Editors' ChoiceFabry Disease

Cleaning Up the Clutter

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Science Translational Medicine  16 Mar 2011:
Vol. 3, Issue 74, pp. 74ec36
DOI: 10.1126/scitranslmed.3002363

Imagine a young boy instructed to tidy up his room on a regular basis. He does a fair job of general cleaning, but he neglects the items accumulating in the closet and under the bed. After several weeks of this behavior, the room may still be somewhat functional, but he is unable to locate a few of his toys. It is clear that order in the room will not be fully restored without addressing the items stashed away in the closet or hidden under the bed.

In patients with Fabry disease—a genetic deficiency of α-galactosidase A (α-Gal)—lysosomal deposits of the glycolipid globotriaosylceramide (Gb3) can accumulate in various tissues and cells, including endothelial cells. This accumulation has been implicated in the progression of renal, cerebrovascular, and cardiac vasculopathy. Enzyme replacement therapy with galactosidases can reduce tissue Gb3 levels, but persistent vasculopathy may lead to life-threatening complications.

To improve the delivery of α-Gal to vascular endothelial cells, Hsu et al. developed nanocarriers coated with antibodies that target intercellular adhesion molecule 1 (ICAM-1), a glycoprotein that is up-regulated in vascular endothelial cells in Fabry disease. The release of α-Gal from the nanocarriers was enhanced in response to lysosomal pH as well as the presence of Gb3. In an in vitro Fabry disease model, the nanocarriers colocalized with fluorescent Gb3 in the lysosomes of endothelial cells, and the rate of Gb3 degradation more than doubled compared with treatment with nontargeted α-Gal. In vivo radiotracer experiments in mice showed that in comparison to nontargeted α-Gal, the nanocarriers increased enzyme delivery by 40% in the kidneys, 270% in the brain, and 410% in the heart.

Therefore, ICAM-1–specific nanocarriers that improve endothelial targeting in Fabry disease could be used to augment patient therapy by cleaning up the excess Gb3 that clutters the lysosomes of endothelial cells.

J. Hsu et al., Enhanced endothelial delivery and biochemical effects of α-galactosidase by ICAM-1-targeted nanocarriers for Fabry disease. J. Controlled Release 149, 323–331 (2011). [Abstract]

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