AAV-MEDIATED GENE DELIVERY ATTENUATES NEUROINFLAMMATION IN FELINE SANDHOFF DISEASE

作者：Bradbury Allison M; Peterson Tiffany A; Gross Amanda L; Wells Stephen Z; Mccurdy Victoria J; Wolfe Karen G; Dennis John C; Brunson Brandon L; Gray Edwards Heather; Randle Ashley N; Johnson Aime K; Morrison Edward E; Cox Nancy R; Baker Henry J; Sena Esteves Miguel; Martin Douglas R

来源：Neuroscience, 2017, 340: 117-125.

DOI：10.1016/j.neuroscience.2016.10.047

• lysosomal storage disorder
• neurodegenerative disease
• neuroinflammation
• microglia activation
• cytokines/chemokines
• AAV gene therapy

Sandhoff disease (SD) is a lysosomal storage disorder characterized by the absence of hydrolytic enzyme beta-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-1 alpha) was also up-regulated in the brain. SD cats were treated with intracranial delivery of adenoassociated viral (AAV) vectors expressing feline Hex, with a study endpoint 16 weeks post treatment. AAV-mediated gene delivery repressed the expansion and activation of microglia and normalized MHC-II and MIP-1 alpha levels. These data reiterate the profound inflammatory response in SD and show that neuroinflammation is abrogated after AAV-mediated restoration of enzymatic activity.

• 出版日期2017-1-6