The Rationale for Substrate Reduction Therapy in Neuronopathic Gauchers Disease


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Enzyme replacement therapy is highly effective in the treatment of Type 1 Gauchers disease but it is unlikely to cross the blood-brain barrier to help Neuronopathic Gauchers disease. Bone marrow transplantation is more effective but risky. Therefore a different approach is required, explained Dr Ashok Vellodi, who runs the paediatric Gauchers Centre at Great Ormond Street Hospital, London at the UK Conference on 30 November 2003.


The theory of substrate reduction therapy is that it prevents the amount of lipids (fatty substance) being formed so that the patient's own enzyme can reduce the remaining accumulated lipids.

In preclinical trials on mice affected by Tay-Sachs disease and Sandhoff disease (which have similarities to neuronopathic Gauchers disease) and in experiments on cells in the laboratory, substrate reduction therapy has shown some success in being able to cross the blood-brain barrier. In Tay-Sachs mice, there has been evidence of less storage in the brain and fewer affected neurones. In a paper published by Dr Fran Platt and her colleagues at the Oxford Glycobiology Institute in 1999, Sandhoff mice fed with OGT918 (Zavesca) showed delayed symptom-onset and increased life expectancy.

However there are difficulties with using animal models which include inconsistent correlation with human disease and no animal equivalence of quality of life data. Experiments have not been carried out on mice models of Gauchers disease as the only Gauchers mouse model has no enzyme and for substrate reduction to work, there must be some existing enzyme produced in the body.

However trials with patients suffering from Type 1 Gauchers disease have shown that Zavesca has been effective in the treatment of non neuro-logical manifestations although there have been side effects of diarrhoea, neuropathy and tremor. It is not yet known how Zavesca crosses the blood-brain barrier. The brain has a very effective barrier to prevent toxic substances entering it and it is possible that Zavesca might reduce the storage or work in some other way.

Research is also being carried out in Israel by Prof Tony Futerman and his team to see if the inhibition of calcium uptake in the brain in a mouse model of Sandhoff disease causes the disease and whether treatment by Zavesca can prevent this.

Proposed randomised trial of Zavesca in Type 3 Gauchers disease

The trial to see if Zavesca can help reduce or prevent neurological symptoms in patients with Type 3 disease is taking place at two centres (Great Ormond Street Hospital in London and at the NIH in the USA).

The randomised study will take one year. Patients will either take the drug or not take it when they will be used as a control group (on a 2:1 ratio). There will be no placebo drug and all patients will switch over to the drug after one year. The study is sponsored by the Celltech Group (which has taken over Oxford GlycoSciences). Zavesca is marketed by Actelion Pharmaceuticals.

One pill of 100mg is about 15 mm long and therefore some children might find it hard to swallow. The dose is 200mg to be taken three times a day. The pills cannot be crushed as the taste is too bitter. In fact only one child has been unable to swallow the drug. It is hoped that an oral dispersible preparation will be developed soon.

The trial requires 30 patients. So far eight children in the USA and 10 in the UK have entered the trial. Twelve have been randomised to receive the drug and five are acting as controls. The youngest child is 2 years old. Recruitment will continue in 2004. Diarrhoea and weight loss has not been major problems so far.


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Source: Gauchers News March 2004.
© Copyright Gauchers Association 2004.