Harlequin Mouse: An Appropriate Model for Studying Progressive Visual Function Loss Due to Retinal Ganglion Cell and Photoreceptor Degeneration

Abstract

Purpose: : Retinal dystrophies caused by mitochondrial impairment are inaccessible to therapy. The major difficulty for fighting these affections is the lack of suitable animal models to evaluate pharmacological treatments or corrective gene therapies. Harlequin (Hq) mouse exhibit a decrease of ~80 % of the AIF (Apoptosis Inducing Factor) gene expression due to a proviral insertion in the gene. The AIF protein is essential for the assembling and/or the activity of the respiratory chain complex I. Hq mice show progressive retinal neuron loss leading to blindness. Our aim is to extensively characterize visual and mitochondrial impairment of Hq mice and to protect retinal cells and visual function of these mice using an optimized AAV2 (Adeno Associated Virus type 2) vector containing the AIF gene with its 3’UTR (3’ untranslated region), allowing mRNA sorting to the mitochondrial surface.

Methods: : Morphological and functional examinations of retinal damage were performed in Hq mice over time. Retinal ganglion cell (RGC) number, microglial activation and reactive gliosis were evaluated by histochemistry. Imaging of eye fundus was performed by optic coherence tomography (OCT). Visual acuity was assessed by subjecting mice to the optomotor test. In vivo electrophysiology (electroretinogram, ERG) permitted the estimation of photoreceptor (PR) activity.

Results: : First signs of RGC and nerve fiber decrease were evidenced in mice aged of 4 months leading to visual performance decline at 6-8 months. ERGs revealed that PR electrophysiology is also compromised at 6-8 months of age. These data was substantiated by a clear diminution of retinal thickness in these mice. Moreover, aged mice showed reactive gliosis and microglial cells activation which might contribute to the degenerative process.

Conclusions: : We demonstrated that Hq mouse is a reliable genetic model that faithfully mimics human retinal degeneration. We are currently establishing the proof of principle that AAV2 vectors are effective in providing a preventive gene therapy to this model.

Keywords: ganglion cells • retina • optic nerve