Therapy of Lysosomal Storage Diseases

Abstract

Lysosomes are membrane-surrounded organelles which are present in all nucleated mammalian cells. They function to degrade both intra- and extracellular macromolecules to low molecular components that are transported to the cytoplasm for reutilization in the biosynthetic pathways of the cell. Up to now more than 50 different lysosomal hydrolases catalyzing the degradation of proteins, lipids, nucleic acids and carbohydrates have been identified. The normal function of the lysosomal compartment also depends on a variety of proteins without hydrolytic activity such as cofactors, transporters, ion channels and nonlysosomal proteins engaged in the posttranslational activation and targeting of lysosomal enzymes. Functional deficiencies, both of hydrolytic or nonhydrolytic polypeptides can result in lysosomal storage diseases (LSDs) which are characterized by the intralysosomal deposition of macromolecules and a multisystemic phenotype leading to early death. Most LSDs appear in severe, early onset forms and milder, late onset variants. This hetereogeneity seems to be due to subtle differences in the residual amount of active protein implying that even a modest increase of the protein level might have beneficial effects on the disease. Consequently, most therapies for LSDs attempt to supply deficient cells with the active counterpart of the defective protein. Such enzyme augmentation therapies contrast with substrate reduction therapies which try to reduce the accumulated storage material by nonenzymatic means. The evaluation of the potentials, limitations and risks of therapeutic strategies in cell culture and animal models for LSDs has been fundamental for the implementation of clinical trials which finally led to the clinical realization of certain treatment concepts.