title: AAV-mediated gene delivery in a feline model of Sandhoff disease corrects lysosomal storage in the central nervous system.
abstract: Sandhoff disease (SD) is an autosomal recessive neurodegenerative disease caused by a mutation in the gene for the β-subunit of β-N-acetylhexosaminidase (Hex), resulting in the inability to catabolize ganglioside GM2 within the lysosomes. SD presents with an accumulation of GM2 and its asialo derivative GA2, primarily in the central nervous system. Myelin-enriched glycolipids, cerebrosides and sulfatides, are also decreased in SD corresponding with dysmyelination. At present, no treatment exists for SD. Previous studies have shown the therapeutic benefit of adeno-associated virus (AAV) vector-mediated gene therapy in the treatment of SD in murine and feline models. In this study, we treated presymptomatic SD cats with AAVrh8 vectors expressing feline Hex in the thalamus combined with intracerebroventricular (Thal/ICV) injections. Treated animals showed clearly improved neurologic function and quality of life, manifested in part by prevention or attenuation of whole-body tremors characteristic of untreated animals. Hex activity was significantly elevated, whereas storage of GM2 and GA2 was significantly decreased in tissue samples taken from the cortex, cerebellum, thalamus, and cervical spinal cord. Treatment also increased levels of myelin-enriched cerebrosides and sulfatides in the cortex and thalamus. This study demonstrates the therapeutic potential of AAV for feline SD and suggests a similar potential for human SD patients.
authors: Boston College Biology Department, Chestnut Hill, MA, USA.
authors: Hannah E
authors: HE
authors: Rockwell
authors: Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, AL, USA Department of Anatomy, Physiology & Pharmacology, College of Veterinary Medicine, Auburn University, AL, USA.
authors: Victoria J
authors: VJ
authors: McCurdy
authors: Boston College Biology Department, Chestnut Hill, MA, USA.
authors: Samuel C
authors: SC
authors: Eaton
authors: Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, AL, USA Department of Clinical Sciences, College of Veterinary Medicine, Auburn University, AL, USA.
authors: Diane U
authors: DU
authors: Wilson
authors: Department of Clinical Sciences, College of Veterinary Medicine, Auburn University, AL, USA.
authors: Aime K
authors: AK
authors: Johnson
authors: Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, AL, USA.
authors: Ashley N
authors: AN
authors: Randle
authors: Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, AL, USA Department of Anatomy, Physiology & Pharmacology, College of Veterinary Medicine, Auburn University, AL, USA.
authors: Allison M
authors: AM
authors: Bradbury
authors: Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, AL, USA.
authors: Heather L
authors: HL
authors: Gray-Edwards
authors: Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, AL, USA Department of Pathobiology, College of Veterinary Medicine, Auburn University, AL, USA.
authors: Henry J
authors: HJ
authors: Baker
authors: Department of Clinical Sciences, College of Veterinary Medicine, Auburn University, AL, USA.
authors: Judith A
authors: JA
authors: Hudson
authors: Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, AL, USA Department of Pathobiology, College of Veterinary Medicine, Auburn University, AL, USA.
authors: Nancy R
authors: NR
authors: Cox
authors: Department of Neurology and Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA, USA.
authors: Miguel
authors: M
authors: Sena-Esteves
authors: Boston College Biology Department, Chestnut Hill, MA, USA.
authors: Thomas N
authors: TN
authors: Seyfried
authors: Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, AL, USA Department of Anatomy, Physiology & Pharmacology, College of Veterinary Medicine, Auburn University, AL, USA martidr@auburn.edu.
authors: Douglas R
authors: DR
authors: Martin
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology / Q000503:physiopathology; D002415:Cats; D002490:Central Nervous System / Q000378:metabolism; D002554:Cerebrosides / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics*; D004195:Disease Models, Animal; D018450:Disease Progression; D005678:G(M2) Ganglioside / Q000378:metabolism; D005732:Gangliosides / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism*; D011788:Quality of Life; D012497:Sandhoff Disease / Q000473:pathology / Q000503:physiopathology / Q000523:psychology / Q000628:therapy*; D012720:Severity of Illness Index; D013116:Spinal Cord / Q000473:pathology / Q000503:physiopathology; D013433:Sulfoglycosphingolipids / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D002554:Cerebrosides; D005732:Gangliosides; D018398:Homeodomain Proteins; D013433:Sulfoglycosphingolipids; D005678:G(M2) Ganglioside; C038244:ganglio-N-triaosylceramide
keywords: Sandhoff disease; adeno-associated virus; ganglioside; gene therapy; β-hexosaminidase