Direct gene transfer to the CNS prevents emergence of neurologic disease in a murine model of mucopolysaccharidosis type I

Daniel A. Wolf, Andrew W. Lenander, Zhenhong Nan, Lalitha R. Belur, Chester B. Whitley, Pankaj Gupta, Walter C. Low, R. Scott McIvor

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68 Scopus citations


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 40× 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.

Original languageEnglish (US)
Pages (from-to)123-133
Number of pages11
JournalNeurobiology of Disease
Issue number1
StatePublished - Jul 2011

Bibliographical note

Funding Information:
We thank Dr. P. Hackett and Dr. E. Aronovich for helpful advice on quantitative PCR reactions, B. Koniar for animal care, and S. Sandberg and R. Cooksley for animal genotyping. We thank the staff at the Powell Gene Therapy Vector Core for preparation and titering of AAV vector used in this study. Lastly, we thank B. Mattsson for assistance in creating high resolution images. This work was supported by NIH grant P01 HD032652 (CBW, RSM) and training grant T32 DA022616-01 (DAW).


  • AAV
  • Gene transfer
  • Hurler syndrome
  • Iduronidase
  • Intracerebroventricular
  • Lysosomal storage disease
  • Mucopolysaccharidosis
  • Water maze


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