AAV-mediated gene delivery attenuates neuroinflammation in feline Sandhoff disease

Neuroscience. 2017 Jan 6;340:117-125. doi: 10.1016/j.neuroscience.2016.10.047. Epub 2016 Oct 26.


Sandhoff disease (SD) is a lysosomal storage disorder characterized by the absence of hydrolytic enzyme β-N-acetylhexosaminidase (Hex), which results in storage of GM2 ganglioside in neurons and unremitting neurodegeneration. Neuron loss initially affects fine motor skills, but rapidly progresses to loss of all body faculties, a vegetative state, and death by five years of age in humans. A well-established feline model of SD allows characterization of the disease in a large animal model and provides a means to test the safety and efficacy of therapeutic interventions before initiating clinical trials. In this study, we demonstrate a robust central nervous system (CNS) inflammatory response in feline SD, primarily marked by expansion and activation of the microglial cell population. Quantification of major histocompatibility complex II (MHC-II) labeling revealed significant up-regulation throughout the CNS with areas rich in white matter most severely affected. Expression of the leukocyte chemokine macrophage inflammatory protein-1 alpha (MIP-1α) was also up-regulated in the brain. SD cats were treated with intracranial delivery of adeno-associated viral (AAV) vectors expressing feline Hex, with a study endpoint 16weeks post treatment. AAV-mediated gene delivery repressed the expansion and activation of microglia and normalized MHC-II and MIP-1α levels. These data reiterate the profound inflammatory response in SD and show that neuroinflammation is abrogated after AAV-mediated restoration of enzymatic activity.

Keywords: AAV gene therapy; cytokines/chemokines; lysosomal storage disorder; microglia activation; neurodegenerative disease; neuroinflammation.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Astrocytes / immunology
  • Astrocytes / pathology
  • Brain / immunology*
  • Brain / pathology
  • Cats
  • Dependovirus / genetics
  • Disease Models, Animal
  • Genes, MHC Class II / physiology
  • Genetic Therapy*
  • Genetic Vectors
  • Gliosis / immunology
  • Gliosis / pathology
  • Gliosis / therapy
  • Immunohistochemistry
  • Microglia / immunology
  • Microglia / pathology
  • Neurons / immunology
  • Neurons / pathology
  • Polymerase Chain Reaction
  • Sandhoff Disease / immunology*
  • Sandhoff Disease / pathology
  • Sandhoff Disease / therapy*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism


  • Adaptor Proteins, Signal Transducing
  • Transcription Factors