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Bone Repair via Ultrasound-mediated Gene Delivery to Endogenous Stem Cells

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Review of “In situ bone tissue engineering via ultrasound-mediated gene delivery to endogenous progenitor cells in mini-pigs” from Science Translational Medicine by Stuart P. Atkinson

Current treatment strategies for massive bone loss and non-healing fractures include bone-grafts from the same patient (autograft) or an unrelated donor (allograft). While somewhat successful, autografts can suffer from problems related to bone harvesting [1] and allografts from poor graft-host integration [2], and so, there remains a need for improved therapeutic options.

In a new Science Translational Medicine article, researchers from the laboratory of Dan Gazit (Cedars-Sinai Medical Center, Los Angeles, USA) now describe an exciting new treatment option: the promotion of bone repair via ultrasound-mediated therapeutic gene delivery to endogenous mesenchymal stem cells (MSCs)!

Specifically, Bez et al. sought to improve on a previous study that employed minimally-invasive ultrasound-mediated therapeutic gene delivery, or sonoporation [3], to successfully overexpress a reporter construct in endogenous MSCs recruited to a fracture site in various animal models [4]. In their new study, the authors aimed to promote bone repair by overexpressing pro-osteogenic human bone morphogenetic protein-6 (BMP-6) in endogenous MSCs recruited to a critical-sized bone fracture in the tibiae of the Yucatán mini-pig; a clinically relevant, large animal model [5].

To aid the recruitment of MSCs, the authors first placed a biodegradable collagen scaffold into a 1-cm critical-sized fracture site and then attempted the sonoporation of subcutaneously injected microbubbles containing a BMP-6 expression plasmid after two weeks, a time point at which MSCs displayed maximal recruitment. Encouragingly, a significant proportion of MSCs incorporated the plasmid and began to transiently express and secrete BMP-6 specifically into the bone fracture. Importantly, not only does this strategy reduce the costs associated with injecting BMP proteins, but it also reduces the side effects observed in response to “megadoses” of related factors in off-target tissues [6]. Encouragingly, this new strategy succeeded and led to complete fracture healing at six weeks post-treatment, a time point when non-treated control animals still presented with unhealed fractures, without any notable ectopic transgene expression or inflammatory response.

The advantages of this strategy are numerous; the procedure is minimally invasive, safe, quick, efficient, and easily translatable into clinical practice; great news for the 2 million or so patients who undergo painful and sometimes-unsuccessful bone grafting procedures. However, the authors hope to make further refinements to this already promising approach by improving the scaffold, exploring repeated treatment to promote faster and improved bone repair, and assessing the effects of longer-term BMP-6 overexpression in endogenous MSCs.

Stay tuned to the Stem Cells Portal to keep up-to-date with this exciting new therapeutic strategy for bone repair!

References

  1. Hierholzer C, Sama D, Toro JB, et al. Plate fixation of ununited humeral shaft fractures: effect of type of bone graft on healing. J Bone Joint Surg Am 2006;88:1442-1447.
  2. Brigman BE, Hornicek FJ, Gebhardt MC, et al. Allografts about the Knee in Young Patients with High-Grade Sarcoma. Clin Orthop Relat Res 2004;232-239.
  3. Sheyn D, Kimelman-Bleich N, Pelled G, et al. Ultrasound-based nonviral gene delivery induces bone formation in vivo. Gene Ther 2008;15:257-266.
  4. Shapiro G, Kallai I, Sheyn D, et al. Ultrasound-mediated transgene expression in endogenous stem cells recruited to bone injury sites. Polymers for Advanced Technologies 2014;25:525-531.
  5. Bez M, Sheyn D, Tawackoli W, et al. In situ bone tissue engineering via ultrasound-mediated gene delivery to endogenous progenitor cells in mini-pigs. Sci Transl Med 2017;9:
  6. Carragee EJ, Hurwitz EL, and Weiner BK. A critical review of recombinant human bone morphogenetic protein-2 trials in spinal surgery: emerging safety concerns and lessons learned. Spine J 2011;11:471-491.