Potential of gene therapy for treating osteogenesis imperfecta.

Osteogenesis imperfecta is a heterogeneous group of genetic disorders that affect connective tissue integrity, with bone fragility being the major clinical feature. Most forms of osteogenesis imperfecta are the result of mutations in the genes that encode the pro alpha1 and pro alpha2 polypeptide chains of Type I collagen. Because osteogenesis imperfecta is an incurable genetic disease, cell therapy and gene therapy are being investigated as potential treatments. Gene therapy for osteogenesis imperfecta however is a major challenge; because most of the mutations in osteogenesis imperfecta are dominant negative, supplying the normal gene without silencing the abnormal gene may not be beneficial. Null mutations in which an allele is not expressed or absent may be amenable to gene therapy or alternatively after silencing a mutant allele, a normal gene could be supplied. In addition, overexpression of the normal collagen gene in cells expressing mutant collagen polypeptide chains potentially could lead to synthesis of a sufficient percentage of normal molecules to normalize clinical status. The authors currently are examining the possibility of developing gene therapy for treating a mouse model of human osteogenesis imperfecta (oim) using bone marrow stromal cells as vehicles for delivering normal collagen genes to bone. In the current study, the potential of gene therapy for treating osteogenesis imperfecta is discussed in the context of the complexity of the mutations in Type I collagen genes that lead to different osteogenesis imperfecta phenotypes.