Stereochemistry Enhances Potency, Efficacy, and Durability of Malat1 Antisense Oligonucleotides In Vitro and In Vivo in Multiple Species

马拉特1 寡核苷酸 体内 效力 离体 药理学 体外 核糖核酸 生物 分子生物学 化学 生物化学 DNA 长非编码RNA 遗传学 基因
作者
Michael Byrne,Vinod Vathipadiekal,Luciano H. Apponi,Naoki Iwamoto,Kandasamy Pachamuthu,Kenneth A. Longo,Fangjun Liu,Richard Looby,Lauren Norwood,Anee Shah,Juili Dilip Shelke,Chikdu Shakti Shivalila,Hailin Yang,Yuan Yin,Lankai Guo,Keith Bowman,Chandra Vargeese
出处
期刊:Translational Vision Science & Technology [Association for Research in Vision and Ophthalmology]
卷期号:10 (1): 23-23 被引量:10
标识
DOI:10.1167/tvst.10.1.23
摘要

Purpose: Antisense oligonucleotides have been under investigation as potential therapeutics for many diseases, including inherited retinal diseases. Chemical modifications, such as chiral phosphorothioate (PS) backbone modification, are often used to improve stability and pharmacokinetic properties of these molecules. We aimed to generate a stereopure MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) antisense oligonucleotide as a tool to assess the impact stereochemistry has on potency, efficacy, and durability of oligonucleotide activity when delivered by intravitreal injection to eye. Methods: We generated a stereopure oligonucleotide (MALAT1-200) and assessed the potency, efficacy, and durability of its MALAT1 RNA-depleting activity compared with a stereorandom mixture, MALAT1-181, and other controls in in vitro assays, in vivo mouse and nonhuman primate (NHP) eyes, and ex vivo human retina cultures. Results: The activity of the stereopure oligonucleotide is superior to its stereorandom mixture counterpart with the same sequence and chemical modification pattern in in vitro assays, in vivo mouse and NHP eyes, and ex vivo human retina cultures. Findings in NHPs showed durable activity of the stereopure oligonucleotide in the retina, with nearly 95% reduction of MALAT1 RNA maintained for 4 months postinjection. Conclusions: An optimized, stereopure antisense oligonucleotide shows enhanced potency, efficacy, and durability of MALAT1 RNA depletion in the eye compared with its stereorandom counterpart in multiple preclinical models. Translational Relevance: As novel therapeutics, stereopure oligonucleotides have the potential to enable infrequent administration and low-dose regimens for patients with genetic diseases of the eye.
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