Second Conference of the Gauchers Association on New Developments

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The Second Conference of the Gauchers Association on New Developments in the Treatment of Gauchers Disease was held at the Clive Hotel London on 20 November 1994 to a packed hall of 130 people.

The day started with the Annual General Meeting of the Association (a report will be sent to members shortly); at the same time a special meeting for doctors in another room enabled those medical experts present to exchange information and views on an informal and confidential level with each other and with the Conference medical speakers. Professor Timothy Cox chaired the meeting.

Opening the Conference, Chairman Jeremy Manuel welcomed the delegates. 'We have a full and informative day in store', he said. 'The growth of the Association has been almost miraculous. Three years ago we knew of just eight people with Gauchers disease, now we know of 160 with 63 receiving Ceredase.'

Prof Cox Reports on UK Progress, Experience and Research
Professor Timothy Cox, who looks after 60 Gauchers patients at Addenbrooke's Hospital Cambridge, explained the history and course of the enzyme deficiency which affects Gaucher patients: 'It was Philippe Gaucher, a French doctor, who first identified the enlarged spleen which is a sign of the disease. But he got it wrong. He thought it was caused by a malignancy.' It was only in the 1960s that a lack of the enzyme glucocerebrosidase was found to be the cause.

Prof Cox explained that the key to the disease lay within the macrophages (cells in the liver, spleen, bone marrow and elsewhere) which spend their entire life eating up other used cells. In the macrophages are lysosomes, 'suicide bags containing many enzymes' which are responsible for breaking up the old cells. In the case of Gauchers disease, the enzyme glucocerebrosidase does not work properly and a build-up of the fatty tissue, glucocerebroside, remains in the macrophages instead of being broken down and passed through the system.

The macrophages become enlarged in the organs and bone marrow and it is these cells which contribute to the symptoms of enlarged spleen and liver. In the bones, the blood supply is cut off, resulting in painful bone crises and spontaneous fractures.

'But genes aren't everything', said Prof Cox. He mentioned two identical twins, one who had symptoms of Gauchers and needed to have the spleen removed. The other twin had no symptoms at all. Something else must have contributed to the onset of symptoms.

Successful Treatment
He went on to describe the successful treatment with Ceredase of some of his patients. The first adult patient to be treated in the UK had suffered bone marrow failure and had been receiving regular blood transfusions. The patient had also suffered pain in the ankles which stopped him working.

On treatment with Ceredase on a very low dose twice a week, his patient made a dramatic recovery. After only a few months, an MRI scan showed an almost complete recovery in the ankles. The patient is receiving an even lower dose now more than 3 years later and remains well. His MRI scan appears perfectly normal.

Important Research
Prof Cox described the research carried out by his colleague Dr Pram Mistry at Cambridge University into where Ceredase goes in the body and how long it stays there. 'I would also like to acknowledge the Association members who took part in this work.'

He said that the history of the development of enzyme replacement therapy was important. The initial infusions of the enzyme glucocerebrosidase were unsuccessful because it went to the wrong places in the body. It was only after the enzyme had been modified and targeted to the mannose receptors (which are attached to macrophages), that the enzyme, subsequently known as Ceredase, became effective. However the enzyme encounters obstacles on its way and there may be receptors apart from mannose which take in the enzyme.

It is known from previous research that Ceredase has a half life of only a few minutes in the blood of patients but it was not known where and how it goes from there. (The half life is the time taken for half of a substance to disappear). Other cells besides macrophages might take up Ceredase.

In a trial to discover where the enzyme went, 9 patients took part. They all had Type 1 Gauchers. In addition one healthy subject took part.

A very small amount of short-lived radioactive iodine was tagged to a small amount of enzyme so that its journey in the body could be followed on a scanner. Both Ceredase and Cerezyme were used. The experiment was approved by the Administration of Radioactive Substances Advisory Committee of the Dept of Health, UK.

Rapid Uptake in Liver and Spleen
Professor Cox showed remarkable slides which depicted the injected enzyme going straight to the areas where they were required - the liver and the spleen and, in some patients with bone involvement, to the very sites which were known to have caused or were still causing trouble.

The scans showed rapid uptake in the liver and slightly less quickly in the spleen although in one severely affected patient, the uptake in the spleen was greater than in the liver.

In one patient, a scan after 5 minutes of infusion showed rapid disappearance from the blood but marked uptake in the liver. At 10 minutes the maximum amount was in the liver but the spleen took up the enzyme more slowly. Scans on the patients were performed over 48 hours to estimate the half life of the tracer in different organs.

Bone marrow uptake was also visible. There was no difference in uptake in the bone marrow between patients with or without their spleens.

Professor Cox commented on the fact that the enzyme went to the foot bones of a patient who had previously been severely affected there. According to a MRI scan, the feet were now back to normal after treatment with Ceredase, although the patient still complained of occasional pain at these sites.

Dr Pram Mistry previously presented a paper on this research to the Trieste Meeting of the The European Working Group on Gauchers Disease. He concluded that there was efficient targeting of the enzyme to the sites of the disease and that a considerable proportion of the tagged enzyme had a half life of 1-2 days in the liver and spleen. He stressed there was a need to find the optimal saturation level of treatment for each patient.

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Source: Gauchers News February 1995