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

• Published in: Cell transplantation Vol. 34; p. 9636897251323966
• Main Authors: Badell-Grau, Rafael A., Pakravesh, Kasra, Thai, Kevin Eric, Son, Frankie, Chen, Rola, Rainaldi, Joseph, Duong, Kalvin, Losay, Pauline, Sivakumar, Anusha, Khare, Veenita, Corl, Alexis N., Pithia, Rushil, Tran, Christine, Esko, Jefferey D., Cherqui, Stephanie
• Format: Journal Article
• Language: English
• Published: Los Angeles, CA SAGE Publications 01.03.2025; Sage Publications Ltd; SAGE Publishing
• Subjects: Acetyltransferase; Acetyltransferases - deficiency; Acetyltransferases - genetics; Acetyltransferases - metabolism; Animals; Carbohydrates; Cell Differentiation; Cell-based therapies for kidney disease; Disease Models, Animal; Enzymatic activity; Fibrosis; Glucosamine; Glucosamine N-acetyltransferase; Glycosaminoglycans; Glycosaminoglycans - metabolism; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - metabolism; Hemopoiesis; Heparan sulfate; Lysosomal storage diseases; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; Microglia; Mucopolysaccharidosis; Mucopolysaccharidosis III - metabolism; Mucopolysaccharidosis III - pathology; Mucopolysaccharidosis III - therapy; Neurology; Phenotype; Phenotypes; Progenitor cells; Sclerosis; Splenomegaly; Transplantation; Transplants & implants; macrophages; glycosaminoglycans (GAGs); transmembrane lysosomal protein; hematopoietic stem and progenitor cells (HSPCs); lysosomal storage disorder (LSD); heparan sulfate (HS); Sanfilippo syndrome; microglia
• ISSN: 0963-6897; 1555-3892; 1555-3892
• DOI: 10.1177/09636897251323966

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 N-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 Hgsnat−/− 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 Hgsnat expression and enzymatic activity along with a significant reduction of the MPS IIIC-specific non-reducing end carbohydrate in the treated Hgsnat−/− mice compared to untreated Hgsnat−/− mice or Hgsnat−/− mice transplanted with Hgsnat−/− HPSCs. In addition, WT HSPC transplant resulted in improved neurological defects, reduction in splenomegaly, and urine retention in the Hgsnat−/− 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 Hgsnat−/− 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. Graphical Abstract