Rescue of the Congenital Hereditary Endothelial Dystrophy Mouse Model by Adeno-Associated Virus–Mediated Slc4a11 Replacement

PURPOSE: Congenital hereditary endothelial dystrophy (CHED) is a rare condition that manifests at an early age showing corneal edema, increased oxidative stress, mitochondrial dysfunction, and eventually apoptosis of the endothelium due to loss of function of the membrane transport protein SLC4A11. This project tested whether replacing Slc4a11 into the Slc4a11(-/-) CHED mouse model can reverse the disease-associated phenotypes. DESIGN: Experimental study. PARTICIPANTS: Five-week-old or 11-week-old Slc4a11(-/-) mice. Age- and gender-matched Slc4a11(+/+) animals were used as controls. A total of 124 animals (62 female, and 62 male) were used in this study. Fifty-three animals of the genotype Slc4a11(+/+) were used as age- and gender-matched noninjected controls. Seventy-one Slc4a11(-/-) mice were administered anterior chamber injections of adeno-associated virus (AAV). METHODS: Anterior chambers of young (5 weeks old) or older (11 weeks old) Slc4a11(-/-) mice were injected once with adeno-associated virus serotype 9 (AAV9) mouse Slc4a11 or AAV9-Null vectors. Corneal thickness was measured using OCT. End point analysis included corneal endothelial cell density, mitochondrial oxidative stress, and corneal lactate concentration. MAIN OUTCOME MEASURES: Corneal thickness, endothelial cell loss, lactate levels, and mitochondrial oxidative stress. RESULTS: In the young animals, AAV9-Slc4a11 reversed corneal edema, endothelial cell loss, mitochondrial oxidative stress, lactate transporter expression, and corneal lactate concentration to the levels observed in wild-type animals. In the older animals, gene replacement did not reverse the phenotype but prevented progression. CONCLUSIONS: Functional rescue of CHED phenotypes in the Slc4a11(-/-) mouse is possible; however, early intervention is critical.