Bone-directed expression of Col1a1 promoter-driven self-inactivating retroviral vector in bone marrow cells and transgenic mice

Molecular Therapy : the Journal of the American Society of Gene Therapy
M L StoverA C Lichtler

Abstract

Gene therapy of bone would benefit from the availability of vectors that provide stable, osteoblast-specific expression. This would allow bone-specific expression of Col1a1 cDNAs for treatment of osteogenesis imperfecta. In addition, such a vector would restrict expression of secreted therapeutic proteins to the bone-synthesizing regions of the bone marrow after ex vivo transduction of marrow stromal cells and reintroduction of the cells into patients. Retrovirus vectors stably integrate into target cell genomes; however, long-term regulated expression from internal cellular promoters has not been consistently achieved. In some cases this is due to a stem cell-specific mechanism for transcriptional repression of retroviruses. We evaluated the ability of self-inactivating ROSA-derived vectors containing a bone-directed 2.3-kb rat Col1a1 promoter to display osteoblast-specific expression. In vitro expression was examined in bone marrow stromal cell cultures induced to undergo osteoblastic differentiation. In vivo expression was evaluated in chimeric mice derived from transduced embryonic stem cells. The results indicate that self-inactivating retrovirus vectors containing the Col1a1 promoter are not permanently inactivated in emb...Continue Reading

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Citations

May 1, 2007·Regenerative Medicine·N KimelmanD Gazit
Oct 2, 2003·Expert Opinion on Biological Therapy·Charles L Densmore
Jul 12, 2005·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·Alexander G PantschenkoGloria A Gronowicz
Feb 27, 2013·Journal of Orthopaedic Research : Official Publication of the Orthopaedic Research Society·David J CornZhenghong Lee
Jan 16, 2004·Gene Therapy·Y GafniD Gazit
May 26, 2018·EMBO Reports·Samuel J AtkinsonStephen D Robinson
Jul 3, 2019·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Aliaa BarakatAli Hafezi-Moghadam

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