Potential efficacy of enzyme replacement and substrate reduction therapy in three siblings with Gaucher disease type III.

We report three siblings with Gaucher disease type III, born between 1992 and 2004. During this period, new developments resulted in different potential therapies, changing clinical practice. The two eldest siblings received enzyme replacement therapy (ERT) from the age of 24 and 5 months respectively, later followed by an increase in dosage. ERT was combined with substrate reduction therapy (SRT) from the ages of 12 and 8 years, respectively. In the youngest sibling the combination of high-dose ERT and SRT was given from the age of 5 months. The two eldest siblings showed significant neurological impairment from the age of 1.5 years, starting with a convergent strabismus and partial oculomotor apraxia, followed by cognitive decline and an abnormal EEG and BAER. In contrast, the neurological development in the youngest sibling is almost completely normal. At the age of 3 years, cognitive development, EEG and BAER are all normal. Disturbed saccadic eye movements, which were already present at the start of therapy, remained stable. In addition to the clinical efficacy, we report on the biochemical response to therapy. Based on our results, the combination of high-dose ERT and SRT should be considered as a possible therapeutic approach for GD III, especially if started at a young age. Further follow-up studies are necessary to explore the long-term therapeutic effects.

Home treatment with enzyme replacement therapy for mucopolysaccharidosis type I is feasible and safe.

OBJECTIVE: Intravenous enzyme replacement therapy (ERT) with recombinant alpha-L-iduronidase may ameliorate the non-neurological symptoms in patients with mucopolysaccharidosis type I (MPS I). Since home-based ERT for Gaucher and Fabry diseases has been reported to be safe and successful, we investigated the feasibility and safety of home therapy in patients with MPS I. SETTING: This two-centre study included 17 ERT-treated MPS I patients between 1 and 35 years of age. A patient was allowed to transfer to home treatment after a minimum period of 6 months of in-hospital administration of ERT and after a self- or home nurse-supported home setting was arranged. RESULTS: Thirteen out of 17 patients transferred to home treatment with a median time to transfer of 13 months (range 7-40 months). Two patients preferred to continue ERT in the hospital, whereas for two other patients the transfer to home was hampered for practical reasons. All patients who received ERT at home were assisted by either a relative or a nurse. In total over 1000 home infusions were performed and no serious complications were observed. Two infusion-associated reactions were observed, both within the first 3 months of in-hospital administration of ERT. All patients except one developed antibodies against the recombinant enzyme, but this was not associated with the development of hypersensitivity reactions. CONCLUSION: ERT for MPS I applied at home is safe and might alleviate the burden of life-long intravenous treatment in these patients.

Quantitative analysis of the targeting of mannose-terminal glucocerebrosidase. Predominant uptake by liver endothelial cells.

Gaucher's disease is an inherited lysosomal storage disorder that is caused by a deficiency of glucocerebrosidase. The resulting accumulation of the substrate glucosylceramide in macrophages of liver, spleen, and bone marrow causes severe clinical symptoms. Gaucher's disease is treated by intravenous administration of a modified glucocerebrosidase (Alglucerase), which has exposed mannose residues to promote uptake by target macrophages. To evaluate the effectiveness of the targeting of Alglucerase, we studied the fate of the enzyme in the rat. Intravenously injected Alglucerase was rapidly cleared from the circulation (half-life 2.0 +/- 0.5 min). The liver was the main site of uptake, with 65.6 +/- 1.2% of the dose present at 10 min after injection. Smaller amounts ( < 3% of the dose) were taken up by spleen and bone marrow. Previous injection with mannan substantially increased the plasma half-life of the enzyme (14.8 +/- 3.2 min versus 1.7 +/- 0.3 min in solvent-preinjected controls) and uptake of the enzyme by liver, spleen and bone marrow was reduced by > 90%. These findings indicate that the enzyme is taken up by these organs via mannose-specific receptors. Subcellular fractionation of the liver indicated that the enzyme is internalized and transported to the lysosomes. By isolating various liver cell types after injection of the Alglucerase, it was found that endothelial cells are the main site of uptake of the enzyme: 60.8 +/- 3.4% of the total liver uptake. Parenchymal and Kupffer cells were responsible for 31.0 +/- 3.1% and 8.2 +/- 0.7% of the hepatic uptake, respectively. We conclude that Alglucerase is rapidly cleared from the circulation by mannose-specific receptors in liver, spleen, and bone marrow. However, less than 10% of the enzyme taken up by the liver is accounted for by Kupffer cells, the hepatic target cells for therapeutic intervention. It is suggested that alterations of the formulation of the therapeutic enzyme may lead to a higher uptake by Kupffer cells and other macrophages, and thus to a more (cost)effective therapy of Gaucher's disease.