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

基于RNAi的丁型肝炎病毒抑制剂的治疗开发

• 批准号: 8586225
• 负责人: Brian H. Johnston
• 金额: $ 38.96万
• 依托单位: SOMAGENICS, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8586225
• 关键词: Acute; Address; Animal Model; Antibodies; Biological Assay; Catalytic RNA; Cell Culture Techniques; Cells; Chronic; Cleaved cell; Collection; Computer software; Development; Disease; Drug Formulations; Elements; Genomics; Genotype; Goals; Health; Health Care Costs; Hepatitis B Virus; Hepatitis C; Hepatitis D; Hepatitis Delta Virus; Hepatitis delta Antigens; Immune; Individual; Infection; Interferon-alpha; Lead; Life Cycle Stages; Lipids; Liver diseases; Messenger RNA; Modality; Modeling; Patients; Pharmaceutical Preparations; Phase; Positioning Attribute; Property; RNA; RNA Interference; Relapse; Satellite Viruses; Savings; Sequence Alignment; Small Business Innovation Research Grant; Staging; System; Testing; Therapeutic; TimeLine; Transcription Process; Transgenic Mice; Viral; Viral hepatitis; Virus; Virus Diseases; Virus Inhibitors; Virus Replication; anti-hepatitis D; base; combat; design; drug withdrawal; effective therapy; efficacy testing; experience; in vivo; inhibitor/antagonist; liver injury; liver transplantation; mouse model; nanoparticle; novel strategies; pre-clinical; programs; public health relevance; small hairpin RNA; small molecule; success; therapeutic development; viral resistance

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.

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，通常会导致加速肝损伤，导致终末期肝病。全球约有 10-1500 万人感染丁型肝炎病毒。由于缺乏对该疾病的急性形式的有效治疗，并且目前对慢性感染的治疗效果有限，因此证明了开发抗 HDV 疗法的新策略是合理的。由于缺乏适用于小分子和抗体等传统治疗方式的 HDV 编码的“可成药”靶标，使得 RNA 干扰成为针对该病毒的有吸引力的替代方法。在这一第一期 SBIR 提案中，我们建议使用 SomaGenics 为其丙型肝炎项目开发的平台来开发抗 HDV 抑制剂，其中化学修饰的合成小 shRNA (sshRNA)，采用脂质纳米粒子配制，在临床前动物模型中产生有效的病毒抑制。为了有效抑制 HDV 复制，我们计划开发针对病毒复制过程中产生的所有三种 RNA 的 sshRNA。这些 sshRNA 抑制剂将使用基于细胞的 HDV 复制测定进行鉴定。这些 sshRNA 抑制剂单独和组合的功效将在转基因小鼠模型中得到验证。拟议的研究应有助于确定 HDV RNAi 治疗方法的最佳 RNA 靶标，并为进一步开发抗 HDV 疗法提供线索。