Beta-Propeller Protein-Associated Neurodegeneration (BPAN) is a-rare neurologic disease associated with early developmental delays and progressive neurodegeneration starting in adolescence. This X-linked disease is caused by mutations in the WDR45 gene encoding WIPI4 protein, involved in autophagosome formation. The goal of this study is to phenotype a novel CRISPR-engineered BPAN mouse model for preclinical therapy development.
Based on disease presentation in patients, we selected a battery of behavioral tests to establish disease-relevant outcome measures for future preclinical testing: open field (spontaneous and exploratory activity, motor and cognitive function), rotarod (motor function, balance, coordination), fear conditioning (learning and memory) and an autistic/social activity test.
We have created and currently testing the first experimental cohort of WDR45 c.ex9+g>a/Y and WDR45 +/Y (WT) mice. WDR45 c.ex9+g>a/Y demonstrate reduced exploratory activity and hyperactive behavior starting at 2 months of age, which is consistent with clinical observations of attention deficits and hyperactivity in BPAN children.
Our observations of the early behavioral deficits in WDR45 c.ex9+g>a/Y mice in the form of hyperactivity and reduced exploratory activity, mimic major cognitive deficits observed in BPAN patients and suggest that this mouse model can be an accurate model of the disease for future therapy testing.