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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45 Citations (Scopus)

Abstract

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
Volume43
Issue number1
DOIs
StatePublished - Jul 1 2011

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Mucopolysaccharidoses
Mucopolysaccharidosis I
Iduronidase
Nervous System Diseases
Central Nervous System
Glycosaminoglycans
Mucopolysaccharidosis II
G(M3) Ganglioside
Intraventricular Infusions
Genes
Enzyme Replacement Therapy
Dependovirus
Hematopoietic Stem Cell Transplantation
Motor Cortex
Lysosomes
Blood-Brain Barrier
Fluorescent Antibody Technique
Hippocampus
Staining and Labeling
Gene Expression

Keywords

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

Cite this

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title = "Direct gene transfer to the CNS prevents emergence of neurologic disease in a murine model of mucopolysaccharidosis type I",
abstract = "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.",
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author = "Wolf, {Daniel A.} and Lenander, {Andrew W.} and Zhenhong Nan and Belur, {Lalitha R.} and Whitley, {Chester B.} and Pankaj Gupta and Low, {Walter C.} and McIvor, {R. Scott}",
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AU - Lenander, Andrew W.

AU - Nan, Zhenhong

AU - Belur, Lalitha R.

AU - Whitley, Chester B.

AU - Gupta, Pankaj

AU - Low, Walter C.

AU - McIvor, R. Scott

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