HERITABLE DISORDERS OF CONNECTIVE TISSUE

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The Section has continued its studies aimed at elucidating the molecular mechanisms of heritable disorders of connective tissue, specifically osteogenesis imperfecta (OI) and Ehlers-Danlos (EDS), and at applying this information to the treatment of these disorders. One primary interest of the Section is to identify the collagen mutations in patients with OI and EDS and determine the relationship between the type and location of the mutation and the severity of the connective tissue disorder. Mutations in the alpha2(I) collagen chain identified by this Section and other labs have provided additional support for the regional model we have proposed. A second primary interest of the Section is to develop selective antisense suppression of the mutant collagen allele as an approach for therapeutic intervention. We have used thio oligos targeted to mutant mRNA nd nuclear RNA in the cultured fibroblasts of a patient with type IV OI. We have achieved selective suppression of the mutant allele and are pursuing approaches such as ribozymes and vector constructs to increase suppression efficiency. A third focus of interest which we have been developing is in the bone biology of OI. We are using cultured osteoblasts to study the way bone cells modify and secrete mutant collagen. We are also pursing the secondary non-collagenous abnormalities of OI matrix. In clinical studies, we are continuing our treatment trial of growth hormone in short children with OI to determine its effects on growth stimulation, bone density and bone morphometric properties. We are continuing our collaborative interests in the neurological aspects of OI and in maximizing the physical functioning of OI children though aggressive rehabilitation.