Wang S, Olumolade O O, Sun T, Samiotaki G, Konofagou E E
Ultrasound and Elasticity Imaging Laboratory, Department of Biomedical Engineering, Columbia University, New York, NY, USA.
1] Ultrasound and Elasticity Imaging Laboratory, Department of Biomedical Engineering, Columbia University, New York, NY, USA [2] Department of Radiology, Columbia University, New York, NY, USA.
Gene Ther. 2015 Jan;22(1):104-10. doi: 10.1038/gt.2014.91. Epub 2014 Nov 6.
Recombinant adeno-associated virus (rAAV) has shown great promise as a potential cure for neurodegenerative diseases. The existence of the blood-brain barrier (BBB), however, hinders efficient delivery of the viral vectors. Direct infusion through craniotomy is the most commonly used approach to achieve rAAV delivery, which carries increased risks of infection and other complications. Here, we report a focused ultrasound (FUS)-facilitated noninvasive rAAV delivery paradigm that is capable of producing targeted and neuron-specific transductions. Oscillating ultrasound contrast agents (microbubbles), driven by FUS waves, temporarily 'unlock' the BBB, allowing the systemically administrated rAAVs to enter the brain parenchyma, while maintaining their bioactivity and selectivity. Taking the advantage of the neuron-specific promoter synapsin, rAAV gene expression was triggered almost exclusively (95%) in neurons of the targeted caudate-putamen region. Both behavioral assessment and histological examination revealed no significant long-term adverse effects (in the brain and several other critical organs) for this combined treatment paradigm. Results from this study demonstrated the feasibility and safety for the noninvasive, targeted rAAV delivery, which might have open a new avenue in gene therapy in both preclinical and clinical settings.
重组腺相关病毒（rAAV）作为治疗神经退行性疾病的潜在疗法已展现出巨大前景。然而，血脑屏障（BBB）的存在阻碍了病毒载体的有效递送。通过开颅手术直接注入是实现rAAV递送最常用的方法，但这种方法会增加感染和其他并发症的风险。在此，我们报告了一种聚焦超声（FUS）辅助的无创rAAV递送模式，该模式能够实现靶向性和神经元特异性转导。由FUS波驱动的振荡超声造影剂（微泡）可暂时“打开”血脑屏障，使全身给药的rAAV进入脑实质，同时保持其生物活性和选择性。利用神经元特异性启动子突触素，rAAV基因表达几乎仅在靶向尾状核 - 壳核区域的神经元中被触发（95%）。行为评估和组织学检查均显示，这种联合治疗模式没有明显的长期不良影响（在脑和其他几个关键器官中）。本研究结果证明了无创、靶向性rAAV递送的可行性和安全性，这可能为临床前和临床环境中的基因治疗开辟了一条新途径。
