Correction of Mucopolysaccharidosis Type I (MPS I) with Multipotent Adult Progenitor Cells (MAPCs) in an Immunodeficient Mouse Model

Abstract

Hurler Syndrome or Mucopolysaccharidosis I (MPS I) is an autosomal recessive lysosomal storage disease characterized by skeletal abnormalities, hepatosplenomegaly, and neurological degeneration. Children who exhibit MPS I lack α-L-iduronidase (IDUA), a crucial enzyme in the degradation pathway of glycosaminoglycans (GAGs), specifically heparan and dermatan sulfate. GAG accumulation in lysosomes interferes with normal cell function creating multi-systemic problems. Current treatments including enzyme replacement therapy and hematopoietic stem cell transplantation are not widely available and fail to correct the majority of symptoms, particularly mental retardation and skeletal anomalies. Using a NOD/SCID immunodeficient mouse model of MPS I, we attempted to correct the enzyme deficiency by transplanting human multipotent adult progenitor cells (MAPCs) directly into the striatum within five days of birth. Through the process of cross-correction, the IDUA enzyme released from the transplanted cells is taken up by the defective cells. The efficacy of the MAPCs was investigated through measurement of IDUA levels in different tissues, immunohistochemical staining, and sensorimotor testing. The transplanted MAPCs were detected throughout the central nervous system along with decreased levels of GAGs indicating sufficient delivery of IDUA to the cells. Sensorimotor coordination on a rotarod test improved in the MAPC-treated MPS I mice compared to untreated MPS I mice. These results denote that transplantation of MAPCs into the striatum greatly reduces GAG tissue levels in the brain and ameliorates sensorimotor function in MPS I mice.