Gene Therapy and Hemophilia A

Doctors have long known how to manage hemophilia, the bleeding disorder that can make a bump on the knee the cause for a hospital visit. Researchers at the Aflac Cancer and Blood Disorders Center of Children’s Healthcare of Atlanta are confident they know how to cure the disease.

“We’ve cured mice 10 different ways,” says Trent Spencer, Ph.D., director of the Gene Therapy Laboratory at the Aflac Cancer Center and Assistant Professor of Pediatrics with Emory University School of Medicine.

“We can cure a mouse of hemophilia with our eyes closed. Getting from a mouse to a human, however, is a massive step and that is what we’re trying to do now.”

Hemophilia A, the most common severe hereditary bleeding disorder, affects roughly 1 in 7,500 males and is caused by a mutation in the gene that produces a protein called Factor VIII. In most cases, there is a family history of hemophilia. However, about 30 percent of the cases are due to a spontaneous mutation of the Factor VIII gene that prevents production of the critical protein and there is no family history. [Spontaneous mutations producing hemophilia A still are genetic]

“This protein is involved in a cascade of mechanisms that lead to clotting of the blood,” says Spencer.

The lack of Factor VIII means someone with hemophilia will bleed longer than is typical. People with severe hemophilia—about 60 percent of those with the disease—may have frequent spontaneous bleeding episodes, usually into the joints or muscles, as a result of trauma so mild that it is not noticed until pain and swelling from bleeding develops several hours later. Repeated bleeding into the joint can cause arthritis and permanent damage over time. Patients with hemophilia may require surgery at an early age to replace their damaged joints with artificial joints.

“Without treatment, most patients don’t survive to reproductive age,” says John S. (Pete) Lollar III, M.D., director of Hemostasis Research for the Aflac Cancer Center of Children’s and chair of Hemophilia of Georgia Inc.

And most patients don’t get treatment.

“It’s recognized that, worldwide, only 30 percent of the hemophiliac population is treated,” says Spencer.

The barrier to treatment is cost. While hemophilia can be managed with either regular injections of recombinant (genetically engineered) Factor VIII or Factor VIII obtained from blood donors, it is a costly regimen with a tab of up to $200,000 a year. As an alternative to repeated jabs with a needle, the patient often is fitted with an injection port and infection is a common complication.

The alternative being developed by Spencer and his team is to plant Factor VIII genes into the bone marrow of patients. And how do they do that?

“What we’ve done is genetically engineered the HIV (human immunodeficiency virus) to transfer the Factor VIII gene,” says Spencer.

In a strange twist, researchers have found HIV is an effective tool in gene therapy. HIV has evolved to deliver their genetic payload into other cells, Spencer explains. Genetically engineered HIV that is wiped clean of disease-causing material has proven effective in transferring disease-curing genetic material.

“We’re building on what others have done,” Spencer says. “So the only thing that is going to be transferred is the Factor VIII gene.”

The gene being transferred has been genetically engineered, as well. Just select bits of ribonucleic acid (RNA) are inserted in the HIV. Think of it as transferring a few key computer files instead of dumping the whole hard drive. Early studies, however, found that the new gene produced low levels of Factor VIII.

“It’s a show stopper if you can’t make enough protein,” says Spencer.

It turns out pork is an excellent source of protein.  Porcine factor VIII, which is found in pig blood, is similar enough to its human counterpart that it is sometimes used to control bleeding episodes suffered by hemophiliac patients. Additionally, recombinant porcine factor VIII is produced in much greater amounts—10 times or more—of the essential protein.

So the Atlanta-based researchers have developed a hybrid Factor VIII gene that is 90 percent human genetic material and 10 percent porcine genetic material. One of the biggest hurdles facing Spencer and his team is finding financing for clinical trials. It seems there is more money to be made in managing a disease than there is in curing it. Annual sales of Factor VIII are approximately $3.5 to $4 billion.

“We’re going to take a multi-billion dollar industry and make it a multi-million dollar industry,” jokes Lollar.

The treatment being developed by Spencer and his team could be done in a day as an outpatient procedure.

“After a successful bone marrow transplant, you’ve created a Factor VIII producing factory in your bone marrow and in your blood,” Spencer says. It is possible that the cells making Factor VIII could continue to do so for the lifetime of the patient—many decades in the case of a young boy with hemophilia.