Osteogenesis imperfecta: Prospects for molecular therapeutics

Osteogenesis Imperfects (OI) is a dominant negative disorder of connective tissue. OI patients present with bone fragility and skeletal deformity with in a broad phenotypic range. Defects in the COL1A1 or COL1A2 genes, coding, respectively, for the alpha 1 and alpha 2 chains of type I collagen, are t he causative mutations. Over 150 mutations have been characterized. Both qu antitative defects, such as null COL1A1 alleles, and qualitative defects, s uch as glycine substitutions, exon skipping, deletions, and insertions, hav e 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 incompl etely understood; several models have been proposed and are being tested. T ransgenic and knock-out murine models for OI have previously been created. We have recently generated a knock-in murine model (the Brittle mouse) carr ying a typical glycine substitution in type I collagen. This mouse will per mit a better understanding of OI pathophysiology and phenotypic variability . It will also be used for gene therapeutic approaches to OI, especially mu tation suppression by hammerhead ribozymes, The present review will provide an update of OI clinical and molecular data and outline gene therapeutic a pproaches being tested on OI murine models for this disorder. (C) 2000 Acad emic Press.