Ocular Characteristics and Disease Progression in a Preclinical Model of Batten Disease

Abstract

Purpose : Batten Disease is a neurodegenerative genetic condition that presents with impaired vision in children before symptoms progress into motor loss, neurological deficits, and premature death. Recently, phase 1 human clinical trials at UT Southwestern Medical Center have begun to administer AAV9-CLN7 gene therapy to the intrathecal space of pediatric patients (NCT04737460). This gene therapy approach prolongs motor function and extends lifespan in a preclinical mouse model for human CLN7 Batten Disease (MGI:6388452); however, alternative approaches to directly target the retina are likely needed to rescue vision loss. We tracked the progression of vision loss and the overall ocular phenotype in this CLN7 knockout (KO) mouse model. Establishing how this preclinical model compares to the human condition allows it to be used to test preclinical efficacy and safety of gene therapy to address the visual deficits found in Batten Disease patients.

Methods : Retina function and morphology were analyzed in vivo in wild-type, heterozygous, and homozygous CLN7 KO mice. Scotopic and photopic electroretinography (ERG) recordings were taken at 2, 4, and 6 months of age. Ocular coherence tomography (OCT), infrared (IR) and autofluorescent (AF) imaging were analyzed at 3 and 5 months of age. Histological analysis of the eyes and retinal cells were analyzed throughout the study from 1 to 6 months of age.

Results : Live imaging of the CLN7 KO mouse model confirmed that it mimics the human Batten Disease clinical progression, showing a reduction in both a- and b-wave amplitudes by scotopic and photopic ERG and a thinning of the outer nuclear layer of photoreceptor cells along with their inner and outer segments. Both IR and AF imaging showed the vasculature attenuation and accumulation of autofluorescent puncta in the KO mice over time. Histological analysis detected a significant loss of the inner nuclear layer cells by 6 months of age, indicative of bipolar cell death seen in human patients but not previously detected in this preclinical model system.

Conclusions : Overall, our findings establish the clinical progression of vision loss and ocular disease in the CLN7 KO mouse model through 6 months of age, when the mice present with neurological deficits and premature death. These results establish the baseline for preclinical testing of therapeutic vectors to treat vision loss for Batten Disease using this CLN7 KO mouse model.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.