Mouse Model of Gene Therapy is Shown to be Effective Against Hemophilia A

By Danielle Bradshaw from In The Cloud Copy

The cells of hemophilia A patients were taken and genetically modified so that they would create an active clotting factor VIII (or FVIII) and implanted into mice with hemophilia. The result was that the mice’s blood levels of FVIII were replenished and the mice showed a great improvement in clotting. If the study’s results can be replicated inside of the human body, it could prove to be a viable form of gene therapy for treating hemophilia as well as for any other condition that requires similar treatment.

What is Hemophilia A?

Hemophilia is a disorder in which the blood is unable to clot in the case of injury, surgery, or dental procedure. In the case of hemophilia A, the blood disorder is genetically inherited, meaning it is passed down from person to person. The disease can range from mild to severe and in latter cases, heavy bleeding can occur even when there is no injury present –  in other words, spontaneous bleeding occurs.

Hemophilia A is typically diagnosed after either surgical procedures or serious injuries. It is caused by low levels of factor VIII which is needed for blood to clot. Hemophilia A is linked by a recessive X gene, and as a result, it is mostly found in men, although women can have the disorder too. In more serious cases, hemophilia A can result in bleeding inside of the joints, organs, or brain and it can lead to shortened life spans due to the medical complications that can arise as a result.

Why the Hemophilia Study Was Attempted

The way that blood clotting is supposed to work is that FVIII is supposed to cause coagulation with directions given by the F8 gene provided by specialized liver cells (endothelial cells) which can be found as a lining inside blood vessels.

Infusing the body with FVIII (or replacement therapy) is supposed to compensate for the inability of blood to clot by helping patient’s bodies produce more FVIII. It’s one of the common methods to treat hemophilia A, but the need for repeated injections many times per week throughout the patient’s lifetime causes constant discomfort, morbidity, and can generally interfere with a person’s everyday life. To combat this, researchers have turned to gene therapy.
Gene therapy is an approach that could replace dysfunctional FVIII genes via harmless viruses, but the gene is so large that it can’t be transmitted with the existing viruses. New, smaller versions of the gene have been used, but rather unsuccessfully.

Details of the Study

The lack of success caused the research team to try a different method of delivery. They decided to use the manufactured cells from patients themselves to synthesize endothelial cells that are capable of creating working FVIII. The researchers needed to collect urine from a group of seven participants and gather epithelial cells from their urinary tract lining. They needed to acquire epithelial cells specifically, because getting blood from hemophiliacs can be difficult. Gathering the cells from urine was a much easier and safer approach.

The team then transformed the gathered epithelial cells into induced pluripotent stem cells (iPSCs). These are stem cells that can be created from almost any kind of cell and made into any cell type after being reverted back to a stem cell. After that, they copied regular full-length FVIII genes, placed them into the iPSCs, and programmed them to make large amounts of what they named HA-FLF8-iECs – or modified endothelial cells.

To test their creation, they placed the new cells under the skin of mice with the disorder and used cells without the modified gene as control subjects. Seven days later, both modified and unmodified cells made blood vessel networks attached to the mice’s bloodstreams. Testing showed that the modified cells made more FVIII than the control group cells. The mice’s tails were then bled to test how much they bled and how well they coagulated. The HA-FLF8-iECs cell-infused mice were shown to have stopped bleeding quicker with much less bleeding overall.

The blood drawn from the treated mice showed that there was a boost in FVIII production six times greater than the control mice and the research team hopes that in the future, this treatment can replace the weekly injections that hemophiliacs currently require with this form of gene therapy.

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