Research supports use of umbilical stem cells to treat hemophilia A

Using a baby’s own umbilical cells as a vehicle to deliver factor VIII (FVIII) – the missing or defective coagulation protein in hemophilia A – may be an effective, sustainable and more affordable therapeutic approach for this disease. blood, suggests a first study.

The results “lay the groundwork for future studies to better understand cellular and molecular factors and to exploit pathways to drive high-level expression of factor VIII in other clinically viable cell types”, Graça Almeida-Porada, MD, PhD, the lead author of the study, said in a press release. Almeida-Porada is a professor at the Wake Forest Institute for Regenerative Medicine (WFIRM), North Carolina, and head of the institute’s Fetal Therapy and Research Program.

The study, “Study of Optimal Autologous Cell Platforms for Prenatal or Perinatal Factor VIII Administration to Treat Hemophilia A, ”Was published in the journal Frontiers in Cellular and Developmental Biology.

The standard treatment for hemophilia A is FVIII replacement therapy, in which patients routinely receive, usually two to three times a week, intravenous infusions of the missing FVIII protein to prevent bleeding episodes.

Although these treatments have revolutionized the clinical management of the disease and increased the life expectancy of patients, they are expensive – they cost more than $ 250,000 per year per patient – and are still not available for around 75 % of patients worldwide.

In addition, they “cannot guarantee lifelong disease management,” the researchers wrote, as about a third of patients develop neutralizing antibodies against the delivered FVIII, reducing its effectiveness and, in the worst case, the disease. making it unnecessary.

“There is an urgent need for more effective, readily available and affordable treatments that offer long-lasting correction,” said Almeida-Porada.

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As such, the potential delivery of FVIII through genetic and / or cellular platforms has emerged as a promising approach to provide long-term correction of hemophilia A.

In addition, since approximately three-quarters of patients with hemophilia A have a family history of the disease and diagnosis can be made as early as seven weeks gestation, prenatal treatment may be possible.

Decades of research, as well as the results of more than 50 clinical cell transplants, have shown “the safety and vast potential of prenatal cell-based therapies”, supporting the use of cells to deliver FVIII and correct disease. before birth, said Almeida-Porada. .

Now, Almeida-Porada and his team have focused on studying the optimal cell type among a panel of cells readily available to function as a cellular vehicle to provide long-lasting FVIII replacement.

“We focused our investigation on the cell types that we found to be most relevant for very early prenatal or postnatal treatment and which could, ideally, come from the patients themselves,” added Almeida-Porada.

These included mesenchymal stem cells (MSCs) derived from amniotic fluid, umbilical cord and bone marrow, and umbilical cord endothelial progenitor cells (EPCs), all of which were cultured in the laboratory. MSCs are able to transform into many other types of cells, while EPCs can give rise to cells that line blood vessels.

EPCs may be ideal candidates, as they naturally produce von Willebrand factor (vWF), the carrier protein of FVIII that prolongs its activity and reduces its ability to trigger immune responses.

The researchers evaluated the ability of cells to be genetically modified to carry a version of the F8 gene, which provides instructions for making FVIII and subsequently producing an active form of clotting factor. The vWF levels were also assessed in each cell type.

The results showed that all cell types tested were viable candidates as FVIII releasing vehicles, but that they produced different levels of FVIII and vWF, depending on their tissue of origin.

“Despite their similar characteristics, these cells have very different abilities to produce factor VIII,” said Almeida-Porada.

Notably, EPCs derived from umbilical cord tissue have been shown to produce the highest levels of FVIII and result in the highest blood clotting activity after genetic modification. These cells far exceeded human hepatic sinusoidal endothelial cells (HHSEC), which are believed to be the body’s primary producers of FVIII, in their ability to produce FVIII after genetic manipulation.

Consistent with previous results, EPCs were also the largest producers of vWF before any genetic modification. But, to the surprise of the researchers, their first place was taken by MSCs derived from the umbilical cord after the introduction of the modification. F8 uncomfortable.

Following genetic manipulation, umbilical cord MSCs were also able to provide levels of FVIII and clotting activity comparable to those of HHSEC.

MSCs from amniotic fluid performed better than those derived from bone marrow, but still not as good as cells derived from the umbilical cord, suggesting that prenatal cell-based approaches may not be as feasible as those derived from the umbilical cord. given shortly after birth.

Combined with the fact that the umbilical cord is “a discarded tissue, it is readily available, and its use has no ethical ramifications,” Umbilical-derived EPCs and MSCs are “particularly attractive candidates for delivery vehicles. cell of FVIII and probably other genes. products too, ”the researchers wrote.

They also noted that since these cells had the highest natural levels of vWF, there might be a link between the generation of vWF and their ability to produce high levels of FVIII after genetic modification.

These results 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 ways to exploit the pathways responsible for driving high-level expression of FVIII in other clinically useful cell types, ”the researchers wrote.

“The goal of this work is to be able to provide a long-lasting and curative treatment option to patients with hemophilia A using their own cells,” said Anthony Atala, MD, one of the authors of the study and director of WFIRM. “We look forward to seeing this work progress. “

The team is actively working on potential ways to improve the efficiency of genetic modification and subsequent production of FVIII.

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