Chemically modified siRNA drugs for ocular disease

摘要 目前对一些眼部疾病的治疗需要频繁地将治疗剂注射到眼睛中，有时 每月一次这给患者和医疗保健系统带来了沉重的负担。临床 实践中注射的频率往往低于所需的频率，这限制了疗效并导致疾病 进展和视力丧失。因此，需要可以提供更长时间的治疗的治疗剂。 每次注射的作用时间。RNAi化学和递送的最新发展已经产生了一种新的方法。 这类治疗剂可以在长达12个月的组织中提供有效的靶基因沉默， 单次注射，这几乎是一种类似疫苗的效果。基于该技术的几种治疗方法在 已在大型II期和III期试验中证明是有效且非常安全的。 该项目旨在开发一种基于完全化学修饰的siRNA缀合物的治疗剂， 比目前使用的治疗剂在眼睛中的作用持续时间更长，从单次给药至少长达六个月 注射 我们之前已经筛选了一组250种siRNA化合物，并确定了几种主要候选化合物 靶向VEGF基因。在拟议的项目中，我们的目标是在动物模型中测试我们的前导siRNA缀合物 为了验证长期功效和安全性，并优化化合物以进一步提高效力， 稳定和安全。 我们旨在通过以下方式实现这一目标： 1.在组织培养中测试化合物的变体，以更好地了解结构-活性关系。 2.优化化合物结构以提高效力、稳定性和安全性。 3.在动物中测试几种缀合化合物以确定施用的中期功效和持续时间。 效果 4.在动物模型中确定治疗效果的作用持续时间。 该项目的预期成果是一种优化的siRNA治疗剂，准备进入IND， 问题研究在项目期间开发的技术和知识也可以作为一个平台， 开发用于一系列眼部疾病的额外治疗剂。

ABSTRACT Current treatments of some ocular diseases require frequent injection of therapeutics into the eye, sometimes as often as every month. This puts a significant burden on both patients and healthcare systems. In clinical practice injections are often done less frequently than is required, which limits efficacy and leads to disease progression and loss of vision. There is therefore a need for therapeutics that can provide much longer duration of action from each injection. Recent developments in RNAi chemistry and delivery have produced a class of therapeutics that can provide potent silencing of target genes in tissues of up to 12 months, from a single injection, which is an almost vaccine like effect. Several therapeutics based on this technology are in late stage of clinical development and have proven to be effective and very safe in large phase II and III trials. This project aims to develop a therapeutic based on fully chemically modified siRNA conjugates with much longer duration of action in the eye than currently used therapeutics, at least up to six months from a single injection. We have previously screened a set of 250 siRNA compounds and have identified several lead candidates targeting the VEGF gene. In the proposed project, we aim to test our lead siRNA conjugates in animal models to validate the long term efficacy and safety, and to optimize the compounds to further improve potency, stability and safety. We aim to achieve this goal by: 1. Test variants of the compounds in tissue culture to better understand structure-activity relationships. 2. Optimizing the compound structure for potency and stability, as well as safety. 3. Testing several conjugated compounds in animals to determine medium term efficacy and duration of effect. 4. Determining the duration of effect of the therapeutic effect in animal model. The expected outcome of this project is an optimized siRNA therapeutic that is ready to enter IND enabling studies. The technology and knowledge developed during the project can also serve as a platform for the development of additional therapeutics for a range ocular diseases.