Research Explores Umbilical Stem Cells as Treatment
Using a baby’s own umbilical cells as vehicles to deliver factor VIII (FVIII) — the missing or defective clotting protein in hemophilia A — may be an effective, long-lasting, and more affordable therapeutic approach for this blood disorder, an early study suggests.
The findings “lay the groundwork for future studies to gain a better understanding of the cellular and molecular factors, and to harness the pathways to drive high level Factor VIII expression in other clinically viable cell types,” Graça Almeida-Porada, MD, PhD, the study’s senior author, said in a press release. Almeida-Porada is a professor at the Wake Forest Institute for Regenerative Medicine (WFIRM), in North Carolina, and the leader of the institute’s Fetal Research and Therapy Program.
The study, “Investigating Optimal Autologous Cellular Platforms for Prenatal or Perinatal Factor VIII Delivery to Treat Hemophilia A,” was published in the journal Frontiers in Cell and Developmental Biology.
Standard treatment for hemophilia A consists of FVIII replacement therapy, in which patients routinely receive — usually two to three times a week — into-the-vein infusions of the missing FVIII protein to prevent bleeding episodes.
While these treatments have revolutionized the disease’s clinical management and increased patients’ life expectancy, they are expensive — costing more than $250,000 a year per patient — and are still unavailable to about 75% of patients around the world.
Moreover, they “cannot guarantee lifelong disease management,” the researchers wrote, as about a third of patients develop neutralizing antibodies against the delivered FVIII, lowering its effectiveness, and in the worst cases rendering it useless.
“There is an urgent need for more effective, readily available and affordable treatments that provide long-lasting correction,” Almeida-Porada said.
As such, the potential delivery of FVIII through gene and/or cellular platforms has emerged as a promising approach to provide long-term correction of hemophilia A.
Also, given that about three quarters of hemophilia A patients have a family history of the disease and diagnosis can occur as early as seven gestational weeks, prenatal treatment may be possible.
Decades of research, along with results from more than 50 clinical cell transplants, have shown the “safety and vast potential of cell-based prenatal therapies,” supporting the use of cells to deliver FVIII and correct the disease before birth, Almeida-Porada said.
Now, Almeida-Porada and her team focused on investigating the optimal cell type among a panel of readily available cells to work as a cellular vehicle to deliver long-lasting FVIII replacement.
“We focused our investigation on cell types that we deemed to be most relevant to either prenatal or very early postnatal treatment and that could, ideally, come from the patients themselves,” Almeida-Porada added.
These included amniotic fluid-, umbilical cord-, and bone marrow-derived mesenchymal stem cells (MSCs) and endothelial progenitor cells (EPCs) from the umbilical cord, which all were grown in the lab. MSCs are capable of maturing into many other cell types, while EPCs can give rise into cells that line blood vessels.
EPCs may be ideal candidates, as they naturally produce von Willebrand factor (vWF), FVIII’s carrier protein that prolongs its activity and reduces its ability to trigger immune reactions.
Researchers evaluated the cells’ ability to be genetically modified to carry a version of the F8 gene, which provides instructions to make FVIII, and subsequently produce an active form of the clotting factor. vWF levels also were assessed in each cell type.
Results showed that all evaluated cell types were viable candidates as FVIII-delivering vehicles, but they produced different levels of FVIII and vWF, depending on their tissue of origin.
“Despite their similar traits, these cells have markedly different abilities to produce Factor VIII,” Almeida-Porada said.
Notably, EPCs derived from umbilical cord tissue were found to produce the highest FVIII levels and result in the strongest blood-clotting activity following genetic modification. These cells far exceeded human hepatic sinusoidal endothelial cells (HHSECs), which are thought to be the body’s main producers of FVIII, in their ability of producing FVIII following genetic manipulation.
Consistent with previous findings, EPCs also were the greatest producers of vWF prior to any genetic modification. But, to the researchers’ surprise, their first place was taken by umbilical cord-derived MSCs after the introduction of the modified F8 gene.
Following genetic manipulation, MSCs from the umbilical cord also were able to provide comparable FVIII levels and clotting activity to those of HHSECs.
MSCs from the amniotic fluid performed better than those derived from the bone marrow, but still not as good as umbilical cord-derived cells, suggesting that prenatal cell-based approaches may not be as feasible as those given shortly after birth.
Combined with the fact the umbilical cord is “a discarded tissue, it is readily available, and its use has no ethical ramifications,” umbilical cord-derived EPCs and MSCs are “particularly attractive candidates for cellular delivery vehicles for FVIII, and likely other gene products as well,” the researchers wrote.
They also noted that since these cells had the highest natural levels of vWF, there may be a link between vWF generation and their ability to produce high levels of FVIII after genetic modification.
These findings highlighted “several promising candidates for use as cell-based FVIII delivery vehicles” and “pave the way for future studies to define the mechanistic basis for these differences [between cells] and develop means of harnessing the responsible pathways to drive high-level FVIII expression in other clinically valuable cell types,” the researchers wrote.
“The goal of this work is to be able to provide a long-lasting and curative treatment option for patients with hemophilia A by using their own cells,” said Anthony Atala, MD, one of the study’s authors and WFIRM’s director. “We look forward to seeing this work progress.”
The team is actively working on potential ways to improve the effectiveness of the genetic modification and subsequent FVIII production.
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