Pompe´s Disease in Historical Perspective and the Way to Therapy

The first time that I (dr. Reuser, ed.) heard of Pompe’s disease was back in 1973, when I was interviewed for a PhD training position in the Department of Cell Biology and Genetics of the Erasmus University Rotterdam. A little later, I became aware of a similar position on the same subject in the Department of Biochemistry of the University of Amsterdam. To me, an ignorant young student, it seemed that Pompe’s disease was one of the better-known metabolic diseases that received wide scientific attention. Nothing was less true. Even to date it takes great effort to publish articles on Pompe’s disease in trendy, high ranking, scientific journals. Albeit, thanks to the patients and scientists who were persistent in their efforts to “raise the awareness” about the disease and decipher the clinical, pathological, and molecular details, the world of patients, the world of science, the world of treating physicians and the world of industry and financing have learned about this disease. Their activities have merged, and at present we are engaged together in clinical trials of enzyme replacement therapy.

Accumulation of glycogen

The course has taken its time. Pompe’s disease was named after the Dutch pathologist Dr J.C. Pompe who presented in 1932 the case of a 7-month-old infant who had died of idiopathic hypertrophy of the heart. In addition to the cardiac problems, the infant had generalised muscle weakness. The crucial observation was that the symptoms were associated with massive accumulation of glycogen within vacuoles in virtually all tissues. In the listing of different glycogen storage diseases, made by Cori and Cori, Pompe’s disease was ranked as number two and named “glycogen storage disease type II” (GSDII). In 1955, Professor Christian DeDuve made history with his discovery of a new intra-cellular compartment that he called “lysosome”.

Lysosomes

Lysosomes contain hydrolytic enzymes which are needed for the degradation of a wide variety of biological compounds. Eight years later, Professor H.G. Hers discovered that the glycogen accumulation in GSDII was caused by a deficiency of the lysosomal enzyme acid alpha-glucosidase. This first finding of an inherited lysosomal enzyme deficiency has led to the concept of “lysosomal storage diseases” and, indirectly, to the enzymatic definition of many other lysosomal storage disorders in the following years. The assay of alpha-glucosidase activity became a diagnostic tool. Since maltose is a convenient substrate in this assay, Pompe´s disease acquired “acid maltase deficiency” as a third name. It did not take long to discover acid maltase deficiency in patients with skeletal muscle weakness, in the absence of cardiac involvement. These patients were reported to have childhood, juvenile or adult forms of Pompe’s disease. The years from 1980 until approximately 1990 were marked by studies on the biosynthesis and structure of acid alpha-glucosidase, culminating in the cloning of the acid alpha-glucosidase gene between 1986 and 1990.

DNA mutations

At present, the GSDII mutation database is filled with close to sixty different mutations in the acid alpha-glucosidase gene. The clinical phenotype of patients is primarily determined by the nature of these mutations and the combination in which they occur. DNA analysis has become an important diagnostic and prognostic tool next to the assay of enzyme activity. It is the only reliable instrument for carrier detection.

Enzyme replacement therapy

Enzyme Replacement Therapy, the most exciting new development in the field, originates from the mid-sixties. Already then, it was attempted to remove the lysosomal glycogen from the patient’s tissues by intravenous administration of the missing enzyme. The rationale behind this type of treatment is that tissues and cells in these tissues take up biological compounds, and that these compounds are then transported to the lysosomes. These early clinical trials were unsuccessful. It was impossible to obtain acid alpha-glucosidase in sufficient quantity and of safe and efficient quality. The development of biotechnology has changed that situation dramatically. Human recombinant acid alpha-glucosidase can now be produced on a large scale. Scientists at this meeting (First Conference of the International Pompe Association, ed.) have explored the possibilities of enzyme production in the milk of transgenic animals and in Chinese hamster ovary cells, and thereby received strong technological and financial support from industrial partners. It is through their combined input that enzyme replacement therapy has found its way from the laboratory to the clinic.

Clinical trials

We can only speak for the situation we are in with our clinical trial in the Sophia Children’s Hospital in Rotterdam, and thereby quote a recent press release issued by our invaluable partner Pharming Group N.V. of Leiden: “The phase II clinical trial with human alpha-glucosidase for Pompe’s disease is on track. Professor Hans Büller, director of the Sophia Children’s Hospital in Rotterdam…and principal investigator of the trial Dr Ans van der Ploeg…expressed their optimism about the trial. All infants enrolled in the trial are alive…and are doing relatively well.

The trial is well underway to meet its objectives…Pharming expects to initiate Phase II pivotal trials…in Europe and the USA” (end of citation)

Conclusion

We would like to end this short historic perspective with highlighting the role of the patients, patient organisations and charities that have kept the “process” alive. Our research team at the Department of Clinical Genetics of the Erasmus University Rotterdam and the Sophia Children’s Hospital has experienced tremendous support by the many letters from patients and the very personal contacts. Patient organisations and charities like the AGSD (UK), the AMDA (USA), the Prinses Beatrix Fonds and the Sophia Foundation for Medical Research have made financial contributions to keep us going. This weekend, here at VSN, patients from around the world have come together to join forces and to found the International Pompe Association. The scientists are here to communicate their latest results and to witness with their industrial partners this joyful event. Congratulations to the IPA!