title: Biomarkers for disease progression and AAV therapeutic efficacy in feline Sandhoff disease.
abstract: The GM2 gangliosidoses, Tay-Sachs disease (TSD) and Sandhoff disease (SD), are progressive neurodegenerative disorders that are caused by a mutation in the enzyme β-N-acetylhexosaminidase (Hex). Due to the recent emergence of novel experimental treatments, biomarker development has become particularly relevant in GM2 gangliosidosis as an objective means to measure therapeutic efficacy. Here we describe blood, cerebrospinal fluid (CSF), magnetic resonance imaging (MRI), and electrodiagnostic methods for evaluating disease progression in the feline SD model and application of these approaches to assess AAV-mediated gene therapy. SD cats were treated by intracranial injections of the thalami combined with either the deep cerebellar nuclei or a single lateral ventricle using AAVrh8 vectors encoding feline Hex. Significantly altered in untreated SD cats, blood and CSF based biomarkers were largely normalized after AAV gene therapy. Also reduced after treatment were expansion of the lysosomal compartment in peripheral blood mononuclear cells and elevated activity of secondary lysosomal enzymes. MRI changes characteristic of the gangliosidoses were documented in SD cats and normalized after AAV gene therapy. The minimally invasive biomarkers reported herein should be useful to assess disease progression of untreated SD patients and those in future clinical trials.
authors.affiliation: 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.forename: Allison M
authors.initials: AM
authors.lastname: Bradbury
authors.affiliation: Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL, USA.
authors.forename: Heather L
authors.initials: HL
authors.lastname: Gray-Edwards
authors.affiliation: Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL, USA.
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Shirley
authors.affiliation: 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.forename: Victoria J
authors.initials: VJ
authors.lastname: McCurdy
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford, UK.
authors.forename: Alexandria N
authors.initials: AN
authors.lastname: Colaco
authors.affiliation: Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL, USA.
authors.forename: Ashley N
authors.initials: AN
authors.lastname: Randle
authors.affiliation: Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL, USA.
authors.forename: Pete W
authors.initials: PW
authors.lastname: Christopherson
authors.affiliation: Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL, USA.
authors.forename: Allison C
authors.initials: AC
authors.lastname: Bird
authors.affiliation: Department of Clinical Sciences, College of Veterinary Medicine, Auburn University, Auburn, AL USA.
authors.forename: Aime K
authors.initials: AK
authors.lastname: Johnson
authors.affiliation: Department of Clinical Sciences, College of Veterinary Medicine, Auburn University, Auburn, AL USA.
authors.forename: Diane U
authors.initials: DU
authors.lastname: Wilson
authors.affiliation: Department of Clinical Sciences, College of Veterinary Medicine, Auburn University, Auburn, AL USA.
authors.forename: Judith A
authors.initials: JA
authors.lastname: Hudson
authors.affiliation: Department of Clinical Sciences, College of Veterinary Medicine, Auburn University, Auburn, AL USA.
authors.forename: Nicholas L
authors.initials: NL
authors.lastname: De Pompa
authors.affiliation: Department of Clinical Sciences, College of Veterinary Medicine, Auburn University, Auburn, AL USA.
authors.forename: Donald C
authors.initials: DC
authors.lastname: Sorjonen
authors.affiliation: Department of Anatomy, Physiology & Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL, USA.
authors.forename: Brandon L
authors.initials: BL
authors.lastname: Brunson
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford, UK.
authors.forename: Mylvaganam
authors.initials: M
authors.lastname: Jeyakumar
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford, UK.
authors.forename: Frances M
authors.initials: FM
authors.lastname: Platt
authors.affiliation: Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL, USA.
authors.forename: Henry J
authors.initials: HJ
authors.lastname: Baker
authors.affiliation: 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.forename: Nancy R
authors.initials: NR
authors.lastname: Cox
authors.affiliation: Department of Neurology and Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Miguel
authors.initials: M
authors.lastname: Sena-Esteves
authors.affiliation: 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: martidr@auburn.edu.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Martin
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000032:analysis*; D001921:Brain / Q000473:pathology; D002415:Cats; D000229:Dependovirus; D004195:Disease Models, Animal; D018450:Disease Progression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D007963:Leukocytes, Mononuclear / Q000473:pathology; D008247:Lysosomes / Q000473:pathology; D008279:Magnetic Resonance Imaging; D012497:Sandhoff Disease / Q000097:blood* / Q000134:cerebrospinal fluid* / Q000473:pathology; D001619:beta-N-Acetylhexosaminidases / Q000008:administration & dosage / Q000235:genetics
chemical_list: D015415:Biomarkers; D001619:beta-N-Acetylhexosaminidases
keywords: Biomarkers; GM2 ganglioside; Gene therapy; Hexosaminidase; Lysosomal storage disorder; Neurodegenerative disease