Gene Therapy Promising For Growing Tooth-supporting Bone

In a patient with a sizeable mouth wound, replacing a tooth takes more than simply implanting a new one---the patient also needs the bone structure to anchor the new tooth in place. Such reconstructive surgery today involves either taking a bone graft from the patient's chin or jaw, which leaves a second wound needing to heal, or using donated bone from a tissue bank, which yields unpredictable results.

William Giannobile, professor of periodontics, prevention and geriatrics, led a team at the U-M School of Dentistry that delivered the gene encoding for bone morphogenetic protein-7 (BMP-7) to large bone defects in rats in an attempt to turn on the body's own bone growth mechanisms. The study showed that animals that got the BMP-7 treatment produced nearly 50 percent more supporting bone around dental implants than those receiving the conventional treatment.

"This study represents a proof-of-concept investigation. We are encouraged about the promise of this treatment," said Giannobile, also an associate professor of biomedical engineering and director of the Michigan Center for Oral Health Research.

More work will need to be done before the approach can be tested in humans, Giannobile added. He said he optimistically would like to see initial trials begin in humans in four to seven years.

BMP-7 is part of a family of proteins that regulates cartilage and bone formation. Recent studies have shown that BMPs are present in tooth development and periodontal repair.

This study mixed BMP-7 genes with an inactivated virus in a gel-like carrier and injected it into wounds. Giannobile said using a virus, with the harmful effects turned off, harnesses the virus' ability to enter into cells and use their genetic machinery.

Once inside the cell, the viruses help BMP-7 genes get where they need to be in the host's cells to boost bone production. Gene expression producing BMP-7 proteins peaked after a week. Giannobile said that was ideal because the team did not want to make any permanent genetic changes. The gene acted quickly to get bone growth started, then disappeared within about 28 days.

Giannobile said a next step in this process could include looking for non-viral approaches to delivering gene therapy to the defect site. Alternatively, scientists could conduct the gene therapy outside the body using a tissue biopsy and then transplant the genetically-modified cells back into the patient, but this would require two surgical procedures instead of one.

The Molecular Therapy paper is titled "BMP Gene Delivery for Alveolar Bone Engineering at Dental Implant Defects," and the work was supported by the National Institutes of Health and National Institute of Dental and Craniofacial Research.

Giannobile is part of a cross-campus program called Tissue Engineering at Michigan, funded in part by the National Institute for Dental and Craniofacial Research. TEAM aims to provide an interdisciplinary, research-intensive environment for those pursuing careers in the oral sciences, with a focus in the area of restoration of oral-craniofacial tissues.

Co-authors on the paper include Courtney A. Dunn, adjunct clinical lecturer in orthodontics; Qiming Jin, research associate in periodontics, prevention and geriatrics; Mario Taba Jr., research fellow in periodontics, prevention and geriatrics; Renny T. Franceschi, associate dean for research and professor of periodontics, prevention and geriatrics, all at the U-M School of Dentistry. Francesci also is a professor of biological chemistry. R. Bruce Rutherford, a former U-M Dentistry professor who now serves as chief scientific officer of private tissue engineering firm Ivoclar Vivadent-Dentigenix, was a co-author, as well.

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For her work on this project, Dunn was recently selected to receive the 2005 Milo Hellman Research Essay Award from the American Association of Orthodontists. This award is given for the most outstanding resident and / or doctorate research done in orthodontics. Dunn performed her research with mentorship from Giannobile.

More about Giannobile: http://ipumich.temppublish.com/public/experts/ExpDisplay.php?ExpID=286

Tissue Engineering at Michigan: http://www.dent.umich.edu/team/overview.html

The journal Molecular Therapy: http://authors.elsevier.com/JournalDetail.html?PubID=622922&Precis=DESC