靶向SARM1的脂质偶联siRNA可实现中枢神经系统沉默并减轻阿尔茨海默样表型
Lipid-conjugated siRNA targeting SARM1 enables CNS silencing and mitigates alzheimer-like phenotypes.
摘要(中文译文)
RNA干扰（RNAi）疗法已在肝脏疾病中取得临床成功，但其在中枢神经系统（CNS）疾病中的应用仍然有限。在此，我们开发了一种脂质偶联的siRNA，用于沉默含无菌α和TIR基序蛋白1（SARM1）——一种与神经炎症性损伤相关轴突变性的关键执行分子，并在类阿尔茨海默病模型中对其进行了评估。针对人SARM1和小鼠Sarm1保守区域的siRNA经设计并在神经细胞中筛选，采用C16脂质偶联联合5'-(E)-乙烯基膦酸酯（5'-VP）修饰以支持体内递送。在小鼠中，小脑延髓池内（ICM）给药两周时点降低了海马Sarm1 mRNA。在脑室内链脲佐菌素（STZ-ICV）模型中，两次ICM给药的VD07C减轻了多动行为，并部分改善了选定的空间记忆相关终点指标。VD07C还降低了海马SARM1蛋白和cADPR，增加了NAD，并与较低的p-Tau、胶质激活标志物及NF-κB/TNF-α表达相关。这些发现提供了分子与功能层面靶点结合的汇聚性证据，并支持在进展性神经退行性模型中进一步评估脂质偶联的SARM1 siRNA。
Abstract
RNA interference (RNAi) therapeutics have achieved clinical success in liver disease, but their application to central nervous system (CNS) disorders remains limited. Here, we developed a lipid-conjugated siRNA to silence sterile alpha and TIR motif-containing protein 1 (SARM1), a key executor of axon degeneration associated with neuroinflammatory injury, and evaluated it in an Alzheimer-like model. siRNAs targeting conserved regions of human SARM1 and mouse Sarm1 were designed and screened in neural cells, and C16 lipid conjugation together with a 5'-(E)-vinylphosphonate (5'-VP) modification was used to support in vivo delivery. In mice, intracisterna magna (ICM) administration reduced Sarm1 mRNA in the hippocampus at the two-week time point. In the intracerebroventricular streptozotocin (STZ-ICV) model, two ICM doses of VD07C attenuated hyperlocomotion and partially improved selected spatial-memory-related endpoints. VD07C also reduced hippocampal SARM1 protein and cADPR, increased NAD, and was associated with lower p-Tau, glial activation markers, and NF-κB/TNF-α expression. These findings provide convergent evidence of molecular and functional target engagement and support further evaluation of lipid-conjugated SARM1 siRNAs in progressive neurodegeneration models.
如何引用
AMA
Ying Cai, Qiongqiong Hou, Zihui Cheng, Yong Cheng, Enhua Zhang, Yizhe Li, et al. Lipid-conjugated siRNA targeting SARM1 enables CNS silencing and mitigates alzheimer-like phenotypes.. Bioorganic chemistry. 2026; doi:10.1016/j.bioorg.2026.110526.
APA
Ying Cai, Qiongqiong Hou, Zihui Cheng, Yong Cheng, Enhua Zhang, Yizhe Li, et al (2026). Lipid-conjugated siRNA targeting SARM1 enables CNS silencing and mitigates alzheimer-like phenotypes.. Bioorganic chemistry. https://doi.org/10.1016/j.bioorg.2026.110526
GB/T 7714
Ying Cai, Qiongqiong Hou, Zihui Cheng, Yong Cheng, Enhua Zhang, Yizhe Li, et al. Lipid-conjugated siRNA targeting SARM1 enables CNS silencing and mitigates alzheimer-like phenotypes.[J]. Bioorganic chemistry, 2026 doi:10.1016/j.bioorg.2026.110526.
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