Therapeutic Development of RNAi-based inhibitors against the Hepatitis Delta Virus

摘要 丁型肝炎病毒（HDV）感染是最严重的病毒性肝炎类型，通常会导致 加速肝损伤，导致终末期肝病。大约1500万到2000万 全世界的人都感染了HDV。缺乏有效的治疗 急性形式的疾病和有限的疗效，目前的治疗慢性 感染证明了开发抗HDV治疗剂的新策略。的 缺乏适合于常规治疗的HDV编码的“可药物化”靶点 小分子和抗体等方式使RNA干扰成为可能， 有吸引力的替代方法来针对这种病毒。然而，高度结构化的GC- 这种最小的RNA病毒丰富的环状基因组使其成为一个具有挑战性的目标， RNA靶向方法，如RNAi。在这个项目的第一阶段，我们能够 使用SomaGenics的sshRNA®（合成的小shRNA）鉴定HDV抑制剂 平台这些sshRNA在细胞中的多个靶位点有效地抑制病毒复制 培养感染模型然后对sshRNA进行化学修饰，以改善其 药物性质。在第2阶段，我们计划将该项目推进到临床前阶段， 使用支持HDV感染的转基因小鼠模型的研究。我们将奉行 将我们的治疗性sshRNA递送至肝脏的双重方法：脂质制剂 纳米颗粒和靶向配体的用途。化学修饰的模式将是 针对每种候选交付方法进行了优化，以便进行仔细比较， 将选择最有希望的方法。最后，sshRNA的组合将是 评估提供更高功效和预防发展的能力 对治疗的抵抗到第二阶段结束时，我们预计将建立一个鸡尾酒， 抑制剂准备进行IND使能安全性研究，然后开始临床试验 问题研究

Abstract Hepatitis D virus (HDV) infection is the most severe type of viral hepatitis, often causing accelerated liver damage that leads to end-stage liver disease. About 15–20 million individuals are infected by HDV worldwide. The absence of an effective treatment for acute forms of the disease and the limited efficacy of current treatments for the chronic infection justify novel strategies towards the development of anti-HDV therapeutics. The lack of HDV-encoded “druggable” targets that are suitable for conventional therapeutic modalities such as small molecules and antibodies makes RNA interference an attractive alternative approach to target this virus. However, the highly structured, GC- rich circular genome of this smallest of RNA viruses make it a challenging target for RNA-targeting approaches such as RNAi. In Phase I of this project, we were able to identify inhibitors of HDV using SomaGenics' sshRNA® (synthetic small shRNAs) platform. These sshRNAs potently inhibit viral replication at multiple target sites in a cell culture infection model. The sshRNAs were then chemically modified to improve their drug-like properties. In Phase 2, we plan to move the program forward into preclinical studies using a transgenic mouse model that supports HDV infection. We will pursue dual approaches to delivery of our therapeutic sshRNAs to liver: formulation with lipid nanoparticles and use of a targeting ligand. Patterns of chemical modification will be optimized for each candidate delivery method to permit a careful comparison, and the most promising approach will be selected. Finally, combinations of sshRNAs will be assessed for ability to provide increased efficacy and forestall the development of resistance to therapy. By the end of Phase II, we expect to have established a cocktail of inhibitors ready for IND-enabling safety studies and then commencement of clinical studies.