Promising autologous cell candidates identified

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

This study examines the use of cells derived from amniotic fluid, neonatal and adult, and is the first in-depth analysis of any of these cell types for their use to deliver factor VIII protein. The research team also performed the first detailed examination of the production levels of factor VIII and its carrier protein, vWF, inside each of these cell types. The challenge for the researchers was to identify cells capable of creating a fully functional factor VIII, which is a large and complex protein.

“We focused our investigation on the cell types that we found most relevant for very early prenatal or postnatal treatment and which could, ideally, come from the patients themselves,” said lead author Graça Almeida-Porada , MD, PhD, professor at WFIRM. “There is an urgent need for more effective, readily available and affordable treatments that offer lasting correction. “

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

Hemophilia A is a genetic disease caused by a deficiency or absence of coagulation factor VIII, a protein essential for blood clotting. Hemophilia A is an X-linked genetic disease, and therefore almost always affects men, and occurs in 1 in 5,000 live male births. About 20,000 people in the United States have hemophilia A, and it is estimated that more than 400,000 people worldwide have this devastating disease, according to []. Although there are several new products available to treat people with hemophilia A, the majority of people are treated with expensive factor VIII infusions 2-3 times per week for their entire lives.

While these treatments have dramatically improved the life expectancy of people with hemophilia A, they are not available to nearly 75% of patients worldwide, costing well over $ 250,000 per year (per patient). and complications can drive the price up to over $ 1. million. In addition, up to 30% of patients with severe hemophilia A develop an immune response (inhibitors) to the infused factor VIII protein, rendering subsequent treatments ineffective and putting the patient at risk of bleeding, putting the patient at risk of bleeding. his life in danger. Additionally, and perhaps most importantly, these treatments are not curative.

The administration of factor VIII through gene and / or cell 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 a key step. current research objective for the Porada laboratories of the WFIRM. . Almeida-Porada leads the WFIRM Fetal Research and Therapy Program [] who 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 host such a research program.

About 75% of people with hemophilia A have a family history and the diagnosis can be made as early as seven weeks gestation. Almeida-Porada said decades of research and data from more than 50 clinical transplants collectively demonstrate “the safety and vast potential of prenatal cell-based therapies.” Using cells as vehicles to transport factor VIII protein is a potentially safe and clinically acceptable approach to correct the disease before birth, she added.

The team compared mesenchymal stromal cells from amniotic fluid, umbilical cord, and bone marrow. While all of the cell types studied were found to be viable candidates for use as cell carriers, 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 human F8 transgene deleted from the B domain, produce the highest levels of factor VIII mRNA and blood clotting activity. These cells far exceeded those of HHSEC, which are cells considered to be the body’s primary site for factor VIII synthesis.

“Our results show that, despite their similar characteristics, these cells have very different abilities to produce factor VIII. As such, these data lay the groundwork for future studies to better understand cellular and molecular factors and to exploit the pathways to lead to a high level of 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 article, said this continued research in cell therapy shows promise. “The goal of this work is to be able to provide a durable and curative treatment option for patients with hemophilia A 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 co-lead author Christopher D. Porada. The authors have no conflicts of interest to report. This work was supported by NIH, NHLBI Grants: HL130856, HL135853, HL148681.

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