Aniridia is a rare congenital syndrome that is associated with reduced visual acuity and progressive loss of vision.
Aniridia patients may also develop systemic health issues associated with defects in the pancreas, digestive, and central nervous systems. The spectrum of symptoms associated with
aniridia is due to haploinsufficiency of the paired box 6 gene (PAX6) and its role in the development and maintenance of the affected tissues. Here, we isolated pancreatic islets from mice heterozygous for Pax6 to test whether a Pax6-specific
miRNA suppression (target protector) strategy can restore
PAX6 protein levels. We show that miR-7 and miR-375 target specific sites within the Pax6
3' UTR in a mouse pancreatic β-
insulinoma cell line. Tough decoys (Tuds) against miR-7 and miR-375 increase expression of a mouse Pax6
3' UTR luciferase reporter and increase
PAX6 protein levels in these cells. Finally, we demonstrate that the shielding of the miR-7 binding site with a target protector restores
PAX6 protein levels in the Pax6 heterozygous islets. The data presented here represent a proof of concept for
RNA-based
therapy for the progressive defects associated with
aniridia and suggest the target protector approach may be a useful therapeutic strategy for other haploinsufficiency diseases.