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.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
PDF的下载单位、IP信息已删除 (2025-6-4)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
木木应助魁梧的向薇采纳,获得10
4秒前
ding应助寒冷的咖啡采纳,获得10
4秒前
阿钉完成签到,获得积分10
6秒前
10秒前
研友_VZG7GZ应助刘浩营采纳,获得10
10秒前
11秒前
传奇3应助@@@采纳,获得10
11秒前
14秒前
flameWei发布了新的文献求助10
14秒前
17秒前
科研通AI2S应助水流众生采纳,获得10
17秒前
21秒前
21秒前
21秒前
慕青应助平常的元蝶采纳,获得10
27秒前
善学以致用应助Skuld采纳,获得10
27秒前
chrainy发布了新的文献求助10
27秒前
CyrusSo524应助黎乐荷采纳,获得10
27秒前
刘浩营发布了新的文献求助10
28秒前
28秒前
29秒前
29秒前
量子星尘发布了新的文献求助10
30秒前
生姜完成签到,获得积分10
31秒前
32秒前
33秒前
zhaozhaozhao发布了新的文献求助10
34秒前
34秒前
34秒前
34秒前
flameWei关注了科研通微信公众号
35秒前
chrainy完成签到,获得积分10
35秒前
Bio应助科研通管家采纳,获得30
35秒前
领导范儿应助科研通管家采纳,获得10
35秒前
大模型应助科研通管家采纳,获得10
35秒前
czh应助科研通管家采纳,获得10
35秒前
慕青应助科研通管家采纳,获得10
35秒前
35秒前
田様应助科研通管家采纳,获得10
35秒前
小二郎应助科研通管家采纳,获得10
35秒前
高分求助中
A new approach to the extrapolation of accelerated life test data 1000
ACSM’s Guidelines for Exercise Testing and Prescription, 12th edition 500
‘Unruly’ Children: Historical Fieldnotes and Learning Morality in a Taiwan Village (New Departures in Anthropology) 400
Indomethacinのヒトにおける経皮吸収 400
Phylogenetic study of the order Polydesmida (Myriapoda: Diplopoda) 370
基于可调谐半导体激光吸收光谱技术泄漏气体检测系统的研究 350
Robot-supported joining of reinforcement textiles with one-sided sewing heads 320
热门求助领域 (近24小时)
化学 材料科学 医学 生物 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 遗传学 基因 物理化学 催化作用 冶金 细胞生物学 免疫学
热门帖子
关注 科研通微信公众号,转发送积分 3988975
求助须知:如何正确求助?哪些是违规求助? 3531316
关于积分的说明 11253424
捐赠科研通 3269917
什么是DOI,文献DOI怎么找? 1804830
邀请新用户注册赠送积分活动 882063
科研通“疑难数据库(出版商)”最低求助积分说明 809068