A vicious cycle 
of inflammation

Topical administration of nanoparticle-encapsulated micro-RNA (miR) inhibitors may provide a new approach to the treatment of Sjögren’s syndrome, according to Emily Greenan MD, Royal College of Surgeons in Ireland, Dublin, Ireland. “Our research has identified miR-dysregulation in Sjögren’s syndrome patients that may play a role in mediating ocular inflammation. We have also formulated and characterised suitable non-immunogenic particles to deliver miR-modulating compounds to the ocular surface,” said Dr Greenan at the Irish College of Ophthalmologists Annual Conference 2019 in Galway, Ireland. In Sjögren’s syndrome patients, dry eye results from a vicious circle of inflammation. It starts with the initial inflammation of the lacrimal gland, which, in turn, decreases the aqueous flow. The resulting tear film hyperosmolarity damages epithelial cells, leading in turn to the release of inflammatory cytokines, propelling the cycle further, Dr Greenan explained. In recent years, miR dysregulation has been identified as a potential biomarker for inflammation in Sjögren’s syndrome patients. She noted that miR molecules are fragments of RNA containing 18-to-23 nucleotides that have a function in the post-transcriptional regulation of gene expression. Therapeutic target Dr Greenan and her associates have conducted a series of experiments to determine whether miR dysregulation may play a role in the dry eye disease of Sjögren’s syndrome patients and whether such dysregulation may represent potential therapeutic target. In the first experiment, they performed conjunctival impression cytology in a cohort of Sjögren’s syndrome patients. Analysis of the miR profile of the samples they obtained showed that, compared to controls, there was an up-regulation of a key regulatory miR, a molecule that previous research has identified as having an immunomodulatory function. They performed further validation studies to confirm increased expression of this regulatory miR and demonstrated its predicted gene target molecule, Pellino 3, was down-regulated. They were also able to show that conjunctival epithelial cells transfected with MiRNA, via a plasmid vector, showed the same down-regulation of the target Pellino 3, whereas cells transfected with antagomirs had an up-regulation of the Pellino molecule. In a subsequent experiment they have been able to inhibit modulate miR expression in cultured human conjunctival cells with an antagomir encapsulated within a nanoparticle. The nanoparticle-encapsulation overcomes many of the barriers to using a topical means of transfecting antagomirs into ocular surface cells, such as extracellular nucleases, the hydrophobic cellular membrane and lysosomal degradation. Emily Greenan: EmilyGreenan@rcsi.ie

Tags: cornea