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Netherland’s Scientists Produce Knockout Mouse Model of Pompe disease

Posted on: January 31, 1998

Human Molecular Genetics, January 1998

“Generalized glycogen storage and cardiomegaly in a knockout mouse model of Pompe disease” by A. J. J. Reuser/A. T. van der Ploeg, et al

Enzyme Replacement Therapy (ERT)..........

Therapy for Glycogen Storage Disease Type II

Acid alpha glucosidase production in milk and
enzyme replacement therapy (ERT)
in a mouse model


Agnes Bijvoet received her Ph.D., in June 1999, from Erasmus University Rotterdam, the Netherlands. Dr. Bijvoet worked in conjunction with Arnold J.J. Reuser, Ph.D., Erasmus University Rotterdam, and Ans T. van der Ploeg, M.D., Ph.D., Sophia Children’s Hospital Rotterdam, to develop a mouse model for Pompe’s disease. This animal model was used to test enzyme produced in transgenic rabbits.

Following are excerpts from her thesis entitled, “Therapy for Glycogen Storage Disease Type II—Acid alpha-glucosidase production in milk and enzyme replacement therapy in a mouse model.”

“The aims of the experimental work described in this thesis were to investigate the pathogenesis of glycogen storage disease type II and to test the feasibility of enzyme replacement therapy using recombinant human acid alpha-glucosidase produced in the milk of transgenic mammals. A knockout mouse model of the disease was made and used as an experimental tool in these studies.”

The methodology is described and “documents the acid alpha-glucosidase deficiency in the homozygous knockout mice and illustrates the lysosomal glycogen storage in liver, heart and skeletal muscle.”

The thesis also documents the generation of transgenic mice (to produce) recombinant human acid alpha-glucosidase in their milk.

“The aim of these studies was to investigate the feasibility of large-scale production of therapeutic lysosomal protein in farm animals…..The recombinant acid alpha-glucosidase was tested for its in vitro and in vivo effect.”

.....The experiments described….. demonstrate the degradation of lysosomal glycogen in heart, skeletal and smooth muscle and the reversal of tissue pathology.”

“Based on these promising results, the genomic construct was used for the industrial production of recombinant human acid alpha-glucosidase in the milk of transgenic rabbits. The potential therapeutic effect of this latter enzyme was demonstrated by treating GSD II knockout mice over a six months period.”

“The work reported in this thesis demonstrates the feasibility of recombinant human acid alpha- glucosidase production in the milk of transgenic rabbits and the potential value of this enzyme for treatment of patients with GSD II. It has laid a solid basis for the start of the phase II clinical trial of enzyme replacement therapy, which has begun at Sophia Children’s Hospital Rotterdam.

“The work described in this thesis has contributed to the understanding of glycogen storage disease type II and will help to elucidate the molecular and pathological processes in patients with this disease. Furthermore, it has stimulated and steered the development of enzyme replacement therapy for this and other lysosomal diseases by the presentation of a new method for the large-scale production of lysosomal enzymes. The potential efficacy of enzyme replacement therapy for GSD II has been demonstrated in a mouse model of this disease. This animal model has additional value for dose finding, for fundamental studies on enzyme replacement therapy, and for testing of alternative therapeutic approaches in the future.”

The studies described in this thesis were performed in the Netherlands at the department of Medical Biotechnology of the Leiden University and the department of Clinical Genetics of the Erasmus University Rotterdam.

The research was supported financially by the “Prinses Beatrix Fonds”, the Sophia Foundation for Medical Research, the Association for Glycogen Storage Disease (UK), the Acid Maltase Deficiency Association (USA), and the Foundation of Clinical Genetics, Rotterdam. Publication of the thesis was financially supported by Genzyme BV and Pharming BV.

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