title: Therapeutic response in feline sandhoff disease despite immunity to intracranial gene therapy.
abstract: Salutary responses to adeno-associated viral (AAV) gene therapy have been reported in the mouse model of Sandhoff disease (SD), a neurodegenerative lysosomal storage disease caused by deficiency of β-N-acetylhexosaminidase (Hex). While untreated mice reach the humane endpoint by 4.1 months of age, mice treated by a single intracranial injection of vectors expressing human hexosaminidase may live a normal life span of 2 years. When treated with the same therapeutic vectors used in mice, two cats with SD lived to 7.0 and 8.2 months of age, compared with an untreated life span of 4.5 ± 0.5 months (n = 11). Because a pronounced humoral immune response to both the AAV1 vectors and human hexosaminidase was documented, feline cDNAs for the hexosaminidase α- and β-subunits were cloned into AAVrh8 vectors. Cats treated with vectors expressing feline hexosaminidase produced enzymatic activity >75-fold normal at the brain injection site with little evidence of an immune infiltrate. Affected cats treated with feline-specific vectors by bilateral injection of the thalamus lived to 10.4 ± 3.7 months of age (n = 3), or 2.3 times as long as untreated cats. These studies support the therapeutic potential of AAV vectors for SD and underscore the importance of species-specific cDNAs for translational research.
authors.affiliation: Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, Alabama, USA.
authors.forename: Allison M
authors.initials: AM
authors.lastname: Bradbury
authors.forename: J Nicholas
authors.initials: JN
authors.lastname: Cochran
authors.forename: Victoria J
authors.initials: VJ
authors.lastname: McCurdy
authors.forename: Aime K
authors.initials: AK
authors.lastname: Johnson
authors.forename: Brandon L
authors.initials: BL
authors.lastname: Brunson
authors.forename: Heather
authors.initials: H
authors.lastname: Gray-Edwards
authors.forename: Stanley G
authors.initials: SG
authors.lastname: Leroy
authors.forename: Misako
authors.initials: M
authors.lastname: Hwang
authors.forename: Ashley N
authors.initials: AN
authors.lastname: Randle
authors.forename: Laura S
authors.initials: LS
authors.lastname: Jackson
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Morrison
authors.forename: Rena C
authors.initials: RC
authors.lastname: Baek
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Seyfried
authors.forename: Seng H
authors.initials: SH
authors.lastname: Cheng
authors.forename: Nancy R
authors.initials: NR
authors.lastname: Cox
authors.forename: Henry J
authors.initials: HJ
authors.lastname: Baker
authors.forename: M Begona
authors.initials: MB
authors.lastname: Cachón-González
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Cox
authors.forename: Miguel
authors.initials: M
authors.lastname: Sena-Esteves
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Martin
mesh_terms: D000818:Animals; D002371:Cat Diseases / Q000201:enzymology* / Q000235:genetics / Q000628:therapy*; D002415:Cats; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000235:genetics; D012497:Sandhoff Disease / Q000201:enzymology* / Q000235:genetics / Q000628:therapy*; D001619:beta-N-Acetylhexosaminidases / Q000235:genetics / Q000378:metabolism*
chemical_list: D001619:beta-N-Acetylhexosaminidases