Functional Biomarkers For Successful Molecular Therapy Of The Outer Retina In Retinal Degenerations

Abstract

 

Purpose

 

Retinal degenerations are severe and frequently blinding human diseases. Several current therapeutic approaches have demonstrated long-lasting amelioration in respective disease models and show promise for a successful translation to human patients. Here, we focus on electroretinographic (ERG) features in the experimental data in order to identify informative biomarkers for upcoming clinical trials.

 

Methods

 

Core of this work is the electrophysiologic evaluation of treated mouse models representing achromatopsia (Cnga3^-/-) or retinitis pigmentosa (Cngb1^-/-). Mice of these lines received adeno-associated virus (AAV)-mediated gene replacement therapy designed to express mouse CNGA3 or CNGB1 under control of respective photoreceptor-specific promoters (mouse S opsin or rhodopsin). Treatment success was monitored with different single flash and flicker protocols of in vivo electrophysiology. The findings were compared to immunohistochemistry, in vivo imaging, and behavioral assays.

 

Results

 

In both disease models, the therapeutic effects were well detectable with several of the explorative ERG protocols used in this study. However, the signal-to-noise ratio varied between the particular tests, depending on the nature of the underlying disease (rod- or cone-specific origin). On this basis, options for biomarkers were developed for potential use in human trials.

 

Conclusions

 

The ERG is a very effective method to assess outer retinal functionality. We show here that specific ERG protocols are well suited to follow therapeutic effects in retinal degenerations. Such tests may thus serve as functional biomarkers for molecular therapy in upcoming clinical trials.

 

Keywords: 508 electrophysiology: non-clinical • 538 gene transfer/gene therapy • 696 retinal degenerations: hereditary