MicroRNA expression in chronic ocular GvHD

Abstract

Purpose : Chronic ocular GvHD (oGvHD) occurs in 30–60% of patients after stem cell transplantation, a potentially lifesaving treatment for hematological malignancies. Its pathogenesis is complex and incompletely understood, surmounting to a cycle of chronic inflammation and fibrosis on the ocular surface. This leads to dry eye (DE) that is often severe, and in cases refractive to currently available treatments. There is no gold standard test nor distinct sign or symptom. Instead diagnosis is made through a set of criteria that place heavy reliance on clinical findings. This need for subspecialist input can delay diagnosis, treatment and lead to poor outcomes and patient distress.
We aimed to identify microRNA (miR) profiles associated with disease signature in the conjunctival epithelial cells (CECs) of patients with chronic oGvHD. Through an exploration of their predicted gene targets we aim to develop a deeper understanding of the epigenetic signaling pathways involved in disease as well as identifying urgently needed biomarkers of diagnostic and therapeutic potential.

Methods : Consecutive patients with a diagnosis of chronic oGvHD as per the National Institute of Health were recruited. CECs were collected via impression cytology. Samples were analyzed via a miR microarray and compared to healthy controls. A LASSO regression model was used to identify miRs associated with disease signature and computational predictive methods to identify high confidence miR target interactions (MTI).

Results : Nine patients, five male (56%) four female (44%) with an average age of 38.6yrs (±11.3) participated. Differentially expressed miRs were identified (n=94, FDR<0.05, fold change±2). A panel of miRs associated with disease signature (n=3) and 50 MTI were identified. Of interest was the upregulation of HDAC4 a known inflammatory pain mediator, NOTCH2 which is overexpressed in DE models and PDGFRA which is expressed in myofibroblasts in corneal injuries. In addition, SCARF1 which is necessary for immunotolerance, PCDH1 which is needed for epithelial repair, NTS a known regulator of pain and inflammation, and IHH which is needed for corneal wound healing were all downregulated.

Conclusions : There is an unmet and urgent need for biological markers in the chronic GvHD. Our results provide for the first time a miR panel with potential diagnostic and therapeutic value, along providing an innovative perspective into the molecular mechanisms underpinning disease development.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.