Gene Therapy Could One Day Cure Hemophilia A Patients

A discovery by Medical College of Wisconsin and BloodCenter of Wisconsin researchers in Milwaukee could be a key to a permanent genetic cure for hemophilia A patients, including a subset who do not respond to conventional blood transfusions. The study of genetically altered hemophilia mice has been published in The Journal of Clinical Investigation.

Hemophilia A affects about one in 5,000 males who lack a hereditary blood clotting protein called Factor VIII (FVIII). Traditional treatment requires infusion of synthetic FVIII two to three times a week to control bleeding episodes. However, about 30% of these patients develop antibodies to FVIII, inactivating its clotting properties. Treatment for adults who have these inhibitory antibodies can cost over $1 million annually if there is a major bleeding episode.

"We developed a Trojan horse approach, cloaking FVIII in a platelet so that it is undetected by the antibodies and its clotting properties are preserved until the platelet sticks to a damaged blood vessel and releases its stored protein, which now includes FVIII," explains Robert R. Montgomery, MD, senior investigator at the BloodCenter of Wisconsin and Professor of Pediatric Hematology at the Medical College. Dr. Montgomery practices at the Children's Hospital of Wisconsin Hematology/Oncology Clinic and he is also affiliated with the Children's Research Institute.

"This is truly a landmark development for hemophilia A patients," says hematologist Joan Gill, MD, Professor of Pediatric Hematology/Oncology at the Medical College and Director of the Comprehensive Center for Bleeding Disorders at the BloodCenter. Dr. Gill practices at the Children's Hospital of Wisconsin Hematology/Oncology Clinic. "We look forward to the day when basic research is completed and clinical trials can begin in patients," she notes.

In Some, Clotting Factor Becomes the Enemy
Normally in an injury, platelets circulating in plasma - the liquid portion of the blood - stick to the site of the blood vessel wound, rapidly stopping bleeding. In hemophilia patients, infusion of FVIII replaces the missing clotting factor to stop the bleeding. However, in about 30% of patients, FVIII is mistakenly seen by the body as a foreign protein and antibodies are sent to destroy it, making the FVIII treatment useless.

Newer FVIII treatment products that bypass this attack can cost $10,000 to $100,000 per treatment episode and costs for a patient can exceed $1 million annually. So far, attempts at gene therapy for a permanent cure have not been successful.

According to the lead author of the study, Qizhen Shi, MD, PhD, an American Heart Association supported postdoctoral fellow, "Our team of scientists has developed an approach in mice that not only could make gene therapy successful for patients with hemophilia who don't have antibodies, but more importantly can be used to treat patients with antibodies.

Hiding FVIII Until Needed
"To get around the antibody attack on FVIII which occurs readily in plasma, we inserted a gene into a blood stem cell so that FVIII is produced and stored in blood platelets, hidden from view and attack, ready to release when a blood vessel is damaged, quickly enabling normal clotting before the antibodies can begin their attack. Our approach was very effective even in mice treated with five to ten thousand times the amount of antibody that would normally prevent treatment of a hemophilia patient with FVIII."

The new method will next be tested in larger animal models before clinical trials can begin in patients. Blood and bone marrow stem cells would be harvested from hemophilia patients in much the same way they are collected from bone marrow donors. The FVIII gene would be introduced into the stem cells, which are then be given back to the donor patient to release the lifesaving FVIII when bleeding occurs

"This process would last for the rest of the patient's life and will work regardless of whether antibodies are present or absent," says Dr. Montgomery. "There will be many more studies needed to apply this approach in patients but this treatment could normalize bleeding for patients with hemophilia.

"What is most exciting about this first design of gene therapy for hemophilia is that it works not only for routine hemophilia but also for the 30% of patients who have developed inhibitory antibodies that make normal replacement treatment impossible," Dr. Montgomery concludes.

The study is funded by the National Institutes of Health. Other researchers include David A. Wilcox, PhD, Associate Professor of Pediatrics; Hartmut Weiler, PhD, Assistant Professor of Physiology; Clive W. Wells, electron microscopy specialist; Brian C. Cooley, PhD, Associate Professor of Orthopaedic Surgery; and Jack Gorski, PhD, senior investigator at the Blood Research Institute.

MCW Health News presents up-to-date information on patient care and medical research by the physicians of the Medical College of Wisconsin.