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

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.

葡萄膜炎是指一系列免疫介导的眼部炎症，会威胁视力，估计会导致西方国家工作年龄人口中 10-15% 的失明病例。尽管耐受性差且长期全身使用会产生副作用，但类固醇仍然是一线治疗选择。尽管有标准护理，仍有相当一部分患者继续面临因眼内炎症突破性发作而导致视力丧失的风险。最近抗 TNF 生物制剂的批准源于我们自己的工作，该工作强调了 TNF 细胞因子在驱动炎症中的关键作用。然而，40% 的病例中，与全身给药途径（治疗全身）相关的炎症反复发作对患者来说是一个重大问题。免疫疗法的一个关键目标是尽量减少患者类固醇的使用，并开发可以直接注射到眼睛中的疗法。我们的项目将通过开发一种预防视力丧失的新型治疗方法来解决当前葡萄膜炎护理标准的缺陷。基因疗法被批准用于眼部，利用病毒（载体）将感兴趣的基因传递到视网膜内的特定细胞类型。它正在积极开发用于治疗多种疾病，包括遗传性视网膜疾病、青光眼和年龄相关性黄斑变性。我们的发展战略的三个指导目标是：表达：AAV 载体能否在眼中表达生物活性治疗分子？诱导性：AAV 载体设计能否调节炎症反应中的治疗表达？功效：这能否改善炎症抑制并为眼睛提供长期保护？我们已经证明，AAV 可以在眼中提供生物活性抗 TNF 生物制剂的稳定表达。此外，我们的炎症反应载体设计使得治疗的表达能够响应炎症的早期迹象而“开启”。最后，我们表明，通过针对 TNF 的作用，治疗可以降低临床疾病的严重程度（眼睛中的炎症和免疫细胞流入）。我们的目标是进一步优化和测试我们的新型载体设计，旨在确定最佳候选者以推进未来的临床研究。我们的目标是一种可以打开和关闭的载体，以响应眼睛的炎症。这将为患者提供持久、安全、不含类固醇且可接受的替代方案，同时减少对医疗保健提供者的需求。