Osteogenesis imperfecta: prospects for molecular therapeutics.

Osteogenesis Imperfecta (OI) is a dominant negative disorder of connective tissue. OI patients present with bone fragility and skeletal deformity within a broad phenotypic range. Defects in the COL1A1 or COL1A2 genes, coding, respectively, for the alpha1 and alpha2 chains of type I collagen, are the causative mutations. Over 150 mutations have been characterized. Both quantitative defects, such as null COL1A1 alleles, and qualitative defects, such as glycine substitutions, exon skipping, deletions, and insertions, have been described in type I collagen. Quantitative and structural mutations are associated with the milder and more severe forms of OI, respectively. A more detailed relationship between genotype and phenotype is still incompletely understood; several models have been proposed and are being tested. Transgenic and knock-out murine models for OI have previously been created. We have recently generated a knock-in murine model (the Brittle mouse) carrying a typical glycine substitution in type I collagen. This mouse will permit a better understanding of OI pathophysiology and phenotypic variability. It will also be used for gene therapeutic approaches to OI, especially mutation suppression by hammerhead ribozymes. The present review will provide an update of OI clinical and molecular data and outline gene therapeutic approaches being tested on OI murine models for this disorder. Copyright 2000 Academic Press.