Postnatal manipulation of Pax6 dosage reverses congenital tissue malformation defects
Cheryl Y. Gregory-Evans, … , Andrew L. Metcalfe, Kevin Gregory-Evans
Cheryl Y. Gregory-Evans, … , Andrew L. Metcalfe, Kevin Gregory-Evans
Published January 2, 2014; First published December 20, 2013
Citation Information: J Clin Invest. 2014;124(1):111-116. https://doi.org/10.1172/JCI70462.
View: Text | PDF
Brief Report

Postnatal manipulation of Pax6 dosage reverses congenital tissue malformation defects

Abstract

Aniridia is a congenital and progressive panocular condition with poor visual prognosis that is associated with brain, olfactory, and pancreatic abnormalities. Development of aniridia is linked with nonsense mutations that result in paired box 6 (PAX6) haploinsufficiency. Here, we used a mouse model of aniridia to test the hypothesis that manipulation of Pax6 dosage through a mutation-independent nonsense mutation suppression strategy would limit progressive, postnatal damage in the eye. We focused on the nonsense suppression drugs 3-[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid (ataluren) and gentamicin. Remarkably, we demonstrated that nonsense suppression not only inhibited disease progression but also stably reversed corneal, lens, and retinal malformation defects and restored electrical and behavioral responses of the retina. The most successful results were achieved through topical application of the drug formulation START (0.9% sodium chloride, 1% Tween 80, 1% powdered ataluren, 1% carboxymethylcellulose), which was designed to enhance particle dispersion and to increase suspension viscosity. These observations suggest that the eye retains marked developmental plasticity into the postnatal period and remains sensitive to molecular remodeling. Furthermore, these data indicate that other neurological developmental anomalies associated with dosage-sensitive genetic mutations may be reversible through nonsense suppression therapeutics.

Authors

Cheryl Y. Gregory-Evans, Xia Wang, Kishor M. Wasan, Jinying Zhao, Andrew L. Metcalfe, Kevin Gregory-Evans

×

Figure 1

Postnatal treatment of Pax6 mice with ataluren.

Options: View larger image (or click on image) Download as PowerPoint
Postnatal treatment of Pax6 mice with ataluren. (A) Effect of systemic...
(A) Effect of systemic ataluren treatment on mice with the Pax6Sey+/– phenotype. The black arrowhead indicates the lenticular stalk; the black arrow indicates the cornea; and the asterisk indicates the ciliary margin. WT, Pax6+/+; Mt, Pax6Sey/+; L, lens; r, retina. Original magnification, ×5. (B) Histological comparison of 1% ataluren suspension and the START formulation instilled topically in Pax6Sey+/– eyes. Original magnification, ×5. (C) PAX6 protein measurements in the retinas and corneal epithelia from Pax6+/+ (WT), Pax6Sey/+ (Sey), and Pax6Sey–1Neu (Neu) mice. Black bars depict wild-type mice; white bars depict untreated mice; checkered bars depict mice after START therapy. *P < 0.001, n = 6. (D) Box-and-whisker plots comparing maximum spatial frequency threshold of topical ataluren (At.) in H20 and the START formulation. Box-and-whisker plots were prepared showing the 5% and 95% quantiles (whiskers), 25% and 75% quartiles (box), and the median marked by a horizontal line.