Gene dosage manipulation alleviates manifestations of hereditary PAX6 haploinsufficiency in mice.

In autosomal dominant conditions with haploinsufficiency, a single functional allele cannot maintain sufficient dosage for normal function. We hypothesized that pharmacologic induction of the wild-type allele could lead to gene dosage compensation and mitigation of the disease manifestations. The paired box 6 (PAX6) gene is crucial in tissue development and maintenance particularly in eye, brain, and pancreas. Aniridia is a panocular condition with impaired eye development and limited vision due to PAX6 haploinsufficiency. To test our hypothesis, we performed a chemical screen and found mitogen-activated protein kinase kinase (MEK) inhibitors to induce PAX6 expression in normal and mutant corneal cells. Treatment of newborn Pax6-deficient mice (Pax6Sey-Neu/+ ) with topical or systemic MEK inhibitor PD0325901 led to increased corneal PAX6 expression, improved corneal morphology, reduced corneal opacity, and enhanced ocular function. These results suggest that induction of the wild-type allele by drug repurposing is a potential therapeutic strategy for haploinsufficiencies, which is not limited to specific mutations.