Dr Roscoe Brady spoke about the history of Gaucher disease, the development of enzyme replacement therapy and his part in this incredible journey at the US Gaucher Conference in Arlington on 2 October 1999. Dr Brady is Chief of the Developmental and Metabolic Neurology Branch at the National Institute of Neurological Disorders and Stroke at NIH. His accomplishments include the identification of the metabolic defects in hereditary lipid storage disorders including Gauchers disease and Niemann-Pick, Fabry and Tay-Sachs diseases.
It was in 1882 that a medical student in Paris called Philippe Gaucher first described in his thesis a young woman with an enlarged spleen with characteristic engorged cells. In 1895 a six year old boy was similarly described with others following and the condition became known as Gaucher disease.
Nearly 20 years later in 1901, Dr N E Brill suggested that Gaucher disease was an inherited disease and that both parents must pass on the gene for the disease; and three years later Dr Brill reported liver, lymph node and bone involvement in such patients.
In 1920 neurological involvement was first discovered in an infant - probably what is now known as Type 2; and this was described again in 1927. But it took another thirty years in 1959 before individuals with late onset neurological symptoms (Type 3) were described.
I became interested in Gauchers disease in 1955 and wanted to look at the accumulation of glucocerebroside, (the fatty material) found in Gauchers patients. After initial experiments in 1960, I concluded that the problem may be due to the breakdown of this fatty material.
In 1964, while working with Dr David Shapiro from the Weizmann Institute in Israel, I learned that the enzyme glucocerebrosidase was deficient in patients with Gaucher disease.
However we made a fortunate discovery: I had thought there would be zero activity of this enzyme but surprisingly there was a residual activity of between 10-20% in patients' tissues.
In 1968 we also found that the highest activity was in the lysosomes (part of a cell) and that is why Gauchers disease is known as a lysosomal storage disease.
In 1981 the gene for the enzyme was localised to chromosome 1, and in 1984 Dr Edward Ginns and his associates at NIH cloned the gene.
It was important that a simple test could be devised to diagnose Gauchers disease as in the past a bone marrow sample had been used. In 1967 Dr John Kampine and I showed that diagnostic enzyme assays could be made using small blood samples. In 1970 it became possible to identify carriers using the same method. 80% were picked up but 20% were missed. From 1971, diagnosis of sufferers and of carriers could also be made from skin analysis.
'In 1966 it occurred to me that one might be able to replace or supplement the insufficient activity of glucocerebrosidase. This was not easy. We had to purify the enzyme from a human source and then had to prove there would be no reaction to this product.
I thought of placenta which had some glucocerebrosidase in it. It took my colleagues and me seven years to purify the enzyme.
In 1973, we put that enzyme into two splenectomised patients with Gaucher disease. The first patient was a 15 year old boy with Type 3 Gauchers disease. We obtained a liver biopsy, gave the enzyme at ½ u/kg/bw (unit per kilo of bodyweight) and two days later performed another liver biopsy. There was a 26% reduction of the accumulation of glucocerebroside in the liver biopsy.
In the second patient we also showed a 26% decrease. But virtually no one believed me. We gave a third patient 2½ u/kg/bw but the reduction was only 8%.
It took another 2½ years to develop a new purification process which was carried out by Scott Furbish and his colleagues in our laboratory. However no reduction of hepatic (liver) glucocerebroside occurred in four out of seven patients who received this preparation.
The problem was that the glucocerebrosidase was not going into the macrophages, the cells in the liver, spleen and bone marrow that accumulate glucocerebroside: 95% of the infused enzyme was going to other cells, primarily hepatocytes in the liver, and being wasted.
John Barranger then joined our team and together with Clifford Steer and Scott Furbish removed oligosaccharides from the enzyme so that the mannose (a sugar at the end of the sugar side chains) would attach to the macrophage.
Of eight patients who were given this sugar-modified form of glucocerebrosidase, only one little boy got better, seven other patients did not. The boy had a very large spleen. He was given 13 u/kg/bw every week and his haemoglobin and platelets gradually rose.
We then deliberately stopped the enzyme infusions and his haemoglobin and platelets gradually decreased to pre-infusion values. When we re-instated his enzyme infusions at 30 u/kg/bw, his blood counts rose to normal range, there was a reduction in the size of his spleen and liver and the damage to his bones improved.
It was at this point that Henri Termeer (now President and Chief Executive Officer of Genzyme Corporation) learned about our work.
Henri raised 10 million dollars to produce enough enzyme for a clinical efficacy trial. We carried out a dose response study and elected to give patients 60 u/kg/bw every two weeks. In this clinical efficacy trial, all 12 patients improved.
The rest has become history. Ceredase worked and the recombinant enzyme Cerezyme is just as good.'
Dr Brady's current research at NIH is on enzyme replacement and gene therapy for Gauchers disease and Fabry disease.
Source: Gaucher's News February 2000. © Copyright Gauchers Association 2000