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

NEUROBIOLOGY OF DISEASE

卷:43

Article

Wolf, Daniel A.¹  Lenander, Andrew W.¹  Nan, Zhenhong²  Belur, Lalitha R.¹  Whitley, Chester B.³  Gupta, Pankaj⁴  Low, Walter C.²  Mclvor, R. Scott¹ 

[1] Univ Minnesota, Gene Therapy Program, Inst Human Genet, Dept Genet Cell Biol & Dev, Minneapolis, MN 55455 USA

[2] Univ Minnesota, Dept Neurosurg, Minneapolis, MN 55455 USA

[3] Univ Minnesota, Dept Pediat, Minneapolis, MN 55455 USA

[4] Vet Adm Med Ctr, Hematol Oncol Sect, Minneapolis, MN 55417 USA

关键词: Mucopolysaccharidosis;    Hurler syndrome;    Lysosomal storage disease;    Iduronidase;    AAV;    Gene transfer;    Intracerebroventricular;    Water maze;   

DOI  :  10.1016/j.nbd.2011.02.015

来源: Elsevier

【 摘 要 】

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 alpha-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. (C) 2011 Elsevier Inc. All rights reserved.

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