Fibronectin "Glued" Retrovirus To Bone Marrow Cells To Improve Outcome For Cancer Patients
INDIANAPOLIS- An encouraging percentage of germ cell tumor patients treated with a new approach to gene therapy have shown good engraftment with manipulated cells, an Indiana University School of Medicine researcher reported June 12 at the annual meeting of the American Society of Gene Therapy in Washington, D.C.
Rafat Abonour, M.D., assistant professor and medical director of the Indiana University Stem Cell Laboratory, reported on the first human trial using fibronectin fragments, a genetically engineered human protein, to enhance the transport of a retrovirus into normal bone marrow cells of patients with advanced germ cell malignancies.
The human protein being used to bring together the retrovirus and the bone marrow cells is fibronectin, which was developed by researchers at the IU School of Medicine in collaboration with Takara Shuzo Co., Ltd, a biotechnology firm in Otsu, Shiga, Japan.
Dr. Abonour said that nearly 10 percent of the stem cells contained the gene more than one year after treatment. In previous studies not using fibronectin fragments, less than 1 percent of the stem cells contained the manipulated gene.
"It has been very difficult for researchers to put any gene in bone marrow and detect those cells in the bone marrow several months later," said Dr. Abonour, principal investigator of the trial. "What this study proved is that the technique using fibronectin fragments may have contributed to the encouraging results of this trial."
Twelve patients with advanced germ cell tumors were enrolled in the Phase I trial and 11 received the genetically manipulated cells. Of those, eight are free of disease more than one year after treatment, Dr. Abonour reported. The other three patients were unable to complete the therapy due to the rapid progression of disease.
The patients enrolled in the trial had refractory or relapsed germ cell tumor. They were first treated with high dose chemotherapy and bone marrow transplants. In the past, about half the germ cell tumor patients whose disease returned have been cured by additional chemotherapy. Typically, bone marrow transplant patients who have relapsed are unable to receive the additional chemotherapy because repeated exposure to these toxic agents destroys their bone marrow cells. The result has been a dangerous delay in treatment or reduction of the dose of these drugs.
In this study, IU researchers attempted to develop a way to make these patients tolerate additional, intense treatment. By introducing a gene called MDR-1 into the bone marrow cells researchers hoped to shield normal cells from further chemotherapy, thus enabling patients to receive the additional chemotherapy needed to eradicate residual disease and prevent return of cancer following bone marrow transplantation.
"MDR-1 works as a pump," explained Dr. Abonour. "Every time the chemotherapy goes into the normal bone marrow cells, the MDR-1 will pump it out. That will prevent the death of the cells."
The fibronectin fragments are crucial to the process because they enhance the delivery of useful genes into bone marrow cells.
"The fibronectin fragments apparently act as the glue that allows the retrovirus to bind to the therapeutic cells," said Dr. Abonour. "They enhance the transfer of the retrovirus containing MDR-1 into bone marrow cells of cancer patients."
Bone marrow cells are essential for producing white blood cells to fight infection, red blood cells to carry oxygen and platelets to prevent bleeding. Maintaining an adequate number of these cells allows patients to receive chemotherapy without dangerous side effects such as infection or bleeding.
Contact: Mary Hardin
mhardin@iupui.edu
317.274.7722
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