsychiatric disorders and to explore new indications of RS-D7 series in this collaborative project. Accordingly, there are three basic research subprojects, three clinical trials, and one core facility in this 3-year collaborative project. We integrated in vitro/in vivo electrophysiology, calcium imaging, preclinical drug screening, behavioral phenotyping, gut-brain axis and pharmacokinetic analysis, language processing, neuropsychological tests, PET scan, MRI imaging, etc. to better understand the basic mechanisms of RS-D7 series and clinical effects of RS-D7pro in mild cognitive impairment, Alzheimer`s disease, and chronic stroke indications. We have collected elaborate preclinical and clinical evidence from RS-D7 to serve as the basis of this integrative project, to further investigate the therapeutic effects and underlying mechanism of neuropsychological disorders: from basic research to clinical outcomes. This is an integrated and multidisciplinary research team at Neurobiology and Cognitive Science Center. Our collaborative team consists of research scientists and physician from different colleges at NTU and NTU Hospital. Our team will cooperate with domestic/foreign pharmaceutical companies and venture capital companies, to establish a company at the end of this project term, or cooperate with domestic/foreign pharmaceutical companies in joint development efforts, until sufficient funds can be obtained to proceed with large-scale synthesis, and investigational new drug application. Ultimately, we anticipate that we may opt for technology transfer or sell after the completion of Phase I/II clinical trials. We look forward to pushing our current achievements to the next level and fulfilling some unmet medical needs for patients with neuropsychological disorders in the near future.