The combination of two clinically approved drugs--Viagra and Plerixafor--rapidly and efficiently mobilizes blood stem cells from the bone marrow into the bloodstream in mice, researchers report October 10th in the journal Stem Cell Reports. This strategy is almost as effective as the current standard protocol for hematopoietic stem cell mobilization.
"Given that both drugs are FDA approved, they could be relatively quickly tested in human volunteers," says senior author Camilla Forsberg, a stem cell biologist at the University of California, Santa Cruz. If proven safe and effective in human clinical studies, "clinicians could consider these findings when selecting treatment strategies for their patients and for volunteer donors of hematopoietic cells used in transplantation therapies."
Hematopoietic stem cell transplantation, which replaces abnormal blood-forming stem cells with healthy cells, is a curative treatment for a variety of blood and immune disorders. This procedure involves mobilizing hematopoietic stem cells from the bone marrow into the bloodstream and then collecting these cells for transplantation either back into the same person or into a recipient. But significant hurdles have caused hematopoietic cell therapies to be reserved mainly for patients who have malignant disease and have run out of other treatment options. Major barriers to using hematopoietic stem cell transplantation include the limited supply of donor cells and the lack of efficient means to harvest them.
The current standard protocol for hematopoietic stem and progenitor cell mobilization involves multi-day injections of granulocyte-colony stimulating factor (G-CSF). Although effective in most cases, G-CSF is costly, produces side effects such as nausea, fatigue, and bone pain in some donors, and is often unsuccessful in cancer patients who have undergone chemotherapy. In addition, it is not suitable for the very ill, the elderly, or individuals with sickle cell disease. Another drug that mobilizes hematopoietic stem cells is Plerixafor, but it is not very effective as a single agent. "Better harvesting protocols would significantly improve the success rate for current indications and open curative hematopoietic cell therapies to a wider spectrum of disorders," Forsberg says.
Recent experiments in the Forsberg lab have shown that increasing vascular permeability helps mobilize hematopoietic stem cells from the bone marrow into the bloodstream. Building on these findings in the new study, Forsberg and her team tested whether Viagra, a vasodilator approved by the U.S. Food and Drug Administration (FDA) for the treatment of erectile dysfunction, might be a viable option for hematopoietic stem cell transplantation. After all, Viagra was originally developed to combat high blood pressure, coronary heart disease, and chest pain and is currently used to treat a variety of vascular disorders.
The researchers found that Viagra alone was not effective, suggesting that individuals who currently take this medication for other reasons do not have to worry about inadvertently mobilizing hematopoietic stem cells. By contrast, mice treated with Plerixafor alone showed a nearly 3-fold increase in hematopoietic cells compared to control mice, consistent with findings from previous studies.
But combination therapy was even better. Mice treated with a single oral dose of Viagra combined with an injection of Plerixafor had approximately 2,500 more hematopoietic stem cells in the bloodstream within 2 hours, representing a 7.5-fold increase compared to control mice. Three days of oral Viagra combined with a single injection of Plerixafor was slightly more effective, resulting in approximately 2,800 more hematopoietic stem cells--an 8.4-fold increase compared to control mice. Moreover, the effectiveness of this approach rivaled that of a 4-day G-CSF treatment regimen, which increased the number of hematopoietic stem cells by approximately 3,400.
The researchers next harvested hematopoietic stem cells from the blood or bone marrow of donor mice treated with either Plerixafor alone or a combination of Viagra and Plerixafor and then transplanted these cells into recipient mice. These experiments revealed that the combination of Viagra and Plerixafor outperforms Plerixafor alone, resulting in the long-term engraftment of functional, self-renewing, multipotent hematopoietic stem cells, suggesting that this approach may be suitable for hematopoietic stem cell transplantation in patients.
However, additional studies in humans are needed to test the safety and effectiveness of this approach. If successful in clinical studies, the combination of Viagra and Plerixafor could be more attractive to volunteer donors and patients because it is a less costly, less time-consuming, more convenient treatment option that has a better side-effect profile than G-CSF. Although this combination therapy may not completely replace G-CSF, it could be more effective or suitable for patients who are very ill or elderly or individuals who have undergone chemotherapy or have sickle cell disease.
Moving forward, the researchers plan to work with clinicians to facilitate translation of these findings to patients. "In our lab, we are also continuing to pursue the molecular and cellular mechanisms that influence hematopoietic stem cell trafficking and how this changes with age and disease, with a focus on vascular integrity," Forsberg says. "One important goal is to overcome variability in hematopoietic stem cell mobilization among different people with different disease profiles and treatment histories."
This work was funded by an American Cancer Society Research Scholar Award, a Koret Scholar Award, and CIRM Shared Stem Cell Facilities and CIRM Major Facilities awards to UCSC.
Stem Cell Reports, Smith-Berdan et al.: "Viagra Enables Efficient, Single-Day Hematopoietic Stem Cell Mobilization" https://www.cell.com/stem-cell-reports/fulltext/S2213-6711(19)30333-9
Stem Cell Reports, published by Cell Press for the International Society for Stem Cell Research (@ISSCR), is a monthly open-access forum communicating basic discoveries in stem cell research, in addition to translational and clinical studies. The journal focuses on shorter, single-point manuscripts that report original research with conceptual or practical advances that are of broad interest to stem cell biologists and clinicians. Visit http://www.