Abstract
Purpose :
While mutations across many essential genes which lead to progressive photoreceptor loss presents challenges to development of common therapeutic strategies, prevalence of nonsense mutations as a mutation class presents an opportunity to apply a common therapeutic agent across a variety of inherited retinal disorders.
Methods :
ELX-03 is a designer Eukaryotic Specific Ribosome Glycoside with improved translational read-through properties and decreased affinity for the prokaryotic and mitochondrial ribosome. Here we demonstrate ELX-03 promotes the read-through of multiple common nonsense mutations in Usher Syndrome and other non-syndromic forms of retinitis pigmentosa via a dual-luciferase reporter assay.
Results :
Usher 1F mutation, R3X demonstrates a 2.5-fold increase in read-through over native readthrough, which represents a 2.7% R3X read-through rate. ELX-03 intravitreal injection in preclinical models is found to be well-tolerated in comparison to gentamicin in both grossopthmalogical examination and electroretinogram. In addition, intravitreal injection is sufficient to achieve ELX-03 read-through permissive concentrations within the retina.
Conclusions :
Together, these data are supportive of a mutation category specific approach to addressing genetically heterogeneous retinal disorders.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.