Abstract
Purpose :
The primary causes of evaporative dry eye (EDE) is the destabilization of the tear film (TF). An important element of the TF is the unique mixture of lipids (meibum) secreted by the meibomian glands (MG). Although changes in meibum quality and quantity correlate with EDE severity, existing EDE treatments do not address the underlying causes of inadequate lipid supply to the TF. Our goal was to manipulate pharmacologically lipid biosynthesis and shift MG lipid homeostasis for the purpose of restoring meibum fluidity, and prevent EDE progression.
Methods :
We utilized AWAT2-deficient mice, modeling human obstructive MG dysfunction (MGD), to test if pharmacologically targeting MG lipid homeostasis rescues dry eye progression. Quantitative and qualitative changes in meibum lipid composition resulting from drug administration were determined by LC/MS and compared to untreated mice and their wild-type littermates. Pathophysiological changes characteristic of MGD were monitored by slit lamp imaging, tear film break-up time, optical coherence tomography, and immunocytochemistry in both treated and control groups of Awat2-/- mice.
Results :
Genetically modified mice treated with the drug demonstrated restored meibum fluidity and slower EDE progression. Slit lamp analysis at various stages during treatment revealed fewer obstructed MG ducts and thinner meibum consistency in treated mice. LC/MS analysis confirmed lipid composition changes shifted towards their wild-type littermates. Treated mice exhibited a significantly prolonged tear film break-up time compared to untreated littermates, indicating improved TF stability.
Conclusions :
We demonstrated that pharmacological intervention targeting the meibogenesis pathway can rescue the EDE phenotype in mice. Importantly, the pathophysiological consequences of MGD can be reversed by improving meibum fluidity without restoring native meibum lipid composition. Thus, we provided an in vivo proof of concept, opening a new avenue for the development of therapeutic strategies against EDE.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.