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Rapid and reliable healing of critical size bone defects with genetically modified sheep muscle

机译：转基因绵羊肌肉可快速可靠地治愈关键尺寸的骨缺损

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Large segmental defects in bone fail to heal and remain a clinical problem. Muscle is highly osteogenic, and preliminary data suggest that autologous muscle tissue expressing bone morphogenetic protein-2 (BMP-2) efficiently heals critical size defects in rats. Translation into possible human clinical trials requires, inter alia, demonstration of efficacy in a large animal, such as the sheep. Scale-up is fraught with numerous biological, anatomical, mechanical and structural variables, which cannot be addressed systematically because of cost and other practical issues. For this reason, we developed a translational model enabling us to isolate the biological question of whether sheep muscle, transduced with adenovirus expressing BMP-2, could heal critical size defects in vivo. Initial experiments in athymic rats noted strong healing in only about one-third of animals because of unexpected immune responses to sheep antigens. For this reason, subsequent experiments were performed with Fischer rats under transient immunosuppression. Such experiments confirmed remarkably rapid and reliable healing of the defects in all rats, with bridging by 2 weeks and remodelling as early as 3-4 weeks, despite BMP-2 production only in nanogram quantities and persisting for only 1-3 weeks. By 8 weeks the healed defects contained well-organised new bone with advanced neo-cortication and abundant marrow. Bone mineral content and mechanical strength were close to normal values. These data demonstrate the utility of this model when adapting this technology for bone healing in sheep, as a prelude to human clinical trials.
机译：骨中较大的节段性缺陷无法愈合，仍然是临床问题。肌肉具有很高的成骨性，初步数据表明表达骨形态发生蛋白2（BMP-2）的自体肌肉组织可有效治愈大鼠的关键尺寸缺陷。翻译成可能的人类临床试验尤其需要证明在大型动物（例如绵羊）中的功效。扩大规模充满了许多生物学，解剖，机械和结构变量，由于成本和其他实际问题，这些变量无法系统地解决。因此，我们开发了一个翻译模型，使我们能够分离出生物学问题，即用表达BMP-2的腺病毒转导的绵羊肌肉是否可以在体内治愈严重的尺寸缺陷。在无胸腺大鼠中进行的最初实验表明，由于对绵羊抗原的意外免疫反应，只有约三分之一的动物具有较强的愈合能力。因此，在瞬时免疫抑制下对Fischer大鼠进行了后续实验。这样的实验证实了所有大鼠中缺陷的快速，可靠的治愈，桥接了2周，并且早在3-4周就进行了重塑，尽管BMP-2的产量仅为纳克级，并且仅持续1-3周。到8周时，已愈合的缺陷包括组织良好的新骨，晚期新皮层和丰富的骨髓。骨矿物质含量和机械强度接近正常值。这些数据证明了当将该技术用于绵羊的骨愈合时，该模型的实用性，作为人类临床试验的序幕。

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