Gene Therapy Technique May Allow Researchers to Suppress Abnormal Protein in Bone Disorder

Researchers at the National Institute of Child Health and Human Development (NICHD) have taken the first preliminary steps for gene therapy of osteogenesis imperfecta (OI), a diverse group of disorders caused by various defects in type I collagen, a major component of bone. The therapy, different from other such attempts in that it seeks to prevent an abnormal protein from being made, has so far been successful in laboratory cultures of skin cells known as fibroblasts, taken from patients with the disorder.

The technique, described in a presentation before the Annual Meeting of the Pediatric Academic Societies (the American Pediatric Society, the Society for Pediatric Research, and the Ambulatory Pediatric Association) in New Orleans on Saturday, May 2, was presented by Paul Dawson, PhD, a postdoctoral fellow in NICHD's Heritable Disorders Branch.

Briefly, OI takes a number of forms, depending on the particular collagen mutation involved, and may range from severe deformity and multiple bone fractures beginning at birth to an absence of deformity and relatively infrequent fracturing. For the most part, the disease results from only one copy of the abnormal gene for type I collagen. Thus, if production of the abnormal protein could be halted, patients with OI who have the severe form of the disease would still have one normally functioning gene and would experience only a mild form of the disease.

The study's authors explained that other gene therapy attempts have sought, with varying degrees of success, to insert functional genes into cells in an attempt to induce cells to make a protein that had previously been lacking. In contrast, the NICHD research effort has aimed to prevent an abnormal protein from being made, in this case, the abnormal type I collagen. To accomplish this end, the researchers made use of molecules known as ribozymes. Ribozymes prevent proteins from being made by breaking apart the molecule of RNA (ribonucleic acid) used to manufacture a particular protein.

The researchers attempted to incorporate a gene that would instruct the cell to manufacture the ribozyme into skin cells from patients with OI. They found that the cells which had incorporated the genes showed a 50 percent reduction in mutant type I collagen RNA levels.

Dr. Dawson stressed that various technical problems would need to be overcome before the technique could be used to treat people with OI. First, researchers would need to find a way to deliver the DNA that encodes the ribozyme into the cells of patients with OI.

Dr. Dawson explained that it may be possible to introduce the ribozymes into OI patients via stem cells--cells in bone marrow which manufacture bone. Theoretically, the stem cells could be removed from a patient and the DNA encoding the ribozymes could be added to these cells. The cells could then be induced to multiply in laboratory cultures, and when large numbers had been produced, introduced back into the patient.

As a first step in perfecting such a strategy, researchers in the NICHD Heritable Disorders Branch are working to develop a new mouse model for the disease.

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