Marrow transplantation and targeted gene therapy to the skeleton

Treatment of genetic or degenerative diseases severely affecting the entire skeleton may necessitate gene therapy invoking transplantation of multipot ential marrow cells. The ability of in vitro expanded adherent marrow cells enriched in pluripotent mesenchymal cell populations to remain competent t o engraft, repopulate host tissues, and differentiate into bone and cartila ge is advantageous for correction of skeletal-related diseases. However, to achieve phenotypic specificity and therapeutic or physiologic levels of pr oteins may require cell type specific expression of the gene. Tissue-specif ic promoter-controlled transgenes provide an efficacious approach to delive r therapeutic gene expression to repopulating chondrocytes and osteoblasts for treatment of cartilage and bone disorders or tumor metastasis to the sk eleton. The bone-specific expression of a reporter gene controlled by the o steoblast-specific osteocalcin promoter after transplantation of a mixed po pulation of marrow cells is shown. Tissue-restricted gene therapy potential ly can be refined by use of a unique peptide targeting signal that directs the hematopoietic, chondrogenic, and osteogenic core binding factor/acute m yelogenous leukemia transcription factors to subnuclear sites that support gene expression.