A novel porcine model of CLN3 Batten disease recapitulates clinical phenotypes

Abstract

Mouse models of CLN3 Batten disease, a rare lysosomal storage disorder with no cure, have improved our understanding of CLN3 biology and therapeutics through their ease of use and a consistent display of cellular pathology. However, the translatability of murine models is limited by disparities in anatomy, body size, life span, and inconsistent, subtle behavior deficits that can be difficult to detect in CLN3 mutant mouse models, limiting their utility in preclinical studies. Here we present a longitudinal characterization of a novel miniswine model of CLN3 disease that recapitulates the most common human pathogenic variant, an exon 7-8 deletion (CLN3{Delta}ex7/8). Progressive pathology and neuron loss is observed in various regions of the CLN3{Delta}ex7/8 miniswine brain and retina. Additionally, mutant miniswine present with vision impairment and motor abnormalities, similar to deficits seen in human patients. Taken together, the CLN3{Delta}ex7/8 miniswine model shows consistent and progressive Batten disease pathology and behavioral impairment mirroring clinical presentation, demonstrating its value in studying the role of CLN3 and safety/efficacy of novel disease modifying therapeutics.