The neuronal ceroid lipofuscinoses (NCL), or Batten Disease are a group of inherited neurodegenerative disorders caused by altered lysosomal function leading to a build-up of auto fluorescent storage material within cells. In this study, we focus on CLN1, an aggressive form of the disease with an early symptom onset developing from 12-24 months of age. Clinical manifestations include blindness, psychological and motor deterioration and seizures with an average life expectancy of 9-12 years old. CLN1 disease is caused by defects in the gene encoding palmitoyl protein thioesterase (PPT1). In the absence of PPT1 function, granular osmiophilic deposits accumulate in the CNS and other tissues.
There is no cure for CLN1 in part due to poor understanding of the regional nature of the disease and a lack of readily available biomarkers. We have generated a CLN1 ovine model using CRISPR-Cas9 gene editing to bridge the translational gap from small animal models to preclinical trials. We aim to contribute to our understanding of: 1. Why is the nervous system preferentially affected at early disease stages? 2. What impact is there on other organ systems? 3. How can (and/or should) we predict disease staging and track progression?
To date, we have carried out proteomic analysis on differentially affected brain regions and identified protein candidates which likely underpin regional vulnerability. In due course, we plan to carry out proteomic analysis of multiple organ systems and bodily fluids to help identify molecular consequences of altered PPT1 throughout the body. Imaging modalities (MRI of the nervous system and full-body CT scans) will be used to indicate gross morphological changes throughout disease progression. We believe this study will play a significant role in informing preclinical therapeutic approaches on regional targeting and timing of intervention.