Transplantation of Wild-Type Hematopoietic Stem and Progenitor Cells Improves Disease Phenotypes in a Mucopolysaccharidosis IIIC Mouse Model

Mucopolysaccharidosis type IIIC (MPS IIIC) is a severe neurodegenerative lysosomal storage disease caused by the loss-of-function of the lysosomal transmembrane protein acetyl-CoA: heparan-α-glucosamine <i>N</i>-acetyltransferase. MPS IIIC is characterized by the accumulation of the glycosaminoglycan (GAG) heparan sulfate. There is no treatment for this disease. We generated a new MPS IIIC mouse model and confirmed disease phenotypes such as GAG accumulation, splenomegaly, neurological defects, and presence of disease-specific non-reducing end carbohydrates. To explore a new therapeutic strategy for this condition, we transplanted wild-type (WT) hematopoietic stem and progenitor cells (HSPCs) into lethally irradiated 2-month-old <i>Hgsnat</i>^-/- mice and analyzed the resulting impact 6 months later. Transplanted HSPCs differentiated into macrophages in tissues and microglia-like cells in the brain. This resulted in a partial restoration of <i>Hgsnat</i> expression and enzymatic activity along with a significant reduction of the MPS IIIC-specific non-reducing end carbohydrate in the treated <i>Hgsnat</i>^-/- mice compared to untreated <i>Hgsnat</i>^-/- mice or <i>Hgsnat</i>^-/- mice transplanted with <i>Hgsnat</i>^-/- HPSCs. In addition, WT HSPC transplant resulted in improved neurological defects, reduction in splenomegaly, and urine retention in the <i>Hgsnat</i>^-/- mice. Furthermore, presence of glomerular hyaline bodies with focal fibrosis and sclerosis was observed in the kidney of the disease controls, whereas these abnormalities were improved in the <i>Hgsnat</i>^-/- mice treated with WT HSPCs. These data support that HSPC transplantation presents a promising therapeutic avenue for MPS IIIC and represents the first step toward the clinical translation of an HSPC-mediated therapy strategy for MPS IIIC.