Abstract
Mucopolysaccharidosis III (MPS III) is a devastating neurodegenerative disease characterized by intralysosomal accumulation of Heparin Sulfate (HS) and neuroinflammation. This disease occurs at a prevalence as high as 4 in 100,000 births. Each subtype of MPS III (A,B,C, and D) corresponds to a deficiency in a different enzyme involved in HS degradation, but MPS IIIA patients have the most severe disease progression. Patients with MPS IIIA, also commonly known as Sanfilippo Syndrome, cannot break down HS which results in low levels of sulfamidase (SGSH). This deficiency leads to three distinct phases of MPS III progression. In the first stage, not enough HS has accumulated to result in a disease phenotype, thus children appear healthy up until around two years of age. In the second stage after two years of age, the child will have delayed intellectual development, such as a speech delay or having a learning disability. As the disease progresses, the child may have severe behavioral problems such as anxiety and hyperactivity. Finally, the child will have dementia and loss of motor function, leaving the patient bedridden until they expire, usually in the early teens.
Because MPS IIIA is a disease of the nervous system, the blood-brain barrier poses a major roadblock to treatment as many interventions rely on intravenous delivery. This project explores the use of SGSH expressing neural stem cells (SGSH-NSCs) injected into the corpuscallosum of immune deficient mice of the C57Bl/6j genetic background as a novel treatment for MPS IIIA. Mice were injected at 2.5 months of age with SGSH-NSCs and their behavior was characterized through the open field, rotarod, and touchscreen behavioral tests to observe clinical differences in levels of anxiety, hyperactivity, coordination, learning and memory. The results of this experiment were largely inconclusive, but touch screen data suggests that the SGSH-NSC treatment may be helpful and is likely not harmful to the treated animals given their longevity. While the study does not produce immediate conclusions, it does provide useful considerations for future experiments and has developed protocols and models that will aid the success in future studies for this novel therapeutic approach.