A team of researchers at the National Cancer Institute (NCI), part of the National Institutes of Health, and their colleagues have reported successful treatment of a rare blood disease, using an animal model and a novel method of gene delivery. The researchers found that the method, which uses a virus called foamy virus as a gene delivery vehicle, might be safer and more efficient than alternative methods that have used other types of viruses. The findings appear online December 23, 2007 in Nature Medicine.

"These results indicate that foamy viruses represent a promising system for blood disorder therapy and suggest that these methods will be effective in treating a variety of human diseases, including cancer," said Dennis Hickstein, M.D., head of NCI's Molecular Oncology and Gene Transfer Section.

In most gene therapy studies, a delivery vehicle, or vector, is used to carry a beneficial gene to a cell so that it can be inserted in the cell's DNA and restore a function that has been lost because the cell's original version of the gene is defective. Viruses are ideal vectors because they have a protective shell that can encapsulate and deliver genes to cells. However, concerns exist with using some types of viruses as vectors, including the possibility that viral DNA might become inserted in the cell's DNA near an oncogene (a cancer-causing gene), thereby activating the oncogene and possibly causing cancer.

The NCI team, led by, Hickstein at NCI's Center for Cancer Research (CCR) and David Russell, M.D., Ph.D., University of Washington School of Medicine, Seattle, found that they could correct a disease called canine leukocyte adhesion deficiency using a foamy virus vector that contained a gene called CD18. By exposing canine bone marrow cells with abnormal CD18 genes to a foamy virus vector that contained a normal copy of the CD18 gene and then infusing the modified cells into dogs with the leukocyte adhesion deficiency, most of the animals showed no signs of the disease for two or more years after treatment. The study also showed that foamy virus vectors are less likely than other viral vectors to insert in or near oncogenes.

In their canine study, the researchers exposed bone marrow cells from five dogs with the leukocyte adhesion deficiency to CD18-containing foamy virus vectors. They found that, in four dogs, the number of leukocytes that expressed CD18 protein increased for 12 months and remained stable for two or more years. These cells had the ability to respond to infection, and the dogs remained healthy without the need for additional treatment.

Human leukocyte adhesion deficiency is a rare disease that affects only a few hundred Americans. "Instead of using a mouse model, we selected a canine model because it more closely mimics leukocyte adhesion deficiency in humans," said Hickstein. Leukocyte adhesion deficiency is caused by mutations in the CD18 gene in leukocytes, which are white blood cells that fight disease. The protein product of this gene, also called CD18, is defective or absent in the leukocytes of people with the disease. Children with the severe form of the disease have recurrent, life-threatening infections and typically die within the first few years of life. Those with a moderate form of the disease can survive into adulthood.

"In future studies, we hope to further improve the safety and the efficacy of the foamy virus vector," said Russell. "Although more testing is needed in the canine model, this study is an important step toward investigating foamy virus vectors in human clinical trials."

Hickstein added, "Our data suggest that foamy virus vectors may be a potential treatment method for blood disorders in humans and canines. Our findings also suggest that these vectors may be a better alternative to other virus vectors since they do not tend to turn on oncogenes."

Bauer TR, Allen JM, Hai M, Tuschong LM, Khan IF, Olson EM, Adler RL, Burkholder TH, Gu Y, Russell DW, and Hickstein DD. February 2008. Successful treatment of canine leukocyte adhesion. Nat. Med. Vol. 14, No.2.

Researchers are from NCI's Center for Cancer Research, Experimental Transplantation and Immunology Branch, Bethesda, Md.; Division of Hematology, Department of Medicine, and Department of Biochemistry, University of Washington, Seattle; and the Division of Veterinary Resources, Office of Research Services, National Institutes of Health, Bethesda, Md.

For more information on research in Dr. Hickstein's lab, please go to http://ccr.cancer.gov/staff/staff.asp?profileid=5825, and for research in Dr. Russell's lab, please go to http://depts.washington.edu/iscrm/research/hematopoietic.html.

For more information about cancer, please visit the NCI Web site at http://www.cancer.gov, or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

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