Biomarkers for disease progression and AAV therapeutic efficacy in feline Sandhoff disease

UMMS Affiliation

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



Document Type


Medical Subject Headings

Animals; Biological Markers; Brain; Cats; Dependovirus; *Disease Models, Animal; Disease Progression; Genetic Therapy; Genetic Vectors; Leukocytes, Mononuclear; Lysosomes; Magnetic Resonance Imaging; Sandhoff Disease; beta-N-Acetylhexosaminidases


Genetics and Genomics | Nervous System Diseases | Neurology | Therapeutics


The GM2 gangliosidoses, Tay-Sachs disease (TSD) and Sandhoff disease (SD), are progressive neurodegenerative disorders that are caused by a mutation in the enzyme beta-N-acetylhexosaminidase (Hex). Due to the recent emergence of novel experimental treatments, biomarker development has become particularly relevant in GM2 gangliosidosis as an objective means to measure therapeutic efficacy. Here we describe blood, cerebrospinal fluid (CSF), magnetic resonance imaging (MRI), and electrodiagnostic methods for evaluating disease progression in the feline SD model and application of these approaches to assess AAV-mediated gene therapy. SD cats were treated by intracranial injections of the thalami combined with either the deep cerebellar nuclei or a single lateral ventricle using AAVrh8 vectors encoding feline Hex. Significantly altered in untreated SD cats, blood and CSF based biomarkers were largely normalized after AAV gene therapy. Also reduced after treatment were expansion of the lysosomal compartment in peripheral blood mononuclear cells and elevated activity of secondary lysosomal enzymes. MRI changes characteristic of the gangliosidoses were documented in SD cats and normalized after AAV gene therapy. The minimally invasive biomarkers reported herein should be useful to assess disease progression of untreated SD patients and those in future clinical trials.

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Citation: Exp Neurol. 2015 Jan;263:102-12. doi: 10.1016/j.expneurol.2014.09.020. Epub 2014 Oct 5.Link to article on publisher's site

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