Each year, an estimated 1 in 10,000 babies are born with osteogenesis imperfecta (OI), a genetic disease that leads to weak, brittle bones. For many of them, the disease brings chronic bone pain and frequent fractures. For some, fractures are so frequent and sometimes severe that bone malformations can occur.
The most common cause of OI is a defect in a gene that controls production of a protein called type 1 collagen, which forms fibers crucial to building strong bones. In most cases, people with OI simply don't make enough of the protein, but in more severe cases some of the collagen they do produce is defective. The defective protein then interacts with other proteins in the cells and in tissues, magnifying the harmful effect of the collagen defect.
While drugs that slow bone breakdown have recently shown some benefit for the disease, the true challenge of treating the OI - and perhaps ultimately curing it - is to find a way to reduce or eliminate the production of the defective protein without affecting the production of normal collagen in the same cells. Scientists supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) have recently made an important advance in achieving this goal by finding a way to cut off communication between the defective gene and collagen-producing cells.
There are various stages in the transfer of information from the level of the gene to the level of protein production. A key mediator in the information transfer process is a molecule called a transcript or "messenger," which is a type of ribonucleic acid (RNA). RNAs most often serve as carriers of genetic information, says study author Richard Wenstrup, M.D., professor of pediatrics and director of the Molecular Genetics Laboratory and Skeletal Dysplasia Clinic at the Cincinnati Children's Hospital Medical Center. However, about 20 years ago, it was discovered that some RNAs called ribozymes act as molecular scissors, cutting the chemical links that hold other RNAs together. Importantly, ribozymes act only at very precisely defined target sites in the RNAs that they cut, and it is possible to design new ribozymes that will cut at desired target sites. Because cutting a messenger RNA, even at just one point along its length, usually blocks further transfer of genetic information, this suggests a novel approach to blocking the effects of the defective collagen genes that cause severe OI.
Dr. Wenstrup and his colleagues have produced an innovative ribozyme design that features many copies of a single ribozyme; this multiple ribozyme may cleave itself into single ribozyme units by using the same cutting mechanism that it employs on mutant collagen RNA. They tested this multiple ribozyme by introducing it into cultured bone cells that had been genetically modified to produce a defective collagen in addition to normal collagen, as happens in OI. The ribozyme significantly reduces production of the defective collagen. Importantly, the properties of the collagen fibers produced by the cells, which were clearly abnormal when the ribozyme was not present, were more nearly normal when the ribozyme was present. "This demonstrates that the ribozyme has the desired specificity, blocking production of the defective collagen, but allowing continued production of normal collagen," says Dr. Wenstrup.
The findings thus far have been limited to cultured cells and mice; much work remains to be done before ribozymes can be tested in people. But the success in targeting collagen production in bone clearly shows that the ribozyme approach has significant potential for treating not only osteogenesis imperfecta but many other genetic conditions involving aberrant proteins.
The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a part of the Department of Health and Human Services' National Institutes of Health, is to support research into the causes, treatment and prevention of arthritis and musculoskeletal and skin diseases; the training of basic and clinical scientists to carry out this research; and the dissemination of information on research progress in these diseases. For more information about NIAMS, call the information clearinghouse at (301) 495-4484 or (877) 22-NIAMS (free call) or visit the NIAMS Web site at http://www.niams.nih.gov. Information on osteogenesis imperfecta and other bone disorders is available from the NIH Osteoporosis and Related Bone Diseases~National Resource Center; phone toll-free 800-624-BONE (2663), or visit https://bones.nih.gov/health-info/bone/osteogenesis-imperfecta.
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Peace BE, et al. Endogenously expressed multimeric self-cleaving hammerhead ribozymes ablate mutant collagen in cellulo. Mol. Ther. 2005;12:128-136.