Drug-Device Combination to image individual immune cell function in vivo with Indocyanine Green Dye

The immune system has a critical role in almost every known disease, but we remain unable to reliably image and track immune cells within the tissues of patients at single cell resolution. If immune cell imaging can be achieved clinically, then diagnostic and therapeutic testing could be performed in patients with ocular and systemic pathology, transforming care and advancing our understanding of human immunology. The eye can be repeatedly and non-invasively imaged as the only transparent organ in humans, including deep tissues such as the retina and choroid. These are subject to a range of autoimmune conditions classified into Posterior Uveitis that account for ~15% of blindness. There is an unmet need in this patient group for better methods to monitor disease activity, personalised responses to treatment and to determine remission. This product development award is for a drug-device combination for consistent immune cell detection by refining the dose and route of administration of an already licensed diagnostic contrast agent in combination with an optimised retinal imaging instrument. Indocyanine Green (ICG) is an intravenously administered near-infrared fluorescent dye used clinically for angiography. Our previous work demonstrated depot systemic administration in mice efficiently labelled macrophages and neutrophils, which can be visualised and tracked in the inflamed retina. A subsequent pilot study of patients receiving ICG at standard angiographic doses did not achieve robust cell labelling, however the conditions did not match those successful in mice. In vitro macrophage cultures demonstrate ICG accumulation in endosomal compartments suggesting uptake of the dye with sufficient exposure. ICG has a short half-life from hepatic elimination, so robust immune cell labelling in humans will be investigated using a 4-hour intravenous infusion. Immune cells could then migrate systemically to be detectable in the eye. A custom sensorless adaptive-optics scanning-laser-ophthalmoscope (SAOSLO) tuned to detect ICG fluorescence will be constructed and optimised for detection of the labelled cells. This approach will achieve higher cellular resolution and sensitivity than existing ICG imaging instruments. The ICG-SAOSLO drug-device combination will be deployed in 10 patients with Posterior Uveitis recruited to a clinical study at Moorfields Eye Hospital. The optimum dose to achieve robust ICG labelling will be ascertained through a dose-escalation approach based on maintaining sustained plasma concentrations. Safety and efficacy data will be obtained for subsequent regulatory and intellectual property submissions. Patients with Posterior Uveitis have been involved in developing this proposal and a Patient Advisory Group will be formed. If successful, the drug-device combination would be shared with UK ophthalmic hospitals for real-world testing through local commissioning and contract manufacture, followed by long-term industry partnership to bring access to specialists internationally. The Posterior Uveitis patient group would be the initial beneficiaries of this product, but it could be applied to many other ocular conditions with known immune interplay, such as diabetic retinopathy or age-related macular degeneration (AMD). Furthermore, as most CNS and systemic conditions manifest in the eye, this product will allow a wider assessment of the immune system to better understand and manage other neurological, autoimmune and cardiovascular disorders.