[Osteogenesis imperfecta and achievements in cell and gene therapy].

Osteogenesis imperfecta (OI) or "brittle bone" disease is characterized by fragile bones, skeletal deformity, and growth retardation. Depending on the mutation and related phenotype, O1 is classified into types I-IV, which are caused by different mutations in collagen genes, and types V-VIII, which are indirectly but not directly collagen related. The most common cause of this inheritable disorder of connective tissue are mutations affecting the COL1A1 and COL1A2 genes of type I collagen. There is no cure for OI and current treatments include surgical intervention, use of prostheses and physical therapy. Pharmacological agents have also been tried with limited success, with the exception of recent use of bisphosphonates, which have been shown to have some effect in bone mass acquisition. Since OI is a genetic disease, these agents are not expected to alter the course of collagen mutations. Recent technology in molecular biology has led to the development of transgenic models of OI, which are necessary for development of cell and gene therapies as potential treatments for OI and are currently being actively investigated. However, the design of gene therapies for OI is complicated by genetic heterogeneity of the disease and by the fact that most of OI mutations are dominant negative where the mutant allele product interferes with the function of the normal allele. Therefore, therapy needs to include suppression of the mutant allele and introduction of the wild type allele. The present review will discuss the classification of OI and molecular changes seen in different types of OI and transgenic murine models that mimic different types of OI. Cell therapy, gene therapy, and a combination of both represent new approaches in OI therapy development that are being investigated as potential future treatments for OI. Modest success of cell therapy, encouraging results of gene therapy in vitro and in animal models as well as their problems and limitations for use in humans will be presented.