Słyk Żaneta, Stachowiak Natalia, Małecki Maciej
Department of Applied Pharmacy, Faculty of Pharmacy, Medical University of Warsaw, 02-091 Warsaw, Poland.
Laboratory of Gene Therapy, Faculty of Pharmacy, Medical University of Warsaw, 02-091 Warsaw, Poland.
Pharmaceuticals (Basel). 2024 Sep 14;17(9):1213. doi: 10.3390/ph17091213.
Recombinant AAV (rAAV) vectors are increasingly favored for gene therapy due to their useful features of vectorology, such as transfection of dividing and nondividing cells, the presence of tissue-specific serotypes, and biosafety considerations. This study investigates the impact of commonly used therapeutic drugs-acetaminophen, budesonide, and simvastatin-on rAAV transduction efficiency in HEK-293 cells. Cells were transduced with an AAV mosaic vector under the control of a cytomegalovirus (CMV) promoter encoding green fluorescent protein (GFP). Transduction efficiency was assessed by qPCR and fluorescent microscopy. Analysis of functional interactions between genes potentially involved in rAAV transduction in drug-exposed cells was also performed. This study showed a clear effect of drugs on rAAV transmission. Notably, acetaminophen enhanced transduction efficiency by 9-fold, while budesonide and simvastatin showed 2-fold and 3-fold increases, respectively. The gene analysis illustrates the possible involvement of genes related to cell membranes in the potentiation of rAAV transduction induced by the drugs under investigation. Attention should be paid to , which is a common drug-modified gene for drugs showing anti-inflammatory effects (budesonide and simvastatin), demonstrating an interaction with the gene encoding the receptor for AAV (HGFR). This study underscores the significance of assessing rAAV pharmacokinetics/pharmacodynamics (PKs/PDs) and drug-gene therapy interactions in optimizing gene therapy protocols.
重组腺相关病毒（rAAV）载体因其在载体学方面的有用特性，如对分裂细胞和非分裂细胞的转染、组织特异性血清型的存在以及生物安全性考虑等，在基因治疗中越来越受到青睐。本研究调查了常用治疗药物对乙酰氨基酚、布地奈德和辛伐他汀对人胚肾293（HEK - 293）细胞中rAAV转导效率的影响。用一种在编码绿色荧光蛋白（GFP）的巨细胞病毒（CMV）启动子控制下的AAV嵌合载体转导细胞。通过定量聚合酶链反应（qPCR）和荧光显微镜评估转导效率。还对药物处理细胞中可能参与rAAV转导的基因之间的功能相互作用进行了分析。本研究显示药物对rAAV传递有明显影响。值得注意的是，对乙酰氨基酚使转导效率提高了9倍，而布地奈德和辛伐他汀分别使转导效率提高了2倍和3倍。基因分析表明，与细胞膜相关的基因可能参与了所研究药物诱导的rAAV转导增强过程。对于显示出抗炎作用的药物（布地奈德和辛伐他汀），应关注一个常见的药物修饰基因，该基因证明与编码AAV受体（HGFR）的基因存在相互作用。本研究强调了在优化基因治疗方案时评估rAAV药代动力学/药效学（PKs/PDs）以及药物 - 基因治疗相互作用的重要性。
