靶向鸟氨酸氨甲酰转移酶缺陷症的 mRNA 疗法。
Targeted mRNA Therapy for Ornithine Transcarbamylase Deficiency.
机构信息
PhaseRx, Inc., 410 W. Harrison Street, Suite 300, Seattle, WA 98119, USA.
PhaseRx, Inc., 410 W. Harrison Street, Suite 300, Seattle, WA 98119, USA.
出版信息
Mol Ther. 2018 Mar 7;26(3):801-813. doi: 10.1016/j.ymthe.2017.12.024. Epub 2018 Jan 4.
Abstract
We describe a novel, two-nanoparticle mRNA delivery system and show that it is highly effective as a means of intracellular enzyme replacement therapy (i-ERT) using a murine model of ornithine transcarbamylase deficiency (OTCD). Our Hybrid mRNA Technology delivery system (HMT) comprises an inert lipid nanoparticle that protects the mRNA from nucleases in the blood as it distributes to the liver and a polymer micelle that targets hepatocytes and triggers endosomal release of mRNA. This results in high-level synthesis of the desired protein specifically in the liver. HMT delivery of human OTC mRNA normalizes plasma ammonia and urinary orotic acid levels, and leads to a prolonged survival benefit in the murine OTCD model. HMT represents a unique, non-viral mRNA delivery method that allows multi-dose, systemic administration for treatment of single-gene inherited metabolic diseases.
摘要
我们描述了一种新型的双纳米颗粒 mRNA 递药系统，并通过鸟氨酸氨甲酰基转移酶缺陷症（OTCD）的小鼠模型显示，该系统在作为细胞内酶替代疗法（i-ERT）的手段时非常有效。我们的 Hybrid mRNA Technology 递药系统（HMT）由惰性脂质纳米颗粒组成，该纳米颗粒在分布到肝脏的过程中保护 mRNA 免受血液中核酸酶的侵害，而聚合物胶束则靶向肝细胞并触发 mRNA 的内体释放。这导致所需蛋白质在肝脏中高水平合成。HMT 递送人 OTC mRNA 可使血浆氨和尿乳清酸水平正常化，并延长 OTCD 模型中小鼠的生存获益。HMT 代表了一种独特的非病毒 mRNA 递药方法，可实现多剂量、系统给药，用于治疗单基因遗传性代谢疾病。
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