Kushwah R, Oliver J R, Cao H, Hu J
Physiology and Experimental Medicine Research Program, Hospital for Sick Children, and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
Gene Ther. 2007 Aug;14(16):1243-8. doi: 10.1038/sj.gt.3302968. Epub 2007 May 24.
Adenoviral vector-mediated gene delivery has been vastly investigated for cystic fibrosis (CF) gene therapy; however, one of its drawbacks is the low efficiency of gene transfer, which is due to basolateral colocalization of viral receptors, immune responses to viral vectors and the presence of a thick mucus layer in the airways of CF patients. Therefore, enhancement of gene transfer can lead to reduction in the viral dosage, which could further reduce the acute toxicity associated with the use of adenoviral vectors. Nacystelyn (NAL) is a mucolytic agent with anti-inflammatory and antioxidant properties, and has been used clinically in CF patients to reduce mucus viscosity in the airways. In this study, we show that pretreatment of the airways with NAL followed by administration of adenoviral vectors in complex with DEAE-Dextran can significantly enhance gene delivery to the airways of mice without any harmful effects. Moreover, NAL pretreatment can reduce the airway inflammation, which is normally observed after delivery of adenoviral particles. Taken together, these results indicate that NAL pretreatment followed by adenoviral vector-mediated gene delivery can be beneficial to CF patients by increasing the efficiency of gene transfer to the airways, and reducing the acute toxicity associated with the administration of adenoviral vectors.
腺病毒载体介导的基因递送已被广泛研究用于囊性纤维化（CF）的基因治疗；然而，其缺点之一是基因转移效率低，这是由于病毒受体的基底外侧共定位、对病毒载体的免疫反应以及CF患者气道中存在厚厚的黏液层。因此，提高基因转移效率可导致病毒剂量减少，这可进一步降低与使用腺病毒载体相关的急性毒性。N-乙酰半胱氨酸（NAL）是一种具有抗炎和抗氧化特性的黏液溶解剂，已在临床上用于CF患者以降低气道中的黏液黏度。在本研究中，我们表明，先用NAL预处理气道，然后给予与DEAE-葡聚糖复合的腺病毒载体，可显著增强向小鼠气道的基因递送，且无任何有害影响。此外，NAL预处理可减轻通常在腺病毒颗粒递送后观察到的气道炎症。综上所述，这些结果表明，先用NAL预处理，然后进行腺病毒载体介导的基因递送，可通过提高向气道的基因转移效率并降低与腺病毒载体给药相关的急性毒性，对CF患者有益。
