• 肽瑞禾

鼻內遞送肽藥物改善阿爾茨海默轉基因小鼠的認知能力下降


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引用 | EMBO Molecular Medicine報導


An intranasally delivered peptide drug ameliorates cognitive decline in Alzheimer transgenic mice

Abstract 阿爾茨海默病 (AD) 是最常見的神經退行性疾​​病。澱粉樣蛋白 β (Aβ) 肽的產生和清除之間的不平衡被認為是 AD 發病機制的主要機制。這一澱粉樣蛋白假說得到了人類抗澱粉樣蛋白抗體 aducanumab 最近在 Ib 期試驗中清除斑塊和減緩前驅或輕度患者的臨床損傷的成功的支持。在這裡,設計了一種結合聚精氨酸 (polyR)(用於電荷排斥)和源自 Aβ 澱粉樣蛋白核心區域(用於序列識別)的片段的肽。使用APP/PS1評估設計的肽 R 8 -Aβ(25-35) 在減少澱粉樣蛋白和改善認知功能方面的功效雙轉基因小鼠。PEI 偶聯的 R 8 -Aβ(25-35) 肽的每日鼻內給藥顯著減少了 Aβ 澱粉樣蛋白的積累並改善了轉基因小鼠的記憶缺陷。鼻內給藥是肽遞送的可行途徑。結合 polyR 和聚集體形成片段的模塊化設計產生了理想的治療效果,並且可以很容易地用於設計其他蛋白質聚集體相關疾病的治療肽。 Alzheimer's disease (AD) is the most common neurodegenerative disease. Imbalance between the production and clearance of amyloid β (Aβ) peptides is considered to be the primary mechanism of AD pathogenesis. This amyloid hypothesis is supported by the recent success of the human anti-amyloid antibody aducanumab, in clearing plaque and slowing clinical impairment in prodromal or mild patients in a phase Ib trial. Here, a peptide combining polyarginines (polyR) (for charge repulsion) and a segment derived from the core region of Aβ amyloid (for sequence recognition) was designed. The efficacy of the designed peptide, R8-Aβ(25–35), on amyloid reduction and the improvement of cognitive functions were evaluated using APP/PS1 double transgenic mice. Daily intranasal administration of PEI-conjugated R8-Aβ(25–35) peptide significantly reduced Aβ amyloid accumulation and ameliorated the memory deficits of the transgenic mice. Intranasal administration is a feasible route for peptide delivery. The modular design combining polyR and aggregate-forming segments produced a desirable therapeutic effect and could be easily adopted to design therapeutic peptides for other proteinaceous aggregate-associated diseases.


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