Hemophilia A

SAN FRANCISCO -- Results of separate phase I trials using gene therapy offered hope in the treatment of hemophilia A and severe combined immunodeficiency disease, investigators reported at the annual meeting of the American Society of Hematology

In the first trial, investigators inserted a gamma common chain ([gamma]c) transgene into CD34 cells that were harvested from five infants with severe combined immunodeficiency-X1 (SCID-X1) disease. People with SCID-X1 lack mature T lymphocytes and natural killer lymphocytes because they have a cyrokine receptor deficiency due to the lack of a yc gene. The modified CD34 cells were then infused back into the patients.

The gene therapy seems to have corrected the immune deficiency in four out of five infants, three of whom have been followed for more than 1 year, reported Dr. Marina Cavazzana-Calvo, professor of hematology at the University of Paris.

The four infants no longer need intravenous immunoglobulin infusions, are free of infections, and seem to respond normally to immunizations. The gene therapy generated lymphocytes that gradually increased to normal levels within 4-6 months of treatment.

The one patient whose SCID-X1 did not resolve developed a disseminated infection as well as massive splenomegaly. The genetically modified CD34 cells probably got trapped in his spleen, Dr. Cavazzana-Calvo speculated.

The second clinical trial used a nonviral approach to gene therapy in six men (aged 20-72 years) who had hemophilia A, which is the most common form of hemophilia. Two patients had HIV infection without AIDS, and all had hepatitis B or hepatitis C infection with stable liver function.

A gene was inserted into cells harvested from an excisional skin biopsy, and the cells were cloned. Autologous fibroblasts expressing the B-domain deleted human factor VIII were then laparoscopically implanted back into the patient's belly fat under general anesthesia. The first three patients received 100 million cells; the next three received 400 million.

The treatment appeared safe after 12-18 months of follow-up with no long-term complications and only tninor adverse events related to the infusion such as mild local postoperative pain, Dr; David A. Roth reported in a separate presentation.

Factor VIII activity levels increased in three patients above baseline, up to 4% of normal in one patient and up to 1%-2% of normal in two patients. The clinical severity of hemophilia A corresponds with factor VIII activity levels, with severe disease found in patients with less than 1% of normal factor VIII activity and moderate severity in those with 1%-5% of normal factor VIII activity levels.

One patient stopped having episodes of spontaneous bleeding after the treatment, although injury-related bleeding still occurred, said Dr. Roth, director of hemophilia clinical research at Beth Israel Deaconess Medical Center, Boston.

COPYRIGHT 2001 International Medical News Group
COPYRIGHT 2001 Gale Group