QRX-411, an Antisense Oligonucleotide (AON) Directing Splice Correction in USH2A mRNA Caused by the Frequent Deep-Intronic c.7595-2144A>G Mutation Associated with Retinitis Pigmentosa in Usher Syndrome Type 2

Abstract

Purpose : The recently discovered intronic c.7595-2144A>G mutation in the USH2A gene is associated with Usher syndrome. Usher syndrome is a genetic orphan disease presenting as a combination of deafness and blindness. Mutations in USH2A gene are the most frequent cause of Usher syndrome accounting for up to 50% of patients worldwide. There is no therapy available to address the blinding aspect of this disease. The c.7595-2144A>G mutation creates a splice donor site that leads to inclusion of a pseudoexon into the mature mRNA. QRX-411 is a single stranded fully phosphorothioated and 2'-O-methyl modified antisense oligonucleotide targeting the frequently found intronic USH2A c.7595-2144A>G mutation. QRX-411 is designed to correct the splicing pattern and restore wild-type mRNA and USH2A function.

Methods : Fibroblasts of an USH2A patient, with compound heterozygous USH2A mutations (c.7595-2144A>G and c.10636G>A), were transfected with QRX-411 and mRNA levels were assessed. Labeled QRX-411 was injected by intravitreal injection into mouse eyes to measure localization in the retina.

Results : QRX-411 demonstrated the ability to restore the wild-type mRNA transcript profile via repair of mutant USH2A mutant mRNA. Localization of labelled QRX-411 in the outer nuclear layer of the retina was shown after intravitreal injection into mouse eyes.

Conclusions : QRX-411 was shown to be effective in restoration of wild-type mRNA in patient-derived fibroblasts carrying the intronic c.7595-2144A>G mutation in the USH2A gene, and could be successfully delivered to the outer nuclear layer of the mouse retina.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.