Allogeneic gene therapy with BMP-2-transduced mesenchymal stem cells combined with immunosuppression enhances bone...

Critical-sized bone defects remain a significant clinical challenge with limited treatment options. This study investigated whether allogeneic adipose-derived stem cells (ADSCs) transduced with a lentiviral vector to express BMP-2 could effectively heal femoral defects in immune competent rats with or without temporary FK506 (i.e., tacrolimus) immunosuppression. Forty-three Lewis rats with 6 mm mid-diaphyseal femoral defects received either BMP-2-transduced or non-transduced allogeneic ADSCs from Sprague-Dawley donors, with or without FK506. At 12 weeks, immunosuppressed rats receiving BMP-2-transduced ADSCs achieved healed bone with significantly higher torsional stiffness, peak torque, and energy to failure compared with those not receiving immunosuppression. Similarly, radiographic healing scores, histology, and micro-CT analysis revealed greater new bone formation in immunosuppressed animals. Non-transduced ADSCs produced minimal bone healing regardless of immunosuppression. FK506 did not enhance in vitro BMP-2 production or osteogenic differentiation, suggesting its primary benefit at the tested dose was immunomodulatory rather than enhancing osteoinductive activity. These findings establish that temporary immunosuppression dramatically enhances the efficacy of allogeneic cell-based gene therapy for bone regeneration without significant complications, potentially enabling development of an "off-the-shelf" product to treat critical-sized bone defects.