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.

摘要 结膜炎（红眼病）使眼睑和巩膜的内表面发炎，影响约600万人 美国人每年症状包括充血、水肿、水样分泌物、瘙痒和烧灼感。 腺病毒（AdV）感染约占感染性结膜炎的70%。腺病毒具有高度传染性， 迅速传播到对侧眼和未受影响的家庭成员和同事。在美国， AdV结膜炎每年导致超过300万个缺课日，同时也导致工作日缺课 对于父母来说，目前还没有FDA批准的腺病毒结膜炎治疗方法， 浪费在无效的抗生素治疗上RNA干扰（RNAi）反应具有很大的潜力， 靶向整个腺病毒基因组，包括产生感染性病毒所需的关键基因， 例如L3蛋白酶。该项目的目标是治疗眼腺病毒的临床前模型， 我们的下一代RNAi前药，称为核糖核中性（siRNNs）。与siRNA不同，siRNN具有 具有许多类似药物的性质，具有极高的稳定性和可输送性。重要的是，RNAi反应持续 >一个月，这意味着患者及其家属只需要一次剂量。 我们假设选择性眼RNAi敲除AdV L3基因（蛋白酶，pVI，Hexon） 将阻止AdV感染性颗粒成熟，从而治疗和预防AdV EKC， 治疗感染眼并防止扩散至对侧眼的可接受的疗效/毒性比， 允许其用于儿童和非感染个体的安全特性。 目的1：优化siRNN在表达眼部荧光素酶的小鼠中的局部递送 我们将优化L3 siRNN RNAi触发器，靶向腺病毒中编码 蛋白酶和递送到眼上皮中。 目的2：用靶向腺病毒L3基因的siRNNs治疗腺病毒兔模型 使用L3 siRNN RNAi触发剂，我们将在中进行预防研究和抗病毒功效研究 兔模型，以抑制感染性腺病毒的产生和传播。 我们的首要目标是使用本研究生成的数据将下一代L3 TAT-siRNN RNAi触发向前宣布IND使能研究的临床候选人。