Treating Adenovirus Conjunctivitis with Next-Gen siRNN RNAi Prodrugs

使用下一代 siRNN RNAi 前药治疗腺病毒结膜炎

• 批准号: 9228066
• 负责人: STEVEN F DOWDY
• 金额: $ 24.52万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9228066
• 关键词: Adenovirus Infections; Adenoviruses; Affect; American; Antibiotic Therapy; Antiviral Agents; Biological Assay; Biotechnology; Cells; Charge; Child; Conjunctivitis; Consequentialism; Contralateral; Data; Development; Dose; Drug Kinetics; Economic Burden; Edema; Epidemic Keratoconjunctivitis; Epithelial Cells; Epithelium; Eye; Eyelid structure; FDA approved; Family; Family member; Genes; Genome; Goals; Hyperemia; In Vitro; Individual; Infection; Luciferases; Mediating; Medical; Modeling; Mus; Nature; Oryctolagus cuniculus; Parents; Patients; Peptide Hydrolases; Pharmaceutical Preparations; Pharmacodynamics; Pre-Clinical Model; Prevention; Prodrugs; Production; Property; Proteins; Pruritus; Publishing; RNA; RNA Interference; Safety; Schools; Sclera; Small Interfering RNA; Solubility; Specificity; Surface; Symptoms; Testing; Therapeutic; Topical application; Toxic effect; Vertebral column; Virus; Virus Diseases; Work; clinical candidate; efficacy study; health economics; high risk; in vivo; in vivo imaging system; knock-down; next generation; ocular surface; particle; pre-clinical; prevent; prophylactic; response; small molecule inhibitor

ABSTRACT Conjunctivitis (pink eye) inflames the inner surface of the eyelid and sclera, and affects ~6 million Americans annually. Symptoms include hyperemia, edema, watery discharge, itching and burning. Adenovirus (AdV) infections account for ~70% of infectious conjunctivitis. AdV is highly contagious, spreads rapidly to the contralateral eye and to unaffected family members and co-workers. In the US, AdV Conjunctivitis causes >3 million missed school days per year with concomitant missed days of work for parents There are no FDA approved treatments for Adenoviral Conjunctivitis and $430M/yr is wasted on ineffective antibiotic therapy. RNA Interference (RNAi) responses have great potential to target the entire Adenovirus genome, including critical genes required for production of infectious virus, such as the L3 Protease. The goal of this project is to treat preclinical models of ocular adenovirus with our next-generation RNAi prodrug, called RiboNucleic Neutrals (siRNNs). Unlike siRNAs, siRNNs have many drug-like properties of extreme stability and deliverability. Importantly, RNAi responses last for >one month, which means patients and their families would only a require a single dose. We hypothesize that selective ocular RNAi knockdown of the AdV L3 gene (Protease, pVI, Hexon) will prevent AdV infectious particle maturation, thereby treating and preventing AdV EKC, with an acceptable efficacy/toxicity ratio to treat the infected eye and prevent spread to the contralateral eye with a safety profile that permits its use in children and prophylactically in uninfected individuals. Aim 1: Optimize siRNN Topical Delivery in Mice Expressing Ocular Luciferase We will optimize L3 siRNN RNAi triggers targeting the critical L3 gene in Adenovirus that encodes the Protease and delivery into the ocular epithelium. Aim 2: Treat Adenovirus Rabbit Models with siRNNs Targeting Adenovirus L3 Gene Using L3 siRNN RNAi triggers, we will perform a Prevention study and an Antiviral Efficacy study in rabbit models to inhibit production and spread of infectious Adenovirus. Our overarching goal is to use the data generated by this study to move the next-gen L3 TAT-siRNN RNAi trigger forward towards declaring a clinical candidate for IND-enabling studies.

抽象的 结膜炎（粉红色的眼睛）膨胀了眼睑和巩膜的内表面，影响约600万 美国人每年。症状包括充血，水肿，水流血，瘙痒和燃烧。 腺病毒（ADV）感染占感染性结膜炎的70％。 ADV具有高度传染性， 迅速传播到对侧眼睛，以及未受影响的家庭成员和同事。在美国， ADV结膜炎的原因> 300万每年错过上学天，而伴随的工作天数 对于父母，没有FDA批准的腺病毒结膜治疗方法 浪费了无效的抗生素疗法。 RNA干扰（RNAi）反应具有很大的潜力 靶向整个腺病毒基因组，包括产生传染病所需的关键基因 例如L3蛋白酶。该项目的目的是用 我们的下一代RNAi前药，称为核糖核中性（Sirnns）。与sirnas不同，sirnns有 极端稳定性和可传递性的许多类似药物的特性。重要的是，RNAi响应持续 >一个月，这意味着患者及其家人只需要一次剂量。 我们假设ADV L3基因的选择性眼RNAi敲低（Protease，PVI，Hexon） 将防止ADV传染性粒子成熟，从而通过 可接受的疗效/毒性比治疗感染的眼睛并防止对侧眼对侧眼 安全性，允许在未感染的个体中使用其在儿童中使用并进行预防。 AIM 1：优化表达眼荧光素酶的小鼠中的SiRNN局部递送 我们将优化针对腺病毒中临界L3基因的L3 SIRNN RNAI触发器编码的临界L3基因 蛋白酶和输送到眼上皮。 AIM 2：用靶向腺病毒L3基因的SIRNN处理腺病毒兔模型 使用L3 Sirnn RNAi触发器，我们将进行预防研究和一项抗病毒功效研究 兔模型抑制感染性腺病毒的产生和传播。 我们的总体目标是使用本研究生成的数据移动下一代L3 Tat-sirnn RNAi向前触发了宣布临床研究的临床候选者。