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

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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.