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 (CLN3Δex7/8). Progressive pathology and neuron loss is observed in various regions of the CLN3Δex7/8 miniswine brain and retina. Additionally, mutant miniswine present with vision impairment and motor abnormalities, similar to deficits seen in human patients. Taken together, the CLN3Δex7/8 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.

NF1+/ex42del miniswine model the cellular disruptions and behavioral presentations of NF1‐associated cognitive and motor impairment

“…Our team has utilized the simple T‐maze and gait walkway in multiple miniswine studies and has optimized these methods to produce repeatable and consistent results. However, we have had mixed results with the FitBark activity monitor, which may be due to the short time that the device was worn by each animal, differences between genotypes, or differences in other factors such as environment 16,30,33,50 . Utilizing the Fitbark for longer periods of time (2 weeks or greater) in future longitudinal miniswine studies might improve data quality, reduce variability, and add an important component to these behavior studies.…”

Longitudinal Deep Multi-Omics Profiling in aCLN3Δex7/8Minipig Model Reveals Novel Biomarker Signatures for Batten Disease

“…We sought to uncover a more diverse set of CLN3-related biomarkers and to gain insights into the molecular function of CLN3 using an untargeted metabolomics and a novel deep multi-nanoparticle-based proteomics in a Yucatan Minipig model of CLN3 Batten disease harboring the most common patient mutation: a ∼1kb deletion in exons seven and eight 11, 12 (Fig. 1).…”