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Dr Pram Mistry is a Consultant and Liver Specialist at the
Royal Free Hospital, London where he has full responsibility for 35
Gauchers patients. He is well known to the Gauchers Association and has
attended all its Conferences. Everyone who has met him cannot speak highly
enough of his care, compassion and dedication. His research into how
enzyme replacement therapy travels through the body and reaches the parts
that most need it has received world-wide acclaim. Dr Mistry explained at
the Gauchers Assocition's Third Conference in February 1997 that there are
many gene mutations that result in reduced activity of the enzyme,
glucocerebrosidase, which causes Gauchers disease.
'The defective enzyme cannot break down a fatty substance, glucocere-broside, which is an important component of cell membranes,' said Dr Mistry. 'The enzyme is present in all cell types, for example muscle and skin, but the accumulation of fat occurs only in certain cells, the macrophages. 'These fat-laden macrophages are the Gauchers cells, found typically in the liver, spleen, bone marrow and lungs. There is a continuous turnover of this fatty substance each day but only a fraction accumulates in a typical Gauchers patient.
'In the early days enzyme prepared from human placenta was of little benefit because it did not reach the Gauchers cells. .Dr Roscoe Brady and his colleagues, Dr John Barranger and Dr Scott Furbish at the National Institutes of Health in the United States, had to overcome major hurdles during development of effective enzyme treatment. Subsequently they discovered that modifying the sugar component of the enzyme gave it the right address to home into Gauchers cells. Ceredase is the modified placental enzyme and the genetically engineered preparation is Cerezyme. The results have been most remarkable.'
Dr Mistry described how enzyme treatment varies in different Centres. 'The largest experience is with 30-60 units per kilogram of bodyweight (u/kg/bw) given every other week. However Dr Ernest Beutler in the United States and Dr Ari Zimran in Israel report good results with 2.3 u/kg/bw given three times a week. In fact Dr Carla Hollak and colleagues have used lower doses and report satisfactory responses in Holland.
'Treating one patient at 60 u/kg/bw every other week requires 50,000 placenta, equivalent to 10-12 tons, and therefore is costly. This emphasises the need to use the treatment efficiently.
Following the Enzyme in the Body
Our initial studies focused on how the enzyme interacts with isolated Gauchers cells grown in the laboratory. The main findings were:
Ceredase and Cerezyme bind to the mannose receptors on Gauchers cells
but other receptors may be involved. Receptors are like letter boxes
through which the enzyme can pass .
Dr Mistry said: 'Dr Brady's group made a striking observation many years ago which showed that the liver has the largest fat accumulation and the bones the least but there is far worse disease in the bones than in the liver of most patients.
Dr Mistry then described how Ceredase and Cerezyme were modified to follow their itinerary through the body after infusion. The patients were continuously scanned to follow where and how the enzyme was reaching parts of the body affected by Gauchers disease. Dr Mistry found that:
Response to Treatment is Variable
Most patients have a good response to enzyme treatment. However some have an extraordinary response while a small number of patients respond poorly. There are a number of factors that can mitigate response:
Dr Mistry then described a 33 year old man with Gauchers disease who was brought as an emergency to the Royal Free Hospital Casualty at 5am about a year ago. However he stressed that what followed is an extremely rare complication of Gauchers disease.
'The young man came in with massive life-threatening bleeding due to advanced liver cirrhosis. He was found to have Gauchers disease in childhood and at age 20 his spleen was removed. By 1995 he was crippled by bone complications and had portal hypertension due to the liver cirrhosis. Although given large doses of Ceredase, he had repeated episodes of liver failure and therefore had to be considered for a liver transplant. But first his condition had to be improved to help him get through this major surgery. This was achieved by intensive Ceredase treatment, improving his nutrition and also treating his bone disease.
After liver transplantation, new drugs were given to prevent rejection which would pose no threat to his precarious bones. He made a remark-able recovery ; his Gauchers disease is under control with twice weekly Ceredase and he does not require morphine for bone pain. He gives himself infusions at home without assistance.
Ceredase Treatment Before Symptoms Develop
Dr Mistry said that the above story emphasises that enzyme treatment should be started before irreversible damage has set in. He illustrated this by describing a woman who came to his Clinic as having Gauchers disease but displaying no obvious symptoms although she had a slightly enlarged spleen and liver. However her genotype (gene mutations) was N370S/84GG which is considered to be a more serious combination. She also had high disease markers in blood tests. On this basis she was started on Ceredase 2 u/kg/bw, twice weekly. One of the disease markers, the enzyme chitotriosidase, showed a dramatic reduction during the course of a year.
Gauchers Clinic at Royal Free Hospital
'In my clinic at the Royal Free Hospital, we start Ceredase treatment at 1-5 u/kg/bw twice weekly; in this way enzyme activity in Gauchers cells in the body is maintained at a consistently normal level,' said Dr Mistry. 'There is concern about the inconvenience and possible complications of frequent infusion, for instance infection, but hardly any such problems have been encountered at the Royal Free.
'My first patient in the UK to receive Ceredase on this regime in 1991 had a rise of haemoglobin from 6 to 15g/dl within six months. 'If low doses have to be given, there is much evidence to suggest that it is most effective when given in divided doses frequently. If your GP asked you to take 50 tablets of penicillin once every two weeks, you would question his reasoning.
'The logic with enzyme treatment is similar. When enzyme treatment is given in this way, there is plenty of scope to individualise therapy on dosage and on frequency.'
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Source: Gauchers News June 1997
© Copyright Gauchers Association 1997