Delivery of Antisense Morpholino Oligonucleotides

反义疗法为治疗多种人类疾病带来了巨大的希望。这些疗法的基础是选择性地抑制特定信使RNA或前信使RNA的表达。由于反义药物具有高度的特异性，理论上与传统药物相比，它们的副作用更少，毒性更小。此外，由于反义剂通过与靶RNA分子中的互补序列结合来发挥作用，因此设计反义剂来特异性地抑制特定的RNA物种是非常简单的。阻碍反义药物有效使用的一个主要因素是这些分子在体内运送到细胞并被细胞内化的效率很低。最近，Mirus公司的研究人员开发了一种新的非病毒颗粒技术，该技术已被证明可以在体内高效地将质粒DNA输送到肝细胞。这项第一阶段研究提出的一个主要目标是确定是否可以利用这种颗粒技术将一类新的高效反义药物--吗啉寡核苷酸--运送到体内的肝细胞。在这些研究中，我们还将开发一种方法来评估反义吗啉寡核苷酸在体内抑制肝细胞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一个障碍是缺乏有效的递送方法。一种高效的体内反义吗啉寡核苷酸递送系统将立即获得大型制药和生物技术公司的使用许可。

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.