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EMBARGOED FOR RELEASE: Wednesday, March 1, at 5:00p.m., EST to coincide with publication in the March issue of Nature Genetics.
NEW HEMOPHILIA TREATMENT SHOWS PROMISE, STUDY CONTINUES
STANFORD --Researchers at Stanford University Medical Center and colleagues in Philadelphia have announced preliminary results for a gene therapy trial designed to test a new treatment for hemophilia B. In a paper published in the March issue of Nature Genetics the researchers proclaim that the first three patients treated showed no adverse effects and there were signs that the patients' condition improved as a result of the treatment.
According to Mark Kay, MD, PhD, associate professor of pediatrics and of genetics, director of Stanford's program in human gene therapy, and lead author of the study, patient safety is paramount in this study. "Once we determine the safety of this, we will look at a larger population of patients," said co-author Bertil Glader, MD, PhD, professor of pediatrics and chief of the division of pediatric hematology/oncology.
The adeno-associated virus (AAV), the vector used in this study, is different from the vector (adenovirus) associated with the death of a patient in a gene therapy trial at the University of Pennsylvania in September. Adenovirus is known to highly stimulate the immune system, but AAV does not have this property, which is why researchers like Kay believe it to be safe for human use.
Kay and his colleagues believe that gene therapy offers a promising way to treat hemophilia B -- a genetic disease in which insufficient amounts of the protein that makes blood clot, known as factor IX, leaves affected individuals at risk of spontaneous and life-threatening bleeds. Unlike many diseases where gene therapy must replace the total amount of a missing protein to modify the disease, patients with severe hemophilia will benefit tremendously if gene therapy can induce an amount of clotting factor merely one percent of that found in healthy people, Kay explained.
"At one percent clotting factor, it changes from severe disease to moderate, which really increases quality of life of the individual," said Kay.
According to Glader, physicians have learned that if the amount of factor in the blood is maintained at one percent of normal, or greater, at all times, most of the joint damage and life-threatening bleeding complications of the disease are prevented. The researchers hope that gene therapy will sustain production of factor IX at this level. In an ongoing study with hemophiliac dogs, one of Kay's colleagues, Timothy Nichols, MD, at the University of North Carolina, Chapel Hill, using the same gene therapy vector, achieved factor IX levels of greater than one percent that have been sustained for more than two years after treatment.
The current study is a phase I trial designed to test the safety of the gene therapy procedure in humans. Nine patients, in three groups of three, will receive a low, medium or high dose of the clotting factor gene. The protocol calls for patients to be treated no less than one month apart so each patient's reaction to the therapy can be carefully monitored before the next is treated.
So far, five people have undergone the gene therapy procedure. Two patients were treated at Stanford and three were treated by Kay's collaborators at the Children's Hospital of Philadelphia. Katherine High, MD, is the principal investigator of the Pennsylvanian team and is senior author of the study.
The Nature Genetics paper describes the results of the first three patients in the trial, each of whom received the lowest dose of treatment. The virus carrying the factor IX gene was injected into the thigh, marking the first time that AAV has been introduced into skeletal muscle. Eight to 12 weeks after the injections, the researchers saw evidence that the gene had been switched on and was making the factor IX protein. The researchers did not expect to see a clinical difference as a result, so were pleased to find that two patients showed an increase in the amount of clotting factor in their blood and they both had a reduction in the amount of external factor IX they had to use to treat bleeding episodes. The third patient had less severe disease and an improvement in his condition was not detected.
None of the patients had an adverse response to the treatment and they have not developed antibodies against the clotting factor protein, which is a concern for any new hemophilia treatment.
Approximately 80 percent of people with hemophilia are afflicted with hemophilia A, caused by insufficient clotting factor VIII, while the remainder have hemophilia B, caused by a deficiency in clotting factor IX. For technical reasons, primarily the large size of the factor VIII gene, Kay and his colleagues are currently focusing on hemophilia B, but hope to eventually expand their research to develop a therapy suited to the more common form of the disease. Current treatment for hemophilia involves regular infusion of clotting factor concentrates to prevent or treat bleeds.
Researchers at Avigen Inc, a biotechnology company in Alameda, Calif., also contributed to the study. Avigen, a company in which Kay and High hold equity, provided the factor IX gene-carrying AAV vector given to patients.
Funding was provided by grants from the National Institutes of Health, the Hoxie Harrison-Smith Foundation and Avigen.
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