Conditional expression of human acid beta-glucosidase improves the visceral phenotype in a Gaucher disease mouse model.

Abstract:

:The reversibility and regression of histological and biochemical findings in a mouse model of Gaucher disease (4L/PS-NA) was evaluated using a liver-enriched activator protein promoter control of a tetracycline-controlled transcriptional activation-responsive human acid beta-glucosidase (hGCase) transgenic system. 4L/PS-NA has the acid beta-glucosidase (GCase) V394L/V394L (4L) point mutation combined with hypomorphic ( approximately 6% wild-type) expression of the mouse prosaposin transgene (PS-NA). The hGCase/4L/PS-NA had exclusive liver expression of hGCase controlled by doxycycline (DOX). In the absence of DOX, hGCase was secreted from liver at levels of approximately 120 microg/ml serum with only approximately 8% of full activity, following exposure to pH 7.4 in serum. The hGCase activity and protein were detected in cells of the liver (massive), lung, and spleen, but not the brain. The visceral tissue storage cells and glucosylceramide (GC) accumulation in hGCase/4L/PS-NA were decreased from that in 4L/PS-NA mice. Turning off hGCase expression with dietary DOX led to reaccumulation of storage cells and of GC in liver, lung, and spleen, and macrophage activation in those tissues. This study demonstrates that conditionally expressed hGCase supplemented the existing mutant mouse GCase to control visceral substrate accumulation in vivo.

journal_name

J Lipid Res

authors

Sun Y,Quinn B,Xu YH,Leonova T,Witte DP,Grabowski GA

doi

10.1194/jlr.M600239-JLR200

subject

Has Abstract

pub_date

2006-10-01 00:00:00

pages

2161-70

issue

10

eissn

0022-2275

issn

1539-7262

pii

M600239-JLR200

journal_volume

47

pub_type

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