量化和减轻反义寡核苷酸在中枢神经系统中诱导的运动表型

IF 12.1 1区 医学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY
Molecular Therapy Pub Date : 2024-12-04 Epub Date: 2024-10-28 DOI:10.1016/j.ymthe.2024.10.024
Michael P Moazami, Julia M Rembetsy-Brown, Samantha L Sarli, Holly R McEachern, Feng Wang, Masahiro Ohara, Atish Wagh, Karen Kelly, Pranathi Meda Krishnamurthy, Alexandra Weiss, Miklos Marosfoi, Robert M King, Mona Motwani, Heather Gray-Edwards, Katherine A Fitzgerald, Robert H Brown, Jonathan K Watts
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引用次数: 0

摘要

反义寡核苷酸(ASOs)正在成为治疗神经系统疾病的一类前景广阔的疗法。反义寡核苷酸直接注入脑脊液后,可广泛分布于大脑各区域,并产生持久的治疗效果。然而,许多硫代磷酸酯(PS)修饰的间隙聚合物 ASO 在注入脑脊液后会出现短暂的运动表型,从运动活动减少到共济失调或急性癫痫发作样表型。我们使用一种行为评分测定法来反映这些效应的时间和性质,结果表明糖和磷酸修饰都会影响急性运动表型。在糖类似物中,DNA 诱导的运动表型最强,而 2'- 取代的 RNA 修饰提高了 PS-ASO 的耐受性。减少含有一段 PS-DNA 的间隙聚合物 ASO 的 PS 含量可改善其毒性特征,但在某些情况下也会降低药效或缩短药效持续时间。我们的研究表明,这种急性毒性并非由主要的核酸感应免疫途径介导。在注射前用二价离子配制 ASO 并避免使用磷酸盐缓冲液可适度改善耐受性,其机制至少部分不同于 PS 含量的降低。总之,我们的工作确定并量化了中枢神经系统寡核苷酸毒理学中一个未被充分研究的方面,探索了其机制,并提出了平台级药物化学和制剂方法,从而提高了这类化合物的耐受性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Quantifying and mitigating motor phenotypes induced by antisense oligonucleotides in the central nervous system.

Antisense oligonucleotides (ASOs) are emerging as a promising class of therapeutics for neurological diseases. When injected directly into cerebrospinal fluid, ASOs distribute broadly across brain regions and exert long-lasting therapeutic effects. However, many phosphorothioate (PS)-modified gapmer ASOs show transient motor phenotypes when injected into the cerebrospinal fluid, ranging from reduced motor activity to ataxia or acute seizure-like phenotypes. Using a behavioral scoring assay customized to reflect the timing and nature of these effects, we show that both sugar and phosphate modifications influence acute motor phenotypes. Among sugar analogs, DNA induces the strongest motor phenotypes while 2'-substituted RNA modifications improve the tolerability of PS ASOs. Reducing the PS content of gapmer ASOs, which contain a stretch of PS-DNA, improves their toxicity profile, but in some cases also reduces efficacy or duration of effect. We show that this acute toxicity is not mediated by major nucleic acid sensing immune pathways. Formulating ASOs with divalent ions before injection and avoiding phosphate-based buffers modestly improved tolerability through mechanisms at least partially distinct from reduced PS content. Overall, our work identifies and quantifies an understudied aspect of oligonucleotide toxicology in the CNS, explores its mechanism, and presents platform-level medicinal chemistry and formulation approaches that improve tolerability of this class of compounds.

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来源期刊
Molecular Therapy
Molecular Therapy 医学-生物工程与应用微生物
CiteScore
19.20
自引率
3.20%
发文量
357
审稿时长
3 months
期刊介绍: Molecular Therapy is the leading journal for research in gene transfer, vector development, stem cell manipulation, and therapeutic interventions. It covers a broad spectrum of topics including genetic and acquired disease correction, vaccine development, pre-clinical validation, safety/efficacy studies, and clinical trials. With a focus on advancing genetics, medicine, and biotechnology, Molecular Therapy publishes peer-reviewed research, reviews, and commentaries to showcase the latest advancements in the field. With an impressive impact factor of 12.4 in 2022, it continues to attract top-tier contributions.
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