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

描述（由申请人提供）：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。全世界约有1000万至1500万人感染HDV。缺乏对急性形式的疾病的有效治疗以及目前对慢性感染的治疗的有限功效证明了开发抗HDV治疗剂的新策略的合理性。缺乏HDV编码的“可药物化”靶点，适用于常规治疗方式，如小分子和抗体，使RNA干扰成为靶向这种病毒的有吸引力的替代方法。在这个I期SBIR提案中，我们建议使用SomaGenics为其丙型肝炎项目开发的平台开发抗HDV抑制剂，其中化学修饰的合成小shRNA（sshRNA）与脂质纳米颗粒一起配制，在临床前动物模型中产生有效的病毒敲除。为了有效地抑制HDV复制，我们计划开发针对病毒复制期间产生的所有三种RNA种类的sshRNA。这些sshRNA抑制剂将使用基于细胞的HDV复制测定来鉴定。将在转基因小鼠模型中验证这些sshRNA抑制剂单独和组合的功效。拟议的研究将有助于确定RNAi治疗HDV的最佳RNA靶点，并为进一步开发抗HDV治疗药物提供线索。

DESCRIPTION (provided by applicant): 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 10-15 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. In this Phase I SBIR proposal, we propose to develop anti-HDV inhibitors using a platform developed by SomaGenics for its hepatitis C program in which chemically modified, synthetic small shRNAs (sshRNAs), formulated with lipid nanoparticles, produced effective viral knockdown in preclinical animal models. To effectively inhibit HDV replication, we plan to develop sshRNAs against all three RNA species generated during viral replication. These sshRNA inhibitors will be identified using a cell-based HDV replication assay. The efficacy of these sshRNA inhibitors, individually and in combination, will be validated in a transgenic mouse model. The proposed studies should help identify the best RNA targets for RNAi therapeutic approaches to HDV as well as provide leads for further development as anti-HDV therapeutics.