AAV8-mediated expression of glucocerebrosidase ameliorates the storage pathology in the visceral organs of a mouse model of Gaucher disease.
BACKGROUND
Gaucher disease is the most common of the lysosomal storage disorders. The primary manifestation is the accumulation of glucosylceramide (GL-1) in the macrophages of liver and spleen (Gaucher cells), due to a deficiency in the lysosomal hydrolase glucocerebrosidase (GC). A Gaucher mouse model (D409V/null) exhibiting reduced GC activity and accumulation of GL-1 was used to evaluate adeno-associated viral (AAV)-mediated gene therapy.


METHODS
A recombinant AAV8 serotype vector bearing human GC (hGC) was administered intravenously to the mice. The levels of hGC in blood and tissues were determined, as were the effects of gene transfer on the levels of GL-1. Histopathological evaluation was performed on liver, spleen and lungs.


RESULTS
Vector administration to pre-symptomatic Gaucher mice resulted in sustained hepatic secretion of hGC at levels that prevented GL-1 accumulation and the appearance of Gaucher cells in the liver, spleen and lungs. AAV administration to older mice with established disease resulted in normalization of GL-1 levels in the spleen and liver and partially reduced that in the lung. Analysis of the bronchoalveolar lavage fluid (BALF) from treated mice showed significant correction of the abnormal cellularity and cell differentials. No antibodies to the expressed hGC were detected following a challenge with recombinant enzyme suggesting the animals were tolerized to human enzyme.


CONCLUSIONS
These data demonstrate the effectiveness of AAV-mediated gene therapy at preventing and correcting the biochemical and pathological abnormalities in a Gaucher mouse model, and thus support the continued consideration of this vector as an alternative approach to treating Gaucher disease.
McEachern
Kerry Anne
KA
Genzyme Corporation, 31 New York Avenue, Framingham, MA 01701-9322, USA.
Nietupski
Jennifer B
JB
Chuang
Wei-Lien
WL
Armentano
Donna
D
Johnson
Jennifer
J
Hutto
Elizabeth
E
Grabowski
Gregory A
GA
Cheng
Seng H
SH
Marshall
John
J
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D000229:Dependovirus / Q000235:genetics*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005776:Gaucher Disease / Q000201:enzymology* / Q000235:genetics / Q000473:pathology* / Q000628:therapy; D015971:Gene Expression Regulation, Enzymologic; D015316:Genetic Therapy; D005962:Glucosylceramidase / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology; D008099:Liver / Q000166:cytology / Q000473:pathology; D008168:Lung / Q000166:cytology / Q000473:pathology; D008264:Macrophages / Q000166:cytology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D013154:Spleen / Q000166:cytology / Q000473:pathology; D016896:Treatment Outcome; D014781:Viscera / Q000473:pathology*
D005962:Glucosylceramidase