Improved management of lysosomal glucosylceramide levels in a mouse model of type 1 Gaucher disease using enzyme and substrate reduction therapy

摘要: Gaucher disease is caused by a deficiency of the lysosomal enzyme glucocerebrosidase (acid β-glucosidase), with consequent cellular accumulation glucosylceramide (GL-1). The managed intravenous administrations recombinant (imiglucerase), although symptomatic patients mild to moderate type 1 for whom replacement therapy (ERT) not an option may also be treated substrate reduction (SRT) miglustat. To determine whether sequential use both ERT and SRT provide additional benefits, we compared relative pharmacodynamic efficacies separate therapies in murine model (D409V/null). As expected, was effective reducing burden GL-1 storage liver, spleen, lung 3-month-old mice. using novel inhibitor synthase (Genz-112638) effective, albeit lesser degree than ERT. Animals administered then Genz-112638 showed lowest levels all visceral organs reduced number cells liver. This likely because deployment following slowed rate reaccumulation affected organs. Hence, whose has been stabilized intravenously glucocerebrosidase, orally could potentially used as convenient maintenance therapy. In naive treatment, followed accelerate clearance offending substrate.