Status of enzyme replacement therapy for Gaucher disease.

At this point in time, enzyme replacement therapy for Gaucher disease appears both biochemically effective (patients 1-3, and 10) as well as clinically promising (patients 4 and 5), although these salutary responses have not been obtained consistently (patients 6-9). The discrepancy may be due to the method employed for the isolation of the enzyme. One current opinion is that glucocerebrosidase prepared by conventional fractionation and ion exchange chromatographic procedures may have been more effective in vivo than enzyme prepared by butanol extraction and hydrophobic column chromatography, which we developed because of the difficulty in obtaining large quantities of glucocerebrosidase by the conventional method. It should be remembered that the enzyme prepared by the latter procedure was fully active on glucocerebroside in liver biopsy specimens in vitro. Furthermore, glucocerebrosidase prepared by the second method exerted a positive effect in 2 young patients, who received relatively large amounts of enzyme, and in an adult who was treated with corticosteroid prior to infusion of the enzyme. At this moment, a possible explanation is that a necessary associated factor, perhaps a lipid, may have been removed by the large-scale isolation procedure. We are attempting to improve the biochemical and clinical responses to enzyme infusion by investigating the effects of lysosomal modifying agents and by enhancing the uptake and localization of the infused enzyme in lysosomes of cells that contain the stored glucocerebroside.