Eleftheriadou I, Trabalza A, Ellison S M, Gharun K, Mazarakis N D
Gene Therapy, Centre for Neuroinflammation & Neurodegeneration, Division of Brain Sciences, Faculty of Medicine, Imperial College London, Hammersmith Hospital Campus, London, UK.
Gene Therapy, Centre for Neuroinflammation & Neurodegeneration, Division of Brain Sciences, Faculty of Medicine, Imperial College London, Hammersmith Hospital Campus, London, UK; Centre of Chronic Immunodeficiency, University Medical Center Freiburg, AG Henneke, Freiburg, Germany.
Mol Ther. 2014 Jul;22(7):1285-1298. doi: 10.1038/mt.2014.49. Epub 2014 Mar 26.
To understand how receptors are involved in neuronal trafficking and to be able to utilize them for specific targeting via the peripheral route would be of great benefit. Here, we describe the generation of novel lentiviral vectors with tropism to motor neurons that were made by coexpressing onto the lentiviral surface a fusogenic glycoprotein (mutated sindbis G) and an antibody against a cell-surface receptor (Thy1.1, p75(NTR), or coxsackievirus and adenovirus receptor) on the presynaptic terminal of the neuromuscular junction. These vectors exhibit binding specificity and efficient transduction of receptor positive cell lines and primary motor neurons in vitro. Targeting of each of these receptors conferred to these vectors the capability of being transported retrogradely from the axonal tip, leading to transduction of motor neurons in vitro in compartmented microfluidic cultures. In vivo delivery of coxsackievirus and adenovirus receptor-targeted vectors in leg muscles of mice resulted in predicted patterns of motor neuron labeling in lumbar spinal cord. This opens up the clinical potential of these vectors for minimally invasive administration of central nervous system-targeted therapeutics in motor neuron diseases.
了解受体如何参与神经元运输，并能够通过外周途径将它们用于特定靶向，将具有极大的益处。在此，我们描述了新型慢病毒载体的产生，这些载体对运动神经元具有嗜性，它们是通过在慢病毒表面共表达一种融合糖蛋白（突变的辛德毕斯病毒G）和一种针对神经肌肉接头突触前末端细胞表面受体（Thy1.1、p75（NTR）或柯萨奇病毒和腺病毒受体）的抗体而构建的。这些载体在体外表现出对受体阳性细胞系和原代运动神经元的结合特异性和高效转导。靶向这些受体中的每一种都赋予这些载体从轴突末端逆行运输的能力，从而导致在分隔的微流控培养物中体外转导运动神经元。在小鼠腿部肌肉中体内递送柯萨奇病毒和腺病毒受体靶向载体，导致腰脊髓中运动神经元标记的预测模式。这为这些载体在运动神经元疾病中以微创方式施用中枢神经系统靶向治疗药物开辟了临床潜力。
