CRISPR generated mouse model of central areolar choroidal dystrophy with a Prph2 mutation reproduces human dystrophy features.

Abstract

Purpose : Central choroidal dystrophies are retinal diseases that involve progressive retinal degeneration and the atrophy of the choriocapillaris. These dystrophies usually present an autosomal dominant inheritance pattern in which patients carry a single mutation in the PRPH2 gene. The aim of this work was to generate a mouse model with the same p.Arg195Leu mutation that was described in diagnosed human patients.

Methods : The heterozygous mouse model Prph2^KI/WT has been designed and generated using the CRISPR system to introduce the Arg195Leu mutation in the same allele as the patients. The functional state of the retina was studied using electroretinography under photopic and scotopic conditions and the optomotor test was used to determine visual acuity. In vivo structural state of retinal layers was assessed by optical coherence tomography imaging. The number of photoreceptor rows was quantified in cryosections using immunohistochemistry.

Results : Genetic sequencing of the Prph2^KI/WT mouse revealed the same codon mutation found in humans suffering from this dystrophy. Importantly, mice presented a degeneration pattern comparable to patients. From 3 months of age, the mouse optomotor response was significantly reduced indicating a visual acuity decrease. At 6 months, the mice presented reduced scotopic and photopic ERG responses, with smaller a-wave and b-wave amplitudes, and the number of photoreceptor rows was decreased as well as the retinal thickness.

Conclusions : The new Prph2KI/WT mouse model presents a similar degeneration pattern than that observed in patients and may facilitate the analysis of the pathophysiological process, being a suitable model for evaluating different therapeutic strategies.

Support. Ministerio de Ciencia e Innovación (FEDER- PID2019-106230RB-I00). Ministerio de Universidades (FPU16/04114, FPU18/02964). Instituto Carlos III (RETICS-FEDER RD16/0008/0016). Retina Asturias/Cantabria. FARPE-FUNDALUCE. Generalitat Valenciana (IDIFEDER/2017/064, ACIF/2020/203). Es Retina Asturias (2019/00286/001).

This is a 2021 ARVO Annual Meeting abstract.