Gene therapy-directed osteogenesis: BMP-7-transduced human fibroblasts form bone in vivo

An ex vivo gene therapy strategy was used to achieve localized skeletal reg eneration in vivo. When an adenovirus vector engineered to express bone mor phogenetic protein 7 transduced human gingival fibroblasts or rat dermal fi broblasts, these nonosteogenic tissues formed bone and supported the develo pment of hematopoietic tissue when transplanted into immunocompromised mice . Transduced gingival fibroblasts formed marrow-containing ossicles in 100% of transplants after 1-2 weeks in vivo (n = 30). Immunostaining with murin e and human-specific antisera raised against osteonectin and in situ hybrid ization of human-specific Alu genomic sequence demonstrated that the newly formed bone organ was a chimera of both the human donor and the mouse recip ient cells. In experiments of greater clinical relevance, AdCMVBMP-7-transd uced dermal fibroblasts repaired critical size skeletal defects in rat calv ariae (n = 6). The results of this study suggest a bifunctional role of BMP -7-transduced fibroblasts. The transduced, nonosteogenic cells not only sec reted biologically active BMP-7 in vitro and in vivo, but also differentiat ed into bone-forming cells in vivo. This model exploits the use of an easil y biopsied, self-regenerating tissue such as gingiva or skin and suggests t hat local regeneration of tissues by ex vivo gene therapy may not require t hat autogenous cells be cultured from the tissue that is to be regenerated.