The calcium connection and problems of enzyme replacement therapy with the blood-brain barrier


Neuronopathic Gaucher's News Contents
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Tony Futerman, Professor of Biological Chemistry at the Weizmann Institute in Israel spoke about the abnormal physiology (function) of calcium in the brain in neuronopathic Gaucher disease and the problem of enzyme replacement therapy crossing the blood-brain barrier, at the Type 3 Gaucher Disease Family Conference on 27 November 2004.


'It is important to understand how the biochemical mechanisms work in the brain of Type 2 and Type 3 Gaucher Disease in order to target drug therapy for the neuronopathic form of the disorder,' explained Prof Futerman.

Everyone has genes in their cells which produce proteins or enzymes which metabolise (break down) waste material in the body. The enzyme glucocerebrosidase which breaks down the membrane of old blood cells is insufficient in patients with Gaucher Disease and the waste material (lipids) accumulates in different parts of the body. In neuronopathic disease, the waste material accumulates in the brain.

The calcium connection

'Our interest in this field began in 1999 when my colleagues and I showed changes in the way that neurons handle calcium in a mouse model of Type 2 Gaucher Disease. Since then, we have confirmed these changes in laboratory tests and very recently have seen that there are indeed changes in calcium in post-mortem brain tissue obtained from Type 2 and 3 patients. 'We believe that we have discovered at least one mechanism that may be involved in the brain of neuronopathic patients.

'Perhaps in the future, we can help sufferers by removing the calcium in the brain and take advantage of existing calcium-altering drugs. I must stress that this is not related to how much calcium is consumed in a patient's daily diet and their food consumption should not be altered.

Enzyme replacement therapy

'The problem with enzyme replacement therapy for patients with neuronopathic Gaucher Disease is that it does not cross the blood-brain barrier and therefore is not effective for these patients in the brain. 'However we know that some proteins can get into the brain. If we could get enzyme replacement therapy into the brain, I believe it would get into the neurons and would work. Maybe it does not get into the brain because it does not stay long enough in the blood circulation.

'I suggest that it may be possible to modify enzyme replacement therapy so that it can get into the brain. 'Recently, we solved the 3D-structure of the enzyme and this work may help in the context of ways of improving enzyme replacement therapy.

'Gaucher Disease is a lysosomal storage disease with 40 other diseases in this group. However we know very little about the brain dysfunction in these diseases because of their rarity. 'In the case of Gaucher Disease, only 5% of patients have Type 2 or Type 3. Enzyme replacement therapy works for Type 1, and somewhat for Type 3, and therefore the neuronopathic form of the disease has got left behind in terms of basic research.

In addition there is no mouse model for Type 3 Gaucher Disease or for Type 1. This impedes our ability to perform essential experiments. Only so much can be carried out on cells in a dish in a laboratory and it is unethical to undertake initial tests on human beings.'


Neuronopathic Gaucher's News Contents
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Source: Gauchers News May 2005.
Copyright © Gauchers Association 2005.