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A pioneer of research into Gauchers disease as well as many other genetic diseases, Dr Ernest Beutler is Chairman of the Department of Molecular and Experimental Medicine, housed in the ultra-modern Scripps Research Institute at La Jolla, California. Dr Beutler is in charge of a team of scientists who have access to the latest technology and resources to advance their work on Gauchers disease, both in his laboratory and in the General Clinical Research Centre where excellent nursing and record keeping enables the progress of patients to be fully monitored. Susan Lewis reports on his current work:
A strong advocate of low dose therapy, Dr Beutler has studied 119 patients with Gauchers disease in the past 13 years. His first Gauchers patient to receive Ceredase was a very sick woman in her 30's.
'She was blue around the mouth and had to take oxygen,' describes Dr Beutler. 'She had had her spleen removed previously and had a very enlarged liver. She weighed 40 kilograms (just over 6 stones).
Low Dose Therapy
'Her parents could not afford treatment on the high dose, they said they would have to sell their house to pay for it. We paid for the enzyme from our research funds so it was necessary to treat her at the lowest possible cost. Now six years later, she is well and recently married. She is actually working on gene therapy in another hospital in America.'
In a 1995 article describing the clinical course of 32 treated and 13 untreated patients, Dr Beutler wrote: 'Treatment with alglucerase (Ceredase) resulted in gradual normalisation of blood counts, decrease in the size of liver and spleen and parallel decreases in the serum angiotensin converting enzyme and chitotriosidase levels (markers used to determine the progress of Gauchers disease).
'Skeletal symptoms were decreased in all patients and skeletal lesions (abnormalities) showed modest improvement in patients treated for two years or more.
Change of Dose Indistinguishable
'The response of patients to low dose/high frequency (2.3 u/kg 3 x weekly; 30 u/kg/month) therapy was indistinguishable from the response observed and previously reported by others with much larger doses. Changing the dosage from 30u/kg/month to 120/kg/month was not attended by any significant changes in response.
'In the case of nine patients, the dose of alglucerase (Ceredase) was either increased from 30u to 120 u/kg/month (six patients) or decreased from 120u to 30u/kg/month (3 patients). No distinct effect of either increasing or decreasing the dose 4-fold could be identified.'
Dr Beutler described in the article the effect of dose frequency on the response to therapy.
'At high doses of alglucerase (Ceredase 120u/kg/month) the results in the three patients that we treated three times weekly were not appreciably different from those reported by those who administer the drug twice monthly. We studied three patients whose physicians had administered low dose (30u/mo) therapy twice monthly. These patients responded to therapy but their responses were less robust than those of most, but not all, of those patients treated with fractionated (more frequent) doses.'
Comparing a report of patients treated on a low dose (20u/kg/month) every two weeks, he wrote: 'Their results were clearly inferior to those obtained with fractionated therapy, even when the dose is only 15 u/kg/month. These considerations lead us to suggest that fractionation is important when small doses are given but is probably considerably less important when doses as large as 60 or 120 u/kg/month are administered.'
Dr Beutler points out that data concerning the extent of fractionation are, however, contradictory. 'In a small study Dr Zimran in Israel found little decrease in efficacy (effectiveness) when small doses were given every two weeks.'
Accordingly, Dr Beutler states, 'We are attempting to achieve a compromise between the convenience of less frequent administration and the greater efficacy of more frequent administration. Currently, we are starting patients on small doses (30u/kg/month) on a weekly basis. Even if this less frequent dosing results in a slightly slower response, the greater convenience may counterbalance this disadvantage.'
Cost As Low As Possible
Dr Beutler strongly believes that the cost of the drug to the patient (or the insurers or authority paying for it) should be as low as possible. In addition while the drug remains in short supply, lower doses would allow more needy patients access to it.
Dr Beutler is currently studying pulmonary (lung) disease in eight Gauchers patients. He says that 5% of Gauchers patients suffer from pulmonary disease which is most commonly manifested either as increased blood pressure in the lung (pulmonary hypertension) or shunting (leakage of blood through the lung that prevents it from receiving a proper load of oxygen). Both of these types of disorder may produce shortness of breath.
Dr Beutler, working together with a team of lung specialists, has found that enzyme therapy improves shunting but not pulmonary hypertension in Gauchers disease patients. 'Indeed, as the leak through the lung is corrected, the pulmonary pressure may rise', he says. è
'We are currently working on different approaches to gene therapy', says Dr Beutler. 'My research group reported test tube correction of the enzyme deficiency in Gauchers cells using a retrovirus over ten years ago but the impediments to viral correction in patients is daunting. Accordingly, the gene transfer technology that is being explored in my laboratory deals with introducing the gene using non-viral methods. The DNA (gene) is attached to small particles of fat (liposomes) that are then infused.
'Such studies have been quite encouraging in mice but I must warn that human application of this technology is a long way off.
'I am concerned that some Gauchers disease patients have been misled into believing that gene therapy for Gauchers disease is just around the corner. In reality, it seems to me to be no closer than it was ten years ago when my team performed the original test tube studies with retroviruses.'
Dr Beutler has calculated that the most common mutation of the gene which causes Gauchers disease, 1226G also known as N370S 2, could have originated only 400 to 800 years ago. He also says that the more severe 84GG mutation is more like 2,000 years old.
The Clinical Course of Treated and Untreated Gaucher Disease. A Study of 45 Patients, E Beutler et al, Blood Cells Molecules and Diseases, Volume 21, Issue 10, May 30 1995. Download Dr Beutler's original article.
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Source: Gauchers News February 1997.
© Copyright Gauchers Association 1997.