Mechanisms of distribution of mouse beta-galactosidase in the adult GM1-gangliosidosis brain.

[gm1 gangliosidosis]

GM 1 -gangliosidosis is a lysosomal storage disease (LSD ) caused by an autosomal recessive deficiency of lysosomal acid beta -galactosidase (betagal ). This leads to accumulation of GM 1 -ganglioside and its asialo derivative GA 1 in the central nervous system (CNS ), and progressive neurodegeneration . Therapeutic AAV-mediated gene delivery to the brain for LSDs has proven very successful in several animal models . GM 1 -gangliosidosis is also a prime candidate for AAV-mediated gene therapy in the CNS . As global neuropathology characterizes the most severe forms of this disease , therapeutic interventions need to achieve distribution of betagal throughout the entire CNS . Therefore , careful consideration of routes of administration and target structures from where metabolically active enzyme can be produced , released and distributed throughout the CNS , is necessary . The goal of this study was to investigate the pattern and mechanism of distribution of betagal in the adult GM 1 -gangliosidosis mouse brain upon hippocampal injection of an AAV vector-encoding betagal . We found evidence that three different mechanisms contribute to its distribution in the brain : (1 ) diffusion ; (2 ) axonal transport within neurons from the site of production ; (3 ) CSF flow in the perivascular space of Virchow-Robin . In addition , we found evidence of axonal transport of vector-encoded mRNA .

Diseases
Validation

Diseases presenting "deficiency of lysosomal acid" symptom

gm1 gangliosidosis

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