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

葡萄膜炎描述了眼睛中的一系列免疫介导的炎症，并且威胁视力，估计在西方国家的工作年龄人群中导致10 - 15%的失明病例。类固醇仍然是一线治疗选择，尽管耐受性差和长期全身使用相关的副作用。尽管进行了标准治疗，但相当一部分患者仍然面临着眼内炎症突破性发作导致视力丧失的风险。抗TNF生物制剂的最近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，与全身递送途径（治疗全身）相关的40%病例中的复发性炎症发作代表了患者的显著问题。免疫疗法的一个关键目标是最大限度地减少患者的类固醇使用，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部，它利用病毒（载体）将感兴趣的基因传递到视网膜内定义的细胞类型。它正在积极开发用于各种疾病，包括遗传性视网膜疾病，青光眼和年龄相关性黄斑变性。我们开发策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：AAV载体设计是否允许对炎症反应进行调节的治疗表达？功效：这是否可以改善炎症抑制并提供长期保护？我们已经表明，AAV可以在眼睛中提供生物活性抗TNF生物制剂的稳健表达。此外，我们的炎症响应载体设计使得治疗的表达能够响应于炎症的早期迹象而“开启”。最后，我们表明，通过靶向TNF的作用，治疗导致临床疾病严重程度降低（炎症和免疫细胞流入眼睛）。我们的目标是进一步优化和测试我们的新型载体设计，目的是确定最佳候选人，以推进未来的临床研究。我们的目标是一个可以打开和关闭的载体，对眼睛的炎症做出反应。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要求。

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.