Stem Cells Engineered to Become Targeted Drug Factories
A group of Brigham and Women’s Hospital, and Harvard Stem Cell Institute researchers, and collaborators at MIT and Massachusetts General Hospital have found a way to use stem cells as drug delivery vehicles.
HSCI Principal Faculty member Jeffrey Karp, PhD, has pioneered a way to deliver drugs to targeted areas of inflammation using stem cells.
The researchers inserted modified strands of messenger RNA into connective tissue stem cells—called mesenchymal stem cells. This stimulated the cells to produce adhesive surface proteins and secrete interleukin-10, an anti-inflammatory molecule.
When injected into the bloodstream of a mouse, these modified human stem cells were able to target and stick to sites of inflammation and release biological agents that successfully reduced the swelling.
“If you think of a cell as a drug factory, what we’re doing is targeting cell-based, drug factories to damaged or diseased tissues, where the cells can produce drugs at high enough levels to have a therapeutic effect,”
Jeffrey Karp, PhD, research leader, Harvard Stem Cell Institute, principal faculty member and Associate Professor, Brigham and Women’s Hospital, Harvard Medical School, and Affiliate faculty at MIT.
Karp’s proof of concept study, published in the journal Blood, is drawing early interest from biopharmaceutical companies for its potential to target biological drugs to disease sites. While ranked as the top sellers in the drug industry, biological drugs are still challenging to use, and Karp’s approach may improve their clinical application as well as improve the historically mixed, clinical trial results of mesenchymal stem cell-based treatments.
Mesenchymal stem cells have become cell therapy researchers’ tool of choice because they can evade the immune system, and thus are safe to use even if they are derived from another person.
To modify the cells with messenger RNA, researchers used the RNA delivery and cell programming technique previously developed in the MIT laboratory of Mehmet Fatih Yanik, PhD.
This RNA technique is harmless, as it does not modify the cells' genome, which can be a problem when DNA is used (via viruses) to manipulate gene expression.
“This opens the door to thinking of messenger RNA transfection of cell populations as next generation therapeutics in the clinic, as they get around some of the delivery challenges that have been encountered with biological agents,” said Oren Levy, PhD, co-lead author of the study and Instructor of Medicine in Karp’s lab. The study was also co-led by Weian Zhao, PhD, at University of California, Irvine who was previously a postdoctoral fellow in Karp’s lab.
One such challenge with using mesenchymal stem cells is they have a “hit-and-run” effect, since they are rapidly cleared after entering the bloodstream, typically within a few hours or days.
The Harvard/MIT team demonstrated that rapid targeting of the cells to the inflamed tissue produced a therapeutic effect despite the cells being rapidly cleared.
The scientists want to extend cell lifespan even further and are experimenting with how to use messenger RNA to make the stem cells produce pro-survival factors.
“We’re interested to explore the platform nature of this approach and see what potential limitations it may have or how far we can actually push it,” Zhao said. “Potentially, we can simultaneously deliver proteins that have synergistic therapeutic impacts.”
Mesenchymal stem cells (MSCs) are promising candidates for cell-based therapy to treat several diseases and are compelling to consider as vehicles for delivery of biological agents. However, MSCs appear to act through a seemingly limited “hit-and-run” mode to quickly exert their therapeutic impact, mediated by several mechanisms, including a potent immunomodulatory secretome. Furthermore, MSC immunomodulatory properties are highly variable and the secretome composition following infusion is uncertain. To determine whether a transiently controlled antiinflammatory MSC secretome could be achieved at target sites of inflammation, we harnessed mRNA transfection to generate MSCs that simultaneously express functional rolling machinery (P-selectin glycoprotein ligand-1 [PSGL-1] and Sialyl-Lewisx [SLeX]) to rapidly target inflamed tissues and that express the potent immunosuppressive cytokine interleukin-10 (IL-10), which is not inherently produced by MSCs. Indeed, triple-transfected PSGL-1/SLeX/IL-10 MSCs transiently increased levels of IL-10 in the inflamed ear and showed a superior antiinflammatory effect in vivo, significantly reducing local inflammation following systemic administration. This was dependent on rapid localization of MSCs to the inflamed site. Overall, this study demonstrates that despite the rapid clearance of MSCs in vivo, engineered MSCs can be harnessed via a “hit-and-run” action for the targeted delivery of potent immunomodulatory factors to treat distant sites of inflammation.
The research was a highly collaborative effort. In addition to Karp, Levy, and Zhao, collaborators included co-corresponding author Yanik, and Harvard Stem Cell Institute Affiliated Faculty member Charles Lin, PhD, at Massachusetts General Hospital.
The work was supported by the National Institutes of Health, the American Heart Association, and a Prostate Cancer Foundation Challenge Award.
Original press releas: http://www.eurekalert.org/pub_releases/2013-09/ru-msa091013.php