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Xia Wang, Andrew Metcalfe, Xianghong Shan, Kevin Gregory-Evans, Cheryl Y Gregory-Evans; Postnatal nonsense suppression therapy rescues Pax6-deficient congenital eye defects. Invest. Ophthalmol. Vis. Sci. 2014;55(13):2359.
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Aniridia is a progressive bilateral pan-ocular eye disease characterized by partial or complete absence of the iris caused by haploinsufficiency of PAX6. The most common type of PAX6 mutations in aniridia are nonsense mutations leading to a premature stop codon, present in 50% of aniridia cases. The aim of this study was to test the therapeutic efficacy of small molecule drug in treating animals at the early post-natal stage to improve the phenotype of the heterozygous Pax6Sey mouse model of aniridia.
Pax6Sey heterozygous newborn mice received daily subcutaneous injection of Ataluren from P4 until P21. Drug efficacy was tested by histology, electrophysiology, optokinetic tracking, and quantitative real-time PCR.
Early postnatal treatment of Pax6Sey newborn mice with Ataluren rescued the histological phenotypes such as proliferative defects in the retina and normalized the lens, iris and cornea defects in the Pax6Sey mutants. Untreated Pax6Sey mice do not exhibit ERG responses, however, the treated mice showed characteristic dark-adapted rod responses, dark oscillatory potentials, photopic cone responses and a 12Hz flicker that were 70-95% of wildtype responses. In treated mice, optokinetic tracking demonstrated a spatial threshold frequency of 0.41 cycles/degree, equivalent to that in normal mice. In untreated Pax6Sey mice at P21, the increased Pitx2 expression and decreased Bmp4 and Tgfb2 expression were observed in the developing iris, however, these genes were normalized in Pax6Sey mutants after Ataluren treatment.
Postnatal delivered nonsense suppression therapy stably reversed the histological, molecular and functional defects observed in the Pax6Sey mutant eye, suggesting that the postnatal eye is still responsive to Pax6 dosage. These finding demonstrate that the congenital tissue malformation defects in aniridia can be corrected postnatally through safe, non-invasive drug delivery and maybe relevant to other childhood birth defects.
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