Cell Type Distribution of Intrathecal Antisense Oligonucleotide Activity in Deep Brain Regions of Non-Human Primates.

IF 4.7 2区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Jeannine A Frei, Juliana E Gentile, Yuan Lian, Meredith A Mortberg, Juliana Capitanio, Paymaan Jafar-Nejad, Sonia M Vallabh, Hien T Zhao, Eric Vallabh Minikel
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引用次数: 0

Abstract

Intrathecally administered RNase H1-active gapmer antisense oligonucleotides (ASOs) are promising therapeutics for brain diseases where lowering the expression of one target gene is expected to be therapeutically beneficial. Such ASOs are active, to varying degrees, across most or all cell types in the cortex and cerebellum of mouse and non-human primate (NHP) brain regions with substantial drug accumulation. Intrathecally delivered ASOs, however, exhibit a gradient of exposure across the brain, with more limited drug accumulation and weaker target engagement in deep brain regions of NHP. Here, we profiled the activity of a tool, ASO, against Malat1 in three deep brain regions of NHP: thalamus, caudate, and putamen. All neuronal subtypes exhibited knockdown similar to, or deeper than, the bulk tissue. Among non-neuronal cells, knockdown was deepest in microglia and weakest in endothelial stalk. Overall, we observed broad target engagement across all cell types detected, supporting the relevance of intrathecal ASOs to diseases with deep brain involvement.

非人灵长类动物脑深部鞘内反义寡核苷酸活性的细胞类型分布。
鞘内给药RNase h1活性间隙子反义寡核苷酸(ASOs)是治疗脑部疾病的有希望的治疗方法,其中降低一个靶基因的表达有望在治疗上有益。这些ASOs在小鼠和非人类灵长类动物(NHP)具有大量药物积累的大脑区域的皮层和小脑中的大多数或所有细胞类型中都有不同程度的活性。然而,鞘内递送的ASOs在整个大脑中呈现梯度暴露,在NHP的深部脑区具有更有限的药物积累和更弱的靶标参与。在这里,我们分析了一种工具ASO在NHP的三个深部脑区(丘脑、尾状体和壳核)中对Malat1的活性。所有神经元亚型都表现出与大组织相似或比大组织更深的敲除。在非神经元细胞中,小胶质细胞中敲除最深,内皮细胞柄中敲除最弱。总的来说,我们在所有检测到的细胞类型中观察到广泛的靶标参与,支持鞘内ASOs与深部脑受累疾病的相关性。
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来源期刊
Nucleic acid therapeutics
Nucleic acid therapeutics BIOCHEMISTRY & MOLECULAR BIOLOGY-CHEMISTRY, MEDICINAL
CiteScore
7.60
自引率
7.50%
发文量
47
审稿时长
>12 weeks
期刊介绍: Nucleic Acid Therapeutics is the leading journal in its field focusing on cutting-edge basic research, therapeutic applications, and drug development using nucleic acids or related compounds to alter gene expression. The Journal examines many new approaches for using nucleic acids as therapeutic agents or in modifying nucleic acids for therapeutic purposes including: oligonucleotides, gene modification, aptamers, RNA nanoparticles, and ribozymes.
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