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.

葡萄膜炎描述了一系列由免疫介导的眼睛炎症，并威胁到视力，据估计，在西方国家，10%-15%的劳动年龄人口失明是由葡萄膜炎引起的。尽管长期全身使用的耐受性和副作用较差，但类固醇仍是一线治疗选择。尽管接受了标准的护理，但仍有相当一部分患者面临因突破性的眼内炎症发作而丧失视力的风险。最近批准的抗肿瘤坏死因子生物制品源于我们自己的工作，强调了肿瘤坏死因子在驱动炎症中的关键作用。然而，在40%的病例中，与全身给药途径(全身治疗)相关的反复发炎是患者面临的一个重大问题。免疫治疗的一个关键目标是最大限度地减少患者使用类固醇，并开发可以直接进入眼睛的治疗方法。我们的项目将通过开发一种新的治疗方法来解决目前葡萄膜炎护理标准的不足，以防止视力丧失。基因疗法被批准用于眼科治疗，它利用病毒(载体)将感兴趣的基因输送到视网膜内特定的细胞类型。它正在积极开发用于治疗各种疾病，包括遗传性视网膜疾病、青光眼和老年性黄斑变性。我们开发战略的三个指导目标是：表达：AAV载体能否在眼睛中表达生物活性治疗分子？诱导性：AAV载体设计是否允许在炎症反应中调节治疗性表达？有效性：这能否改善炎症抑制并在眼睛中提供长期保护？我们已经证明，AAV可以在眼睛中提供具有生物活性的抗肿瘤坏死因子生物活性物质的强健表达。此外，我们的炎症反应载体设计使治疗的表达能够对炎症的早期迹象做出反应。最后，我们表明，通过靶向肿瘤坏死因子的作用，治疗可以降低临床疾病的严重程度(炎症和免疫细胞进入眼睛)。我们的目标是进一步优化和测试我们的新型载体设计，以确定未来临床研究的最佳候选者。我们的目标是一种可以开关的载体，对眼睛中的炎症做出反应。这将为患者提供持久、安全、不含类固醇和可接受的替代方案，同时减少对医疗保健提供者的要求。