Ex vivo regional gene therapy with human adipose-derived stem cells for bone repair

The treatment of complex bone loss scenarios remains challenging. This study evaluates the efficacy of ex vivo regional gene therapy using transduced human adipose-derived stem cells (ASCs) overexpressing bone morphogenetic protein-2 (BMP-2) to treat critical-sized bone defects.

Critical-sized femoral defects created surgically in immunocompromised rats were treated with ASCs transduced with a lentivirus encoding BMP-2 (Group 1, n = 14), or green fluorescent protein (Group 2, n = 5), nontransduced ASCs (Group 3, n = 5), or rhBMP-2 (Group 4, n = 14). At 12 weeks, femurs were evaluated for quantity and quality of bone formation with plain radiographs, micro-computed tomography, histology/histomorphometry, and biomechanical strength testing.

Thirteen of 14 samples in Group 1 and all 14 samples in Group 4 showed radiographic healing, while no samples in either Groups 2 or 3 healed. Groups 1 and 4 had significantly higher radiographic scores (p < 0.001), bone volume fraction (BV/TV) (p < 0.001), and bone area fraction (BA/TA) than Groups 2 and 3 (p < 0.001). Radiographic scores, BV/TV, and BA/TA were not significantly different between Groups 1 and 4. No difference with regards to mean torque, rotation at failure, torsional stiffness, and energy to failure was seen between Groups 1 and 4.

Human ASCs modified to overexpress BMP-2 resulted in abundant bone formation, with the quality of bone comparable to that of rhBMP-2. This strategy represents a promising approach in the treatment of large bone defects in the clinical setting.

Large bone defects may require sustained protein production to induce an appropriate osteoinductive response. Ex vivo regional gene therapy using a lentiviral vector has the potential to be part of a comprehensive tissue engineering strategy for treating osseous defects.