Reprogrammed skin fibroblasts as model systems for studying the pathophysiology of peroxisome biogenesis disorders

Inherited defects in peroxisome function are causally responsible for a diverse group of rare multi-systemic neurodegenerative disorders (e.g. peroxisome biogenesis -disorders, PBDs). The exact roles peroxisomes play in the pathophysiology of PBDs and effective treatments that can rescue peroxisome function are yet to be discovered. The inability to obtain the human neural and hepatic cell types that are most relevant to the disease phenotype in PBD patients has impeded drug discovery efforts. Thus far, diagnostic tests and mechanistic studies involving these disorders are performed using primary skin fibroblasts derived from patients even though these cells are not affected in the diseases. Therefore, it would be beneficial to develop more appropriate cell-based model system to elucidate the nature of peroxisome involvement in these diseases and to identify candidate treatments that can be translated into clinical trials. Here, we hypothesize that induced pluripotent stem cells (iPSCs) from patients with PBDs will provide the basis for investigating peroxisome function in cell lineages most affected by disease. In this study, we first generated normal and PBD patient-specific iPSCs followed by their differentiation into hepatic cell lineages, in particular, hepatocytes because of their pivotal role in the development and clinical manifestation of PBDs. Biochemical analyses of peroxisome activities and hepatic functions on these novel cellular resources not only will enable us to gain insight into the vulnerability of different cell types, but also can increase the sensitivity of drug screens which could in turn accelerate therapeutic intervention.