Gene transfer of human acid sphingomyelinase corrects neuropathology and motor deficits in a mouse model of Niemann-Pick type A disease

James C. Dodge, Jennifer Clarke, Antonius Song, Jie Bu, Wendy Yang, Tatyana V. Taksir, Denise Griffiths, Michael A. Zhao, Edward H. Schuchman, Seng H. Cheng, Catherine R. O'Riordan, Lamya S. Shihabuddin, Marco A. Passini, Gregory R. Stewart

Research output: Contribution to journalArticlepeer-review

78 Scopus citations

Abstract

Niemann-Pick type A disease is a lysosomal storage disorder caused by a deficiency in acid sphingomyelinase (ASM) activity. Previously we showed that storage pathology in the ASM knockout (ASMKO) mouse brain can be corrected by adeno-associated virus serotype 2 (AAV2)-mediated gene transfer. The present experiment compared the relative therapeutic efficacy of different recombinant AAV serotype vectors (1, 2, 5, 7, and 8) using histological, biochemical, and behavioral endpoints. In addition, we evaluated the use of the deep cerebellar nuclei (DCN) as a site for injection to facilitate global distribution of the viral vector and enzyme. Seven-week-old ASM knockout mice were injected within the DCN with different AAV serotype vectors encoding human ASM (hASM) and then killed at either 14 or 20 weeks of age. Results showed that AAV1 was superior to serotypes 2, 5, 7, and 8 in its relative ability to express hASM, alleviate storage accumulation, and correct behavioral deficits. Expression of hASM was found not only within the DCN, but also throughout the cerebellum, brainstem, midbrain, and spinal cord. This finding demonstrates that targeting the DCN is an effective approach for achieving widespread enzyme distribution throughout the CNS. Our results support the continued development of AAV based vectors for gene therapy of the CNS manifestations in Niemann-Pick type A disease.

Original languageEnglish
Pages (from-to)17822-17827
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number49
DOIs
StatePublished - 6 Dec 2005

Keywords

  • Adeno-associated virus
  • Axonal transport
  • Deep cerebellar nuclei
  • Gene therapy
  • Lysosomal storage diseases

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