Chemically modified siRNA drugs for ocular disease

用于眼部疾病的化学修饰 siRNA 药物

• 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
• 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

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 当前对某些眼部疾病的治疗需要经常注入眼睛，有时 与每个月一样。这给患者和医疗保健系统带来了重大负担。在临床上 练习注射通常比要求的频率少，这限制了功效并导致疾病 进步和视力丧失。因此，需要提供更长更长的治疗剂 每次注射的行动持续时间。 RNAi化学和交付的最新发展产生了 可以从12个月的组织中提供有效的靶基因的治疗剂类别 单一注射，几乎是类似疫苗的效果。基于这项技术的几种治疗剂 临床发育的后期阶段，已证明在大型II期和III期试验中非常有效且非常安全。 该项目旨在开发基于完全化学修饰的siRNA结合的治疗方法 眼中的动作时间比目前使用的治疗学更长 注射。 我们以前已经筛选了一组250个siRNA化合物，并确定了几个铅候选者 靶向VEGF基因。在拟议的项目中，我们旨在测试动物模型中的铅siRNA结合物 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。 我们的目标是通过： 1。组织培养物中化合物的变体，以更好地理解结构活性关系。 2。优化效力和稳定性以及安全性的复合结构。 3。测试动物中的几种共轭化合物，以确定中期功效和持续时间 影响。 4。确定动物模型中治疗作用的效果持续时间。 该项目的预期结果是一种优化的siRNA治疗性，准备进入IND启用 研究。项目期间开发的技术和知识也可以作为 开发用于范围眼部疾病的其他治疗剂。