Abstract
Purpose :
Accumulation of toxic lipofuscin bisretinoids in the RPE represents a primary pathologic defect in Stargardt’s disease; it may also contribute to pathogenesis of dry AMD. We developed a novel cyclopentyl fused pyrrolidine RBP4 antagonist which was capable of antagonizing the retinol-dependent RBP4-TTR interaction in circulation. The compound partially restricted retinol supply to the RPE, induced partial reduction in visual cycle retinoids, and drastically inhibited bisretinoid synthesis. Here we report the data on ocular safety of this compound.
Methods :
To assess the potential ability of the drug candidate to induce symptoms of delayed dark adaptation we studied the effect of compound dosing on the rate of the visual cycle in Balb/c mice. Compound was administered orally for 2 weeks at the dose that induced approximately 80% of serum RBP4 reduction. The rate of the visual cycle was measured electrophysiologically (restoration of the ERG b-wave amplitude following the exposure to bleaching light) and biochemically (restoration of 11-cis-retianal after the photobleach). The propensity of the drug candidate to induce symptoms of nyctalopia was evaluated after 2 weeks of dosing by studying the ERG responses under scotopic conditions using a single flash at different levels of light intensity. Photopic ERG characteristics have also been studied.
Results :
Compound reduced levels of 11-cis-retinal and all-trans-retinal; however, it did not reduce the rate of the visual cycle in wild type mice as measured both electrophysiologically and biochemically which underscores the fact that the compound does not act as a visual cycle inhibitor. Compound administration was not associated with changes in measured scotopic or photopic ERG parameters.
Conclusions :
Our data supports the conclusion that the drug candidate is able to reduce the concentration of lipofuscin bisretinoids in the RPE without suppression of the ERG b-wave recovery in rods after photobleaching. Similarly, the rate of the 11-cis-retinal recovery was not affected by compound dosing. Compound reduced the load of the visual cycle without reducing its rate. Compound had no detectable effects on scotopic and photopic ERG. Our study detected no ocular safety issues for the test compound indicating that this drug candidate may potentially be considered as a treatment for dry AMD and Stargardt disease.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.