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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Sunday, 17 May 2009

The Turning of the Tide

Writing about Calum brought back a lot of memories. It was the saddest time of our lives. However, from now on, the story becomes brighter. Not that there isn't pain and sadness ahead for many - to this day, in fact. But from here on in, I'll be talking about the development of a treatment for Pompe disease. This is where hope first appears in this narrative. This, my friends, is the turning of the tide.

To quickly recap: Pompe discovered and described the disease. Hers explained it. What follows is the story of how Arnold Reuser and Ans van der Ploeg worked out how Pompe disease could be treated - and went on to demonstrate that their theory actually worked.

As we have seen, following Hers' discovery of lysosomal storage diseases, many attempts were made to treat Pompe disease by enzyme replacement therapy. None worked because enzyme was simply soaked up by the liver - it did not reach the muscles, which is where it needs to go, in order to shift glycogen. The whole concept of enzyme replacement therapy therefore fell out of favour. The situation seemed hopeless.

However, Arnold Reuser, a researcher at Erasmus University in Rotterdam, and his then PhD student, Ans van der Ploeg, had other ideas. They looked again at enzyme replacement therapy. In particular, they made use of the recent discovery that enzymes made their way into the lysosome using a receptor for the sugar mannose-6-phosphate. They reasoned that enzymes with this sugar attached - phosphorylated enzyme - might be more efficient at getting to the lysosome than the enzyme previously used in enzyme replacement therapy. The mannose-6-phosphate would effectively act as an address label, ensuring that the enzyme reached the lysosomes in the muscles. An interesting theory - but was it right?

Their first experiment was to take cell lines isolated from Pompe patients - human muscle cells grown in a dish in the laboratory. These cells showed the classic Pompe symptom of glycogen accumulated in the lysosomes. Reuser & Van der Ploeg added the phosphorylayed enzyme - and the glycogen was degraded.

This was obviously an important step forward, however it was not enough to demonstrate that this approach would work. After all, cells growing in a thin layer in a laboratory dish are one thing - living organisms with blood, liver and muscle are quite another. And this presented a seemingly imovable obstacle. The phosphorylated enzyme was difficult to produce and only small amounts -extracted from bovine testes - were available. This was not enough to treat a child, even if permission had been obtained for such a speculative approach. The only animal model known at that time was a type of cattle - which would require even more of the enzyme. How could this be resolved?

The answer came in a series of experiments which I can only describe by using one of the highest words of praise in the scientific lexicon: elegant.

Reuser and Van der Ploeg realised that they only had enough enzyme to use on mice. However, these mice did not have Pompe disease and therefore had normal levels of alpha-glucosidase and no glycogen accumulation. So how could they be used to demonstrate uptake of the enzyme? The solution was to use antibodies that reacted with the phosphorylated enzyme produced from bovine testes but not against the normal mouse enzyme.

The bovine enzyme was administered to the mice, and the increase in alpha-glucosidase activity in different tissues measured. It was possible to work out how much of this activity was due to the bovine enzyme using the bovine-specific antibodies. Firstly the whole tissue activity was measured, and then the activity when the antibodies had reacted with the bovine enzyme. By comparing these two figures, it was possible to see how much of the activity was caused by the mouse enzyme and how much was due to the added bovine enzyme. This also showed that the bovine enzyme had made its way to the various tissues, including heart and muscle.

Reuser and Van der Ploeg found that the addition of the bovine enzyme to the mice resulted in a 43% increase in enzyme activity in muscle and 70% in the heart.

They noted that even after 6 days, enzyme activity in mice was 10-20% above normal. As enzyme activity of more than 20% of normal does not usually result in Pompe symptoms, they concluded that, in some cases at least, a slight increase in alpha-glucosidase activity might be enough to prevent glycogen storage.

These results were published in February 1991. The paper is entitled Intravenous Administration of Phosphorylated Acid Alpha-Glucosidase Leads to Uptake of Enzyme in Heart and Skeletal Muscle of Mice. Thanks to the wonder of the internet, you can read the whole paper online at the website of the Journal of Clincial Investigation

The paper also notes that the amounts of enzyme required would be very large - beyond what it was then possible to produce. However the speculated - correctly - that it might be possible to produce it using the cloned human gene for the enzyme.

With characteristic understatement, Reuser and Van der Ploeg concluded that "...we think that the original idea of enzyme replacement therapy for treatment of lysosomal storage diseases deserves new attention."

I'll say! While the paper was in preparation, results showing the success of such an approach on Gaucher disease (another lysosomal storage disease) were published. Gaucher disease was something of a special case, for reasons too complicated to go into here, however it underlined the feasibility of the approach.

Here's a suggestion. If you are affected by Pompe disease, follow that link and print out that paper. Read it and try and understand it (go on, it's not as difficult as it might look). Put it in a nice folder. Even better, frame it and put it on your wall. That paper is an important part of your life story because, building on what went before, it made a treatment for Pompe disease a real possibility for the first time. Cherish it.