• Allison M Bradbury, Tiffany A Peterson, Amanda L Gross, Stephen Z Wells, Victoria J McCurdy, Karen G Wolfe, John C Dennis, Brandon L Brunson, Heather Gray-Edwards, Ashley N Randle, Aime K Johnson, Edward E Morrison, Nancy R Cox, Henry J Baker, Miguel Sena-Esteves, and Douglas R Martin.
• Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL, USA; Department of Anatomy, Physiology & Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL, USA. Electronic address: brada@upenn.edu.
• Neuroscience. 2017 Jan 6; 340: 117-125.

AbstractSandhoff 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.Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

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