title: Mucopolysaccharidosis-like phenotype in feline Sandhoff disease and partial correction after AAV gene therapy.
abstract: Sandhoff disease (SD) is a fatal neurodegenerative disease caused by a mutation in the enzyme β-N-acetylhexosaminidase. Children with infantile onset SD develop seizures, loss of motor tone and swallowing problems, eventually reaching a vegetative state with death typically by 4years of age. Other symptoms include vertebral gibbus and cardiac abnormalities strikingly similar to those of the mucopolysaccharidoses. Isolated fibroblasts from SD patients have impaired catabolism of glycosaminoglycans (GAGs). To evaluate mucopolysaccharidosis-like features of the feline SD model, we utilized radiography, MRI, echocardiography, histopathology and GAG quantification of both central nervous system and peripheral tissues/fluids. The feline SD model exhibits cardiac valvular and structural abnormalities, skeletal changes and spinal cord compression that are consistent with accumulation of GAGs, but are much less prominent than the severe neurologic disease that defines the humane endpoint (4.5±0.5months). Sixteen weeks after intracranial AAV gene therapy, GAG storage was cleared in the SD cat cerebral cortex and liver, but not in the heart, lung, skeletal muscle, kidney, spleen, pancreas, small intestine, skin, or urine. GAG storage worsens with time and therefore may become a significant source of pathology in humans whose lives are substantially lengthened by gene therapy or other novel treatments for the primary, neurologic disease.
authors.affiliation: Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL, USA. Electronic address: grayhea@auburn.edu.
authors.forename: Heather L
authors.initials: HL
authors.lastname: Gray-Edwards
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 Clinical Sciences, College of Veterinary Medicine, Auburn University, Auburn, AL, USA.
authors.forename: Merrilee
authors.initials: M
authors.lastname: Holland
authors.affiliation: Department of Clinical Sciences, College of Veterinary Medicine, Auburn University, Auburn, AL, USA.
authors.forename: Adrien-Maxence
authors.initials: AM
authors.lastname: Hespel
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; 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: 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: Patricia M
authors.initials: PM
authors.lastname: Beadlescomb
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: MR R&D Siemens Healthcare, Malvern, PA, USA; Auburn University MRI Research Center, Auburn, AL, USA.
authors.forename: Nouha
authors.initials: N
authors.lastname: Salibi
authors.affiliation: Auburn University MRI Research Center, Auburn, AL, USA; Department of Electrical and Computer Engineering, Auburn University, Auburn, AL, USA.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Denney
authors.affiliation: Auburn University MRI Research Center, Auburn, AL, USA.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Beyers
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: Meredith L
authors.initials: ML
authors.lastname: Voyles
authors.affiliation: Department of Clinical Sciences, College of Veterinary Medicine, Auburn University, Auburn, AL, USA.
authors.forename: Ronald D
authors.initials: RD
authors.lastname: Montgomery
authors.affiliation: Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL, USA; 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: 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: 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: Henry J
authors.initials: HJ
authors.lastname: Baker
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.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Martin
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000825:Animal Structures / Q000473:pathology; D000818:Animals; D002415:Cats; D004195:Disease Models, Animal; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D009083:Mucopolysaccharidoses / Q000235:genetics / Q000473:pathology / Q000628:therapy; D010641:Phenotype; D012497:Sandhoff Disease / Q000235:genetics* / Q000503:physiopathology / Q000628:therapy* / Q000652:urine; D001619:beta-N-Acetylhexosaminidases / Q000235:genetics* / Q000627:therapeutic use*
chemical_list: D001619:beta-N-Acetylhexosaminidases
keywords: Bone; GM2 gangliosidosis; Gene therapy; Heart; Lysosomal storage disease; Sandhoff disease