Mucopolysaccharidosis-like phenotype in feline Sandhoff disease and partial correction after AAV gene therapy

UMMS Affiliation

Department of Neurology; Gene Therapy Center; Wellstone Center for FSHD



Document Type



Genetics and Genomics | Nervous System Diseases | Neurology | Therapeutics


Sandhoff disease (SD) is a fatal neurodegenerative disease caused by a mutation in the enzyme beta-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.

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Citation: Mol Genet Metab. 2015 May 8. pii: S1096-7192(15)30010-X. doi: 10.1016/j.ymgme.2015.05.003. Link to article on publisher's site

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