ICF: A novel dual-target gene therapy for safe and efficacious treatment of chronic non-infectious uveitis

ICF：一种安全有效治疗慢性非感染性葡萄膜炎的新型双靶点基因疗法

• 批准号: MR/Z50385X/1
• 负责人: Dave Copland
• 金额: $ 31.7万
• 依托单位: University of Bristol
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FZ50385X%2F1
• 关键词: ICF; novel; dual; target; gene; ICF; novel; dual; target; gene

Uveitis describes a range of immune-mediated inflammation in the eye and is sight-threatening, estimated to cause 10 - 15% of cases of blindness in working-age populations in Western countries. Steroids remain the first-line treatment choice, despite poor tolerability and side effects associated with long-term systemic use. A substantial portion of patients continue to face the risk of vision loss from breakthrough episodes of intraocular inflammation despite standard of care. The recent approval of anti-TNF biologics stems from our own work which highlighted the critical role of the TNF cytokine in driving inflammation. However, recurrent flares of inflammation in 40% of cases, associated with the systemic route of delivery (treating the whole body) represents a significant problem for patients. One key goal for immunotherapy is to minimise patients' steroid use and develop therapeutics that can be administered directly into the eye. Our project will address the deficiencies of current standard of care for uveitis by developing a novel treatment to prevent visual loss. Approved for ocular use, gene therapy utilizes a virus (vector) to deliver a gene of interest to defined cell types within the retina. It is actively being developed for a variety of disorders including inherited retinal diseases, glaucoma and age-related macular degeneration. The three guiding objectives underlying our development strategy are:Expression: Can AAV vectors express bioactive therapeutic molecules in the eye? Inducibility: Can AAV vector design allow regulated therapeutic expression in response to inflammation?Efficacy: Can this improve suppression of inflammation and provide long-term protection in the eye? We have shown that AAV can provide robust expression of bioactive anti-TNF biologics in the eye. Furthermore, our inflammation responsive vector design enables expression of the therapy to be "switched-on" in response to early signs of inflammation. Finally, we show that treatment results in reduced clinical disease severity (inflammation and immune cell influx in the eye) by targeting the actions of TNF. We aim to further optimise and test our novel vector designs, with the aim of identifying the best candidate to progress towards future clinical studies. Our goal is a vector that can be switched on and off, responding to inflammation in the eye. This will provide long-lasting, safe, steroid free, and acceptable alternative for patients, whilst reducing the demands on health care providers.

葡萄膜炎描述了眼睛中的一系列免疫介导的炎症，并且正在威胁视力，估计会导致西方国家的工作年龄人群失明的10-15％。尽管耐受性差和长期使用相关的副作用，但类固醇仍然是一线治疗选择。尽管有标准的护理，但很大一部分患者仍然面临眼内炎症突破性发作的风险。抗TNF生物制剂的最新认可源于我们自己的工作，这突出了TNF细胞因子在驱动炎症中的关键作用。但是，在40％的病例中，炎症的复发耀斑与全身分娩途径（治疗全身）有关，这对患者来说是一个重要的问题。免疫疗法的一个关键目标是最大程度地减少患者的类固醇使用，并开发可直接用于眼睛的治疗剂。我们的项目将通过开发一种新的治疗方法来防止视觉丧失来解决当前葡萄膜炎护理标准的缺陷。基因治疗被批准用于眼部，利用病毒（Vector）为视网膜内定义的细胞类型提供了感兴趣的基因。它正在积极开发针对多种疾病，包括遗传性视网膜疾病，青光眼和与年龄相关的黄斑变性。我们开发策略的三个指导目标是：表达：AAV矢量可以在眼中表达生物活性治疗分子吗？诱导性：AAV矢量设计是否可以允许响应炎症的治疗表达？功效：这可以改善对炎症的抑制并在眼中提供长期保护吗？我们已经表明，AAV可以在眼中提供生物活性抗TNF生物制剂的稳健表达。此外，我们的炎症反应性载体设计使该治疗的表达能够“切换”，以应对早期炎症迹象。最后，我们表明治疗导致临床疾病严重程度（眼睛炎症和免疫细胞流入）通过靶向TNF的作用。我们旨在进一步优化和测试我们的新型矢量设计，以确定最佳候选人迈向未来的临床研究。我们的目标是一个可以打开和关闭的矢量，以应对眼睛的炎症。这将为患者提供持久，安全，无类固醇和可接受的替代品，同时减少对医疗保健提供者的需求。