Amicus Therapeutics Explores a New Way to Treat Gauchers Disease

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A potential new method for treating Gauchers disease produced by Amicus Therapeutic was described in the last edition of Gauchers News. This is a further update.

Amicus Therapeutics, a biopharmaceutical company based in New Jersey USA, is developing small molecule, orally administered drugs called pharmacological chaperones to treat a number of genetic diseases.

It expects to initiate clinical trials of AT2101, an experimental treatment for Gauchers disease, in the second half of 2006.

'Recent evidence suggests that Gaucher disease is one of a growing list of conditions which may be further classified as disorders of protein misfolding and amenable to pharmacological chaperone therapy, 'explains Dr Pedro Huertas, Chief Development Officer at Amicus Therapeutics.

'The protein involved in Gaucher disease is the enzyme glucocerebrosidase which functions to break down the fatty substance glucocerebroside which collects in the liver, spleen, bone marrow and sometimes other parts of the body.

'Normally, a protein or enzyme is made of a specific sequence of amino acids that assumes a 3-dimensional shape by being twisted, bent, and folded. Proteins are folded in the endoplasmic reticulum area of the cell and, once properly folded, move out to other parts of the cell where they are biologically active.

'Certain types of mutations (changes) in the gene for glucocerebrosidase, called missense mutations, allow the enzyme to be made but cannot fold properly. The misfolded enzyme is unstable and remains in the endoplasmic reticulum where it may accumulate, clump together and have damaging effects. Such damaging effects are thought to be in addition to the effects created by storage of the fatty substance in the lysosomes caused by the reduction or loss of the glucocerebrosidase enzyme. ' It is estimated that approximately 75% of people with Gaucher have a missense mutation such as N370S or L444P.

'Pharmacological chaperones are small molecules designed to attach to the misfolded proteins in the endoplasmic reticulum, stabilizing them so that they can fold properly, which in turn allows them to travel normally in the cell. Once the stable protein arrives at its cellular target (the lysosome, in the case of Gaucher disease), the pharmacological chaperone detaches and the protein can perform its proper function. Amicus is exploring this approach as a potential therapy for Gaucher disease. 'Phase II clinical trials of the company's leading drug for Fabry disease, AmigalTM, are currently taking place in the UK, USA, Brazil and Australia.'

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Source: Gauchers News June 2006.
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