The mucopolysaccharidoses (MPSs) are a group of 11 storage diseases caused by disruptions in glycosaminoglycan (GAG) catabolism, leading to their accumulation in lysosomes. Resultant multisystemic disease is manifested by growth delay, hepatosplenomegaly, skeletal dysplasias, cardiopulmonary obstruction, and, in severe MPS I, II, III, and VII, progressive neurocognitive decline. Some MPSs are treated by allogeneic hematopoietic stem cell transplantation (HSCT) and/or recombinant enzyme replacement therapy (ERT), but effectiveness is limited by central nervous system (CNS) access across the blood-brain barrier. To provide a high level of gene product to the CNS, we tested neonatal intracerebroventricular (ICV) infusion of an adeno-associated virus (AAV) serotype 8 vector transducing the human α-L-iduronidase gene in MPS I mice. Supranormal levels of iduronidase activity in the brain (including 40x normal levels in the hippocampus) were associated with transduction of neurons in motor and limbic areas identifiable by immunofluorescence staining. The treatment prevented accumulation of GAG and GM3 ganglioside storage materials and emergence of neurocognitive dysfunction in a modified Morris water maze test. The results suggest the potential of improved outcome for MPSs and other neurological diseases when a high level of gene expression can be achieved by direct, early administration of vector to the CNS.

Mucopolysaccharidosis type I (MPS I) is an autosomal recessive inherited disease caused by deficiency of the glycosidase α-L-iduronidase (IDUA). Deficiency of IDUA leads to lysosomal accumulation of the glycosaminoglycans (GAG) heparan and dermatan sulfate and associated multi-systemic disease, the most severe form known as Hurler syndrome. Since 1981, the treatment of Hurler patients has often included allogeneic bone marrow transplantation (BMT) from a matched donor. However, mouse models of the disease were not developed until 1997. To further characterize the MPS I mouse model and to study the effectiveness of BMT in these animals, we engrafted a cohort (n=33) of 4–8 week-old Idua−/− animals with high levels (88.4 ± 10.3%) of wild-type donor marrow. Engrafted animals displayed an increased lifespan, preserved cardiac function, partially restored IDUA activity in peripheral organs, and decreased GAG accumulation in both peripheral organs and in the brain. However, levels of GAG and GM3 ganglioside in the brain remained elevated in comparison to unaffected animals. Since these results are similar to those observed in Hurler patients following BMT, this murine transplantation model can be used to evaluate the effects of novel, more effective methods of delivering IDUA to the brain as an adjunct to BMT.

No abstract