Characterizing and treating peripheral nervous system dysfunction in Sanfilippo Syndrome

Title: Characterizing and treating peripheral nervous system dysfunction in Sanfilippo Syndrome Mucopolysaccharidosis Type IIIA (MPS IIIA), also known as Sanfilippo Syndrome Type A, is a rare autosomal recessive disorder that affects one in every 70,000 children worldwide, and currently there are no approved therapies. Patients with MPS IIIA are unable to catabolize a subtype of cellular polysaccharides, known as heparan sulfate (HS), due to inherited mutations in the gene encoding for the lysosomal enzyme, N- sulfoglucosamine sulfohydrolase (SGSH). Deficiency in this enzyme leads to intra-lysosomal storage and accumulation of HS, which results in severe neuropathology, including regression of intellectual and motor abilities, behavioral problems, hearing loss, and dementia. Children born with this disorder exhibit developmental abnormalities, organ failure, and neurodegeneration, which often result in death within the first two decades of life. To date, MPS IIIA neuropathologic and therapeutic studies have focused predominantly on changes in the central nervous system, especially in the brain, but little is known about the disease pathology in the peripheral nervous system (PNS). Intriguingly, both MPS IIIA patients and mouse models display symptoms of degeneration of the sensory and autonomic nervous system, including retinopathy, bowel issues, and cardiomyopathy. Yet, the molecular mechanisms triggering the underlying peripheral neuropathy are virtually unknown. The main objectives of this proposal are to develop novel disease models for MPS IIIA and to identify therapeutic agents to lower the accumulation of HS in MPS IIIA cells. In Aim 1 of this proposal, our team will utilize patient-derived induced pluripotent stem cells (iPSCs) to generate peripheral neural stem cell models to recapitulate PNS phenotypes and dysfunction found in MPS IIIA patients. iPSCs from MPS IIIA patients with an intermediate and severe clinical phenotype, respectively, will be differentiated into neural crest cells, peripheral sensory neurons, and sympathetic neurons and evaluated for disease pathology, cell morphology, and neural electrophysiology. In Aim 2 of the project, we will repurpose FDA-approved drugs recently identified through drug screens to reduce HS biosynthesis for substrate reduction therapy for MPS IIIA. Promising compounds will be assessed for their impact on HS content and lysosomal storage in primary human fibroblasts from MPS IIIA patients. Efficacy of active agents will then be assayed for reduction of lysosomal storage of glycosaminoglycans in iPSC-derived PNS models generated in Aim 1. Overall, the innovative strategies proposed here will develop novel cellular models to improve our knowledge about the molecular underpinnings of PNS dysfunction in MPS IIIA and will promote the discovery of new therapies by addressing the underlying cause of the disorder, lysosomal accumulation of heparan sulfate.