title: Widespread correction of central nervous system disease after intracranial gene therapy in a feline model of Sandhoff disease.
abstract: Sandhoff disease (SD) is caused by deficiency of N-acetyl-β-hexosaminidase (Hex) resulting in pathological accumulation of GM2 ganglioside in lysosomes of the central nervous system (CNS) and progressive neurodegeneration. Currently, there is no treatment for SD, which often results in death by the age of five years. Adeno-associated virus (AAV) gene therapy achieved global CNS Hex restoration and widespread normalization of storage in the SD mouse model. Using a similar treatment approach, we sought to translate the outcome in mice to the feline SD model as an important step toward human clinical trials. Sixteen weeks after four intracranial injections of AAVrh8 vectors, Hex activity was restored to above normal levels throughout the entire CNS and in cerebrospinal fluid, despite a humoral immune response to the vector. In accordance with significant normalization of a secondary lysosomal biomarker, ganglioside storage was substantially improved, but not completely cleared. At the study endpoint, 5-month-old AAV-treated SD cats had preserved neurological function and gait compared with untreated animals (humane endpoint, 4.4±0.6 months) demonstrating clinical benefit from AAV treatment. Translation of widespread biochemical disease correction from the mouse to the feline SD model provides optimism for treatment of the larger human CNS with minimal modification of approach.
authors.affiliation: 1] Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL, USA [2] Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL, USA.
authors.forename: V J
authors.initials: VJ
authors.lastname: McCurdy
authors.affiliation: Biology Department, Boston College, Chestnut Hill, MA, USA.
authors.forename: H E
authors.initials: HE
authors.lastname: Rockwell
authors.affiliation: Biology Department, Boston College, Chestnut Hill, MA, USA.
authors.forename: J R
authors.initials: JR
authors.lastname: Arthur
authors.affiliation: 1] Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL, USA [2] Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Bradbury
authors.affiliation: Department of Clinical Sciences, College of Veterinary Medicine, Auburn University, Auburn, AL, USA.
authors.forename: A K
authors.initials: AK
authors.lastname: Johnson
authors.affiliation: Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL, USA.
authors.forename: A N
authors.initials: AN
authors.lastname: Randle
authors.affiliation: Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL, USA.
authors.forename: B L
authors.initials: BL
authors.lastname: Brunson
authors.affiliation: Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL, USA.
authors.forename: M
authors.initials: M
authors.lastname: Hwang
authors.affiliation: Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL, USA.
authors.forename: H 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: N E
authors.initials: NE
authors.lastname: Morrison
authors.affiliation: Department of Clinical Sciences, College of Veterinary Medicine, Auburn University, Auburn, AL, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Johnson
authors.affiliation: 1] Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL, USA [2] Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL, USA.
authors.forename: H J
authors.initials: HJ
authors.lastname: Baker
authors.affiliation: 1] Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL, USA [2] Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL, USA.
authors.forename: N R
authors.initials: NR
authors.lastname: Cox
authors.affiliation: Biology Department, Boston College, Chestnut Hill, MA, USA.
authors.forename: T N
authors.initials: TN
authors.lastname: Seyfried
authors.affiliation: Department of Neurology and Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Sena-Esteves
authors.affiliation: 1] Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL, USA [2] Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL, USA.
authors.forename: D R
authors.initials: DR
authors.lastname: Martin
mesh_terms: D000818:Animals; D002415:Cats; D000229:Dependovirus / Q000235:genetics / Q000276:immunology; D018450:Disease Progression; D005732:Gangliosides / Q000378:metabolism; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D056724:Immunity, Humoral; D007276:Injections, Intraventricular; D012497:Sandhoff Disease / Q000473:pathology / Q000628:therapy*; D014161:Transduction, Genetic; D016896:Treatment Outcome; D001619:beta-N-Acetylhexosaminidases / Q000096:biosynthesis / Q000235:genetics
chemical_list: D005732:Gangliosides; D001619:beta-N-Acetylhexosaminidases