Research ArticleEYE DISEASE

Gene dosage manipulation alleviates manifestations of hereditary PAX6 haploinsufficiency in mice

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Science Translational Medicine  09 Dec 2020:
Vol. 12, Issue 573, eaaz4894
DOI: 10.1126/scitranslmed.aaz4894

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Eye-opening treatment for haploinsufficiency

Aniridia is a genetic disorder predominantly affecting the eye, caused by PAX6 haploinsufficiency due to mutations in one allele. Patients present vision loss and, in some cases, other systemic abnormalities. Increasing the expression of PAX6 early in life could block the progression of the disease. Now, Rabiee et al. used a pharmacological approach in vitro and in a rodent model of Pax6 haploinsufficiency (Pax6+/−). Through chemical screening, the authors showed that MEK inhibitors could increase PAX6 expression in corneal cells. Treating Pax6+/− mice early in life with the inhibitor reduced eye abnormalities, suggesting that MEK inhibitors might be effective for treating postnatal abnormalities in patients with PAX6 haploinsufficiency.


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.

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