Monday, July 7, 2014

Carrying Therapeutic Cargo Using Engineered Red Blood Cells

Human red blood cells supported on a glass slide.
Red blood cells - Source

Red blood cells carry oxygen throughout your body, but could they be harnessed to carry more valuable payloads too?  That's what a team of scientists out of Cambridge, MA attempted to find out.  Red blood cells (RBC) are presumably great candidates for in vivo delivery of natural and synthetic compounds because they are distributed throughout the body, are biocompatible, have a half-life in humans of 120 days, have a high surface-to-volume ratio, and can be removed by the immune system if damaged.  But, and perhaps most importantly, they also lack nuclei, mitochondria, and genetic material when they mature.  That means that any modifications that are made to the DNA of RBC precursors is eliminated when they mature and lost their nuclei, and can't cause tumors or other abnormal growth after transfusion. 

The traditional methods of engineering RBC have not been ideal for therapeutic use, sometimes disrupting membrane integrity, and other times reducing RBC half-life and product delivery.  In this study, researchers led by Dr. Harvey Lodish and Dr. Hidde Ploegh used a new method to engineer RBC that exploited the cell's ability to attach payloads to its plasma membrane, thus maintaining membrane integrity and resulting in only minimal modifications.

Sortase, PDB 3O0P
The scientists took advantage of a small bacterial protein, known as sortase, which selectively modifies surface proteins based on a specific amino acid sequence signal.  By exploiting sortase-catalyzed reactions, the scientists were able to create RBC that could have different surface proteins attached to them under native conditions, without damaging the cell membrane.  All they had to do was modify RBC precursors to express proteins with those specific signaling sequences, and provide the desired substrate for the sortase-catalyzed reaction.  The RBC precursors will express the proteins on the cell surface, even after enucleation.

To show that their method works, the researchers first used mouse RBC to demonstrate the successful attachment of biotin to surface proteins, though the RBC half-life in mice was slightly reduced (though it was longer than the half-life of RBC engineered using other methods).  The researchers also report that a similar experiment worked in human RBC.  The surface proteins were engineered with a binding specificity that allows them to target specific cell types; that means that therapeutic cargo could be delivered to tumor cells, specifically, and not to other cells in the body!

The authors are confident that this method may surpass the current stem cell and protein-based therapies because there is little risk for tumor development, since RBC lack genetic material and are controlled by the immune system.  Dr. Lodish believes that engineered RBC can one day be used to control blood cholesterol levels, treat ischemic strokes or deep-vein thrombosis, or even chronic inflammation.  And while the idea of army involvement in scientific research skeeves me out, apparently the U.S. army is interested in this technique to create treatments against biological weapons.

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