Human acid alpha-glucosidase from rabbit milk has therapeutic effect in mice with glycogen storage disease type II
Pompe's disease or glycogen storage disease type II (GSDII) belongs to the family of inherited lysosomal storage diseases. The underlying deficiency of acid alpha-glucosidase leads in different degrees of severity to glycogen storage in heart, skeletal and smooth muscle. There is currently no treatment for this fatal disease, but the applicability of enzyme replacement therapy is under investigation. For this purpose, recombinant human acid alpha-glucosidase has been produced on an industrial scale in the milk of transgenic rabbits. In this paper we demonstrate the therapeutic effect of this enzyme in our knockout mouse model of GSDII. Full correction of acid alpha-glucosidase deficiency was obtained in all tissues except brain after a single dose of i.v. enzyme administration. Weekly enzyme infusions over a period of 6 months resulted in degradation of lysosomal glycogen in heart, skeletal and smooth muscle. The tissue morphology improved substantially despite the advanced state of disease at the start of treatment. The results have led to the start of a Phase II clinical trial of enzyme replacement therapy in patients.
|Keywords||Animals, Animals, Genetically Modified, Glucan 1,4-alpha-Glucosidase/genetics/*metabolism/therapeutic use, Glycogen Storage Disease Type II/*drug therapy/enzymology, Humans, Mice, Mice, Inbred C57BL, Mice, Knockout, Microscopy, Electron, Milk/*enzymology, Myocardium/ultrastructure, Rabbits, Recombinant Proteins/genetics/metabolism/therapeutic use, Research Support, Non-U.S. Gov't|
Bijvoet, A.G., Reuser, A.J.J., van Hirtum, H., Kroos, M.A., van de Kamp, E.H., Schoneveld, O., … van der Ploeg, A.T.. (1999). Human acid alpha-glucosidase from rabbit milk has therapeutic effect in mice with glycogen storage disease type II. Human Molecular Genetics. Retrieved from http://hdl.handle.net/1765/9189