AAV-induced re-expression of Dp71 in retinal Müller glial cells recovers electroretinographic responses in Dp71-null mice

Abstract

Purpose : ERG b-waves are associated with retinal bipolar cells activity but a contribution of Müller glial cells (MGCs) is still debated. Targeted disruption of the glial dystrophin Dp71 in mice and selective rescue of Dp71 function in MGCs may provide insights into the contribution of these cells to the ERG.

Methods : We recorded ERG responses to scotopic and photopic flashes (1), to mesopic and photopic 4 Hz rapid-on and –off sawtoth modulation (2) and to sine wave modulation at different temporal frequencies (3) from Dp71-null mice before and after intravitreal injections of ShH10-GFP-2A-Dp71 (an AAV designed to selectively target MGCs; Vacca et al. 2016 Hum. Mol. Genet. 25:3070-3079) and in wildtype (WT) littermates.

Results : Before treatment, Dp71-null mice displayed reduced b-waves in scotopic and photopic flash ERGs (1) and smaller response amplitudes to photopic rapid-on sawteeth (2) and to sine wave flicker responses at low temporal frequencies (3). These responses were completely recovered 12 weeks after ShH10-GFP-2A-Dp71 injections and reached the same level as found in the WT mice.

Conclusions : ERG b-waves and other components involving ON-bipolar and cone pathways are influenced by Müller glial cells' integrity. Deficits of retinal function can be successfully reversed by gene therapeutic intervention with ShH10-GFP-2A-Dp71 mediating re-expression of Dp71.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.