Nucleic Acid Aptamer Selection against TfR for the Therapeutic Treatment of Lysosomal Storage Diseases

Lysosomal Storage Diseases are inherited metabolic disorders that result from dysfunctional lysosomal enzymes. These enzymes facilitate the digestion of macromolecules within eukaryotic cells (Fong 2010). The absence of functional lysosomal enzymes results in the accumulation of macromolecules within the cell and can lead to many harmful effects on cells, tissues and organs (Futerman 2004). An efficient method of enzyme delivery could alleviate many of the problems associated with these diseases. The selection of an aptamer against a target membrane bound protein involved in endocytosis could provide efficient system of enzyme delivery to lysosomes. Post-selection modification of the aptamer would be necessary to link an enzyme to the aptamer. This method of aptamer-mediated endocytosis and post-selection modification could have a significant impact on the future of targeted enzyme delivery, as the design is very versatile.

Figure 1. Transferrin receptor-mediated endocytosis of Fe3+.

The transferrin receptor (TfR) is a membrane bound protein that facilitates the transport of iron into cells (Ray 2010). The binding of transferrin-Fe+3 to TfR signals for endocytosis of the entire molecule [1]. The molecule is transported to the endosomal compartment, iron is released and the rest of the molecule is incorporated back into the membrane. An aptamer will be selected against the transferrin receptor and modified post-selection with the addition of a functional lysosomal enzyme. This will enable the delivery of functional enzymes to lysosomes through aptamer-mediated endocytosis.

Though this form of enzyme replacement therapy is relatively new, there have been successful results, indicating that this therapeutic application of aptamers may be key to the future of lysosomal enzyme delivery. Researchers at UCLA have demonstrated the delivery of enzymes to cells deficient in lysosomal enzymes using the aptamer-mediated endocytosis method (Neufeld 2007). Chen et al. selected an aptamer against TfR and modified the aptamer with the attachment of α-l-iduronidase, a lysosomal enzyme. This aptamer complex was taken up by α-l-iduronidase-deficient mouse fibroblasts. The selection of an aptamer against TfR for aptamer-mediated endocytosis could have a revolutionary impact on the delivery of enzymes and treatment of various lysosomal storage disorders.

Human TfR from ARP- $259/ 50ug- http://www.biocompare.com/ProductDetails/1537096/Human-Transferrin-Receptor.html?

References

Chen, Chi-hong B. et. al. "Aptamer-based Endocytosis of a Lysosomal Enzyme." PNAS 105.41 (2008): 15908-5913.

Fong, Chin-To. "Lysosomal Storage Disorders." Merck & Co., Inc. Feb. 2010. Web. 04 Sept. 2010. .

Futerman, Anthony H., and Gerrit Van Meer. "The Cell Biology of Lysosomal Storage Disorders." Nature 5 (2004): 554-65.

Neufeld, Elizabeth F. "Aptamer Mediated Correction of Lysosomal Enzyme Deficiency." The Regents of the University of California. UCLA,

Ray, Partha, and Rebekah R. White. "Aptamers for Targeted Drug Delivery." Pharmaceuticals 3 (2010): 1761-778.

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