Reversibility of cellular and organ pathology in enzyme replacement trials in animal models of lysosomal storage diseases

Abstract

Enzyme replacement therapy (ERT) has now become a feasible treatment option for several lysosomal storage diseases (LSDs). Although the rationale behind this approach is straightforward, there are many factors that may influence the efficacy of treatment. The reversibility of cellular and organ pathology depends on several factors including the particular organ targeted, the dose and biodistribution of enzyme, the accessibility of the target cell to the infused enzyme, the abundance of receptors for mannose-6-phosphate and other ligands in the target tissue and the activity of endocytosis. In addition, each lysosomal enzyme is unique and its ability to reverse pathology must be individually determined according to source, glycosylation and phosphorylation status. The extent to which cellular pathology may be corrected depends upon the delivery of sufficient enzyme to the diseased tissues.

Conclusion: Studies in animal models have identified numerous factors that influence the therapeutic efficacy of ERT. This would suggest that in patients affected by LSDs rigorous evaluation of each therapeutic preparation will be needed.