Scientists supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases have made an important step toward using gene therapy to treat severe cases of osteogenesis imperfecta (OI), a genetic disease in which bone is fragile and highly vulnerable to fracture. Severe cases of the disease can lead to serious bone malformation and even death.

David Russell, M.D., Ph.D., associate professor of medicine at University of Washington in Seattle and his colleagues developed methods for targeting viral insertions (harmless viruses specially modified to infect a cell and inactivate a gene) to the gene that produces type I collagen. Type I collagen is a protein that forms a network of fibers in bone and provides much of its strength. The vast majority of cases of osteogenesis imperfecta are due to mutations in the gene that produces the protein.

Everyone has two copies of the gene - one from their mother, one from their father - so mutations that merely inactivate one copy of the gene (and don't affect the other) produce mild cases. But when mutations result in an abnormal version of collagen, abnormal collagen molecules interact with normal collagens, disrupting the fiber network and drastically reducing the strength of bone. The scientists reasoned that by turning off the affected genes in these more severe cases, they could transform them into milder cases.

They tested their theory by targeting bone-forming cells where they begin - in the bone marrow. Because the cells that form bone arise from precursor cells in the bone marrow, they believed it would be possible to remove those cells, inactivate them with a specially modified virus in the laboratory, and then return them to the body. The greatest challenge in that process was to target the viruses to the specific genes that they wanted to inactivate without affecting normal genes with other functions. It was a challenge they were able to meet, for the most part.

Using bone marrow cells from OI patients with severe forms of the disease, the scientists were able to correctly target the collagen gene with the modified virus in 90 percent of the cells into which the viruses were inserted. Just as important, cells in which the mutant collagen gene was inactivated were shown to produce normal collagen and retain the ability to develop into mature bone-forming cells.

Although gene therapy is likely to remain experimental for some time, advances like this bring scientists significantly closer to being able to repair genetic errors, not just for OI, but for many other diseases that are due to the activity of abnormal genes. This may enable those born with genetic errors to escape lifelong and often devastating consequences.

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Chamberlain JR, et al. Gene targeting in stem cells from individuals with osteogenesis imperfecta. Science 2004;303(5661):1198-1201.

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