Chemically modified siRNA drugs for ocular disease

摘要 目前一些眼科疾病的治疗方法需要频繁地向眼睛内注射治疗药物，有时 每个月都是如此。这给患者和医疗系统都带来了沉重的负担。在临床上 实际注射的频率通常低于所要求的频率，这限制了疗效并导致疾病。 进展性和失明。因此，需要一种能够提供更长时间的治疗方法 每次注射的作用持续时间。RNAi化学和递送方面的最新发展产生了 一类治疗方法，可以在长达12个月的时间内有效地沉默组织中的靶基因，从 单次注射，几乎是疫苗一样的效果。基于这项技术的几种疗法正在进行中 这是临床开发的后期阶段，在大型II和III期试验中已被证明是有效和非常安全的。 该项目旨在开发一种基于完全化学修饰的siRNA偶联物的治疗性药物 在眼睛中的作用持续时间比目前使用的治疗方法更长，至少从一次治疗到六个月 注射。 我们之前已经筛选了一组250个siRNA化合物，并确定了几个主要候选化合物 靶向血管内皮生长因子基因。在拟议的项目中，我们的目标是在动物模型中测试我们的先导sirna偶联物。 为了验证其长期有效性和安全性，并对化合物进行优化以进一步提高效力， 稳定和安全。 我们的目标是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，提高药效、稳定性和安全性。 3.在动物身上测试几种结合化合物，以确定中期疗效和持续时间 效果。 4.动物模型疗效持续时间的测定。 该项目的预期结果是一种优化的siRNA疗法，准备进入IND使能 学习。在项目期间开发的技术和知识也可以作为 针对一系列眼科疾病的附加疗法的发展。

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.