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ASN Neuro. 2015 Apr 13;7(2). pii: 1759091415569908. doi: 10.1177/1759091415569908. Print 2015 Mar-Apr.

AAV-mediated gene delivery in a feline model of Sandhoff disease corrects lysosomal storage in the central nervous system.

Author information

1
Boston College Biology Department, Chestnut Hill, MA, USA.
2
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.
3
Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, AL, USA Department of Clinical Sciences, College of Veterinary Medicine, Auburn University, AL, USA.
4
Department of Clinical Sciences, College of Veterinary Medicine, Auburn University, AL, USA.
5
Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, AL, USA.
6
Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, AL, USA Department of Pathobiology, College of Veterinary Medicine, Auburn University, AL, USA.
7
Department of Neurology and Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA, USA.
8
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.

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.

KEYWORDS:

Sandhoff disease; adeno-associated virus; ganglioside; gene therapy; β-hexosaminidase

PMID:
25873306
PMCID:
PMC4720176
DOI:
10.1177/1759091415569908
[Indexed for MEDLINE]
Free PMC Article

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