Today's News

Saturday, March 3, 2001

Gene therapy may be useful for treating fractures

By Laird Harrison

Genetically altered cells may fix bones that can't be helped even with new growth factor drugs, University of California, Los Angeles Professor Jay R. Lieberman, MD, told participants in a Wednesday afternoon instructional course on gene therapy.

"We're in the midst of an orthopaedic revolution," he said. "The 19th century was the age of amputation. The 20th century was the age of reconstruction. The 21st Century will hopefully be the age of regeneration."

At least one growth factor drug is approved for use in Europe and Australia and is in the final approval stages in the United States. For some types of fracture such a drug may be the best therapy. But in cases where a lot of bone is missing, said Dr. Lieberman, "will a single exposure to an exogenous factor be enough? In many cases, no. Gene therapy is much more powerful, once you figure out how to use it."

Already, Dr. Lieberman and three other panelists said, they have genetically modified cells to grow bone in rodents, rabbits, dogs and sheep. "We believe gene therapy can easily be adapted for human use," said Dr. Liberman.

The panelists said they are genetically programming cells to make bone and cartilage over a long period of time taking a variety of approaches.

Genes can be delivered to cells through a variety of vectors, said moderator Freddie H. Fu, MD, of the University of Pittsburgh. The adenovirus and adeno-associated viruses are the most efficient, but hardest to control.

In theory the genes in the virus can be modified so that infected cells do not reproduce the virus. However, the virus still poses a risk of affecting the patient's immune system. Cancer researchers are continuing to use the adenovirus in human experiments despite the well-publicized death of a patient infected with adenovirus, but orthopaedists are particularly hesitant because bone fractures are not usually life-threatening.

DNA and gene guns pose less risk as vectors but are much less efficient. Ligands require making the cell walls permeable.

Researchers have also differed in the cells they chose as the target for the gene therapy. Dr. Lieberman argued for the use of bone marrow cells because they already have BMP-2 receptors.

University of Pittsburgh Professor Johnny Huard, PhD, on the other hand, said he had been able to isolate a type of stem cell from muscles and genetically modify them to make bone. These muscle stem cells offer the advantage that they are much more readily available than bone marrow cells.

"We were able to improve bone healing in a critical size defect in scid mice," Huard said. "Ninety-five percent of the injected cells were incorporated into the bone." In another experiment, he said, his team injected human cells transduced with rhBMP-2. "We found human bone forming in mouse skeletal muscle," he said.

For an experiment in regenerating cartilage, University of California, San Diego Professor David Amiel, PhD, transduced chondrocytes from rib perichondrium with TGFbeta-1. His team used a detergent to make the cell membrane permeable and a ligand to transfect the cells. They were able to find expression of the gene in the transfected cells.

In addition to chondrocytes and stem cells, blood cells and even adipocytes-which could be harvested through liposuction-may also prove adaptable for bone growth, Dr. Lieberman said.

Dr. Fu suggested fetal cord cells as yet another possibility: "In the future I think we will be able to harness enough fetal cells from our own offspring to use for our family," he said.

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Last modified 03/March/2001 by IS