Delivery of Antisense Morpholino Oligonucleotides

反义吗啉代寡核苷酸的递送

• 批准号: 6404305
• 负责人: David Lawrence Lewis
• 金额: $ 11.12万
• 依托单位: MIRUS BIO CORPORATION
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-28 至 2002-07-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6404305
• 关键词: antisense nucleic acid; drug delivery systems; drug design /synthesis /production; gene delivery system; laboratory mouse; liver cells; oligonucleotides; peptide chemical synthesis; technology /technique development

Antisense therapies hold tremendous promise for treating a wide variety of human diseases. These therapies are based on the selective inhibition of expression of specific messenger RNA or pre-messenger RNAs. Because they are highly specific, antisense agents could in theory have fewer side effects and display less toxicity than traditional drugs. In addition, because antisense agents exert their effects by binding to a complementary sequence in a target RNA molecule, designing antisense agents to specifically inhibit a particular RNA species is extremely straightforward. A major factor hindering the effective use of anfsense agents is the low efficiency at which these molecules are delivered to, and internalized by, cells in vivo. Recently, researchers at Mirus Corporation have developed a novel, non-viral particle technology that has been shown to be highly effective at delivering plasmid DNA to hepatocytes in vivo. A major goal of the research proposed in this Phase 1 study is to determine if this particle technology can be utilized to deliver a new, highly effective class of antisense agents, named morpholino oligonucleotides, to hepatocytes in vivo. In these studies, we will also develop an assay to assess the ability of antisense morpholino oligonucleotides to inhibit the expression of an endogenous gene in hepatocytes in vivo. PROPOSED COMMERCIAL APPLICATIONS: A roadblock in the development of antisense reagents for use in treating disease is the lack of efficient delivery methods. An efficient in vivo delivery system for antisense morpholino oligonucleotides would immediately be licensed for use by larger pharmaceutical and biotechnology companies.

反义疗法在治疗多种人类疾病方面具有巨大的前景。这些疗法基于选择性抑制特定信使RNA或前信使RNA的表达。因为它们是高度特异性的，反义药物在理论上可以比传统药物具有更少的副作用和更低的毒性。此外，由于反义试剂通过结合靶RNA分子中的互补序列来发挥其作用，因此设计特异性抑制特定RNA种类的反义试剂是非常简单的。阻碍反义试剂有效使用的主要因素是这些分子在体内递送至细胞并被细胞内化的低效率。最近，Mirus公司的研究人员开发了一种新型的非病毒颗粒技术，该技术已被证明在体内将质粒DNA递送到肝细胞方面非常有效。在这项1期研究中提出的研究的一个主要目标是确定这种颗粒技术是否可以用于在体内向肝细胞递送一类新的高效反义药物，即吗啉代寡核苷酸。在这些研究中，我们还将开发一种测定法来评估反义吗啉代寡核苷酸抑制肝细胞中内源性基因表达的能力。拟议的商业应用：开发用于治疗疾病的反义试剂的障碍是缺乏有效的递送方法。一种有效的反义吗啉代寡核苷酸体内输送系统将立即被大型制药和生物技术公司许可使用。