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A breach in the blood-brain barrier.

A fundamental problem affecting the efficacy of drugs is their ability to be delivered from the site of administration to the site of pathology. Nowhere is this issue a more confounding problem than for protein drugs designed to treat the neuropathology associated with many lysosomal storage diseases (LSDs) where the blood-brain barrier (BBB) stands in the way. Although an increasing number of lysosomal storage diseases are amenable to treatment by enzyme replacement therapy (ERT), those with neurological consequences have remained challenging to treat. The report by Vogler et al. (1) in this issue of PNAS provides an encouraging demonstration that a therapeutic lysosomal enzyme can be delivered across the BBB, thereby reversing storage in brain tissue. Overcoming the BBB can be seen as the latest in a series of drug-targeting challenges that have faced researchers attempting to treat LSDs by delivering therapeutic enzymes to the lysosome of afflicted cells.

Lysosomal storage diseases are a group of >40 genetic disorders with heterogeneous symptoms (2). Each results from the deficiency of a lysosomal hydrolase that functions in the lysosome to degrade macromolecules, primarily glycoconjugates such as sphingolipids, glycosaminoglycans (GAG, formerly mucopolysaccharides), glycogen, or glycoproteins. The pathology associated with these diseases depends on the nature of the accumulated glyconjugate and the tissues in which the storage material accumulates. Many of the lysosomal storage diseases affect brain tissue.

ERT has become the treatment modality of choice for an increasing number of LSDs. ERT is a therapeutic strategy to correct an enzyme deficiency by infusing the missing enzyme into the bloodstream. As the blood perfuses patient tissues, an enzyme is taken up by cells and transported to the lysosome, where the enzyme acts to eliminate the storage material.

ERT was established as a therapeutic paradigm by the work of Roscoe Brady and colleagues at the …