Uptake of Enzyme Replacement Therapy


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Research into the uptake of enzyme replacement therapy in patients with Type 1 Gauchers disease, carried out by Dr Pram Mistry, Dr Philip Wraight and Prof Timothy Cox at the University of Cambridge Clinical School, Addenbrooke's Hospital, Cambridge, was published in the medical journal, The Lancet, on 7 December 1996. The following is a brief extract:


The uptake and tissue distribution of radiolabelled enzyme was followed in eight patients, three men and five women, and one healthy individual. Five patients had had a splenectomy. All had been receiving Ceredase 5 u/kg twice a week and were found to have satisfactory clinical and laboratory evidence of response to treatment (except one patient who did not respond to 35 u/kg infusions given once a week for 6 months).

The tracer enzyme was rapidly cleared from blood with a half-life of 4-7 minutes. (Half life means when 50% of the enzyme has disappeared). Concomitantly, there was avid uptake by the liver (about 30% of the injected dose), the spleen (about 15%) and the bone marrow. 40-55% of the tracer was cleared rapidly from the liver and spleen (half-life 1-2 hours) and 45-60% was cleared slowly (half-life 34-42 hours). The half-life in the bone marrow was 14.1 hour.

Uptake was intense and homogeneous throughout the liver in all participants. However, splenic uptake in some patients was patchy because of fibrosis and infarction. There was also significant uptake by the bone marrow, particularly at sites of skeletal disease. Uptake in the bone marrow continued to increase over the first 4 hours. In the healthy participant, no significant marrow uptake was detected.

Infusion of enzyme at dose of 5 u/kg bodyweight was used in all patients. However when it was administered at a seven fold higher dose (35 u/kg over 1 hour), the receptor-mediated uptake was saturated, as shown by the increase in blood-clearance half-life of tracer enzyme from 4.5 min to 12 min.


Therapeutic Delivery of Proteins to Macrophages: Implications for Treatment of Gauchers Disease, The Lancet, Vol 348, Dec 7 1996.

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Source: Gaucher's News February 1997. © Copyright Gauchers Association 1997