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Biodistribution of lentiviral transduced adipose-derived stem cells for “ex-vivo” regional gene therapy for bone repair

Gene Therapy volume 30, pages 826–834 (2023)Cite this article

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Abstract

Ex-vivo gene therapy has been shown to be an effective method for treating bone defects in pre-clinical models. As gene therapy is explored as a potential treatment option in humans, an assessment of the safety profile becomes an important next step. The purpose of this study was to evaluate the biodistribution of viral particles at the defect site and various internal organs in a rat femoral defect model after implantation of human ASCs transduced with lentivirus (LV) with two-step transcriptional activation (TSTA) of bone morphogenetic protein-2 (LV-TSTA-BMP-2). Animals were sacrificed at 4-, 14-, 56-, and 84-days post implantation. The defects were treated with either a standard dose (SD) of 5 million cells or a high dose (HD) of 15 million cells to simulate a supratherapeutic dose. Treatment groups included (1) SD LV-TSTA-BMP-2 (2) HD LV-TSTA-BMP-2, (3) SD LV-TSTA-GFP (4) HD LV-TSTA-GFP and (5) SD nontransduced cells. The viral load at the defect site and ten organs was assessed at each timepoint. Histology of all organs, ipsilateral tibia, and femur were evaluated at each timepoint. There were nearly undetectable levels of LV-TSTA-BMP-2 transduced cells at the defect site at 84-days and no pathologic changes in any organ at all timepoints. In conclusion, human ASCs transduced with a lentiviral vector were both safe and effective in treating critical size bone defects in a pre-clinical model. These results suggest that regional gene therapy using lentiviral vector to treat bone defects has the potential to be a safe and effective treatment in humans.

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Fig. 1: Representative Histology.
Fig. 2: Representative Radiograph and CT scan.

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All data generated or analyzed during this study are included in this published article and its supplementary information files.

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Authors and Affiliations

  1. Department of Orthopaedic Surgery, Keck School of Medicine of the University of Southern California, 2011 Zonal Ave, HMR 702, Los Angeles, CA, 90089, USA

    Jennifer A. Bell, Kevin Collon, Cory Mayfield, Matthew C. Gallo, Stephanie W. Chang, Osamu Sugiyama, Amy H. Tang & Jay R. Lieberman

  2. Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA, USA

    Roger Hollis & Donald B. Kohn

  3. Department of Pathology, Keck School of Medicine of University of Southern California, 1975 Zonal Ave, Los Angeles, CA, 90089, USA

    Shefali Chopra

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  1. Jennifer A. Bell
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  6. Osamu Sugiyama
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Contributions

JB, KC, and CM contributed to animal surgeries, study design, data analysis, and manuscript writing. SC, MG, OS, and AT contributed to study design, manuscript writing, cell preparation, organ harvest and ddPCR preparation. RH and DK contributed to study design, data interpretation, manuscript revision. SC contributed to study design, pathology preparation and interpretation, and manuscript review. JL contributed to study design, data analysis, manuscript review. All authors approved the final revision of this manuscript.

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Correspondence to Jennifer A. Bell.

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Competing interests

Dr Lieberman’s work has been funded by the NIH. All other authors have no competing interests.

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Bell, J.A., Collon, K., Mayfield, C. et al. Biodistribution of lentiviral transduced adipose-derived stem cells for “ex-vivo” regional gene therapy for bone repair. Gene Ther 30, 826–834 (2023). https://doi.org/10.1038/s41434-023-00415-z

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