An international research team led by scientists from the Hong Kong University of Science and Technology (HKUST) has developed a novel strategy using brain-wide genome-editing technology that can reduce Alzheimer’s disease (AD) pathologies in genetically modified AD mouse models. This advanced technology offers immense potential to be translated as a novel long-acting therapeutic treatment for AD patients.
In China alone, over 500,000 patients are estimated to be living with a hereditary form of AD - familial Alzheimer’s disease (FAD), which is a congenital form of AD highly associated with family history. Although FAD has a clear genetic cause and can be diagnosed before cognitive problems occur, no effective treatment currently exists.
There is enormous potential in the use of genome-editing technology1 as therapeutic strategies for diseases caused by inherited mutations, such as FAD. It is especially useful for correcting disease-causing genetic mutations before symptoms appear, for which it is considered a “once-and-for-all” treatment as its effects can last a lifetime. However, several hurdles have prevented its clinical development and application - most notably the lack of an effective, efficient, and non-invasive means to deliver genome-editing agents into the brain. Furthermore, existing genome-editing technologies are unable to generate beneficial outcomes throughout the whole brain.
Recently, a team led by Prof. Nancy Ip, Vice-President for Research and Development at HKUST, developed a new genome-editing system that not only crosses the blood–brain barrier, but also delivers an optimized genome-editing tool to the entire brain. Using a newly engineered delivery vehicle for genome-editing, this strategy achieves efficient brain-wide genome editing through a single non-invasive intravenous administration. This effectively disrupts FAD-inflicted mutations in AD mouse models and ameliorates AD pathologies throughout the entire brain, paving the way to novel therapeutic development for the disease.
Meanwhile, the research team also found in the mouse models that the level of amyloid, a protein thought to drive neurodegeneration in AD, remained low for 6 months post-treatment (about 1/3 of their normal lifespan), demonstrating that this single-shot genome-editing strategy has lasting effects. More importantly, no side effects were detected so far in the mice.
“As the first demonstration of efficient brain-wide genome editing to alleviate Alzheimer’s disease pathology throughout the whole brain, this is really an exciting development,” said Prof. Ip, who is also the Morningside Professor of Life Science and Director of the State Key Laboratory of Molecular Neuroscience at HKUST. “Our work is an important milestone for the use of genome editing in treating hereditary brain diseases, and contributes to the development of precision medicine for inherited forms of neurodegenerative diseases.”
This research was a collaborative effort among scientists from HKUST; the California Institute of Technology; and the Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences. The results were recently published in Nature Biomedical Engineering.
HKUST
HKUST Scientists Develop Genome-editing Strategy for Potential Alzheimer's Disease Therapy
An international research team led by scientists from the Hong Kong University of Science and Technology (HKUST) has developed a novel strategy using brain-wide genome-editing technology that can reduce Alzheimer’s disease (AD) pathologies in genetically modified AD mouse models. This advanced technology offers immense potential to be translated as a novel long-acting therapeutic treatment for AD patients.
In China alone, over 500,000 patients are estimated to be living with a hereditary form of AD - familial Alzheimer’s disease (FAD), which is a congenital form of AD highly associated with family history. Although FAD has a clear genetic cause and can be diagnosed before cognitive problems occur, no effective treatment currently exists.
There is enormous potential in the use of genome-editing technology1 as therapeutic strategies for diseases caused by inherited mutations, such as FAD. It is especially useful for correcting disease-causing genetic mutations before symptoms appear, for which it is considered a “once-and-for-all” treatment as its effects can last a lifetime. However, several hurdles have prevented its clinical development and application - most notably the lack of an effective, efficient, and non-invasive means to deliver genome-editing agents into the brain. Furthermore, existing genome-editing technologies are unable to generate beneficial outcomes throughout the whole brain.
Recently, a team led by Prof. Nancy Ip, Vice-President for Research and Development at HKUST, developed a new genome-editing system that not only crosses the blood–brain barrier, but also delivers an optimized genome-editing tool to the entire brain. Using a newly engineered delivery vehicle for genome-editing, this strategy achieves efficient brain-wide genome editing through a single non-invasive intravenous administration. This effectively disrupts FAD-inflicted mutations in AD mouse models and ameliorates AD pathologies throughout the entire brain, paving the way to novel therapeutic development for the disease.
Meanwhile, the research team also found in the mouse models that the level of amyloid, a protein thought to drive neurodegeneration in AD, remained low for 6 months post-treatment (about 1/3 of their normal lifespan), demonstrating that this single-shot genome-editing strategy has lasting effects. More importantly, no side effects were detected so far in the mice.
“As the first demonstration of efficient brain-wide genome editing to alleviate Alzheimer’s disease pathology throughout the whole brain, this is really an exciting development,” said Prof. Ip, who is also the Morningside Professor of Life Science and Director of the State Key Laboratory of Molecular Neuroscience at HKUST. “Our work is an important milestone for the use of genome editing in treating hereditary brain diseases, and contributes to the development of precision medicine for inherited forms of neurodegenerative diseases.”
This research was a collaborative effort among scientists from HKUST; the California Institute of Technology; and the Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences. The results were recently published in Nature Biomedical Engineering.
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Brain-Wide Cas9-Mediated Cleavage Of A Gene Causing Familial Alzheimer's Disease Alleviateds Amyloid-Related Pathologies In Mice (Reference Reading)
港澳台傳媒報導
科大研發新型基因編輯策略 有助治療阿爾茨海默症
由香港科技大學（科大）領導的國際研究團隊，近期成功研發出一種新型全腦基因編輯技術，在小鼠模型中證明可以改善阿爾茨海默症（AD）的病理症狀，有潛力發展成爲AD的新型長效治療手段。
據估計，中國有超過50萬人罹患遺傳性的阿爾茨海默症，即家族性阿爾茨海默症（FAD）。FAD是一種與家族史高度相關的先天性阿爾茨海默症。雖然FAD患者有明確的遺傳病因，亦可在認知出現問題之前獲得診斷，但目前還未有有效的治療方法。
基因編輯技術1在治療例如FAD這類由遺傳基因突變引發的疾病方面，展現出巨大潛力。它可以在疾病症狀出現之前，糾正引發疾病的基因突變，並且可以達到「一次治療，長期有效」的治療效果。不過，基因編輯技術的臨床發展和應用還存在一些障礙。例如，目前尚缺乏有效、高效、非侵入式的運送工具，將基因編輯工具運送到大腦。此外，現有的基因組編輯技術，還無法在全腦範圍發揮有效的治療作用。
近日，由科大副校長(研究及發展)葉玉如教授領導的研究團隊，研發出一種新型全腦基因編輯技術。該技術使用新型的運送工具，可以跨越血腦屏障，通過單次、無創的靜脈注射，將優化的基因編輯工具運送到整個大腦，實現高效的全腦基因編輯。研究發現，這種技術可以有效破壞AD轉基因小鼠模型中的FAD基因突變，並在全腦範圍改善AD的病理症狀，為開發新型AD治療方法打下基礎。
同時，研究團隊還發現，AD轉基因小鼠在接受基因編輯技術治療的6個月後，即小鼠平均壽命的三分之一，其大腦中被認為引發AD神經退行病變的澱粉樣蛋白斑塊，仍然保持較低水平，證明了該基因編輯技術的單次治療可以維持長期療效。研究亦未在小鼠身上發現任何明顯的副作用。
身兼科大晨興生命科學教授及分子神經科學國家重點實驗室主任的葉教授表示：「我們的研究工作首次實現了高效的全腦基因編輯，同時在全腦範圍有效改善AD的病理症狀。這是一項令人振奮的進展，在基因編輯技術應用到遺傳性腦疾病治療領域是一個重要里程碑，有助推動相關疾病的精準醫療發展。」
這項研究由科大、美國加州理工學院以及中國科學院深圳先進技術研究院的研究團隊合作進行。研究結果已獲國際權威科學期刊《Nature Biomedical Engineering》刊載 。
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国内传媒报导
科大研发新型基因编辑策略，有助治疗阿尔茨海默症
由香港科技大学（科大）领导的国际研究团队，近期成功研发出一种新型全脑基因编辑技术，在小鼠模型中证明可以改善阿尔茨海默症（AD）的病理症状，有潜力发展成为AD的新型长效治疗手段。
据估计，中国有超过50万人罹患遗传性的阿尔茨海默症，即家族性阿尔茨海默症（FAD）。FAD是一种与家族史高度相关的先天性阿尔茨海默症。虽然FAD患者有明确的遗传病因，亦可在认知出现问题之前获得诊断，但目前还未有有效的治疗方法。
基因编辑技术1在治疗例如FAD这类由遗传基因突变引发的疾病方面，展现出巨大潜力。它可以在疾病症状出现之前，纠正引发疾病的基因突变，并且可以达到「一次治疗，长期有效」的治疗效果。不过，基因编辑技术的临床发展和应用还存在一些障碍。例如，目前尚缺乏有效、高效、非侵入式的运送工具，将基因编辑工具运送到大脑。此外，现有的基因组编辑技术，还无法在全脑范围发挥有效的治疗作用。
近日，由科大副校长(研究及发展)叶玉如教授领导的研究团队，研发出一种新型全脑基因编辑技术。该技术使用新型的运送工具，可以跨越血脑屏障，通过单次、无创的静脉注射，将优化的基因编辑工具运送到整个大脑，实现高效的全脑基因编辑。研究发现，这种技术可以有效破坏AD转基因小鼠模型中的FAD基因突变，并在全脑范围改善AD的病理症状，为开发新型AD治疗方法打下基础。
同时，研究团队还发现，AD转基因小鼠在接受基因编辑技术治疗的6个月后，即小鼠平均寿命的三分之一，其大脑中被认为引发AD神经退行病变的淀粉样蛋白斑块，仍然保持较低水平，证明了该基因编辑技术的单次治疗可以维持长期疗效。研究亦未在小鼠身上发现任何明显的副作用。
身兼科大晨兴生命科学教授及分子神经科学国家重点实验室主任的叶教授表示：「我们的研究工作首次实现了高效的全脑基因编辑，同时在全脑范围有效改善AD的病理症状。这是一项令人振奋的进展，在基因编辑技术应用到遗传性脑疾病治疗领域是一个重要里程碑，有助推动相关疾病的精准医疗发展。」
这项研究由科大、美国加州理工学院以及中国科学院深圳先进技术研究院的研究团队合作进行。研究结果已获国际权威科学期刊《Nature Biomedical Engineering》刊载。
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