Use of EPO for treating brain disorders is currently limited by its inability to cross the BBB. To overcome this shortcoming researchers writing in Molecular Pharmaceutics used a molecular Trojan horse (MTH) fusion protein to develop a brain-penetrating form of EPO.
In this instance the MTH fusion protein had to be genetically engineered because there is no known monoclonal antibody (MAb) which could be used as a BBB MTH in rats and mice. Once created the MAb was fused to EPO to create a brain-penetrating from of the neuroprotector.
Having created a viable fusion protein for crossing the BBB in mice the researchers expect follow-up work to look at the neuroprotective effect of EPO. This will evaluate a number of brain disorders, including brain ischemia, spinal cord injury, or chronic neurodegenerative disorders.
A possible application of brain-penetrating EPO is in the treatment of strokes. Neuroprotection is possible in the hours following a stroke but the BBB is intact. Consequently, use of EPO to treat strokes could be improved by brain-penetrating variants, according to the researchers.
Reengineered EPO was administered intravenously. Researchers found the fusion protein was quickly cleared from the blood, 14-times faster than EPO alone, and entered the brain in high levels.
Faster clearance from the blood is due to increased uptake from certain organs, such as the liver and spleen. However, the larger size of the fusion protein limits uptake by peripheral tissues, such as heart, lung and kidney.
Reducing the time EPO spends in the blood minimises the affect it can have on the formation of blood cellular components, a process called haematopoiesis.