RNA-LEVEL THERAPEUTICS FOR HEPATITIS B AND DELTA VIRUSES

每年发生数千万例B型肝炎病毒（HBV）感染， 导致后遗症，估计每年夺去一百万人的生命。 此外，HBV感染可能伴随着第二次致命的 嗜肝性病原体，与丁型肝炎的临床结果。 虽然 有效的HBV疫苗是可用的，它不能用于治疗慢性 HBV是一种困扰全世界约3亿人的疾病， 大约一百万美国人。 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，没有一种被证明是 对大多数患者有效。 因此，我们正在解决 寻找治疗B型肝炎和丁型肝炎的新疗法。 我们的许多 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HBV RNA疗法通过多种途径起作用， 生物化学途径，并将需要新的输送系统。 的 治疗性RNA和将它们递送到细胞的系统将被 同时进行评估，每一个都有可能产生重大影响。 为开发新的抗病毒疗法做出贡献。 主要 所采用的技术是RNA合成所需的技术， 鉴定，DNA水平的基因工程，蛋白质和抗体 制备以及细胞和病毒的体外增殖。 RNA治疗控制HBV和Delta肝炎 本提案的具体目标是： （i）通过治疗用途靶向HBV RNA以进行周转或失活， 抗乙肝病毒RNA分子。 （二）开发全合成和病毒运载系统， 将抗HBV RNA导入肝细胞。 （iii）设计一种受体介导的摄取系统， 细胞，从而允许安全使用细胞毒性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.