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

Mol Ther. 2005 May;11(5):754-62. doi: 10.1016/j.ymthe.2005.01.011.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Brain / metabolism
  • Brain / pathology*
  • Cholesterol / metabolism
  • Dependovirus / genetics*
  • Disease Models, Animal*
  • Genetic Therapy*
  • Genetic Vectors / genetics*
  • Humans
  • Lysosomes / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Niemann-Pick Diseases / genetics*
  • Niemann-Pick Diseases / metabolism
  • Niemann-Pick Diseases / pathology*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Sphingomyelin Phosphodiesterase / deficiency
  • Sphingomyelin Phosphodiesterase / genetics
  • Sphingomyelin Phosphodiesterase / metabolism


  • RNA, Messenger
  • Cholesterol
  • Sphingomyelin Phosphodiesterase