title: AAV-mediated gene delivery attenuates neuroinflammation in feline Sandhoff disease.
abstract: 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.
authors: 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.
authors: Allison M
authors: AM
authors: Bradbury
authors: Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL, USA.
authors: Tiffany A
authors: TA
authors: Peterson
authors: Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL, USA.
authors: Amanda L
authors: AL
authors: Gross
authors: Department of Clinical Sciences, College of Veterinary Medicine, Auburn University, Auburn, AL, USA.
authors: Stephen Z
authors: SZ
authors: Wells
authors: 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.
authors: Victoria J
authors: VJ
authors: McCurdy
authors: Department of Anatomy, Physiology & Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL, USA.
authors: Karen G
authors: KG
authors: Wolfe
authors: Department of Anatomy, Physiology & Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL, USA.
authors: John C
authors: JC
authors: Dennis
authors: Department of Anatomy, Physiology & Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL, USA.
authors: Brandon L
authors: BL
authors: Brunson
authors: Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL, USA.
authors: Heather
authors: H
authors: Gray-Edwards
authors: Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL, USA.
authors: Ashley N
authors: AN
authors: Randle
authors: Department of Clinical Sciences, College of Veterinary Medicine, Auburn University, Auburn, AL, USA.
authors: Aime K
authors: AK
authors: Johnson
authors: Department of Anatomy, Physiology & Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL, USA.
authors: Edward E
authors: EE
authors: Morrison
authors: Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL, USA; Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL, USA.
authors: Nancy R
authors: NR
authors: Cox
authors: Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL, USA.
authors: Henry J
authors: HJ
authors: Baker
authors: Department of Neurology and Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA, USA.
authors: Miguel
authors: M
authors: Sena-Esteves
authors: 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.
authors: Douglas R
authors: DR
authors: Martin
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000276:immunology / Q000473:pathology; D001921:Brain / Q000276:immunology* / Q000473:pathology; D002415:Cats; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D005802:Genes, MHC Class II / Q000502:physiology; D015316:Genetic Therapy; D005822:Genetic Vectors; D005911:Gliosis / Q000276:immunology / Q000473:pathology / Q000628:therapy; D007150:Immunohistochemistry; D017628:Microglia / Q000276:immunology / Q000473:pathology; D009474:Neurons / Q000276:immunology / Q000473:pathology; D016133:Polymerase Chain Reaction; D012497:Sandhoff Disease / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D014157:Transcription Factors
keywords: AAV gene therapy; cytokines/chemokines; lysosomal storage disorder; microglia activation; neurodegenerative disease; neuroinflammation