Dr J C Pompe

Dr J C Pompe
Discoverer of Pompe disease

About this blog

What you can read here is the story of the development of enzyme replacement therapy (ERT), the first effective treatment for Pompe disease. It is an incredible story, rich with events, characters and science. Above all, it is the story of an international community of scientists, doctors, patients and companies, working together towards a common goal.

It is not a story that features in Geeta Anand's book, The Cure , or the film based on it, Extraordinary Measures despite the fact that they are ostensibly about the development of ERT for Pompe ( you can link straight to the relevant articles covering the events described in the book and film here, here and here).

This blog represents my small attempt to set the record straight and to give the story back to its rightful owners - the international Pompe community. It is written here in roughly chronological order i.e. you'll need to start at the bottom of the April 2009 archive page and work your way up.

It is also a personal account and, although I've tried to make it as objective as possible, there is an inevitable degree of subjectivity. For that reason I have included contributions from other members of the worldwide Pompe community and would be delighted to receive more. Feedback is also welcome.

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Thursday, 3 December 2009

1997: Lift off!

Looking back, 1997 was an absolutely pivotal year.

Browsing the email archive, I see that this was when many leading lights of today's patient community first made contact with each other - for example, Thomas Schaller, Helmut Erny, Juan Magdaraog, Bet Cook, Helen Walker and Bob Morrison.  The international network was growing and starting to become a community.  Increasingly, this included scientific and medical professionals from around the world too.

I have to make a small confession here. Researchers and doctors are often, for entirely understandable reasons, uncomfortable about talking with individual patients or parents. That's one reason why patient groups are such a good idea. However it did occur to me that my own scientific background would be of use in making initial contacts. Seldom has a PhD been so shamelessly exploited - and to such good end.

I was kept also busy by a whole range of people getting in touch from all over the world. This could be quite difficult at times, such as speaking with someone who had just been told their child had a terminal illness. No matter how many people I spoke with, that never got easier. I guess some things should never be easy.

However towards the end of 1996, came some news that was like a dream come true. A Dutch pharmaceutical company, Pharming, announced a £14 million collaboration with the Rotterdam group to run a clinical trial of ERT for Pompe's. Fantastic! They also announced that were going to produce it in the milk of genetically engineered animals - a novel method. More on that, and on Pharming, later.

Arnold Reuser and Ans van der Ploeg kept us well informed of developments, of course. The March 1997 edition of the Pompe's Bulletin included this article by them (note that the fruits of the conference organised by the Houses are already obvious):

Enzyme Therapy for Glycogen Storage Disease Type II: Dream or Reality?
by Arnold JJ Reuser, Biochemist, Clinical Genetics Erasmus University, Rotterdam and Ans T van der Ploeg, Paediatrician, Sophia Children's Hospital, Rotterdam
A number of recent events have brought the answer to this question near. When Dr. Kevin O'Donnell asked us for the latest news, we thought it would be nice to put these recent events in a historic perspective.

At the basis of enzyme therapy for lysosomal storage diseases, such as GSDII, is the discovery of lysosomes in the mid fifties by the later Nobel price winner Dr. Christian De Duve. Lysosomes form a compartment inside the cell in which large sized biological substances from inside and outside the cell are degraded by over 40 different enzymes.

In the early sixties a deficiency of one of these enzymes, namely acid a-glucosidase, also known as acid maltase, was discovered by Dr. H.G. Hers as the cause of glycogen storage disease type II. Together, these discoveries have led to the concept of lysosomal storage diseases and given rise to the idea that patients could possibly benefit from administration of the lysosomal enzyme they are deficient in. Why did it take more than 30 years before enzyme therapy was successfully put into practice, and only so far for a single disease, Gaucher disease?

One major cause of delay was the technical inability to produce lysosomal enzymes pure and in sufficient amounts for clinical application. The second was the initial unawareness that cell type specific receptors can be used to target the administered enzyme to the affected cell and promote uptake by lysosomes.

In late onset (juvenile and adult) GSDII the target tissue is skeletal muscle. In infantile GSDII skeletal muscle and heart has to be reached, and it is possible that other tissues are also in need of therapeutic enzyme. Both heart and skeletal muscle have cell surface receptors that can be utilised for enzyme targeting, and a-glucosidase can be made to fit these receptors. Thus, it was demonstrated in an artificial system with cultured muscle cells, that glycogen stored in cells of patients was degraded by the a-glucosidase added to the culture media. Mice receiving a-glucosidase intravenously, showed an increase of a-glucosidase activity in muscle and heart tissue. But, these mice were healthy so that the therapeutic effect of enzyme therapy could not be tested.

In parallel to these studies, there has been a search for natural sources of a-glucosidase and biotechnological production methods. The latter activity has been successful, as many of you will know. Chinese hamster ovary cell lines suitable for human a-glucosidase production were developed by Dr. J.J. Hopwood and colleagues from Adelaide, Australia, and by Dr. Y-T. Chen and colleagues from Durham, North Carolina, in collaboration with our research group in Rotterdam. The production capacity of the "Hopwood" cell line was tested in a bioreactor, designed and built by BioCell Technology with financial support from the AGSD (UK).

With this reactor we have now produced enough human recombinant a-glucosidase to perform the necessary preclinical tests, but we have learnt that the production capacity of the cell line in this reactor is too low to enter safely into a clinical test in humans. Does this mean that the project is bound to fail? On the contrary, the activities developed in conjunction with the CHO production line and the promising results obtained have stimulated other parties to join and support the project. Very importantly, the Dutch based biotechnology company Pharming B.V. has now set its goal on the production of human recombinant a-glucosidase in the milk of transgenic rabbits and has entered into a collaboration with our research group at the Erasmus University and the Academic Hospital Rotterdam to realize a clinical test within two years.

This news was made public by Pharming B.V. at a press conference held in November last year in Geel, Belgium, where a production facility will be built. The collaboration program foresees in development of a complete production process. With financial support of the Prinses Beatrix Fonds (a Dutch charity fund for neuro-muscular diseases) we have already demonstrated that human recombinant a-glucosidase produced in milk of transgenic mice has all the required characteristics, including a targeting signal. Importantly, the concentration of human recombinant acid a-glucosidase in the mouse milk is far higher than in the CHO cell culture medium.

Production in rabbit milk will solve the problem of production capacity. In the research program it is further planned to generate a mouse model of GSDII. To our knowledge at least three laboratories world wide are pursuing this goal, and the first mouse models may become available this year. The therapeutic effects of human recombinant a-glucosidase produced in CHO cells and in rabbit milk can then be tested. If the test results are positive, the clinical trial in humans can start as soon as the a-glucosidase production process is ready.

Although the final results of this technical, costly and emotional adventure are still uncertain we should feel encouraged that after so many years of waiting a realistic and promising attempt at enzyme therapy for GSDII will be taken.
I can hardly describe the sense of excitement at this time. It really seemed that the fledgling Pompe community could, at last, dare to hope.

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