Premium
Improved management of lysosomal glucosylceramide levels in a mouse model of type 1 Gaucher disease using enzyme and substrate reduction therapy
Author(s) -
Marshall John,
McEachern Kerry Anne,
Chuang WeiLien,
Hutto Elizabeth,
Siegel Craig S.,
Shayman James A.,
Grabowski Greg A.,
Scheule Ronald K.,
Copeland Diane P.,
Cheng Seng H.
Publication year - 2010
Publication title -
journal of inherited metabolic disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 102
eISSN - 1573-2665
pISSN - 0141-8955
DOI - 10.1007/s10545-010-9072-z
Subject(s) - glucocerebrosidase , enzyme replacement therapy , substrate reduction therapy , medicine , gaucher's disease , lysosomal storage disease , spleen , disease , recombinant dna , glucocerebroside , enzyme , gastroenterology , biochemistry , biology , gene
Gaucher disease is caused by a deficiency of the lysosomal enzyme glucocerebrosidase (acid β‐glucosidase), with consequent cellular accumulation of glucosylceramide (GL‐1). The disease is managed by intravenous administrations of recombinant glucocerebrosidase (imiglucerase), although symptomatic patients with mild to moderate type 1 Gaucher disease for whom enzyme replacement therapy (ERT) is not an option may also be treated by substrate reduction therapy (SRT) with miglustat. To determine whether the sequential use of both ERT and SRT may provide additional benefits, we compared the relative pharmacodynamic efficacies of separate and sequential therapies in a murine model of Gaucher disease (D409V/null). As expected, ERT with recombinant glucocerebrosidase was effective in reducing the burden of GL‐1 storage in the liver, spleen, and lung of 3‐month‐old Gaucher mice. SRT using a novel inhibitor of glucosylceramide synthase (Genz‐112638) was also effective, albeit to a lesser degree than ERT. Animals administered recombinant glucocerebrosidase and then Genz‐112638 showed the lowest levels of GL‐1 in all the visceral organs and a reduced number of Gaucher cells in the liver. This was likely because the additional deployment of SRT following enzyme therapy slowed the rate of reaccumulation of GL‐1 in the affected organs. Hence, in patients whose disease has been stabilized by intravenously administered recombinant glucocerebrosidase, orally administered SRT with Genz‐112638 could potentially be used as a convenient maintenance therapy. In patients naïve to treatment, ERT followed by SRT could potentially accelerate clearance of the offending substrate.