Chemically modified siRNA drugs for ocular disease

用于眼部疾病的化学修饰 siRNA 药物

基本信息

批准号：
10081644
负责人：
Alexey Wolfson
金额：
$ 29.4万
依托单位：
ADVANCED RNA TECHNOLOGIES, LLC
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-30 至 2022-03-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10081644
关键词：
Address Age related macular degeneration Animal Model Animals Biodistribution Blindness C57BL/6 Mouse Cells Chemicals Chemistry Clinical Trials Development Disease Disease Progression Dose Doxycycline Extravasation Eye Eye diseases Fibrosis Frequencies Generations Genes Goals Growth Healthcare Systems In Vitro Injections Italy Knowledge Label Lead Liquid substance Liver Measurement Measures Medical Messenger RNA Modeling Mus Neurons Opsin Outcome Patients Penetration Pharmaceutical Preparations Phase Phase II/III Trial Photoreceptors Physicians Property Proteins RNA Interference Retina Rhodopsin Ribose Safety Small Business Innovation Research Grant Small Interfering RNA Stimulus Structure Structure-Activity Relationship Technology Testing Tetanus Helper Peptide Text Therapeutic Therapeutic Effect Therapeutic Uses Time Tissues Toxic effect Transgenic Mice United States VEGF165 VEGFA gene Vaccines Validation Variant Vascular Endothelial Growth Factors Vision Visual base clinical development clinical practice design effectiveness testing efficacy testing improved in vivo inducible gene expression intravitreal injection lead candidate mouse model neovascular new growth new technology novel novel strategies novel therapeutics prevent promoter recruit rho screening therapeutic candidate therapeutic siRNA tissue culture treatment effect uptake

项目摘要

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.

抽象的目前对某些眼部疾病的治疗需要频繁地将治疗剂注射到眼睛中，有时需要每月一次。这给患者和医疗保健系统带来了沉重的负担。在临床上练习注射的频率通常低于要求的频率，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 化学和递送的最新发展产生了一类疗法可以在组织中提供长达 12 个月的有效沉默目标基因，从单次注射，几乎具有类似疫苗的效果。几种基于该技术的治疗方法正在研究中处于临床开发后期，并在大型 II 期和 III 期试验中被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 缀合物的治疗方法，其中含有多种成分。与目前使用的治疗方法相比，在眼睛中的作用持续时间更长，单次治疗至少长达六个月注射。我们之前筛选了一组 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先导 siRNA 缀合物验证长期功效和安全性，并优化化合物以进一步提高效力，稳定性和安全性。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、稳定性以及安全性。 3. 在动物体内测试几种缀合化合物以确定中期疗效和持续时间影响。 4.确定动物模型中治疗效果的持续时间。该项目的预期成果是一种优化的 siRNA 疗法，已准备好进入 IND 阶段，从而使研究。项目期间开发的技术和知识也可以作为一个平台开发针对一系列眼部疾病的额外疗法。