AAV vector-mediated correction of brain pathology in a mouse model of Niemann-Pick A disease

Marco A. Passini, Shannon L. Macauley, Michael R. Huff, Tatyana V. Taksir, Jie Bu, I. Huan Wu, Peter A. Piepenhagen, James C. Dodge, Lamya S. Shihabuddin, Catherine R. O'Riordan, Edward H. Schuchman, Gregory R. Stewart

Research output: Contribution to journalArticlepeer-review

84 Scopus citations


Niemann-Pick A disease (NPA) is a fatal lysosomal storage disorder caused by a deficiency in acid sphingomyelinase (ASM) activity. The lack of functional ASM results in cellular accumulation of sphingomyelin and cholesterol within distended lysosomes throughout the brain. In this study, we investigated the potential of AAV-mediated expression of ASM to correct the brain pathology in an ASM knockout (ASMKO) mouse model of NPA. An AAV serotype 2 vector encoding human ASM (AAV2-hASM) was injected directly into the adult ASMKO hippocampus of one hemisphere. This resulted in expression of human ASM in all major cell layers of the ipsilateral hippocampus for at least 15 weeks postinjection. Transduced cells were also present in the entorhinal cortex, medial septum, and contralateral hippocampus in a pattern consistent with retrograde axonal transport of AAV2. There was a substantial reduction of distended lysosomes and an almost complete reversal of cholesterol accumulation in all areas of the brain that were targeted by AAV2-hASM. These findings show that the ASMKO brain is responsive to ASM replacement and that retrograde transport of AAV2 functions as a platform for widespread gene delivery and reversal of pathology in affected brain.

Original languageEnglish
Pages (from-to)754-762
Number of pages9
JournalMolecular Therapy
Issue number5
StatePublished - May 2005

Bibliographical note

Funding Information:
We thank Nelson Yew (Genzyme), Denise Griffiths (Genzyme), Louise Janes (Genzyme), Trent Richardson (Genzyme), Leah Curtin (Genzyme), and Antoneta Radu (Children’s Hospital of Philadelphia) for assistance and Seng Cheng (Genzyme) and Richard Sidman (Harvard University) for critically reading the manuscript. We gratefully acknowledge NIH Grant R01 HD 28607 to E.H.S.


  • AAV
  • Acid sphingomyelinase
  • Adeno-associated virus
  • Axonal transport
  • CNS
  • Cholesterol
  • Gene therapy
  • Lysosomal storage disease
  • Neurodegeneration

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery


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