RNA-LEVEL THERAPEUTICS FOR HEPATITIS B AND DELTA VIRUSES

每年有数千万人感染乙肝病毒， 导致后遗症，估计每年夺走100万人的生命。 此外，乙肝病毒感染可能伴随着第二个致命的 嗜肝病原体，以丁型肝炎为主的临床结果。虽然 一种有效的乙肝疫苗是可用的，它不能用于治疗慢性 乙肝病毒，一种折磨着全球约3亿人的疾病， 大约有一百万美国人。此外，虽然干扰素和其他 药物已经在临床试验中进行了评估，没有一种药物被证明是正确的 对大多数患者有效。因此，我们正在解决以下需求 寻找治疗乙肝和三角洲肝炎的新疗法。我们中的许多人 所有涉及RNA生物化学的方法都有可能成为 适用于治疗其他病毒性疾病。 我们设计的抗HBVRNA疗法通过多种途径发挥作用 生物化学途径，并将需要新的输送系统。这个 治疗性RNA和将它们输送到细胞的系统将是 并行评估，每个评估都有可能产生显著的 对新的抗病毒疗法的开发做出了贡献。主 将采用的技术是RNA合成所需的技术和 生物学特性、DNA水平的基因工程、蛋白质和抗体 制备，细胞和病毒的体外繁殖。 RNA疗法在控制乙肝和丁型肝炎中的作用 这项建议的具体目标是： (I).通过治疗用途针对HBVRNA的周转或失活 抗乙肝病毒核糖核酸分子。 (Ii)开发完全合成和病毒递送系统，用于 将抗HBVRNA导入肝细胞。 (三).设计针对乙肝病毒感染的受体介导的摄取系统 因此，可以安全地使用细胞毒性RNA寡核苷酸。

Tens of millions of hepatitis B virus (HBV) infections occur annually, leading to sequelae which claim an estimated one million lives each year. Furthermore, HBV infections may be accompanied by a second deadly hepatotropic pathogen, with delta hepatitis the clinical result. Although an effective HBV vaccine is available, it cannot be used to treat chronic HBV, a condition afflicting about 300 million people world wide and approximately one million Americans. Moreover, while interferons and other drugs have been evaluated in clinical trials, none has proven to be effective for the majority of patients. Thus, we are addressing the need for new therapeutics to treat hepatitis B and delta hepatitis. Many of our approaches, which all involve RNA biochemistry, have the potential to be adapted for the treatment of additional viral diseases. The anti-HBV RNA therapeutics we have designed act through a variety of biochemical pathways and will require new delivery systems. The therapeutic RNAs and the systems for delivering them to cells will be evaluated in parallel, with each having the potential to make a significant contribution to the development of new antiviral therapies. The main techniques to be employed are those needed for RNA synthesis and characterization, DNA-level genetic engineering, protein and antibody preparation, and cell and virus propagation in vitro. RNA Therapeutics for Control of HBV and Delta Hepatitis The Specific Aims of this Proposal Are: (i).To target HBV RNAs for turnover or inactivation by the therapeutic use of anti-HBV RNA molecules. (ii).To develop both fully synthetic and viral delivery systems for the introduction of anti-HBV RNAs into liver cells. (iii).To design a receptor-mediated uptake system specific for HBV-infected cells and thereby allow the safe use of cytotoxic RNA oligonucleotides.