Rescue of the Congenital Hereditary Endothelial Dystrophy Mouse Model by Adeno-Associated Viruse-Mediated 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 into the CHED mouse model can reverse the disease-associated phenotypes.

DESIGN

Experimental study.

PARTICIPANTS

Five-week-old or 11-week-old mice. Age- and gender-matched 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 were used as age- and gender-matched noninjected controls. Seventy-one mice were administered anterior chamber injections of adeno-associated virus (AAV).

METHODS

Anterior chambers of young (5 weeks old) or older (11 weeks old) mice were injected once with adeno-associated virus serotype 9 (AAV9) mouse 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- 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 mouse is possible; however, early intervention is critical.