Promising autologous cell candidates identified as potential delivery vehicles for Hemophilia A treatment

While people with severe Hemophilia A can be treated with Factor VIII replacement products two to three times a week throughout their lifetime, this treatment is short-lived, expensive, and not always available. Wake Forest Institute for Regenerative Medicine (WFIRM) researchers are investigating the possibility of using a patient’s own cells as vehicles to deliver long-lasting Factor VIII protein to treat their disease.

This study investigates the use of amniotic fluid-derived, neonatal, and adult cells, and is the first in-depth analysis of any of these cell types for their use to deliver the Factor VIII protein. The research team also conducted the first detailed look at the levels of production of Factor VIII and its carrier protein, vWF, inside each of these cell types. The challenge for the researchers was to identify cells with the capability to create fully functional Factor VIII, which is a large and complex protein.

“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,” said senior author Graça Almeida-Porada, MD, PhD, a professor at WFIRM. “There is an urgent need for more effective, readily available and affordable treatments that provide long-lasting correction.”

This study was recently published in the journal Frontiers in Cell and Developmental Biology.

Hemophilia A is a genetic disorder caused by a deficiency in, or the absence of, coagulation Factor VIII, an essential protein for blood to clot. Hemophilia A is an x-linked genetic disease, and thus almost always affects males, and it occurs in 1 in 5,000 live male births. Roughly 20,000 individuals in the United States suffer from hemophilia A, and it is estimated that more than 400,000 people worldwide have this devastating disease, according to www.hemophilia.org [wfirm.us3.list-manage.com]. Although there are several new products available to treat persons with Hemophilia A, still, the majority of people are treated with infusions of expensive Factor VIII products 2-3 times per week for their entire life.

While these treatments have dramatically improved the life expectancy of people with hemophilia A, they are unavailable to nearly 75% of the world’s patients, they cost well over $250,000 a year (per patient), and complications can send the price tag to more than $1 million. Moreover, as many as 30% of patients with the severe form of hemophilia A develop an immune response (inhibitors) to the infused Factor VIII protein, rendering subsequent treatments ineffective and placing the patient at risk of life-threatening bleeding events. In addition, and perhaps most important, these treatments are not curative.

The delivery of Factor VIII through gene and/or cellular platforms has, therefore, emerged as a promising approach to provide long-term correction of hemophilia A. Finding better treatments and potential cures for hemophilia is an ongoing research focus for the Porada labs at WFIRM. Almeida-Porada leads the WFIRM Fetal Research and Therapy Program [wfirm.us3.list-manage.com] which pursues basic and translational research to develop optimal prenatal treatment approaches for genetic disorders and other life-threatening conditions. WFIRM is the only institute or center in North Carolina to currently house such a research program.

Approximately 75% of people affected by Hemophilia A have a family history, and diagnosis can occur as early as seven gestational weeks. Almeida-Porada said that decades of research and data from more than 50 clinical transplants collectively demonstrate the “safety and vast potential of cell-based prenatal therapies.” Using cells as vehicles to carry the Factor VIII protein is a potentially safe and clinically acceptable approach to correct the disease prenatally, she added.

The team compared mesenchymal stromal cells from amniotic fluid, umbilical cord, and bone marrow. While all the cell types investigated were found to be viable candidates for use as cellular vehicles, there were marked differences in the levels of Factor VIII produced by similar cell types isolated from different tissues. They found that cells derived from umbilical cord tissue, after transduction with a vector encoding a B domain-deleted human F8 transgene, yield the highest levels of Factor VIII mRNA, and blood clotting activity. These cells far exceeded that of HHSEC, which are cells thought to be the body’s primary site of Factor VIII synthesis.

"Our results show that, despite their similar traits, these cells have markedly different abilities to produce Factor VIII. As such, these data 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,” said Almeida-Porada.

WFIRM Director Anthony Atala, MD, who is also a co-author of the paper, said this continued cell therapy research is promising. “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. We look forward to seeing this work progress.”

Co-authors include: Christopher Stem, Christopher Rodman, Ritu M. Ramamurthy, Sunil George, Diane Meares, Andrew Farland, Christopher B. Doering, H. Trent Spencer, and senior co-author Christopher D. Porada. The authors have no conflicts of interest to report. This work was supported by NIH, NHLBI grants: HL130856, HL135853, HL148681.