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Protein-based recombinant drugs—like Factors VIII and IX for hemophilia or insulin for diabetes—are costly to manufacture and require patients to endure IV hookups or frequent injections. A technique developed at Children's, combining gene therapy with tissue engineering, may someday enable the body itself to make these drugs on demand.
In a recent proof-of-concept study in the journal Blood, researchers led by Juan Melero-Martin, PhD, in Children's Department of Cardiac Surgery, reversed anemia in mice by getting them to grow blood vessels that secreted erythropoietin (EPO). The team isolated endothelial colony-forming cells from the blood, inserted genetic code instructing the cells to make EPO and then added mesenchymal stem cells. This mix was then suspended in a gel and injected subcutaneously.
The implanted cells spontaneously formed networks of blood vessels, lined with EPO-secreting endothelial cells. Within a week, the new vessels joined with the animals' own and released EPO into the blood. EPO circulated throughout the body and reversed anemia, significantly boosting hematocrits as compared with control mice.
The system also included an on/off control: the EPO-making gene was silent until the mice received doxycycline, which disabled a repressor protein linked to the gene. In fact, the researchers could turn EPO on and off—and make the animals' hematocrit go up and down—just by adding or subtracting doxycycline from their drinking water.
Future challenges will include finding more practical control mechanisms, ideally tying drug production to the body's own regulatory systems, like those sensing blood oxygen levels. A bigger challenge will be to get endothelial cells to store and release therapeutics at a moment's notice, necessary for drugs like insulin.
Dr. Melero-Martin is also interested in using engineered blood vessels to help tissues regenerate, secreting factors that attract stem cells or induce cell differentiation. "Blood vessels are one of the few tissues where we have good control over engraftment," he notes. "And we have the ability to put instructions inside."
More information:
on.chbos.org/pv0212bloodvessels
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